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Movement disorders in childhood …
- Updated 01.02.2024
- Released 08.27.2005
- Expires For CME 01.02.2027
Movement disorders in childhood
Introduction
Overview
Childhood movement disorders are a diverse group of neurologic conditions manifested by an excess of abnormal or involuntary movements (hyperkinesias), a paucity of movement, or other disorders of motor control (eg, ataxia). Diagnosis and treatment rest on recognition of the primary phenomenology of the movements. The author has categorized the principal childhood movement disorders based on phenomenology. Once phenomenology has been identified, treatment can be initiated and differential etiology can be narrowed. In this article, the most common causes of each category of movement disorders will be expounded. Pediatric movement disorders is a rapidly developing area of medicine with many recent genetic advances and an ever-expanding understanding of clinical phenotypes and pathophysiology of the previously described entities. Advances include identification of the genetic basis, expansion of the known clinical phenotypes of many of the genetic dystonias, choreas, and ataxias, and knowledge about the natural history and treatment of NMDA receptor encephalitis. The scope of this article is to give a general overview of movement disorders affecting the pediatric population. Individual conditions are often discussed in more detail in other MedLink Neurology articles. Relevant review references are also provided.
Classification of childhood movement disorders
The taxonomy of childhood movement disorders can be organized according to the phenomenology of the involuntary movements. Major subdivisions include hyperkinetic disorders, hypokinetic disorders, and cerebellar disorders. Other classification schemes include key descriptors of the underlying condition (eg, paroxysmal disorders, neurometabolic disorders, drug-induced movement disorders, psychogenic disorders, or benign movement disorders). All of these can present with a broad array of involuntary movements crossing phenomenology categories; therefore, they are classified separately (“mixed”) to recognize unique phenomenology, etiology, or prognosis.
The Taskforce on Childhood Movement Disorders defines hyperkinetic movements as “any unwanted excess movement” (348), which includes dystonia, myoclonus, chorea, athetosis, tics, stereotypies, and tremor. All of these hyperkinetic disorders are seen from a variety of etiologies in children. Hypokinetic disorders are common in adults, but are rare in children. These movements are characterized by paucity, slowness, and incoordination of movements. The prototypical hypokinetic movement disorder is parkinsonism. Catatonia is another etiology of paucity of pediatric movements. Uncoordinated movement called ataxia, and inability to perform motor movements called apraxia, are separate categories of pediatric deficits. Many practitioners separate spasticity into its own category, and it will not be covered in this overview of movement disorders.
Definitions of hyperkinetic movements are as follows:
• Tremor: A rhythmic back-and-forth or oscillating involuntary movement about a joint axis. The movement may seem oscillatory or sinusoidal. It can occur at rest (rest tremor), with posture-holding (postural tremor), with volitional movement (kinetic tremor), or can worsen as the target is approached (intention tremor). | |
• Chorea: An ongoing, random-appearing sequence of one or more discrete involuntary movements or movement fragments. Movements may be worsened by attempts at movement or stress. In children, chorea often is minimal to not present at rest, unlike in adults, where it is typically present even when still. | |
• Athetosis: Slow, distal chorea that prevents maintenance of a stable posture. | |
• Ballism (ballismus): An involuntary, large-amplitude flinging- or throwing-type choreiform movement that involves more proximal musculature. In adults, ballism is frequently unilateral, often because of a lesion in the contralateral subthalamic nucleus or its connections. In children, it more frequently accompanies chorea such as in dyskinetic cerebral palsy. | |
• Dystonia: Involuntary sustained or intermittent muscle contractions causing twisting and repetitive movements, abnormal postures, or both. The postures can be sustained or brief, and they are triggered by voluntary movement. The phenomenon of “overflow” may be seen, in which there is a close association of an unwanted movement with an intended movement, or spread of the involuntary movement to surrounding or distant muscles. “Mirror movements” is another phenomenon in dystonia where movements seen in one limb are unintentionally “mirrored” on the opposite side (eg, voluntary movements of the right fingers may produce similar left finger movements). | |
• Myoclonus: A sequence of repeated, often nonrhythmic, brief, shock-like jerks due to sudden involuntary contraction or relaxation of one or more muscles. | |
• Tics: Repeated, individually recognizable, intermittent movements or vocalizations that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. Individual tics have very little variability between repetitions. Complex tics can evolve over time, but are unlikely without preceding simple tics. Simple tics usually start in the face or neck. | |
• Stereotypies: Repetitive, often rhythmic movements that can be voluntarily suppressed. They often occur while engrossed in tasks and are easily stopped by distraction. Typically, stereotypies involve the whole body (eg, rocking) or the hands or feet (eg, flapping). |
Hyperkinetic movement disorders
Tremor
Tremor is defined as an involuntary, rhythmic, oscillatory movement produced by contractions of antagonist muscles. It can occur at rest, with action, or with posture-holding, and involve the limbs, trunk, head, voice, and tongue. Limb tremor is often worsened by caffeine, stress or anxiety, and improves with alcohol and during sleep. The rhythmical movement is thought to result from synchronization of discharges produced by disinhibited oscillators (neuronal networks with autorhythmic properties) located within the basal ganglia, thalamus, and brainstem. A heterogeneous group of disorders producing such movements is discussed here.
Essential tremor. Onset of childhood essential tremor is usually in the 2nd decade, but can present as early as the first few years of life. Postural and kinetic tremor of the hands and arms are most common, and may interfere with writing, feeding, or tasks requiring fine motor coordination. Head tremor is less common. Task-specific tremor, such as primary handwriting tremor, may be more prominent than in adult essential tremor (194).
Essential tremor is an autosomal dominant, highly penetrant condition. Different genetic loci have been identified in various families, but no single gene defect has been found to be causative (196; 80). The exact pathophysiology of essential tremor is not known, but a disturbance in the cerebello-thalamo-cortical loop is thought to produce the symptoms (51).
In a study of 39 patients with childhood-onset essential tremor who had a mean age of onset of 8.8 ± 5.0 years and a mean age of evaluation of 20.3 ± 14.4 years; we found that some had their initial symptoms as early as infancy (194). A family history of tremor was noted for 79.5% of the patients. Eighteen (46.2%) patients had some neurologic comorbidity, such as dystonia, which was noted in 11 (28.2%) patients. Only 24 (61.5%) patients were treated with a specific anti-tremor medication; five of the 12 patients who were treated with propranolol experienced improvement. Other studies of childhood-onset essential tremor also found male preponderance, paucity of head tremor, and a very high frequency of family history (385). Some investigators have suggested that “shuddering attacks” of infancy might be the initial manifestation of essential tremor (207), though a study refutes this suggestion (186).
There is a male preponderance in childhood essential tremor, and nearly 100% have a positive family history, particularly when family members are examined. Essential tremor often progresses in severity with advancing age and may not require therapy in childhood. If needed, beta blockers such as propranolol may be effective in up to 50% of patients (121).
There is evidence to suggest that most (but not all) cases of essential tremor with onset by 18 years of age are familial, with the presence of at least one affected first- or second-degree relative (248).
Angelman-associated tremor. The myoclonic action tremor seen in Angelman syndrome can affect the limbs, head, and trunk. Studies of tremor in Angelman syndrome using EEG with jerk-locked averaging suggest that the tremor reflects cortical myoclonus (153).
STXBP1-associated tremor. Pathogenic variants in the STXBP1 gene are known to cause early infantile epileptic encephalopathy with characteristic EEG changes and structural anomalies in the brain (Ohtahara syndrome), as well as milder forms of epilepsy. It has been recognized that this gene can also be associated with action tremor, cognitive deficits, and ataxia, even in the absence of epilepsy (104; 139).
Geniospasm. Geniospasm, or familial chin trembling, is a hereditary disorder characterized by episodic tremor or spasm of the mentalis muscle that typically worsens during stress, periods of emotion, or concentration. Episodes may last for several minutes. In some families, the condition can present from birth or in early infancy. It often occurs without other neurologic abnormalities. Geniospasm is an autosomal dominant condition with high penetrance. Several families have been described. Although probably genetically heterogenous, a clear genetic link has not yet been elucidated. In general, the disorder is not bothersome, and no treatment is required. In some cases, the symptoms may wake the patient from sleep and may be associated with nocturnal tongue biting. Submentalis botulinum toxin injections have been described as efficacious in a small number of patients (180).
Spasmus nutans. Spasmus nutans (“nodding spasm”) is a condition defined by a clinical triad of head titubation, torticollis, and rapid, asymmetric, low-amplitude nystagmus. The head bobbing may occur intermittently (“spasms”), is small in amplitude, and can be horizontal or vertical. It may occur as a compensatory mechanism for the nystagmus (154).
Pathophysiology of this condition is poorly understood. Historically, spasmus nutans was thought to have been associated with optic pathway gliomas, based on a small number of case reports. A large case study suggests that this may not in fact be the case (43). Some patients may have associated optic nerve hypoplasia. Others may have nonspecific anomalies, including callosal dysgenesis or ventriculomegaly, but more commonly are normal.
Spasmus nutans is generally a self-limited condition that resolves during childhood but may be associated with developmental delay. There may be some residual amblyopia, strabismus, nystagmus, torticollis, and head tremor (315).
Bobble-head doll syndrome. Bobble-head doll syndrome is a movement disorder unique to children with onset before 5 years of age and is manifested by continuous or episodic, rhythmic anterior-posterior head oscillations at a frequency of 2 to 3 Hz. The movements are less commonly lateral or rotatory. Episodes disappear during sleep, decrease with concentration, and are suppressible. Postural and truncal tremors, upper motor neuron signs, and endocrine abnormalities are common associated features. Loss of consciousness may occur in rare cases.
Imaging studies in bobble-head doll syndrome are often abnormal, with findings of a third ventricle tumor, suprasellar arachnoid cyst, aqueductal stenosis, communicating hydrocephalus, cyst of the cavum septum pellucidum and cavum septum interpositum, cystic choroids plexus papilloma of the third ventricle, and trapped fourth ventricle and aqueduct all being reported (33; 126). Bobble-head doll syndrome is likely related to increased intracranial pressure and CSF flow (426). Progressive compression of brainstem nuclei is the proposed cause of symptoms. Tremor and head movements may be a result of thalamic compression, whereas endocrinopathy may be caused by hypothalamic compression. Head movements may also transiently improve CSF flow.
There are no specific epidemiologic features to bobblehead doll syndrome. The symptoms generally improve with treatment of the underlying structural abnormality or with ventriculoperitoneal shunting or endoscopic procedures to reduce CSF pressure.
Shuddering attacks. Shuddering attacks are considered a benign movement disorder of infancy or early childhood involving repeated, daily bursts of whole body shuddering without impaired awareness or consciousness. Episodes are sudden in onset and may last several seconds (340). EEGs are normal during the events (207). Patients may experience up to 100 events a day, and they may be precipitated by specific activities (399).
The etiology and pathophysiology of shuddering attacks are unknown. There is no consistent evidence for epilepsy, gestational insults, or developmental abnormalities as the cause. The frequency of shuddering may match frequencies commonly seen in essential tremor (176). A family history of essential tremor has been noted in some series, and some childhood essential tremor cases have been preceded by shuddering attacks, leading some to believe the two conditions are related (407). In a series, 7% of nonepileptic spells in 666 pediatric patients were diagnosed as shuddering attacks (55).
The frequency and severity of shuddering attacks decrease with time, with eventual spontaneous remission. Infants generally subsequently develop normally. There is no treatment required. In a series of 12 children with this disorder, mean age at onset was 13 months (range 8 months to 2 years), and there was no family history of essential tremor (186). Complete remission was noted by 3 to 7 years of age. No patients developed essential tremor during mean follow-up of 6.3 years.
Chorea, athetosis, and ballism
Chorea consists of irregular, purposeless movements that flow randomly from one part of the body to another. The movements may be disguised by a voluntary movement (parakinesia) (64). There are few primary causes of chorea in childhood, and most forms are a secondary symptom of a more widespread neurologic or neurometabolic dysfunction. Genetic syndromes causing chorea in children include the NKX2-1-related disorder brain-lung-thyroid syndrome (formerly called “benign hereditary chorea”), GNAO1-related disorder, ADCY5, and PDE10A.
The most common causes of secondary chorea are rheumatic fever (Sydenham chorea), systemic lupus erythematosus, and post-pump chorea or other hypoxic-ischemic insults to the basal ganglia (280). Anti-NMDA receptor encephalitis may present with chorea, typically associated with other psychiatric and neurologic manifestations that can include psychosis, catatonia, seizures, and other involuntary movements (400). Chorea seems to be more common in children with anti-NMDA receptor encephalitis, particularly in those ages 6 and younger (23).
Athetosis is a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture (348). This can be thought of as a more distal, slower variant of chorea. Ballism is large-amplitude, proximal chorea and is characterized by brief, involuntary, flinging or throwing movements of an extremity with prominent proximal muscle involvement. Lesions of the subthalamic nucleus can cause contralateral hemiballismus.
Management of these hyperkinetic movement disorders often involves the use of benzodiazepines or dopamine receptor blocking agents. However, these drugs, particularly typical neuroleptics, may cause tardive dyskinesia. In contrast, inhibitors of vesicular monoamine transporter type 2 (VMAT2), including reserpine, tetrabenazine, and newer drugs such as valbenazine and deutetrabenazine, deplete presynaptic stores of monoamines such as dopamine, serotonin, and norepinephrine in nerve terminals. By decreasing the amount of these neurotransmitters available for release, particularly dopamine, these drugs improve a variety of hyperkinetic movement disorders. Tetrabenazine is available in the United States from specialty pharmacies and is FDA-approved for management of chorea related to Huntington disease, although it can be beneficial in many hyperkinetic movement disorders.
NKX2-1-related disorder brain-lung-thyroid syndrome (formerly “benign hereditary chorea”). Pathogenic variants in this gene can also be associated not only with chorea, but also with motor delay, cognitive deficits, hypothyroidism, perinatal respiratory distress requiring intubation, pulmonary hypertension, asthma, and recurrent pulmonary infections. Chorea can often prove refractory to medical therapies (317). Brain, lung, and thyroid involvement is present in approximately 30% of cases with NKX2-1 pathogenic variants (320).
NKX2-1 mutations are inherited in an autosomal dominant fashion. The protein product is a transcription factor that binds to regulatory elements of several lung and thyroid genes, and some patients manifest an expanded phenotype that has been referred to as the “brain-thyroid-lung syndrome.” These patients display a broad range of manifestations that can include not only chorea but also thyroid pathology such as congenital hypothyroidism or thyroid carcinoma, and disrupted morphogenesis of the bronchial tree that can manifest as neonatal respiratory distress, respiratory failure, or lung carcinoma. Some patients have had cognitive deficits or psychosis (183).
NKX2-1-deficient mice have lung, thyroid, and pituitary defects. In addition, there are developmental structural defects of the basal ganglia (28). Based on animal models, NKX2-1 is likely to mediate the tangential migration of striatal interneurons in the brain (220).
The prevalence of benign hereditary chorea has been projected to be about 1:500,000, and the penetrance may be 100% in males and 75% in females (220). Brain MRI is typically normal, although it may have pituitary abnormalities (398).
In contrast to other forms of childhood chorea, symptoms are not progressive, with chorea often abating in adolescence or early adulthood. If treatment of chorea is required, neuroleptics or tetrabenazine may be tried. In some cases of brain-thyroid-lung syndrome, the response to neuroleptics may be paradoxical, requiring use of other agents to treat the chorea (122). Levodopa has been suggested in several case reports, and methylphenidate has shown improvement in chorea (406).
Sydenham chorea (historically known as “St. Vitus’ dance”). Sydenham chorea is one of the major criteria for diagnosis of acute rheumatic fever, and in fact represents one of few circumstances in which a presumptive diagnosis of rheumatic fever can be made without strict adherence to the Jones criteria (13). Onset is usually from 5 to 15 years of age, with generalized chorea affecting the face, neck, trunk, and extremities following an infection such as pharyngitis or rheumatic fever (380). Infections with group A beta-hemolytic streptococcal strain (GABHS) are causative. Hemichorea may occur in 20% to 30%. Symptoms begin insidiously weeks to months after a GABHS infection and progress over several weeks. Sydenham chorea is often associated with elevated ASO and anti-DNaseB titers, though 25% can be seronegative, and levels do not correlate with severity. Ten percent to 30% of cases are associated with carditis, but other rheumatic fever features may not be present. Additional neurologic findings include hypotonia, weakness, Babinski signs, incoordination, and dysarthria (140). Behavioral changes, including impulsivity and obsessive-compulsive behaviors, may also develop. Recurrence of chorea is possible (224), especially associated with pregnancy or use of oral contraceptives (280).
In a retrospective study of 40 patients with Sydenham chorea followed for a mean of 2 to 6 years, Kilic and associates found that 70% were female, the mean age at onset was 11.3 years, and the most commonly involved heart valve was the mitral valve (213). Chorea lasted on average 5 months (range 1 to 12 months).
Imaging studies are usually normal but have shown enlargement of the caudate and other basal ganglia structures during the acute phase. Molecular mimicry is thought to underlie the mechanism by which GABHS produce neurologic abnormalities (217), and anti-basal ganglia antibodies may be demonstrated in 47% to 100% of cases by indirect immunofluorescence (367). The antibodies target neuronal surfaces and have been shown to induce calcium/calmodulin-dependent protein kinase II activity, resulting in abnormal cell signaling within the basal ganglia. A study has found tubulin to be a target of neuronal antibodies in Sydenham chorea (216).
Acute rheumatic fever has been the leading cause of childhood chorea, but the incidence of Sydenham chorea has been decreasing with time. Females are twice as likely to be affected. Patients harboring the D8/17 B lymphocyte alloantigen may be more likely to develop Sydenham chorea, which may account for the familial predisposition to acute rheumatic fever (119). In a series, 33% of 584 patients with rheumatic fever developed chorea, and these were less likely to have carditis or arthritis (414).
This manifestation of acute rheumatic fever usually remits spontaneously within several months to 1 year, but medical treatment controls the movements and reduces disability for patients. Treatment should include eliminating the underlying infection (typically oral or intravenous penicillin), prophylaxis to prevent recurrent rheumatic fever (intramuscular or oral penicillin), and if needed, symptomatic therapies (306). The American Academy of Pediatrics recommends prophylactic treatment with penicillin until the age of 21. Antiepileptic drugs such as valproate and carbamazepine have shown efficacy in reducing chorea, but neuroleptics or tetrabenazine may be required (306). Of note, tetrabenazine has been reported to cause quadriparesis and dysarthria in a patient with Sydenham chorea (438). Early treatment with prednisone can shorten the duration of illness compared to placebo (61). Some authors suggest that steroids be reserved for those with “chorea paralytica” or when unacceptable side effects occur with other therapies (306), whereas others advocate for their use in most cases. In one open-label report of 10 patients with “chorea paralytica” unresponsive to neuroleptics and antiepileptics, administration of a combination of IV methylprednisolone (25 mg/kg per day for 5 days) followed by oral deflazacort therapy (0.9 mg/kg per day for 3 months) resulted in resolution of chorea in all patients by 21 days following steroid initiation and no recurrence of chorea after 4 years (133). IVIG and plasma exchange have not been well studied.
Antiphospholipid syndrome and SLE-associated chorea. Antiphospholipid syndrome is a multisystem autoimmune condition characterized by vascular thromboses associated with persistently positive antiphospholipid antibodies (05). Elevated antiphospholipid antibody titers can also be present as part of systemic lupus erythematosus (SLE). Chorea may be the presenting feature of SLE in childhood, with or without other overt symptoms of the syndrome (316; 73). In SLE cases, chorea is usually associated with elevated antiphospholipid antibody titers, but chorea can also occur as part of the primary antiphospholipid syndrome. It may be unilateral or bilateral, and it may recur in relation to fluctuating antibody titers, similar to other SLE or antiphospholipid syndrome symptoms. In older children, the chorea may be precipitated by concomitant use of estrogen-containing oral contraceptives or pregnancy (72).
Although brain imaging is typically normal in antiphospholipid syndrome and SLE-associated chorea, some scans show evidence of infarcts (72). Functional neuroimaging studies have indicated there is striatal hypermetabolism (117). Cerebral vasculopathy and infarcts in a specific vascular territory are not consistently present.
A combination of vascular and autoimmune factors is thought to underlie the mechanism by which antiphospholipid antibodies contribute to chorea, though this is not known with certainty (349; 22; 117). A role for estrogen receptors has been proposed given the observation that hormonal changes and contraceptives may precipitate chorea and that the disorder is much more frequently present in women.
Of all patients with the antiphospholipid syndrome, 1.6% will develop chorea, but it is more common in childhood cases. Ten percent of children who have SLE will get chorea, and 50% of children with chorea due to SLE are younger than 16 years old (280). Chorea generally responds to medications and may wax and wane with antibody titers. Neuroleptics, benzodiazepines, or tetrabenazine may be used. Steroids or other immunosuppressants may be indicated to treat the underlying autoimmune manifestations of SLE.
Post-pump chorea. Post-pump chorea (chorea after cardiopulmonary bypass, postoperative chorea) is a disorder seen in infants or children in the first few years of life following surgery involving cardiopulmonary bypass. The movement disorder is a generalized chorea with onset within two weeks following the procedure. Other features include seizures and developmental delay.
Pathologic studies have shown gliosis and neuronal loss predominantly in the globus pallidus, and to a lesser extent in the caudate and putamen. These regions of the brain are highly susceptible to hypoxic-ischemic insult, and lesions in these areas may be seen on brain imaging. Hypoxic-ischemic insults may be incurred during reperfusion after the deep hypothermia used during the surgery (141). Hypothermia is associated with reduced cerebral metabolic rate and blood flow. There may be persistently reduced blood flow during rewarming with subsequent loss of cerebrovascular autoregulation.
In a 10-year study, 1.2% of patients undergoing cardiopulmonary bypass developed post-pump chorea (267). Affected patients had longer pump time, were cooled to lower temperatures than controls, and were more likely to have suffered circulatory arrest.
Chorea may be transient (weeks to months) or persistent. The presence of brain lesions on imaging and cyanotic heart disease is associated with persistent chorea (175). In a study of long-term outcomes in 15 children with chorea following cardiac procedures, chorea persisted for years (between 1.25 and 10.5 years, median 4.8) in seven patients (47%). In addition, neuropsychiatric evaluation showed deficits in memory, attention, and language, with a median full-scale IQ of 67 (range 40-122). All children save one had undergone procedures involving cardiopulmonary bypass (the other was a 6-week-old infant who developed chorea 3 days after a 48-hour course of mild hypothermia for supraventricular tachycardia). Age at surgery ranged from 1.5 to 52 months (111).
Tetrabenazine, benzodiazepines, and neuroleptics may be helpful. Supportive care for other medical issues and developmental delay should also be considered.
GNAO1 encephalopathy. Pathogenic variants in GNAO1 were first recognized to cause Ohtahara early infantile epileptic encephalopathy, sometimes with associated involuntary movements. The phenotype has been markedly broadened to include cases of patients without seizures but with chorea, dystonia, hypotonia, and intellectual disability. A predominant dystonic phenotype has also been described (431). Patients may present in early childhood with global developmental delay and hypotonia, and then they may develop involuntary movements later in childhood. The chorea or dystonia may be progressive, episodic, or waxing and waning, and may be triggered in the setting of febrile illness. The involuntary movements are often severe enough to warrant ICU-level care and may be associated with lactic acidosis, long bone fractures, rhabdomyolysis, and resultant kidney injury (11; 229; 255; 346).
Chorea in GNAO1-related disorder is commonly refractory to medical therapies. Deep brain stimulation of the globus pallidus internus can be effective in markedly reducing the life-threatening chorea, especially in those with medically refractory chorea (301).
ADCY5-related dyskinesia. ADCY5 is a gene previously associated with the diagnosis of familial dyskinesia with facial myokymia, a syndrome first described in 2001 that was characterized by generalized chorea with perioral and/or orbital movements in childhood. The facial movements are now known to be a mixture of myoclonus and chorea, and several abnormal movements have been described in this disorder including chorea, dystonia, and myoclonus. A hallmark feature of the disease is exacerbations of abnormal movements in an episodic manner lasting for minutes to hours and may be worsened by sleep, emotional stress, laughter, or illness. Other neurologic features may include focal epilepsy, axial hypotonia, developmental delay, spasticity, oculomotor apraxia, cognitive impairment, and psychiatric symptoms. There have also been patients described with features of alternating hemiplegia of childhood, and distinguishing features include interepisodic abnormal movements (412). Genotype-specific correlations and mosaicism appear to play an important role in phenotypic variability (74; 272; 65).
PDE10A-related disorder. In 2016, PDE10A was described as a gene responsible for childhood onset generalized chorea (271). Patients present with dysarthria and mildly progressive, generalized chorea with onset in childhood. Development and cognition are relatively spared. Brain MRI is notable for bilateral striatal necrotic lesions (282).
FOXG1 syndrome. Forkhead Box G1 (FOXG1) syndrome is pediatric neurologic syndrome characterized by microcephaly, facial dysmorphology, intellectual disability, epilepsy, and involuntary movements. Numerous different pathogenic variants of the FOXG1 gene have been described, including intragenic sequence changes (missense, nonsense, and frameshift), deletions, duplications, and complex rearrangements. Involuntary movements typically include dystonia and/or chorea (70).
Neuroacanthocytosis. Neuroacanthocytosis is a term that refers to neurologic disorders in which symptoms are accompanied by the presence of spiculated red blood cells, or acanthocytes, on peripheral smear, and, thus, includes a number of genetically heterogeneous inherited conditions (81). There are four prototypical conditions in which there is acanthocytosis and neuronal degeneration in the basal ganglia, namely chorea-acanthocytosis, McLeod syndrome, pantothenate kinase-associated neurodegeneration, and Huntington disease-like 2 (416). Abetalipoproteinemia (Bassen-Kornzweig syndrome) and other disorders associated with acanthocytosis will be reviewed separately (See section on Ataxia).
Mean age at onset of neuroacanthocytosis is in the 30s, though childhood cases have been reported (370; 39). Cognitive and psychiatric problems, axonal polyneuropathy, areflexia, and elevated creatine phosphokinase levels are prominent, in addition to hyperkinetic movements, including orofacial dyskinesias (resulting in dysarthria and dysphagia), tics and self-mutilatory behavior (particularly tongue and lip biting), dystonia, and chorea (179). Parkinsonism may occur as the disease progresses. Acanthocytes are seen in peripheral blood samples and represent more than 3% of all red blood cells.
Mutations in chorein (VPS13A, 9q21) produce the phenotype and laboratory abnormalities, though the exact function and mechanism by which the abnormal protein causes neurologic deficits is not known (335). It may be an erythrocyte membrane structural protein or may assist with protein trafficking (91). Lipid profiles are normal in contrast to abetalipoproteinemia. Imaging studies show caudate and generalized brain atrophy, similar to Huntington disease (171).
Neuroacanthocytosis may be more common in Japan, but British and Arabian families have also been described. Symptoms are progressive, but in some cases a plateau lasting several years may be reached. Weight loss or aspiration may occur due to orofacial dyskinesias. Treatments for neuroacanthocytosis are symptomatic (416). Botulinum toxin injections may help reduce the orofacial dyskinesias, typically manifested by involuntary tongue protrusion (374). Deep-brain stimulation has been attempted with various results (90).
Postinfectious chorea. Different infections have been associated with chorea in children:
• Mycoplasma pneumoniae. Generalized chorea is rare but can occur (32). | |
• HIV. Generalized chorea or hemichorea-hemiballismus may be seen (404). | |
• Lyme disease. CNS Lyme disease may cause a variety of neurologic symptoms including generalized chorea (53). | |
• Herpes simplex encephalitis. Generalized chorea may occur during the initial infection or may be the first sign of relapse (421). | |
• West Nile Virus infection can lead to a variety of neurologic symptoms and movement disorders including myoclonus, ataxia, chorea, tremor, parkinsonism, and opsoclonus-myoclonus (241). |
In most cases, the chorea is due to primary CNS infection from the bacteria or virus. Chorea may occur in the context of more generalized encephalitis. In HIV cases, chorea may be due to primary HIV infection or associated with opportunistic infections, especially toxoplasmosis.
The exact pathogenesis is not known. Chorea can occur in the context of more widespread encephalitis. Damage to or inflammation of the basal ganglia structures underlies the movement disorder. In some cases, chorea may be due to a secondary CNS vasculopathy.
HIV may be the leading cause of infectious chorea. The vast majority of reported cases of Lyme disease in the United States occur in the Northeastern states: 25% in children under 14 years of age. The incidence of this type of chorea is unknown but is rare. Symptoms often resolve with treatment of the underlying infection.
Although chorea is less common as a movement disorder in adult anti-NMDA receptor encephalitis, it appears to be common in this disorder in younger children (23). This is typically considered a postinfectious process in children, unlike in adults where it has a higher chance of being paraneoplastic, especially in the setting of ovarian teratomas in pubertal females.
Dystonia
Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation (278). These disorders can be classified according to age at onset and can be described according to their body distribution.
• Generalized dystonia affects most or all of the body, but particularly the trunk and legs. | |
• Focal dystonia is localized to a specific part of the body. | |
• Multifocal dystonia involves two or more unrelated body parts. | |
• Segmental dystonia affects two or more adjacent parts of the body. | |
• Hemidystonia involves the ipsilateral arm and leg. |
In contrast to adult-onset dystonia, which is more common, more likely focal, and appears sporadically (350), childhood-onset dystonia often starts in a limb, tends to generalize, and has a monogenic origin (246).
In addition, transient dystonic movements or postures may be present in otherwise typically developing children, which do not necessarily reflect a more worrisome underlying condition. Reported examples of this include benign paroxysmal torticollis, paroxysmal tonic upgaze of infancy, and benign idiopathic dystonia of infancy (278). Of course, as the benign course may not be apparent at the onset of symptoms, further investigation may be warranted.
Functional neuroimaging studies utilizing positron emission tomography (PET) and functional MRI (fMRI) as well as metabolic studies of regional glucose metabolism using [18F]-fluorodeoxyglucose-PET (FDG-PET) to study primary dystonia suggest that the pathology may lie in circuits of the cortico-striato-pallido-thalamo-cortical and cerebellothalamo-cortical pathways (239). In the primary dystonias, dystonia is the only sign of the disease; the cause is most often genetic, and the disease is generalized. The two most common forms are DYT1 and DYT6. In secondary forms, dystonia is not present in isolation. The etiology may be genetic or neurometabolic, or the dystonia can be the result of factors such as hypoxic-ischemic insult, infection, trauma or toxic exposure. Next-generation sequencing (whole exome and whole genome sequencing) and genome-wide association studies (GWAS) have identified a number of new dystonia genes such as CIZ1, ANO3, TUBB4A, GNAL and PRRT2, and have expanded the phenotypes of known dystonia genes (24). Moghimi and Klein provide good reviews on genetic forms of dystonia (219; 283).
The isolated dystonias described here are generally progressive conditions with various degrees of functional disability and morbidity that mainly depend of the severity and distribution of the dystonia. For example, severe truncal dystonia may result in scoliosis, respiratory compromise, and even death, particularly if it progresses rapidly as in “dystonic storm” or “status dystonicus.” A proposed practice guide has been published for the management of status dystonicus by Allen and colleagues (09). A general management strategy includes a trial of levodopa, as up to 10% of childhood-onset dystonias are dopa-responsive-dystonias, and mild to modest improvements may be seen in other forms of generalized dystonia. Other medication options include anticholinergics, benzodiazepines, antispasmodics, and muscle relaxants. Botulinum toxin injections may be helpful (162; 187). Deep-brain stimulation of the globus pallidus interna has been shown to provide significant and sustained benefit for children and adolescents with isolated generalized dystonia (40; 314). Deep brain stimulation may also provide functional improvement for children with acquired dystonia, although there remains a relative paucity of studies to demonstrate benefit in this population (305; 116).
Isolated monogenic dystonias.
DYT1 (DYT-TOR1A), early-onset generalized dystonia. DYT1 (TOR1A, 9q34, torsinA) represents the most common form of genetic, childhood-onset dystonia. Symptoms usually start after 6 years of age with action dystonia, such as writer’s cramp or foot inversion when running. Dystonia usually presents in a distal limb and progresses proximally to involve the entire body, but phenotypic heterogeneity may exist even within the same family (307). The type of presentation varies with age at onset; older-onset cases are more likely to display a focal dystonia such as cervical dystonia, writer's cramp, spasmodic dysphonia, or blepharospasm-oromandibular dystonia at symptom onset (308). Symptoms can rapidly progress, a state referred to as "dystonic storm." Severe abnormal postures can lead to wheelchair dependence, orthopedic problems, and scoliosis. Facial and oromandibular dystonia may cause difficulty with eating or swallowing. Cranial involvement before 21 years of age may be the strongest predictor of non-DYT1 status (118; 359).
Inheritance is autosomal dominant but with incomplete penetrance (20% to 30%) (134).The gene product of the DYT1 gene is torsinA (9q34). TorsinA is an AAA+ ATPase in the endoplasmic reticulum that has structural similarity to heat shock proteins (415). Its exact function is not understood but it may be involved in protein handling within the nuclear envelope, where the mutated torsinA localizes (294). Ultrastructural studies also have demonstrated torsinA in presynaptic nerve terminals, suggesting that this protein somehow modulates striatal signaling (17). Pathologic specimens from affected patients reveal perinuclear inclusion bodies in the midbrain reticular activating system and periaqueductal gray matter (266). These inclusions stain positive for ubiquitin, torsinA, and laminin A/C, which supports the belief that protein handling and the nuclear envelope are somehow integral to the pathophysiology of DYT1. Allelic polymorphisms may account for the variable penetrance (221). Differential expression of torsinA and torsinB over time in the developing mouse brain has been found, suggesting some role of the torsin proteins in neural development, migrating, or synaptogenesis (411; 148). There is no neuronal loss, suggesting that this is a “neurofunctional” disorder rather than a neurodegenerative one.
DYT1 is more frequently represented in Ashkenazi Jews, probably due to a founder mutation, but may be also seen in other populations. It accounts for most cases of childhood-onset generalized dystonia in this population (06).
Treatment of this and other forms of dystonia includes a combination of supportive care and various medications, including benzodiazepines, anticholinergics, and muscle relaxants. Deep-brain stimulation of the globus pallidus interna can improve axial and extremity dystonia, but fixed dystonic postures and oromandibular symptoms are less likely to improve (442; 101).
DYT2 (DYT-HPCA). This disorder has been described in consanguineous Spanish Gypsy families. It is characterized by lower extremity dystonia with rapid generalization. Inheritance is autosomal recessive. Mean age at onset is 15 years of age.
DYT4 (DYT-TUBB4A), “whispering dysphonia.” DYT4 has been described in an Australian family. Age of onset is 13 to 37 years of age and is characterized by focal or generalized dystonia with prominent dysphonia. Inheritance is autosomal dominant.
DYT6 (DYT-THAP1), adolescent-onset dystonia with mixed phenotype. DYT6 (THAP1, 8p11) is characterized by limb dystonia that spreads into the craniocervical regions, often with dysphonia. The disorder was originally described in the Amish-Mennonite community, and it may be the second most common inherited primary dystonia. Onset is later than DYT1, with mean age of onset about 19 years of age. Inheritance is autosomal dominant with 60% penetrance. THAP1 is thought to be involved in apoptotic pathways (47; 106).
DYT13. Described in a large Italian family, this dystonia is characterized by craniocervical involvement that becomes segmental (30). Average age at onset is 15 years of age (range 5 to 43 years of age). Inheritance is autosomal dominant. Most present with jerky, myoclonic-like dystonic movements of the neck or shoulders. Generalization occurs in a minority of cases. It is an autosomal dominant disorder that localizes to 1p36.32-p36.13; the gene product is unknown. There is incomplete penetrance (58%). Only one family in the United States has been reported. Progression is mild, and the disease course is benign in most affected individuals. Independence is maintained.
DYT16 (DYT-PRKRA), early-onset generalized dystonia-parkinsonism. DYT16 (PRKRA) has been described in Brazilian families. It is characterized by generalized dystonia that starts in a limb and progresses to bulbar involvement. Age at onset is 2 to 12 years of age. Inheritance is autosomal recessive. PRKRA is thought to activate a protein kinase in response to stress.
DYT17, autosomal recessive dystonia. DYT17 has been described in a Lebanese family, with onset of torticollis in adolescence, followed by progression to segmental or generalized dystonia.
DYT24 (DYT-ANO3), autosomal dominant dystonia. DYT24 (ANO3) has been described and is characterized by craniocervical dystonia with laryngeal and upper-limb involvement.
DYT25 (DYT-GNAL), autosomal dominant dystonia. DYT25 (GNAL) has been described as a cause of cervical dystonia. It is characterized by a predominance of neck, facial, and laryngeal dystonia in a segmental or focal pattern for most, but several patients in kindreds of these families had generalized features. Onset was in childhood for several patients, but in adulthood for the majority (132). At least one family has had more of a chorea phenomenology.
DYT27 (DYT-COL6A3), autosomal recessive dystonia. Pathogenic variants in COL6A3 are known to be associated with a spectrum of skeletal muscle pathology, ranging from Bethlem myopathy to Ullrich congenital muscular dystrophy. It has now been associated with a form of recessive isolated segmental dystonia, affecting the craniocervical region and upper limbs in the first two decades of life, with associated cognitive deficits. The gene has been found to be expressed in neurons of the mouse brain, including in the cerebellum and striatum, with highest expression in the brainstem and midbrain (440).
DYT28 (DYT-KMT2B), autosomal dominant dystonia. DYT28 (KMT2B) is a childhood onset progressive disorder, which is characterized by a lower extremity focal dystonia presenting in early childhood that later generalizes. There is prominent cervical, cranial, and laryngeal involvement leading to speech impairment and dysphagia. Additionally, intellectual disability is common, and affected individuals may also display psychiatric symptoms, eye movement abnormalities, spasticity, and sensorineural hearing loss. Pharmacologic treatment may provide some improvement in dystonia; however, increasing evidence suggests bilateral globus pallidus interna deep brain stimulation leads to significant clinical improvement and should be considered early (274; 02).
Combined monogeic dystonia syndromes.
Parkinsonism-dystonia (DYT5a, 5b, 12).
• DYT5a (dopa-responsive dystonia, Segawa disease, GCH1). This is a childhood-onset dystonia with a wide phenotypic spectrum that includes lower > upper extremity dystonia, parkinsonism, and diurnal fluctuation that is clearly responsive to levodopa. Although one of the clinical hallmarks of this condition is diurnal fluctuation of symptoms with progression during the day and marked improvement following sleep, only half of the cases exhibit this feature. A marked and sustained response to levodopa is the diagnostic feature of this disorder. At onset, extremity dystonia (lower > upper extremities), parkinsonism, and postural instability predominate. Tremor and other parkinsonian features may develop in the 2nd decade. Diurnal fluctuation subsides by the third decade, and symptoms stabilize by the fourth decade. In some cases, the presentation may resemble atypical cerebral palsy. In a series of 34 patients, the classic phenotype was found in 23 patients, with a female predominance and early onset (mean age 4.5 years) of lower extremity symptoms, but 11 cases had atypical presentation including male preponderance, cranial-cervical dystonia, spasmodic dysphonia, mild young-onset phenotype that did not require treatment, or adult-onset parkinsonism (402). | |
The pattern of inheritance is typically autosomal dominant with incomplete penetrance (30%). The responsible gene is GCH1 (14q22.1-q22.2), which encodes GTP cyclohydrolase I, the rate-limiting enzyme in the conversion of GTP to tetrahydrobiopterin (BH4). BH4 is a cofactor for tyrosine hydroxylase, an enzyme that is required for dopamine synthesis. Homozygous mutations may occur and are associated with a more severe phenotype. Nearly 100 mutations have been identified, including some in the intron regions. | |
• DYT5b (dopa-responsive dystonia plus). Two rare autosomal recessive forms of dopa responsive dystonia have been found to be due to mutations in tyrosine hydroxylase on 11p15.5 or due to sepiapterin reductase deficiency (SR gene). In tyrosine hydroxylase deficiency there is a 4:1 F:M distribution. Prevalence is 0.5 to 1.0 per million. This disorder is autosomal recessive in nature, often with a more severe phenotype than DYT5a, though it is less common. Two phenotypes exist (429): an infantile-onset, progressive, hypokinetic-rigid syndrome with dystonia, and a complex encephalopathy with neonatal onset. The causative abnormality is a mutation in the gene encoding tyrosine hydroxylase (an enzyme required for dopamine synthesis) on 11p15.5, causing a TH deficiency. The laboratory hallmark is of decreased CSF homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid. The relative concentrations correlate with disease severity. Treatment is with levodopa. Sepiapterin reductase deficiency also results in a dopa responsive dystonia plus phenotype with a CSF neurotransmitter pattern showing very low levels of homovanillic acid and 5-hydroxyindoleacetic acid, and high levels of biopterin and sepiapterin in the CSF that are the diagnostic. Patients may respond dramatically to treatment with L-DOPA and 5-hydroxytryptophan (03). | |
• DYT12 (rapid-onset dystonia-parkinsonism, ATP1A3). This disorder is characterized by the abrupt onset of dystonia and parkinsonism within hours to days. The limbs and face are affected with dysarthria and dysphagia. Parkinsonism is characterized by bradykinesia, slow gait, and postural instability. There is a rostrocaudal gradient of development of symptoms, which are also worse with stress (fever, heat exposure, prolonged exercise, childbirth, or emotional stress) and alcohol. The presence of rapid and abrupt onset, a rostrocaudal gradient, and prominent bulbar findings should prompt evaluation for this condition (45). Age at onset is 4 years of age or older, with usual onset in late adolescence or early adulthood. Inheritance is autosomal dominant with reduced penetrance. Associated symptoms may include seizures and depression. | |
• Pathogenic variants in ATP1A3 have now been recognized to cause a variety of neurologic phenotypes and will likely continue to expand. Recognized phenotypes now include rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood, cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (381). | |
DYT12 is an autosomal dominant disorder that localizes to 19q13 (439), where the Na+/K+-ATPases (sodium pumps) are encoded (93; 107). These are P-type ATPase pumps that catalyze active transport of cations across cell membranes and maintain ionic gradients through hydrolysis of ATP. The alpha-subunit is the catalytic subunit, and three isoforms (alpha1, 2, and 3) are expressed in the nervous system. A large family without linkage to the ATP1A3 gene has been described (205). | |
Families in the United States, Ireland, and Poland have been described. Most patients remain stable or demonstrate slight improvement years after the abrupt onset of symptoms. Symptoms are not dopamine responsive, although this does not preclude a trial of levodopa. |
Myoclonus-dystonia (DYT11, 15).
• DYT11 (DYT-SGCE) (dystonia-myoclonus, 7q21SGCE). DYT11 is characterized by bilateral, alcohol-sensitive, myoclonic jerks involving mainly the arms and axial muscles. Dystonia, usually torticollis and writer's cramp, occurs in most affected patients and may be the only symptom of the disease. Patients often have prominent psychiatric symptoms, including panic attacks and obsessive-compulsive behavior. SGCE mutations are a major cause of familial myoclonus-dystonia, found in 30% to 50% of cases (272b). | |
• Onset is in childhood or early adolescence, but the disease course can be variable, including progression or spontaneous remission (295; 343). Myoclonus is of subcortical origin, involving subcortical and brainstem circuits (256; 343). | |
• Most cases are autosomal dominant and due to mutations in the epsilon-sarcoglycan gene (SGCE, 7q21) (69). SGCE is part of the dystrophin-glycoprotein complex, which links the cytoskeleton to the extracellular matrix. There is reduced penetrance with a maternal imprinting phenomenon. | |
• In a series of 23 children with dystonia presenting with other hyperkinetic “jerky” movements, eight patients were diagnosed with myoclonus-dystonia (seven with the SGCE mutation) (16). In some of the SGCE mutation carriers, gait disorder due to lower extremity dystonic symptoms and unsteadiness with frequent falls, and associated with superimposed myoclonic jerks, developed before the age of 18 months. Symptoms later evolved to include the more typical neck and upper limb regions. | |
• DYT15. Symptoms begin from 7 to 15 years of age and are markedly responsive to alcohol. Inheritance is autosomal dominant with reduced penetrance. Myoclonus is characterized mainly by jerky movements of the upper limbs, hands, and axial muscles. Patients may also have upper > lower limb dystonia. | |
• Other forms. Exome sequencing and linkage analysis in small cohorts have led to the discovery of other genes associated with a phenotype similar to epsilon sarcoglycan-positive myoclonus-dystonia. A mutation in KCTD17, a gene coding for a protein involved in ciliogenesis that is expressed highly in the putamen and thalamus, has been associated with autosomal-dominant myoclonus-dystonia in a German family (272a). Pathogenic variants in RELN may also be associated with myoclonus-dystonia (159). RELN codes for Reelin, a large glycoprotein secreted by Cajal-Retzius cells, cortical and hippocampal GABAergic interneurons, and cerebellar granule cells. A mutation in the CACNA1B gene, which codes for a neuronal voltage-gated calcium channel, was also associated with myoclonus-dystonia with concomitant cardiac arrhythmias in a Dutch family (158). However, a subsequent study found a similar frequency of the variant among affected patients and healthy controls (272a). | |
• Treatment. Treatment for myoclonus-dystonia remains symptomatic, and may include benzodiazepines, anticholinergics, levodopa, anticonvulsants, and dopamine-depleting medications (277). There is also evidence that zonisamide may be helpful in the management of both the myoclonus as well as dystonia (161). Botulinum toxin may be helpful for dystonic postures (215). Pallidal deep brain stimulation may also be effective (365). |
Deafness-dystonia.
• Mohr-Tranebjaerg syndrome (Dystonia-deafness syndrome and Deafness-dystonia-optic atrophy syndrome). This is a rare disorder characterized by childhood-onset sensorineural hearing loss and dystonia. Other neurologic abnormalities include vision loss, spasticity, dementia and mental retardation. Vision loss is predominantly from cortical dysfunction, but optic atrophy also contributes. Female carriers may have torticollis or writer’s cramp (382). The disorder localizes to Xq22 and is due to a mutation in the deafness/dystonia protein 1/translocase of the mitochondrial inner membrane 8a (DDP1/TIMM8a) (341). DDP1/TIMM8a is similar to a family of yeast proteins in the mitochondrial intermembrane space that mediate the import and insertion of inner membrane proteins. Familial clustering is noted. |
Other etiologies of dystonia.
Dystonia can occur as part of neurometabolic disorders or genetic conditions (described elsewhere in this article), or as the result of factors such as hypoxic-ischemic insult, infection, trauma, or toxic exposure. The dystonia is part of the larger clinical picture in which other movement disorders or neurologic manifestations may also occur.
• Neurodegenerative: Huntington disease, Parkinson disease, the spinocerebellar ataxias, neuroacanthocytosis | |
• Metabolic disorders: Wilson disease, inborn errors of metabolism | |
• X-linked: Pelizaeus-Merzbacher, Mohr-Tranebjaerg syndrome |
Hemidystonia. Hemidystonia can result from head trauma, stroke or hemorrhage, perinatal injury (often hypoxic-ischemic brain injury), structural abnormality (eg, cysts, arteriovenous malformations), or infection (eg, abscess, encephalitis). Hemidystonia is often a result of damage to the basal ganglia structures, especially the putamen (78).
Posttraumatic dystonia. Dystonia occurring after peripheral injury (300) may occur with or without complex regional pain syndrome, previously referred to as reflex sympathetic dystrophy (195; 388). The exact mechanisms by which a peripheral injury results in dystonia are not clear, but secondary central dysfunction due to cortical and subcortical reorganization may play a role.
Delayed onset dystonia. Patients with dyskinetic cerebral palsy may also develop focal dystonias, with the potential for these to worsen several years into the disease course (357). The exact mechanism of delayed-onset progressive movement disorders in patients with static encephalopathy is not known. There is growing body of evidence that genetics and inflammation may play a role in the pathogenesis of cerebral palsy (160). Although “neuroplasticity” and variable “vulnerability” have been often invoked to explain different outcomes after early brain insult, some investigators have suggested that the two represent extremes along a “recovery continuum” (12).
Focal idiopathic dystonia.
Blepharospasm, oromandibular dystonia, spasmodic dysphonia, writer’s cramp, and task-specific dystonia. These are all examples of focal dystonias that are much more common in the adult population than in children.
Torticollis. Torticollis beginning in infancy can be a result of congenital muscular torticollis or superior oblique palsy (212; 302). Congenital muscular torticollis is the commonest form and can be associated with masses within the sternocleidomastoid muscle, tightness of that muscle, or plagiocephaly of the skull due to positioning (204). The abnormal head position can be managed with physical therapy and progressive stretching exercise, botulinum toxin injections (83), or by surgical release (204). If left untreated, fibrosis may develop.
Sudden-onset, fixed head rotation in a child should trigger a work-up for underlying conditions. Grisel syndrome is atlantooccipital rotatory subluxation following an upper respiratory infection (434). Other causes include oculomotor abnormalities, orthopedic disorders of the atlantoaxial joint, spinal cord abnormalities (eg, syrinx or tumor), CNS infections, increased intracranial pressure, or rheumatic conditions. Grisel syndrome is presumably due to laxity of ligaments due to inflammatory ligamentous laxity following the infection. Acute infectious torticollis outbreaks have been reported, particularly in China. Other conditions are due to mechanical strain on the joint. Risk of cervical cord compromise is high in many of these conditions, so emergent diagnosis and treatment is essential. The dislocation can be reduced, but patients may require halo placement for prolonged stabilization.
Anti-NMDA-receptor encephalitis. Anti-NMDA receptor encephalitis is a condition in which antibodies against the NR1 subunit of the N-methyl D-aspartate (NMDA) receptor are associated with a characteristic clinical syndrome. As dystonia is often part of the constellation of signs, it will be reviewed here. The illness often presents in stages, and may begin with a flu-like illness. Classically, in adults and adolescents, within two weeks patients develop neuropsychiatric symptoms (eg, behavioral changes, anxiety, confusion, psychosis). In young children, these changes may be less obvious, manifesting as irritability or hyperactivity, prior to developing other characteristic features (89). For this reason, awareness of and vigilance for this disorder is paramount.
Patients often develop mutism (often with echolalia or echopraxia), followed by seizures, worsening encephalopathy, a catatonic-like state, abnormal movements, akinesis alternating with agitation, autonomic failure, and hypoventilation (89). Orofacial dyskinesia (oromandibular-lingual stereotypy, dystonia, or myorhythmia) is a classic feature of the disorder in adults and teenagers, but may be less common in children. Patients typically have more than one type of abnormal movement, which can include chorea, dystonia, stereotypy, myorhythmia, catalepsy, and ataxia (23; 284). Management of progressive symptoms often requires prolonged ICU care. In adult females many, but not all, cases are associated with a tumor such as ovarian teratoma. In pediatric cases, associated tumors are less common (127). CSF titers of anti-NMDA-receptor antibodies are higher in patients with tumors and lower after effective treatment. Serum antibodies can also be measured. Removal of the tumor and immune therapy such as IV steroids, IVIG, plasma exchange, and rituximab can result in clinical improvement and prevent or minimize relapses. Evidence suggests that earlier diagnosis and utilization of rituximab or cyclophosphamide in refractory cases may decrease relapse rates and neurologic morbidity (400; 56). The clinical course of improvement can be prolonged over months to years.
Myoclonus
Myoclonus is defined as brief, jerk-like contractions of a muscle or muscle groups resulting in a sudden and unexpected movement (“positive” myoclonus) (see MedLink Neurology article on Myoclonus). “Negative” myoclonus may also occur, resulting in brief loss of posture, (eg, asterixis). Myoclonus can be classified etiologically: physiologic myoclonus, essential myoclonus, epileptic myoclonus, or secondary myoclonus. Alternatively, myoclonus can also be subdivided based on the anatomic origin of the abnormal neuronal discharges responsible for the movement: cortical, subcortical (ie, brainstem), or spinal (102; 277). The pathophysiology and management are similar to adult cases, but the etiologies may differ significantly, especially in the case of cortical myoclonus. Children are more likely than adults to have cerebral malformations or genetic/metabolic diseases that may commonly result in myoclonus.
In the case of suspected genetic and metabolic disorders, care must be taken to evaluate for clues to the underlying etiology, particularly because in some instances (such as in Wilson disease), early identification can modify the course of the disease. Other examples of disorders in which myoclonus can present include mitochondrial disorders (eg, MERFF, MELAS, Leigh syndrome), lysosomal storage disorders (eg, Niemann-Pick type C, neuronal ceroid lipofuscinosis, Krabbe disease), and disorders with prominent ataxia (eg, ataxia-telangiectasia, Friedreich ataxia, some autosomal dominant spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy), among others (409).
Myoclonus can be a physiologic phenomenon, but can also be a prominent feature of myoclonic epilepsies, which typically present in childhood. Therefore, the first step in classifying a myoclonic disorder is to determine if it is epileptic or nonepileptic (280). This is most easily accomplished by performing electroencephalography. Epileptic causes will not be reviewed here except for cases of Rasmussen encephalitis, which may be associated with other movement disorders.
Physiologic myoclonus. Myoclonus can be a normal phenomenon, for example, many people experience a generalized body jerk during drowsiness that may jolt them awake (sleep myoclonus). Neonates and infants frequently experience this type of myoclonus (benign neonatal sleep myoclonus, benign myoclonus of early infancy), but in such cases, the absence of progressive symptoms, developmental regression, or intellectual impairment should reassure the parents and the physician that no pathology exists.
Cortical myoclonus. Cortical myoclonus is characterized by myoclonic jerks originating from abnormal electrical activity in the cerebral cortex that can be observed on conventional EEG or EEG back-averaging. The jerks may be spontaneous, stimulus-sensitive, or action-induced and can be associated with enlarged somatosensory evoked potentials (SSEPs). Cortical discharges may also cause epileptic events, and seizures may be associated with cortical myoclonus, including epilepsia partialis continua (which is often not seen on scalp EEG recordings and may require other modalities such as magnetoencephalography). Cortical myoclonus usually occurs irregularly, but it may appear to be rhythmic.
Cortical myoclonus is not specific to a particular condition. Causes of cortical dysfunction include acute or subacute encephalopathy due to toxic-metabolic, hypoxic, or infectious etiologies, focal brain lesions (eg, infarct, hemorrhage, tumor), cortical malformations, or neurodegenerative disorders. Cortical neurons in the vicinity of a lesion, rather than in the lesion itself, may be electrically unstable and hyperexcitable, resulting in myoclonic jerks and epilepsy (304). The motor cortex is involved in the execution of fractionated rather than mass actions. Cortical myoclonus is, therefore, multifocal, typically involving fractionated movement of the fingers, and may involve high-frequency rhythmic bursts. Long-loop cutaneous and stretch reflexes play an important role in cortical organization of movement; light touch and stretch may consequently lead to reflex jerks of the stimulated area (362).
Lance-Adams syndrome. Lance-Adams syndrome is a multifocal, stimulus-sensitive myoclonus due to global cerebral anoxia.
Rasmussen encephalitis. Rasmussen encephalitis is a rare, progressive, disease of unknown pathogenesis that begins in the first decade of life affecting previously normal children. Unilateral cortical hemispheric dysfunction results in epilepsia partialis continua, contralateral hemiplegia with or without hemiatrophy, dementia, and inflammation of the brain (401). MRI demonstrates hemispheric atrophy. PET scans demonstrate hypometabolism of that hemisphere, and SPECT scans demonstrate a corresponding area of hypoperfusion. Rasmussen encephalitis is linked to circulating antibodies to the glutamate receptor-3 (GLUR3) (166). It is not clear if the presence of these antibodies is causative of the syndrome or a secondary phenomenon. Other movement disorders can be seen in Rasmussen encephalitis, including dystonia, chorea, and myoclonus (131). The exact pathophysiologic mechanisms are not understood, but the disorder is presumably related to immune mechanisms. The movement disorders result from insults to the basal ganglia. Rasmussen encephalitis is a progressive condition that may require treatment with immunosuppressants, IVIG, or even surgical management with hemispherectomy.
Subcortical myoclonus. Brainstem motor systems are particularly involved in axial and bilateral movements and are tightly linked to subcortical reflex centers. Subcortical myoclonus is generalized, especially involving axial musculature, and is stimulus-sensitive. Auditory stimuli are particularly prone to elicit subcortical myoclonus, as is seen in hyperekplexia, startle syndromes, and brainstem reflex myoclonus. Examples include myoclonus-dystonia, opsoclonus-myoclonus-ataxia, and reticular reflex myoclonus.
Palatal myoclonus. Palatal myoclonus is due to structural damage within Mollaret triangle, an anatomic region of the brainstem encompassing the red nucleus, dentate nucleus and inferior olivary nucleus. Two forms are recognized--essential palatal myoclonus: clicks caused by contractions of the tensor veli palatine that disappear during sleep, and symptomatic palatal myoclonus: ear clicks caused by contractions of the levator veli palatine that usually do not abate during sleep (100). It is also sometimes referred to as palatal “tremor.” In four pediatric patients with essential palatal myoclonus, age at onset was 6 to 7 years, and they were successfully treated with piracetam (60).
Middle-ear myoclonus. Audible ear clicks caused by contractions of the tensor tympani and stapedius muscles (21).
Hyperekplexia (123). This is a syndrome of exaggerated persistent startle reaction to unexpected auditory, somatosensory and visual stimuli, generalized muscular rigidity, and nocturnal myoclonus. It can present in utero with abnormal movements, or at any time until adulthood. Patients present with marked irritability and recurrent startles in response to minimal stimuli. Consistent generalized flexor spasm in response to tapping of the nasal bridge (without habituation) is the clinical hallmark. Tonic spasms mimicking seizures can cause apnea and death.
Mutations in the alpha1 subunit of inhibitory glycine receptor (GLRA1) gene are causative in some cases. These mutations uncouple the ligand binding and chloride channel function of inhibitory glycine receptor and result in increased excitability in pontomedullary reticular neurons and abnormal spinal reciprocal inhibition. The disorder is often familial, with autosomal dominant inheritance, characterized by complete penetrance and variable expression. Rarer genetic abnormalities have been found in other postsynaptic proteins of the glycine pathway, including the glycine receptor beta subunit (GLRB), gephyrin (GPHN) and collybistin (ARHGEF9) (167). A mutation in the presynaptic glycine transporter 2 (GlyT2, SLC6A5) can also cause this syndrome and may be the second most common cause (336). Patients with this syndrome present with hypertonia, exaggerated startle response to tactile or acoustic stimuli, and life-threatening apneas. In this genetic cause, there is defective subcellular GlyT2 localization and/or decreased glycine uptake, and the possibility of altered glycine and sodium binding sites. Patients with SLC6A5 mutations are more likely to have serious infantile apneas and cognitive developmental difficulties (397).
Symptoms can be severe enough to produce apnea and even death. Clonazepam is the treatment of choice for this disorder, though it may not influence the degree of stiffness significantly. A simple maneuver like forced flexion of the head and legs towards the trunk is known to be lifesaving when prolonged stiffness impedes respiration. Developmental outcome by 2 years of age is normal.
Opsoclonus-myoclonus-ataxia syndrome (“dancing eyes dancing feet”). Opsoclonus-myoclonus-ataxia syndrome is a paraneoplastic or postinfectious movement disorder that typically presents between 6 and 36 months of age, although it may also occur in older children and adults (88). Opsoclonus is defined by chaotic, multidirectional, and conjugate eye movements. The myoclonus and ataxia in this condition are otherwise typical. Conditions associated with opsoclonus-myoclonus-ataxia syndrome include tumors of neural crest origin (most typically a neuroblastoma) and encephalitis syndromes, such as those seen with Epstein-Barr virus, enterovirus, mumps, parainfluenza, and coxsackie virus. In some cases of opsoclonus-myoclonus associated with peripheral neuroblastic tumors, symptom onset may be triggered by a vaccination or a viral infection (373). Opsoclonus myoclonus ataxia has been associated with COVID-19 (185). Opsoclonus-myoclonus occurs in up to 2% to 3% of patients with neuroblastoma, but neuroblastoma is found in up to 50% of cases presenting with opsoclonus-myoclonus; nearly 100% of children with opsoclonus-myoclonus associated with neuroblastoma survive (342).
It must be noted that any of the classic symptoms can be absent. Behavioral change and sleep disturbance have also been described (152). Ataxia may be the most common presenting feature, and a robust level of suspicion for opsoclonus-myoclonus-ataxia syndrome must be present when a child with acute cerebellar ataxia does not improve predictably or if symptoms recur.
The disorder is thought to be immune-mediated, with antigens produced by the neural crest tumor or infections agent cross-reacting to cerebellar tissue (35). Oligoclonal bands may be present in the cerebrospinal fluid, may correlate with symptom severity, and may improve with treatment (331). Symptoms are steroid-responsive; IVIg, azathioprine, and cyclophosphamide have also been used (330; 92), and rituximab has been found to be effective. Opsoclonus-myoclonus generally follows a relapsing course; infections and reduction in steroid dosage are the usual precipitants of relapses. Subsequent motor, cognitive, behavioral, and language development are typically delayed (281). The long-term picture may be dominated the most by cognitive and behavioral problems rather than ataxia or myoclonus (218). Longer latency to diagnosis and treatment may result in greater risk of such difficulties (95).
Spinal myoclonus. Spinal myoclonus is a slow, repetitive movement that can be stimulus sensitive. It tends to involve a group of muscles innervated by a certain spinal segment (segmental myoclonus). It often does not abate with voluntary movement or sleep, which is a typical feature of other forms of myoclonus and other movement disorders, including some forms of tremor and dystonia. Spinal myoclonus can arise from certain segments and subsequently spread slowly both rostrally and caudally. This is likely due to conduction through the propriospinal tract that connects multiple segmental levels (thus, it may be termed propriospinal myoclonus). This form of spinal myoclonus leads to predominantly axial jerks that spare the face and are not stimulus-sensitive.
Spinal myoclonus has been associated with various spinal cord insults, including mass lesions, ischemia, infection, inflammatory conditions (eg, transverse myelitis) and as part of a paraneoplastic syndrome. It may occur as a result of loss of glycinergic inhibition with subsequent uninhibited, synchronous neuronal activity in the area of the damaged cord (211). Several spinal segments may be involved. In segmental spinal myoclonus, hyperexcitability may occur from direct insult related to viral irritation, inflammation, or structural abnormalities such as syringomyelia, glioma, or ischemia. Outcome and prognosis vary with etiology.
Postinfectious myoclonus. Myoclonus following infections (including encephalitis) is not common but is characteristic of certain pathogens. Multifocal myoclonus associated with Group A streptococcal infection has been described in one patient (369). It is likely an immune phenomenon caused by antibodies to streptococcal epitopes cross-reacting with brain tissue.
Enterovirus 71 causes hand-foot-mouth disease in children. The most common presentation is rhombencephalitis, which can be associated with myoclonic jerks and tremor, with or without ataxia. Myoclonus ranges from mild jerks during sleep to frequent myoclonus during sleep and wakefulness. Enteroviral rhombencephalitis may be due to direct invasion of the brain stem by the virus. Outbreaks of enterovirus 71 infections are rare but potentially fatal. The presence of myoclonus may be predictive of poor outcome (178).
Subacute sclerosing panencephalitis is a latent neurologic consequence (within years) of measles infection. It is a neurodegenerative disorder that presents with myoclonus in up to 60% of cases (184). The EEG is characteristic, with periodic slow spike-and-wave discharges. Subacute sclerosing panencephalitis is rare in countries with vaccination programs and carries a high mortality rate despite supportive treatment.
Coronavirus disease 19 (COVID-19) causes a range of symptoms to include respiratory failure with fever, cough, myocarditis, and fatigue, although several neurologic symptoms have been associated to include acute cerebrovascular accident, Guillain-Barre syndrome, and opsoclonus-myoclonus-ataxia. Generalized myoclonus has been associated with infection (333).
Drug-induced myoclonus. Psychiatric medications (including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), lithium, antipsychotics), anti-infectious agents, narcotics, anticonvulsants, anesthetics, contrast media, cardiac medications (including calcium channel blockers, antiarrhythmics), and drug withdrawal can all cause myoclonus (198).
Medications used in the treatment of myoclonus include clonazepam, tetrabenazine, levetiracetam, sodium valproate, piracetam, acetazolamide, carbamazepine, and 5-hydroxytryptophan (5-HTP) (188).
Tics
Tics are sudden, brief, intermittent, involuntary or semivoluntary movements (motor tics) or sounds (phonic or vocal tics) (394). They typically consist of simple or coordinated, repetitive or sequential movements, gestures, and utterances that mimic fragments of normal behavior. Tics may be simple or complex. Profane gestures (copropraxia) or utterances (coprolalia) may also be present but occur in less than 10% of those with chronic tics lasting greater than a year. Motor and phonic tics are often preceded by premonitory sensations, which consist of localizable paresthesia or discomfort; these sensations are temporarily relieved after the execution of the tic (233). Patients are able to suppress their tics, which helps to differentiate these movements from other hyperkinetic movement disorders (190). Tics are also suggestible and may be exacerbated by stress, excitement, boredom, fatigue, and exposure to heat. The frequency of tics may also increase during relaxation after a period of stress. Tics may be classified as follows: provisional (transient) tic disorder of childhood (when the tics have lasted for less than 1 year); persistent (chronic) motor or phonic tic disorder (for more than 1 year), or adult-onset tics.
Tourette syndrome (189; 209; 199; 191; 193) (see MedLink Neurology article on Tourette syndrome). This is the most common cause of tics. Diagnostic criteria (394) include: both multiple motor tics and one or more phonic tics must be present at some time during the illness, although not necessarily concurrently; tics must occur intermittently throughout a period of more than 1 year; the anatomical location, number, frequency, type, complexity, or severity of tics must change over time; the onset must occur before the age of 18 years; involuntary movements and noises must not be explainable by other medical conditions.
Psychiatric comorbidities are common in Tourette syndrome. Attention deficit hyperactivity disorder is generally accepted to occur in 40% to 70% of Tourette syndrome cases, with an average age at onset of 4 years, whereas obsessive-compulsive disorder is reported in 20% to 60% of cases, with an average age at onset of 7 years old. Tics themselves will generally manifest somewhere in time between the onset of these two comorbidities, with motor tics presenting in a rostral-caudal fashion of bodily involvement, and phonic tics progressing from simple to complex phenomenology.
Secondary tics may occur in other neurologic disorders, including primary dystonia, Huntington disease, neuroacanthocytosis, NBIA 1, tuberous sclerosis, Wilson disease, and pervasive developmental disorders. Infections, drugs, and toxins should also be considered (269). Patients with genetic and chromosomal disorders, such as Down syndrome or Fragile X syndrome, may also have tics.
Tourette syndrome, along with its typical comorbidities, is postulated to be a neurodevelopmental disorder involving multiple neurotransmitter systems within cortical-basal ganglia-thalamo-cortical loops. A focus of inappropriate activity within distinct clusters of striatal matrisomes leads to aberrant inhibitory input to a specific set of globus pallidus interna (GPi) and/or substantia nigra pars reticulata (SNr) neurons. In turn, these GPi/SNr neuronal groups yield reduced inhibition to the thalamus, thereby releasing thalamocortical loops from tonic suppression and producing involuntary movements. The distinct, repetitive, predictable pattern of a tic is determined by which matrisomal clusters were originally activated; multiple tics would result from activation of multiple sets of matrisomes. Abnormal dopaminergic transmission may also play a role.
There is a strong familial component to Tourette syndrome, with the risk of developing tics increasing proportionally with the degree of genetic relatedness to a person with tics (264). However, despite numerous sophisticated genetic studies, the underlying pathophysiology remains elusive. The contribution of genetic factors may be complex and may involve bilinear or polygenic inheritance (372). There is some evidence that multiple genes may each contribute to relative risk (430).
Tourette syndrome is largely present across all cultures worldwide, with fairly uniform phenomenology, and with similar prevalence figures of 0.4% to 3.8% reported in children aged 5 to 18 years. An overall international prevalence figure of 1% is proposed, though rates seem to be much lower in sub-Saharan Africa and in African Americans. Males are approximately five times as likely to be affected with Tourette syndrome. Family members may have milder symptoms or a forme fruste of the disorder, with various degrees of tics, obsessive-compulsive disorder, and ADHD (164). The prevalence of Tourette syndrome may be 0.7% but is much higher (4.2%) if all tic types are included.
Tourette syndrome generally is exacerbated before puberty and at least partially remits after adolescence, though some patients remain symptomatic throughout adulthood. The worst ever period of tic activity generally occurs around 10 years of age. Mild phonic or motor tics may not interfere with daily activities, but more severe ones can lead to difficulties with self-esteem, social interactions, family dynamics, school functioning and attendance, and even injury. Some tics may be self-injurious, leading to bruising or excoriations, with more severe cases reported resulting in cervical myelopathy, vertebral artery dissection, and blindness from repeated retinal detachments (75). Attention deficit hyperactivity disorder, obsessive-compulsive disorder, impulse control problems and other behavioral disturbances may also cause significant social and learning disability.
Mild tics may respond well to alpha-2 agonists such as clonidine or guanfacine. Topiramate has been found to be safe and effective in a double-blind, placebo-controlled trial (192), and up to 75% of patients may have a moderate to marked improvement (230). For more significant tics, dopamine-modulating medications are the mainstay, including dopamine receptor blocking medications (neuroleptics) such as haloperidol, pimozide, fluphenazine, or risperidone, or the dopamine-depleting medication (VMAT2 inhibitor) tetrabenazine (393). Ecopipam, a D1 receptor antagonist, has also showed promise in management of tics (144). Tetrabenazine is favored over neuroleptics in adults with Tourette syndrome to minimize the risk of tardive dyskinesia (188). Tardive dyskinesia is rare in children (427). Botulinum injections may be helpful for focal motor or phonic tics. SSRIs for obsessive-compulsive disorder and stimulants for attention deficit hyperactivity disorder are often warranted, and combinations of these medications are often needed. In some cases when tics continue to be impairing and treatments have been ineffective, deep brain stimulation is considered (260).
Stereotypy. Stereotypies are repetitive, ritualistic, and patterned movements or behaviors that may or may not be accompanied by an associated urge. They are common during periods of excitement, stress, fatigue, or boredom, but serve no particular function and are seemingly self-satisfying to the individual performing them. They may occur more commonly while engrossed in tasks and cease with distraction. They can occur in typically-developing children (physiologic stereotypy) or occur in pathologic states (34). Diagnosis is based on the following phenomenology:
• Involuntary, repetitive, rhythmic movements | |
• Predictable pattern and location | |
• Seem purposeful but serve no particular function | |
• Tend to be prolonged (seconds to minutes), occur in clusters several times per day | |
• Suppressible, without interference in daily activities | |
• Associated with periods of excitement, stress, fatigue, or boredom | |
• Absent during sleep | |
• Cease with distraction (eg, calling name) |
Stereotypies may at first appear similar to tics, but can be differentiated based on the following features:
• Stereotypies typically begin earlier (under 2 years). | |
• They are more likely to occur in a consistent pattern. | |
• They often involve arms, hands, or the entire body (as opposed to tics that typically start in the face or neck). | |
• They are more rhythmic, with flapping and waving. | |
• They are generally more continuous and prolonged in duration. | |
• They are not associated with premonitory urges or desires to reduce an inner tension. | |
• Although both may occur during periods of excitement or stress, stereotypic movements often occur when the child is engrossed in an activity (eg, computer games, arcade games). | |
• Stereotypies can be stopped by distraction, but the child rarely makes a conscious effort to control the movements. |
The underlying pathophysiologic mechanism for motor stereotypies is not fully understood but may include frontostriatal or dopaminergic pathways. Physiologic stereotypies in normal children typically begin before the age of 3 years, and comorbidities may occur in up to 50%, including attention deficit hyperactivity disorder, tics or Tourette syndrome, and obsessive-compulsive behaviors. About 22% may exhibit symptoms for more than 10 years, 44% for 6 to 10 years, 21% for 3 to 5 years, 9% for 1 to 2 years, and 11% for less than 1 year. Only about 4% have complete cessation (165).
Attention deficit hyperactivity disorder and learning disabilities are common, and there is an increased family history of stereotypies or tic disorders (252). The male to female distribution is 2:1.
Alternatively, stereotypies can occur in association with autism spectrum disorder as well as with other neurodevelopmental disabilities such as Prader-Willi syndrome, Rett syndrome, Fragile X syndrome, and Down syndrome. Stereotypies are more common in individuals with low IQ compared to those with IQ in the normal range. However, studies show a markedly higher prevalence of stereotypy in those with autism than in those without autism, irrespective of IQ (38; 147).
Most stereotypies are mild and do not require treatment. Many will remit spontaneously, particularly those in typically-developing children. If treatment is required, behavioral therapy tends to be helpful, and dopamine receptor blockers or dopamine depleters such as tetrabenazine may be considered.
Hypokinetic movement disorders
The hallmark of hypokinetic and bradykinetic disorders is paucity and slowness of movement, often with associated rigidity. This is manifested by decreasing amplitudes of repetitive movements, at times associated with fatigue and motor breaks (“freezing”). Parkinsonism is the most typical bradykinetic movement disorder and is manifested by various combinations of tremor, bradykinesia, rigidity, and postural instability. Pathophysiologic mechanisms generally involve depletion of dopamine, and treatment often entails a trial of levodopa or dopamine agonists. Patients with true Parkinson disease usually experience a robust response to such medications, whereas those with other disorders may not improve at all. Although parkinsonian disorders including idiopathic Parkinson disease are the most common etiologies for bradykinesia in adults, several genetic and metabolic conditions can produce this phenotype in children. Some disorders can occur in both adults and children but with opposing core clinical features. For example, Huntington disease is manifested by hyperkinesia (eg, chorea) in adulthood but is a predominantly bradykinetic disease in childhood (eg, Westphal, rigid, variant of Huntington disease, juvenile Huntington disease). On the other hand, neuroacanthocytosis has hyperkinesia (eg, chorea and tics) as the dominant feature in childhood, whereas bradykinesia emerges with progression of the disease.
There are many new tools that are helpful in diagnosing specific childhood genetic or chromosomal disorders that can lead to parkinsonism. Chromosomal microarray, karyotype, individual gene or whole exome sequencing (436), and metabolic studies have been recommended for individuals with unexplained developmental delay/intellectual disability, autism spectrum disorder, or multiple congenital anomalies (275).
Catatonia is a rare cause of paucity of movement in children. It rarely is seen in autistic children who in mid to late teenage years develop further regression and paucity of movement not associated with changes in tone. The “waxy flexibility” seen in this disorder is one of the hallmarks of this condition in which the child will sustain a pose once positioned in awkward pose. Patients with NMDA receptor encephalitis can also appear catatonic during portions of the illness.
Juvenile parkinsonism. Juvenile parkinsonism is defined as parkinsonism with onset at 20 years of age or younger. Tremors, bradykinesia, rigidity, and postural instability occur, often symmetrically (293). Dystonia and autonomic dysfunction may be more common in juvenile parkinsonism than in adult Parkinson disease (63). These patients are more likely to experience social adjustment difficulties, lower quality of life, and depression (355).
The cause of juvenile parkinsonism is often not found. Japanese studies were first to identify an autosomal recessive form of juvenile parkinsonism (AR-JP), now known to harbor the parkin gene mutation (PARK2, 6q25.2-27) (31). This genetic form may account for more than 50% of juvenile parkinsonism and young-onset Parkinson disease. Patients with PARK2 usually progress slowly and respond well to levodopa but experience motor fluctuations and levodopa-induced dyskinesias early in the course of treatment. On pathologic examination, juvenile parkinsonism cases due to the parkin mutation have depigmentation in the substantia nigra and typically lack Lewy bodies. At autopsy, these cases show fibrillar alpha-synuclein-immunoreactive aggregates and tau neuritic inclusions (110). Different forms of autosomal recessive juvenile or young-onset parkinsonism may vary in their clinical course (312):
• Parkin (PARK2), DJ-1 (PARK7), and PINK1 (PARK6): pure parkinsonian phenotype characterized by sustained levodopa responsiveness and absence of dementia. | |
• PLA2G6 (PARK14), FBXO7 (PARK15) (96), and Spatacsin (SPG11): rapidly progressive parkinsonism with early levodopa responsiveness, followed by cognitive decline and loss of levodopa effect. |
An Italian kindred with autosomal dominant juvenile parkinsonism (AD-JP) was found to have mutations in alpha-synuclein (SNCA, 4q21). The age at onset varied in this family, with some developing symptoms before 20 years of age. AD-JP in this so-called Contursi kindred (named after the village in Italy where they are from) carries a mean age to death of 9.2 years (range 2 to 20 years) but is otherwise phenomenologically similar to adult Parkinson disease (146). As with other forms of Parkinson disease, treatment with dopaminergic agents improves motor function.
Dopa-responsive dystonia (DYT5) from GTP cyclohydrolase (GCH1, 14q22.1-q22.2), tyrosine hydroxylase deficiency, or sepiapterin reductase deficiency mutations can all be associated with parkinsonism in addition to or instead of dystonia. Please see the above discussions on these disorders in the section on dystonia (section II).
Juvenile Huntington disease (Westphal variant). In contrast to the adult form of Huntington disease that has predominant choreiform movements, personality changes, and dementia, juvenile Huntington disease typically presents with bradykinesia, rigidity, dystonia and epilepsy, and is often associated with paternal transmission due to greater anticipation from male parentage. Huntington disease is a relentlessly progressive, neurodegenerative condition. Juvenile Huntington disease patients may have a more rapid progression of symptoms, with age of death usually in the 2nd or 3rd decade (242).
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Myoclonus, ataxia, and hung-up knee-jerk reflexes in juvenile Huntington diseaseThis young woman has juvenile Huntington disease manifested by ataxia and generalized action myoclonus. She has jerky tremors (properly termed "myoclonic movements") mostly in her upper extremities, worse on intention, and hung-up...
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Myoclonus, blepharospasm, ataxia, chorea, and other findings in juvenile Huntington diseaseThis young man has juvenile Huntington disease. Initially, he appears bright but displays blepharospasm, sometimes accompanied by facial grimacing, apraxia of eye opening, impersistence of tongue protrusion, generalized chorea, an...
A review of 12 patients divided childhood-onset Huntington disease into two groups: those with onset at less than 10 years of age and those with onset at over 10 years of age (149). The most frequent symptom at onset was cognitive decline in the earlier-onset group and oropharyngeal dysfunction in the later-onset group. Seizures only occurred if age at onset was under 10 years. Chorea and dystonia manifested later in the course of patients with younger-onset Huntington disease, whereas bradykinesia and rigidity dominated in the later-onset group. A small case series described speech delay predating onset of motor symptoms in some juvenile Huntington disease cases (437). In a retrospective review of 29 patients diagnosed with juvenile Huntington disease, Ribaï and colleagues found a high prevalence of psychiatric and cognitive disturbances as the initial feature (65.5% of patients) with absent rigidity. Misdiagnosis was common in these individuals. Maternal transmission occurred in 25% of cases, and 46% had fewer than 60 repeats. During the course of the disease, dystonia was the most frequent movement disorder (72%), followed by parkinsonism (rigidity and hypokinesia) (62%) (338). MRI may show atrophy of the caudate and putamen (285). Magnetic resonance spectroscopy in juvenile Huntington disease may show widespread elevated glutamate and low striatal creatine (337).
Huntington disease is due to an unstable triplet repeat expansion (> 39 CAG repeats) in the IT15 gene (4p16.3) encoding huntingtin. The exact function of the huntingtin protein, which is ubiquitously present in the brain and other parts of the body, is not known. Abnormal CAG expansion within mutant huntingtin leads to cleavage of the protein and aggregation of protein fragments. Caspase 6 may play an integral role in this process (156). Intranuclear inclusion bodies containing fragments of huntingtin have been demonstrated, the formation of which could represent a coping response to toxic mutant protein (15). Atrophy of the cortex and striatum (particularly putamen) has been demonstrated by volumetric imaging studies, and predominant degeneration of the medium spiny neurons has been shown at autopsy (173; 344).
Huntington disease occurs in 10 out of 100,000 Caucasians, but the prevalence varies depending on geographic region and may be as high as 700 out of 100,000 in Lake Maracaibo, Venezuela, a location with a known founder effect. About 5% to 10% of all Huntington disease cases have onset before 20 years of age. Most of these have triplet repeat lengths of over 60. There is no clear correlation with the number of triplet repeats and severity of the disease, but there is an inverse correlation the number of CAG repeats and age at onset (128). Genetic anticipation with earlier age at onset in subsequent generations is often observed in families with Huntington disease.
Despite growing knowledge about the pathogenesis of neurodegeneration in Huntington disease that is now being translated into potential disease modifying strategies, there is still no cure. High-dose coenzyme Q10 was found to improve motor function and survival in a transgenic mouse model of Huntington disease and reduced markers of oxidative stress (368). Psychiatric issues may be managed with antidepressants. Tetrabenazine, a dopamine-depleting drug, is now approved in the United States for controlling chorea (182). In children, chorea is less common, and tetrabenazine may worsen parkinsonism seen in juvenile Huntington disease. Atypical neuroleptics may be used to treat psychosis and other psychiatric problems. Dopaminergic agents may be tried to treat the bradykinesia. Seizures may be managed with anticonvulsants. Physical therapy and supportive care for other medical issues should be considered. Reports suggest fetal neural transplants may stabilize the disease for a few years (18), but this has not been studied in pediatric patients. The development of an intrathecally delivered antisense oligonucleotide has shown promise in clinical trials in the adult onset disease (428). Children with juvenile Huntington disease may benefit from a multidisciplinary approach with a treatment team that may include a neurologist, general pediatrician, psychiatrist and/or psychologist, nutritionist, and others (332).
In the case of onset of parkinsonism from infancy to early childhood, the main inborn errors of metabolism to consider are neurotransmitter defects and mitochondrial disorders. For onset in childhood to adolescence, additionally one should consider neurodegeneration with brain iron accumulation, lysosomal disorders, ceroid lipofuscinosis, Niemann-Pick C, Wilson disease, gangliosidosis, and cerebrotendinous xanthomatosis, especially as some of these diseases are treatable (135). In addition, Huntington disease-like diseases, HDL1, HDL2, HDL3, and HDL4 (same as SCA17) (354), dentatorubral pallidoluysian atrophy, and neuroferritinopathy, a progressive but potentially treatable disorder caused by mutations in the ferritin light chain gene (FTL1), located on 19q13.3-q13.4 (76), should be considered, although most of these disorders begin in adulthood.
Ataxia
Ataxia refers to incoordination of movements resulting from insults to the cerebellum or cerebellar pathways. Upper extremity involvement may result in dysmetria or dysdiadokinesis; lower-extremity involvement may manifest with impaired heel-to-shin testing or a wide-based, “drunken” gait. Truncal ataxia may also occur, leading to difficulty sitting unsupported. Speech changes may also be seen, with difficulty regulating the rhythm. Ocular abnormalities, including nystagmus, are common. Depending on the specific etiology, other neurologic or general physical manifestations may be present. Of the progressive hereditary ataxias, most (but not all) begin during childhood. The evaluation of childhood ataxia, therefore, begins with determination of whether the disorder is thought to be inherited and, if so, the mode of inheritance. The autosomal dominant ataxias are commonly referred to as spinocerebellar ataxias (SCAs) and may have additional upper motor neuron findings. Many such disorders have been described, but most are rare. Acute-onset childhood ataxias, by contrast, are often attributable to benign, self-limited processes (142).
The Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society published a diagnostic algorithm for patients with early-onset cerebellar ataxia (defined as ataxia that begins before 25 years of age) (44). Acute-onset ataxias include acquired causes whereas chronic and progressive conditions should be further delineated according to mode of inheritance, including autosomal dominant, autosomal recessive, X-linked, and maternal. The most common autosomal recessive ataxia is Friedreich ataxia, but other causes can be distinguished by the presence or absence of cerebellar atrophy and other associated features (44). A diagnosis of Niemann Pick type C disease should be considered in young patients with progressive ataxia, vertical supranuclear ophthalmoplegia, and psychiatric symptoms (334).
Laboratory testing can be guided by mode of inheritance and other considerations, such as presence of non-nervous system manifestations. With the advancements of genetic testing, many are turning to more advanced methods to include whole genome sequencing. A proposed diagnostic testing approach is provided by Coarelli and colleagues (82). Treatment for ataxia relies mostly on supportive care, unless a specific metabolic deficiency syndrome is identified.
Autosomal dominant disorders
A good review of the pathophysiology and distinguishing features of autosomal dominant spinocerebellar ataxias is provided by Durr and Marras and is summarized here. Spinocerebellar ataxias may be caused by CAG triplet repeat expansions (SCAs 1, 2, 3, 6, 17 and DRPLA), non-coding expansions (SCA8, 10, 12), or conventional mutations (SCAs 5, 11, 13, 14, 15/16, 20, 27, 28) (112; 258). In most cases of triplet repeat expansions, the number of expansions correlates inversely with age at onset, genetic anticipation occurs, and the expansion length is associated with the type and degree of clinical symptoms. These SCAs are more often fatal than other types. Genotype-phenotype correlations are generally harder to make in cases of conventional mutations due to their rarity, but these cases tend to be more likely to have childhood onset, are slowly progressive without clear association of childhood onset with more severe disease course, and tend to be characterized by a slowly progressive pure cerebellar syndrome with some congenital features. Triplet repeat expansion spinocerebellar ataxias tend to involve more widespread neuronal loss and brainstem greater than cerebellar atrophy (often only vermian atrophy) on MRI, whereas conventional mutation spinocerebellar ataxias involve predominant Purkinje cell loss and pure and global cerebellar atrophy on imaging.
It is difficult to differentiate the spinocerebellar ataxias based on clinical features alone. However, a study suggests that those with SCA5, SCA6, and SCA8 had a predominant cerebellar syndrome, whereas those with SCA1, SCA2, SCA3, SCA4, and SCA7 are more likely to have extracerebellar involvement (263). Deafness is often seen in SCA4 whereas vision loss is seen in SCA7 (433). The prevalence of specific spinocerebellar ataxias varies between different populations, but spinocerebellar ataxias 1 to 3 account for 40% to 80% of all autosomal dominant spinocerebellar ataxias (112). Genetic testing can often begin with these. If macular degeneration is present, SCA7 should be tested. Conventional mutation spinocerebellar ataxias are difficult to diagnose because gene sequencing is required, which is time consuming and expensive. Treatment is symptomatic and supportive only. No medications improve ataxia though case reports exist of improvement with various therapies.
Autosomal recessive disorders
Friedreich ataxia is the most common autosomal recessive ataxia, and the most common inherited ataxia overall (27). Friedreich ataxia-like conditions include ataxia with vitamin E deficiency, abetalipoproteinemia, and Refsum disease. Friedreich ataxia-like conditions with more prominent cerebellar atrophy include late-onset Tay-Sachs and spinocerebellar atrophy with axonal neuropathy (27). Early-onset recessive ataxias also include ataxia-telangiectasia, ataxia with oculomotor apraxia, autosomal recessive spastic ataxia of Charlevoix-Saguenay, infantile-onset spinocerebellar ataxia, Cayman ataxia, and Marinesco-Sjogren syndrome.
Friedreich ataxia. The essential clinical features of Friedreich ataxia are onset before 25 years of age, progressive gait and limb ataxia, dysarthria, absent deep tendon reflexes (except for forms with retained reflexes), sensory loss, and pyramidal weakness. Many patients also exhibit dystonia. The majority of patients have cardiomyopathy, with evidence of increased myocardial mass, left ventricular dilation, and abnormal electrocardiogram (424). The degree of cardiomyopathy does not correlate with neurologic symptoms, but congestive heart failure and arrhythmia are the most common cause of death (405). Neuropathy, distal wasting, scoliosis, sensorineural deafness, optic atrophy, and diabetes are common. Some of the skeletal abnormalities, including scoliosis, may be a consequence of associated dystonia (177).
Late-onset Friedreich ataxia cases and cases with retained tendon reflexes may occur, involving the same molecular defect (287). These other forms have a milder phenotype, usually without cardiomyopathy, and shorter repeat length. Late-onset Friedreich ataxia is characterized by dysarthria, pyramidal signs, and sensory axonal neuropathy, but no optic atrophy, sensorineural deafness, diabetes, or clinical evidence of cardiomyopathy. Compound heterozygotes do not conform to a specific phenotype.
The disease is caused by a GAA-trinucleotide repeat expansion in the first intron of the FRDA gene on 9q13-21. Patients may carry 90 to 1300 repeats with mutations on both alleles, but heterozygotes (carriers) and compound heterozygotes may occur (361). The gene product is frataxin, a mitochondrial protein of unclear function, which is deficient in the disease state (222). Frataxin levels are reduced. In yeast, deletion of its homologue is associated with defects in oxidative phosphorylation and intramitochondrial iron accumulation. Increased iron deposition has been demonstrated in myocardial biopsies from Friedreich ataxia patients, and oxidative stress occurs in cardiac muscle and cultured fibroblasts (58). Frataxin is thought to have multiple iron-related functions in the normal state (222). Progressive atrophy of the dentate nucleus is seen on pathologic examination, but the reasons for selective vulnerability of this region are unknown. Expansion size inversely correlates with age at onset and wheelchair confinement, and directly correlates with incidence of cardiomyopathy. A Turkish family with the typical Friedreich ataxia phenotype has been described with an FRDA2 mutation on 9p23-p11 (77).
Friedreich ataxia is the most common cause of autosomal recessive ataxia in Europe. The estimated prevalence in Caucasians is 2:100,000. Pseudodominant inheritance is described in the case of one homozygote parent and one heterozygote parent (313). Prognosis is determined by severity of the cardiomyopathy, if present. Idebenone is a short-chain benzoquinone and a synthetic analogue of coenzyme Q. It is a potent free-radical scavenger. Studies have suggested that it may reduce cardiac hypertrophy in Friedreich ataxia patients (345). Ribaï and colleagues found that therapy with idebenone did not improve cardiac function, although cardiac hypertrophy did improve, whereas Lagedrost and colleagues found no changes in left ventricular hypertrophy or cardiac function after 6 months of therapy (339; 234). Furthermore, ataxia scores continued to progress at the same rate regardless of idebenone use. Di Prospero and colleagues reported a dose-dependent improvement on measures of neurologic function and activities of daily living (105), but a Phase III, double-blind, placebo-controlled study lasting 6 months in 70 patients failed to show significant neurologic improvement (250). CoQ10 and vitamin E, which both also have antioxidant properties, have also been suggested to improve cardiac muscle function (413). Regardless, many patients with Friedreich ataxia initiate therapy with CoQ10 as there are relatively low risks. Riluzole has also been used for short-term management of ataxia in these patients (441). Omaveloxolone has been shown to restore mitochondrial function in patients with Friedreich ataxia and has been FDA approved for treatment with improvement in the Friedreich Ataxia scale by approximately 2 to 3 points after 72 months compared to placebo (249). Cardiac evaluation and diabetes management are indicated. Supportive care for scoliosis and neuropathy should be considered.
Ataxia-telangiectasia. Ataxia-telangiectasia is classically characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy, related to pathogenic variants in the ATM gene. Classically, childhood-onset progressive cerebellar ataxia is followed by conjunctival telangiectases and progressive neurologic decline (25).
However, the clinical spectrum of symptomatology related to pathogenic variants in ATM is very broad, with atypical and varied presentations with and without the ocular and/or cutaneous telangiectasias that were thought to be characteristic in the past (387).
Ataxia begins in the trunk, but within several years involves the limbs. Slurred speech, hypomimia, and oculomotor apraxia are typical; 90% may have chorea and dystonia, which can be severe. Telangiectasias are typically not present until after 5 years of age. Myoclonus and intention tremor are also common. Deep tendon reflexes are decreased or absent in older patients. Intelligence is normal. Sinopulmonary infections are typical, due to immunodeficiency. IgA, IgE, and IgG may all be deficient. Thirty percent may also have T-cell deficiencies. Sixty percent to 80% of patients have a poorly defined immunodeficiency. Insulin-resistant diabetes is infrequent. Patients have a 38% risk of developing cancer. Eighty-five percent of these malignancies are leukemia (often T-cell) or B-cell lymphoma. Hypersensitivity to ionizing radiation and premature aging has been observed. It is important to note that since the identification of the ATM gene, studies have broadened the phenotype significantly, indicating that the constellation of symptoms can be quite variable; in some cases, patients with ATM gene mutations present with varies combinations of the above symptoms but do not develop ataxia or telangiectasias (387).
Ataxia-telangiectasia is caused by mutations on 11q22-q23 within the ATM gene (138), which contains a region homologous to a protein family with a phosphatidylinositol 3-kinase domain (25). These appear to be involved in pathways that assess DNA damage. Diagnosis is confirmed by DNA testing, which typically includes ATM gene sequencing and deletion analysis. The diagnosis is supported by the presence of conjunctival telangiectasias, cerebellar atrophy on MRI, laboratory evidence of immunodeficiency, elevated serum alpha-fetoprotein (AFP), and lymphocyte radiosensitivity. Serum AFP levels are typically at least two standard deviations above normal for age (376).
Ataxia-telangiectasia is the second most common cause of progressive cerebellar ataxia in childhood, after Friedreich ataxia. The prevalence is 1 in 100,000 live births. Most patients become wheelchair bound by 10 years of age. The median age of death is near 20 years of age and generally occurs as a result of overwhelming infections and malignancy. Patients with null mutations (total loss of expression or function of the gene product) have lower life expectancy (276). Cancer is a major risk factor for death among this group, whereas respiratory tract infections are the leading cause of death in patients with hypomorphic mutations. A short-term study suggests efficacy of betamethasone in improving neurologic symptoms (52). Management of infections with appropriate antibiotics prolongs life and reduces morbidity. Any malignancies should be treated with appropriate chemotherapy.
Refsum disease. Refsum disease is characterized by retinitis pigmentosa, deafness, chronic polyneuropathy, cardiomyopathy, cerebellar ataxia, and ichthyosis. CSF protein is elevated without pleocytosis. Patients accumulate phytanic acid in blood and tissues. Onset is typically from 2 to 7 years of age. Brain MRIs show characteristic changes involving the corticospinal tracts, cerebellar dentate nuclei, and corpus callosum (57).
Deficiency of phytanoyl-CoA hydroxylase (PAHX or PHYH), a peroxisomal protein catalyzing the first step in the alpha-oxidation of phytanic acid, causes the disease in the majority of cases. Some, however, are due to PEX7 mutations, a gene encoding for peroxin 7, which is a receptor for peroxisomal targeting signals (408). Missense mutations, deletions, or insertions all produce inactive protein, leading to accumulation of phytanic acid, an unusual branched-chain fatty acid (3,7,11,15-tetramethylhexadecanoic acid) derived from dietary plant chlorophyll. Humans are dependent on dietary intake of this fatty acid. Whether the pathophysiology of this disorder is due primarily to toxicity from phytanic acid or to other metabolic abnormalities is not understood (425).
This disorder is extremely rare. No sex or race predilection is known. Prognosis is good if patients are treated with dietary restriction of phytanic acid. Dermatologic evaluation is also indicated for management of skin changes.
Hartnup disease. This disorder is characterized by a pellagra-like light-sensitive rash, cerebellar ataxia, emotional instability, and aminoaciduria. Neurologic symptoms vary, but are reversible. Intermittent cerebellar ataxia, a wide-based gait, spasticity, delayed motor development, and tremulousness are the most frequent symptoms. Headaches and hypotonia may also occur. Ocular manifestations include double vision, nystagmus, photophobia, and strabismus. Gingivitis, stomatitis, and glossitis suggest niacin deficiency. Diarrhea may precede attacks. Triggers for attacks include exposure to sunlight, febrile illness, poor nutrition, sulfonamides, and, possibly, emotional stress.
The disease is caused by a defect in the neutral amino acid transporter, encoded on the SLC6A19 gene at 5p15.33 (423). Failure of intestinal transport leads to accumulation of metabolites toxic to the CNS. Urinary excretion of amino acids is increased. Abnormal tryptophan transport causes niacin deficiency, resulting in the pellagra-like features.
The incidence of Hartnup disease in Massachusetts is 1 in 14,219 births, approximately the same incidence as that of phenylketonuria (244). The overall prevalence is 1 in 24,000, making it one of the most common human amino acid disorders.
Prognosis is good. Many patients are asymptomatic. A high-protein diet may overcome the deficient transport of amino acids and reduce the frequency of attacks. Patients should be advised to protect themselves from the sun.
Abetalipoproteinemia (Bassen-Kornzweig syndrome). This disorder presents in infancy with steatorrhea, failure to thrive due to malabsorption, a progressive spinocerebellar syndrome, peripheral neuropathy, and retinal pigmentation. Peripheral acanthocytes may be seen. Neurologic symptoms are all due to vitamin E deficiency. Abetalipoproteinemia is due to mutations of the MTTP gene (384). Cases are similar to the autosomal dominant hypobetalipoproteinemia, with mutations in the gene for apolipoprotein B on 2p23-24. Plasma beta-lipoproteins, chylomicrons, and low-density lipoproteins are nearly absent, resulting in inadequate fat absorption and transportation from the intestine. Serum triglyceride and cholesterol levels are extremely low.
The disorder clusters in families; several families from various countries have been described. If untreated, patients die by the fourth decade. Vitamin E supplementation results in significant neurologic recovery.
Ataxia with vitamin E deficiency. This disorder is especially prevalent in children and can be uncomfortable. Symptoms are similar to those of Friedreich ataxia, with the following exceptions: cardiomyopathy is less common (only 19% of cases), head titubation is seen in 28%, and dystonia occurs in 13% (29). Postural and kinetic tremor is also common. Vitamin E levels are low, without evidence of malabsorption. Vitamin E supplementation is indicated to treat and prevent irreversible damage (391).
Ataxia with vitamin E deficiency is caused by mutations in the gene for alpha-tocopherol transfer protein (alpha-TTP) on 8q13 (391). A study in 27 North African and European families has identified 13 different mutations (68). If treated appropriately, there can be significant clinical improvement with normalization of serum vitamin E levels. A high-fat diet is also recommended.
Early-onset ataxia with oculomotor apraxia and hypoalbuminemia. Ataxia with oculomotor apraxia (AOA) is characterized by early-onset cerebellar ataxia and is differentiated from other autosomal recessive ataxias by the presence of ocular apraxia, early areflexia, late peripheral neuropathy, slow progression, severe motor disability, and absence of both telangiectasias and immunodeficiency. Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA), described in Japan, is characterized by marked cerebellar atrophy, peripheral neuropathy, mental retardation, and, occasionally, oculomotor apraxia (289). Patients with both disorders develop hypoalbuminemia and hyperlipidemia in adulthood. Many also have choreiform movements and intention tremor. Based on genetic studies, AOA and EOCA-HA are thought to represent the same entity and are together referred to as early-onset ataxia with oculomotor apraxia and hypoalbuminemia.
Type 1 disease maps to 9p13, with mutations in the aprataxin gene (363). This gene encodes a new, ubiquitously expressed protein sharing distant homology with polynucleotide kinase 3'-phosphatase (PNKP). PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and reactive oxygen species. The disorder clusters in families, but has been found to be the second most common form of autosomal recessive ataxia in Portugal after Friedrich ataxia and the most common in Japan. Neurologic dysfunction is generally progressive. Treatment is with supportive care only.
Type 2 disease (AOA2) is attributed to mutations in the senataxin (STX) gene (86; 386). Mean age at onset is in the second decade, with slowly progressive cerebellar ataxia and axonal polyneuropathy; patients become wheelchair bound after 20 years. Oculomotor apraxia is not always present, and strabismus may be observed. Other movement disorders, including tremor or dystonia may be present (237). Serum alpha-fetoprotein is uniformly elevated.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay. The core clinical features are childhood-onset spastic ataxia, dysarthria, saccadic alteration of smooth pursuit, nystagmus, and prominent myelinated fibers radiating from the optic disc (42). Some degree of distal amyotrophy eventually develops, related to chronic axonal neuropathy, and often with a demyelinating component. Spasticity tends to become apparent between the ages of 12 to 24 months when normal gait development begins, and rarely begins after the age of 12 years. Although MRI scans typically are described to show early vermian atrophy and later cerebellar hemispheric and cervical cord atrophy, a series also described linear T2 and T2-FLAIR hyperintensities in the pons (259).
The gene locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay is on 13q12.12, encoding a protein named sacsin. Sacsin is widely expressed and has sequence similarity to the heat shock chaperone proteins, though its exact function is unknown. The disorder was originally described in the Charlevoix-Saguenay-Lac-Saint-Jean region of northeastern Quebec. Since then, further genetic heterogeneity has been described worldwide (42) with considerable clinical variations including mental retardation, later age at onset, ophthalmoplegia, hyperlipidemia, and absence of spasticity and retinal hypermyelination.
In general, there is slow progression with little change after 20 years, though this may vary among family members. Some may be wheelchair bound by 30 years of age. Treatment is supportive only.
Ataxia with hypogonadotropic hypogonadism (Marinesco-Sjogren syndrome). Marinesco-Sjogren syndrome is characterized by bilateral cataracts, mild to moderate mental retardation, cerebellar ataxia due to cerebellar hypoplasia, short stature, hypogonadotrophic hypogonadism, and skeletal deformities, which are related to pronounced hypotonia. Progressive myopathy with weakness and atrophy are prominent. Typical myopathic changes are seen on muscle biopsy. The syndrome is heterogeneous, including reports of peripheral neuropathy, seizures, microcephaly, optic atrophy, hearing loss, acute rhabdomyolysis, and various MRI findings such as cerebral atrophy, loss of matter, agenesis of the corpus callosum, abnormal pituitary gland, posterior fossa cyst, and brainstem atrophy.
Marinesco-Sjogren syndrome localizes to 5q31 (235). The gene product has been identified as SIL1, which acts as a nucleotide exchange factor for an HSP70 chaperone BiP (14; 360). BiP regulates functioning of the endoplasmic reticulum, and the authors propose Marinesco-Sjogren syndrome as a disorder of protein biosynthesis or processing in this organelle. Marinesco first described the syndrome in Romania, and Sjogren later described it in Swedish families. Other families have been described, but the disorder is rare. The disease is slowly progressive. Treatment consists of supportive care.
Spinocerebellar ataxia with axonal neuropathy. This condition is only found in Saudi Arabia. Manifestations include ataxia with cerebellar atrophy, peripheral axonal sensorimotor neuropathy, distal amyotrophy, and pes cavus. The genetic abnormality lies in TDP1, which encodes tyrosyl-DNA phosphodiesterase 1 and involves DNA repair.
Infantile-onset spinocerebellar ataxia. This condition is found in Finland and is characterized by onset of severe ataxia before 2 years of age. It includes hypotonia, sensory neuropathy with areflexia, optic atrophy, ophthalmoplegia, hearing loss, involuntary movements, and epilepsy. The gene, C10orf2, encodes two protein products: Twinkle, a mitochondrial helicase involved in DNA replication, and Twinky, whose function is not known.
Cayman ataxia. This condition occurs in an isolated population on Grand Cayman Island with heavy consanguinity. Ataxia, cerebellar atrophy, hypotonia, and psychomotor retardation are the major findings. The gene ATCAY encodes caytaxin, which may be involved in glutamate synthesis at synapses.
Ataxia with CoQ10 deficiency. This is the most common phenotype associated with CoQ10 deficiency (288). Of 135 muscle biopsies from patients with genetically undetermined cerebellar ataxia and atrophy, 18 had low-muscle CoQ10 levels; 13 of these were cases of childhood-onset ataxia (236). Common associated features are seizures, pyramidal signs, mental retardation, and delayed motor milestones. Muscle histology is normal. This presentation differs from myopathic forms of primary CoQ10 deficiency in which muscle weakness predominates and pathology reveals ragged-red fibers and lipid storage in muscles. No known genetic determinants have been found, and the cellular mechanisms leading to CoQ10 deficiency and the pathophysiology of the various neurologic presentations are not known (288). Symptoms may improve with CoQ10 supplementation.
Cerebrotendinous xanthomatosis. This is an autosomal recessive disorder due to a mutation of the CYP27 gene (27-sterol hydroxylase), which leads to a reduction in synthesis of bile acid and increased bile alcohols in the urine and serum cholestenol. These are then deposited throughout the body, resulting in a varied clinical phenotype affecting several organs including the brain, lens of the eye, and tendon. Neurologic symptoms include spasticity, ataxia, neuropathy, seizures, and cognitive impairment and usually present in adolescence or adulthood. Manifestations outside the CNS include cataracts, tendon xanthomas, skeletal fractures, pulmonary insufficiency, and chronic diarrhea. This disorder is particularly important to recognize as it is treatable with oral chenodeoxycholic acid and prevents further neurologic compromise (334).
Episodic ataxias. Episodic ataxias are discussed below under “paroxysmal movement disorders.”
Acute-onset childhood ataxia.
Acute cerebellar ataxia and acute cerebellitis. Acute cerebellar ataxia is a clinical syndrome characterized by the acute onset of cerebellar dysfunction, often following or sometimes during viral illness, which typically follows a benign, monophasic course with complete recovery and good long-term prognosis. It is the most common cause of acute childhood ataxia (389). Patients typically begin to recover within days of onset and return to prior baseline within a period of weeks. This disorder is thought to be of postinfectious or, in some cases, infectious etiology. Acute cerebellar ataxia exists on a continuum with what has been called acute cerebellitis, a more severe syndrome that includes signs of cerebellar edema and may require emergent surgical intervention (98). Pulse-dose steroids are sometimes considered in more severe cases. If symptoms do not improve in a predictable fashion or recur, concern should be raised for opsoclonus-myoclonus-ataxia syndrome.
Epstein-Barr virus (108), COVID-19 (290), herpes simplex virus 1 (79), human herpes virus 6 (41), varicella zoster virus (130), West Nile virus (296), rubella, rubeola (253), parvovirus B19 (157), rotavirus (383), H influenza, pertussis, diphtheria, and coxsackie viruses have all been described (286). Some cases may be due to autoantibodies cross-reacting with cerebellar proteins, including centrosomes. One case of transient dysautonomia and cerebellitis associated with childhood enteric fever has been described, with resolution of neurologic abnormalities during antibiotic therapy (390).
Wernicke encephalopathy. The triad of ataxia, ophthalmoplegia, and mental status changes may occur in children, often in critically ill, malnourished, or cancer patients. Symptoms are due to thiamine (vitamin B1) deficiency and improve if the syndrome is recognized early and treated with IV thiamine (410; 94).
Miller-Fischer syndrome, variant of Guillain-Barre syndrome. A clinical triad of acute/subacute onset of ataxia, ophthalmoparesis, and areflexia characterizes Miller-Fischer syndrome, usually in the context of a preceding viral illness (203). Similar to Guillain-Barre syndrome, lumbar puncture shows the characteristic albuminocytologic dissociation (high protein, no cells). Extremity weakness is usually absent. Pupillary involvement is possible (137). Most cases are associated with elevated anti-GQ1b antibodies (antiganglioside) and are attributed to an autoimmune phenomenon.
Miller-Fischer syndrome is rarer than Guillain-Barre syndrome, and its frequency in children may be close to 1 in several million. Treatment with IVIg or plasmapheresis may prevent acute worsening. Clinical improvement may occur over weeks to months.
Gluten-associated ataxia. Cerebellar ataxia from celiac disease is more common in adults (150). In a study, 57 (51%) pediatric patients with celiac disease had neurologic manifestations. Of these, six (5%) were ataxic. No correlation was found between the activity of celiac disease and the ataxia. Imaging studies were normal or showed nonspecific findings; one third had cerebellar atrophy and one third had isolated mild ataxia with normal brain imaging. The clinical syndrome consisted of stance and gait ataxia in all patients, limb ataxia in two thirds of patients, and nystagmus in one half of patients.
The mechanism of gluten-associated ataxia is thought to be immunologic. Celiac disease is often associated with elevated antigliadin antibodies and the HLDA DQ2 allele, especially in adult cases (54). It has a low frequency in the United States: 1 in 3000 persons. It is more prevalent in Western Europe (1 in 250 to 300); it is rare in Africans or Asians. Ataxia may respond to a gluten-free diet, although other celiac disease symptoms are more likely to improve.
Conditions associated with mixed movement disorders
Neurometabolic disorders
Neurometabolic disorders often present with variable combinations of psychomotor retardation and/or regression, pyramidal signs, ataxia, hypotonia, and movement disorders (155). The main diseases causing movement disorders are metal storage diseases, neurotransmitter synthesis defects, disorders of energy metabolism, and lysosomal storage diseases. Neurons of the basal ganglia are particularly vulnerable to metal storage, defects of energy metabolism, and lysosomal storage (358). It is beyond the scope of article to review all diseases. Some disorders key to the differential diagnosis of movement disorders will be reviewed in detail, whereas others will be listed and referenced to a review article. When considering neurometabolic disorders manifesting as movement disorders, one should focus on identifying those that are treatable first (114).
Up to one third of these patients will have at least one movement disorder; the most frequent movement disorders are dystonia, myoclonus, chorea, tremor, and parkinsonism. The classification scheme below is based on broad disease mechanisms, but for diagnostic purposes, it may be more helpful to distinguish those neurometabolic disorders associated with basal ganglia lesions on MRI (indicated with an asterisk, *) from those without.
Category |
Disorder |
Predominant Movement Disorder(s) |
Reference |
Metal storage disorders |
Wilson disease* |
See description below | |
Neurodegeneration with brain iron accumulation* |
See description below | ||
Neurotransmitter synthesis defects |
GTPCH I deficiency |
See section on dystonia | |
Tyrosine hydroxylase deficiency |
See section on dystonia | ||
Aromatic amino acid decarboxylase deficiency |
Oculogyric crises, dystonia, chorea, drug-induced dyskinesia |
(329) | |
Nonketotic hyperglycinemia (glycine encephalopathy) |
Myoclonic encephalopathy, spasticity, chorea |
(163) | |
Cerebral folate deficiency |
Ataxia, chorea, hemiballismus, spasticity |
(151) | |
Energy metabolism disorders |
Respiratory chain disorders: Leigh syndrome* |
Dystonia, rigidity, tremor, chorea, hypokinesia, myoclonus, tics (occur with decreasing frequency) |
(251; 125) |
Pyruvate dehydrogenase complex deficiency* |
Episodic dystonia or ataxia |
(26) | |
Biotin-responsive basal ganglia disease* |
Dystonia, parkinsonism, eventual quadriparesis |
(311) | |
GLUT 1 deficiency |
See section on dystonia | ||
Lysosomal storage disorders |
GM1 gangliosidosis, type 3* |
Slowly progressing dementia with parkinsonism and dystonia, especially of the face |
(292) |
GM2 gangliosidosis (Tay-Sachs disease) |
Lack of coordination, hand tremors, progressive dystonia, dysarthria, dyskinesia, chorea, ataxia, spinocerebellar degeneration, motor neuron disease |
(298) | |
Niemann-Pick disease – type C |
Vertical supranuclear gaze palsy, gait instability, ataxia, bulbar signs, action dystonia |
(319) | |
Juvenile neuronal ceroid lipofuscinosis |
Dystonia and parkinsonism |
(432; 223) | |
Gaucher disease |
Type 1: parkinsonism in adulthood |
(226; 262) | |
Aminoacidopathies/ organic acidurias |
Phenylketonuria |
Tremor (33%), dystonia, and parkinsonism (rare) |
(46; 323) |
Homocystinuria |
Dystonia |
(208) | |
Propionic acidemia* |
Chorea, dystonia |
(379) | |
Glutaric aciduria* |
Generalized dystonia, chorea, later akinetic-rigid parkinsonism |
(375; 145) | |
Methylmalonic acidemia* |
Dystonia, tremors |
(261) | |
Lesch-Nyhan disease |
Chorea, dystonia, ballism, spasticity, compulsive self-mutilation, dysarthria, impaired saccades |
(200; 201) |
Wilson disease. Hepatic dysfunction during childhood (asymptomatic hepatomegaly, acute transient or fulminant hepatitis) may be the first clinical presentation of Wilson disease. The average age at onset of Wilson disease is 12 years. Neurologic symptoms begin at an average age of 19 years and include dystonia, dysarthria, gait difficulties, and tremor (classically a “wing-beating” tremor). Psychiatric disturbances may precede neurologic features. Kayser-Fleischer rings, a yellow-brown deposition of copper in Descemet membrane of the cornea, is a characteristic feature, best observed by slit-lamp examination. Three subgroups have been defined with distinctive radiologic features (303):
(1) bradykinesia, rigidity, cognitive impairment, and mood changes; MRI with 3rd ventricle dilatation. | |
(2) ataxia, tremor, reduced functional capacity; MRI with focal thalamic lesions. | |
(3) dyskinesia, dysarthria, personality changes; MRI with focal lesions in the putamen and pallidum. |
Wilson disease is an autosomal recessive disorder caused by mutations in the gene on chromosome 3q14.3 that encodes copper-transporting P-type ATPase (ATP7B), an enzyme that binds copper and aids in its transport across membranes via lysosomal exocytosis (327). Mutations resulting in protein truncation result in a more severe course with higher incidence of acute liver failure and neurologic symptoms, whereas missense mutations are more common (01). Decreased levels of ceruloplasmin are a useful but not necessarily reliable diagnostic marker of disease activity, as those with aceruloplasminemia and heterozygotes may also have reduced or absent levels (418). Failure to adequately excrete copper into bile leads to its accumulation in the liver, brain (especially basal ganglia), cornea, kidney, bones, and blood (48). Brain MRI findings may correlate with severity of disease, and posttreatment imaging follows clinical improvement closely (214).
The diagnosis of Wilson disease is made in the context of typical neuropsychiatric features, presence of Kayser-Fleischer rings, and reduced serum ceruloplasmin (254). Kayser-Fleischer rings are present in 85% to 100% of patients with neuropsychiatric presentations, 33% to 88% of patients with hepatic presentations, and 0% to 59% of asymptomatic cases. They can be present in other liver diseases as a result of secondary copper accumulation. Serum ceruloplasmin levels vary with age and diagnostic levels may be different according to the laboratory detection process. Serum copper concentrations, though generally low, are not reliable indicators of disease. Therefore, if such investigations remain equivocal while diagnostic suspicion remains high, further testing with 24-hour urine collection revealing elevated copper excretion or increased urinary copper excretion after penicillamine challenge supports the diagnosis. Over the last few years, rapid gene sequencing technology has made it possible to quickly and accurately identify ATP7B mutations in over 98% of cases (04). Finally, measuring liver copper content from a biopsy specimen may be required.
Wilson disease occurs with frequency of 1:30,000 and is equally present across ethnicities. Fulminant hepatic failure, hepatic cirrhosis, psychiatric disease, and progressive neurologic dysfunction may occur if the disease is not detected early. Treatment options include avoidance of dietary copper, reduction of copper absorption (potassium, zinc, tetrathiomolybdate), increasing copper chelation and elimination (d-penicillamine, trientine, triethylene tetramine dihydrochloride), dimercaprol (British anti-Lewisite, BAL), and liver transplantation (49). Tetrathiomolybdate has been shown to be superior to trientine (50). Long-term compliance may be a problem for patients, and negatively impacts survival (01). Longitudinal MRI studies suggest more favorable evolution of MRI abnormalities in patients treated with d-penicillamine than with zinc (87).
Neurodegeneration with brain iron accumulation (NBIA). Neurodegeneration with brain iron accumulation is increasingly recognized as a syndrome with many different causes, though the core features remain the presence of a progressive extrapyramidal syndrome and excessive iron accumulation in the brain, particularly in the basal ganglia, and most notably in the globus pallidus (113; 231; 353; 352).
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Dystonia (generalized) and parkinsonism in pantothenate kinase-associated neurodegeneration
This 28-year-old woman presented at 11 years of age with toe walking. She has mild intellectual impairment, emotional difficulties, and anger control problems; severe hypokinetic dysarthria, hypophonia, and drooling; marked bra...
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Dystonia (generalized) and stereotypies in pantothenate kinase-associated neurodegenerationAt 5 years of age, this 17-year-old girl first exhibited hyperactivity and aggressive behavior, which were later associated with slow learning. At 10 years of age, left-foot dystonia appeared (the foot turning inward and downward)...
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Dystonia (tongue protrusion) helped by sensory trick in pantothenate kinase-associated neurodegenerationThis 32-year-old man had onset of dystonic foot inversion and handwriting difficulties due to hand dystonia at 17 years of age. He later developed gait difficulties, falls, dysarthria with unintelligible speech, and difficulties w...
The clinical phenotype can now be sub-divided into type 1 (typical PKAN), type 2 (PLA2G6-associated neurodegeneration, or PLAN), Kufor-Rakeb disease, FA2H-associated neurodegeneration (FAHN), and others, as follows:
Neurodegeneration with brain iron accumulation type I. PKAN, classic presentation - onset is around 3 to 4 years. Presenting signs usually involve gait disturbance. Extrapyramidal features include dystonia, dysarthria, and rigidity. Prominent oromandibular dystonia including tongue protrusion is a characteristic feature. Chorea and ataxia may also be seen. Corticospinal tract involvement includes spasticity, hyperreflexia, and the Babinski sign. Two thirds of cases have a pigmentary retinopathy, although other neuron-ophthalmologic signs can be seen (115). This disorder is progressive, leading to wheelchair dependence within a few years. The clinical course may be marked by periods of acute deterioration from unknown precipitants. PKAN results from mutations in pantothenate kinase 2 (PANK2), which regulates synthesis of acetyl coenzyme A (396; 351). The result is iron accumulation in the brain, typically in the globus pallidus, which, by increasing oxidative stress, contributes to tissue destruction. Cysteine accumulation from PANK2 dysfunction apparently facilitates the iron accumulation, as cysteine is a known iron chelator (168). The preferential involvement of the basal ganglia and retina is attributed to the selective vulnerability of these structures to oxidative stress. The hallmark MRI finding in PKAN is the “eye-of-the-tiger” sign onT2-weighted images, which corresponds to iron accumulation in the globus pallidus and manifests as a central hyperintensity with a surrounding area of hypointensity. These changes may precede symptom onset. Parkinsonsim, including bradykinesia and tremor, are poorly responsive to dopaminergic agents. Spasticity may be managed with muscle relaxants or benzodiazepines. Dystonia may respond to anticholinergic agents, botulinum toxin injections, or high-frequency deep-brain stimulation of the globus pallidus internus (67).
Late onset (atypical PKAN). Age of onset is 20 to 30 years. Motor impairment tends to be less severe than in the classic form. Imaging and genetic features are similar. In atypical PKAN, independent ambulation is lost 15 to 40 years after onset.
Neurodegeneration with brain iron accumulation type 2. PLA2G6-associated neurodegeneration (PLAN) - early onset cases have a form of infantile neuroaxonal dystrophy, characterized by progressive motor difficulties, intellectual disability, cerebellar ataxia, marked truncal hypotonia, pyramidal signs, and early visual disturbances due to optic atrophy. EEG may show fast rhythms and seizures may occur. In a series of 14 patients carrying the PLA2G6 mutation, mean age at symptom onset was 14 months (232). One third of these patients presented in the context of intercurrent illness. All had progressive cognitive and motor regression with axial hypotonia, spasticity, bulbar dysfunction, and strabismus. Many had optic atrophy. All patients in this series eventually developed cerebellar ataxia and dystonia. Later-onset cases may have a rapidly evolving dystonia-parkinsonism combined with pyramidal signs, eye movement abnormalities, cognitive decline, and psychiatric features without cerebellar signs. Brain MRI in early onset cases shows cerebellar abnormalities but this is less common in later onset PLAN. Additionally, iron accumulation is characteristically present without the presence of the central hyperintensity that is seen in typical PKAN. In some cases, there may be an absence of iron accumulation, and the disorder should be suspected any time dystonia-parkinsonism is present. The PLA2G6 gene (chromosome 22q) encodes iPLA2 beta, and is a group VIA calcium-independent phospholipase A2 that hydrolyzes the sn-2 acyl chain of phospholipids, thereby generating free fatty acids and lysophospholipids. As a result, lipid composition of the plasma membrane, vesicles, or endosomes may be altered. Neurodegeneration in PLAN is more widespread than in PKAN and is associated with Lewy body pathology and tau accumulation. Incidentally. PLA2G6 mutations were originally assigned to the PARK14 locus. In contrast to PKAN, patients with PLAN may respond to levodopa.
Kufor-Rakeb disease (PARK9). This is a rare, adolescent-onset autosomal dominant condition characterized by parkinsonism, occasional pyramidal features, and incomplete supranuclear up-gaze palsy in many cases. Oculogyric dystonic spasms, facial-faucial-finger mini-myoclonus, and autonomic dysfunction may be present. Cognitive features include visual hallucinations and dementia. Symptoms are levodopa responsive but dyskinesias can occur early. MRI shows cerebral and cerebellar atrophy. If present, iron accumulation is more typically present in the caudate and putamen. This disorder is due to mutations in ATP13A2 (chromosome 1p), which encodes a lysosomal 5 P-type ATPase. The exact pathophysiology is not well understood.
FA2H-associated neurodegeneration (FAHN, SPG35). This is another rare disorder characterized by childhood-onset gait impairment, spastic quadriparesis, severe ataxia, and dystonia. Strabismus and seizures may be present. Brain MRI typically shows bilateral globus pallidus T2 hypointensity that is consistent with iron deposition, prominent pontocerebellar atrophy, mild cortical atrophy, white matter lesions, and corpus callosum thinning. FA2H catalyzes hydroxylation at the 2 position of the N-acyl chain of the ceramide moiety, resulting in abnormal myelin. This disorder is linked to leukodystrophies and hereditary spastic paraplegia.
Beta-propeller protein associated neurodegeneration (BPAN, WDR45). The WDR45 gene encodes a beta-propeller scaffold protein that regulates autophagy, the dysregulation of which leads to neurodegeneration (170). After the discovery of this mutation, the term beta-propeller protein associated neurodegeneration (BPAN) has been suggested for this phenotype, in place of the prior term, static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) (347). BPAN is characterized by global developmental delay early in childhood, which appears to be static until adolescence or early adulthood, when there is sudden, rapidly progressive onset of parkinsonism, dystonia, and cognitive decline.
Other types of neurodegeneration with brain iron accumulation. These include disorders that are most likely to present in adulthood and so are not discussed in detail here. Disorders include aceruloplasminemia and neuroferritinopathy. Other genetic forms of neurodegeneration with brain iron accumulation may exist but are poorly defined.
The diagnostic approach to neurodegeneration with brain iron accumulation centers on visualization of iron accumulation within the globus pallidus interna on MRI (169). If the typical “eye-of-the-tiger” sign is seen, testing for PKAN mutations confirms the diagnosis. If this sign is absent, testing for the PLA2G6 mutation should be undertaken. Testing for this mutation should also be considered in patients in whom neurologic decline occurs in the context of typical corroborative clinical features without evidence of iron deposition in the globus pallidus, such as spasticity, dystonia, cerebellar atrophy, optic atrophy, seizures, fast EEG rhythms, and denervation by EMG. A clinical and neuroimaging algorithm for evaluating patients with NBIA has been proposed (228) with further excellent reviews of pediatric NBIA by Kurian and colleagues (231).
Paroxysmal movement disorders
The paroxysmal dyskinesias. A classification scheme and diagnostic criteria for these paroxysmal movement disorders has been suggested by Jankovic and Demirkiran (190). These conditions may be sporadic, familial (autosomal dominant), or secondary to other conditions (136). Treatments have not been systematically evaluated in controlled trials, and lifestyle modification to avoid precipitants is often most important.
Paroxysmal kinesigenic dyskinesia. Paroxysmal kinesigenic dyskinesia is characterized by briefly sustained involuntary movements, typically dystonia or chorea, which are precipitated by sudden movement, sudden acceleration or change in direction of movement, or startle. Thoughts of moving may trigger the events. Patients often describe a sensory aura prior to the motor symptoms (188).
Paroxysmal kinesigenic dyskinesia is frequently associated with mutations in the PRRT2 gene on chromosome 16, which has been identified in multiple families of different ethnicities (422). PRRT2 is primarily expressed in the basal ganglia and associates with SNAP25, which is integral in regulating neurotransmitter release. However, the exact mechanism of disease is not understood. PRRT-associated paroxysmal kinesigenic dyskinesia typically presents between 1 and 20 years of age and is most often inherited in an autosomal-dominant fashion. Age of onset in sporadic cases can be more variable. PRRT2 mutations are also associated with benign familial infantile convulsions. Other seizure syndromes, common and hemiplegic migraine, and episodic ataxia are also more prevalent in paroxysmal kinesigenic dyskinesia families than in the general population (188).
Secondary paroxysmal kinesigenic dyskinesia can occur in patients with multiple sclerosis, head trauma, perinatal hypoxic encephalopathy, basal ganglia calcifications, hemiatrophy, and cerebral infarcts or hemorrhages (36). Hypoparathyroidism is an important treatable secondary cause (395). The pathogenesis of paroxysmal kinesigenic dyskinesia is incompletely understood, but is conventionally thought to relate to a channelopathy (257). Sporadic cases are more frequently male, and infantile convulsions are more common in the familial kindreds. Females have a higher remission rate than males. The disorder may start as early as 18 months of age (245). Attacks may interfere with certain activities, but they are not debilitating and tend to decrease during adulthood. Most patients respond well to either carbamazepine or phenytoin, and dose in children is comparable to (or lower than) dose used for epileptic seizures. Other effective anticonvulsants reported include phenobarbital, primidone, valproic acid, levetiracetam, gabapentin, lamotrigine, topiramate, and clonazepam. Aside from anticonvulsants, other medications that have been effective include acetazolamide, levodopa, flunarizine, trihexyphenidyl, and tetrabenazine (279). Management of the primary disease in secondary forms may also improve attacks.
Paroxysmal nonkinesigenic dyskinesia (Mount-Reback type). Paroxysmal nonkinesigenic dyskinesia (PNKD) consists of intermittent attacks with any combination of dystonia, chorea, or ballismus that is not triggered by a voluntary movement, but is often precipitated by stress, fatigue, coffee, alcohol, or menstrual periods. Age of onset is most commonly in childhood. Attack duration may be as long as 10 minutes to 4 hours, whereas the frequency can range from a few episodes per year to several per day. Symptoms may increase in frequency and severity over time (136).
Paroxysmal nonkinesigenic dyskinesia is an autosomal dominant disorder with high penetrance. Three distinct mutations in the PNKD gene, previously referred to as the myofibrillogenesis regulator gene (MR-1), on chromosome 2q35 have been identified. The function of the protein product is not clear, although has been reported to interact with SNAP25 (238; 188). Hydroxyacyl-glutathione hydrolase functions in a pathway to detoxify methyl-glyoxal, a compound present in coffee and alcoholic beverages and produced as a byproduct of oxidative stress. Large families have been described.
Secondary causes include psychogenic, cerebrovascular, multiple sclerosis, encephalitis, cerebral trauma, peripheral trauma, migraine, kernicterus, hypoparathyroidism, hypoglycemia (eg, with insulinoma), and basal ganglia calcifications (36).
Paroxysmal nonkinesigenic dyskinesia is generally nonprogressive; patients are normal between attacks. Attacks may respond to benzodiazepines, whereas anticonvulsants are generally not helpful. Avoidance of triggers should be encouraged. Management of underlying illness in secondary causes should be optimized.
Paroxysmal exertion-induced dyskinesia. Paroxysmal exertion-induced dyskinesia is characterized by choreiform movements lasting 5 to 30 minutes, precipitated by continuous exertion (eg, walking, chewing). Chorea, dystonia, or both affect mainly the legs and can occur in combination with epilepsy, usually primary generalized in nature (378). Paroxysmal exertion-induced dyskinesia can be associated with mutations in SLC2A1 on chromosome 1p35-p31.3, which encodes GLUT1, a glucose transporter of the blood-brain barrier (136). Altered glucose metabolism in the corticostriate pathways underlies the movement disorder, whereas frontal lobe glucose metabolic abnormalities underlie seizures. Anticonvulsants and levodopa generally do not help reduce attacks, though the ketogenic diet may be helpful (378). Mutations in the GTP-cyclohydrolase 1 gene, which is associated with dopa-responsive dystonia, can also be associated with paroxysmal exertion-induced dyskinesia.
Paroxysmal hypnogenic dyskinesia. Paroxysmal hypnogenic dyskinesia consists of nocturnal paroxysmal choreiform or dystonic movements that are often due to frontal lobe seizures (174). Misdiagnosis as nightmares, night terrors, other parasomnias, or even psychiatric disorders may occur.
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) can be caused by a mutation in the gene encoding the neuronal nicotinic acetylcholine receptor alpha-4 subunit (CHRNA4). There is genetic heterogeneity; in similar families linkage to 15q24, close to the CHRNA3/CHRNA5/CHRNB4 cluster, was established. In other families, both loci have been excluded. The exact pathophysiology is not known. Large French-Canadian, Australian Anglo-Saxon, Japanese, and Korean families have been described.
Shorter attacks may respond to anticonvulsants; longer attacks may respond better to neuroleptics or benzodiazepines.
Ataxias.
Episodic ataxia with myokymia (EA-1). Episodic attacks of limb-muscle contraction occur in EA-1, which often result in loss of balance. Generalized attacks of ataxic gait may last for hours and may occur several times a day. The neurologic examination between spells is typically normal, except for continuous rippling myokymia of the face and limbs. Ataxia may begin in infancy; myokymia may present later in childhood.
EA-1 is an autosomal dominant disorder with mutations identified in the voltage-gated potassium channel gene KCNA1 (12p13) (136). The gene product is localized to GABAergic interneurons in the cerebellum and may be important for regulating GABA release (172).
Families with EA-1 have been described. Partial responses to acetazolamide, carbamazepine, phenytoin, and phenobarbital have been reported. Symptoms are largely nonprogressive.
Episodic ataxia with nystagmus (EA-2). EA-2 is characterized by spontaneous episodes of ataxia typically lasting hours. Interictal nystagmus (gaze-evoked or downbeat) is present. Episodes are triggered by stress and exertion and are often dramatically relieved by treatment with acetazolamide. Ataxia begins before 20 years of age; an underlying mild progressive ataxia may also occur (197).
EA-2 demonstrates autosomal dominant (19p13) inheritance, and families have been described. Mutations in the calcium ion channel CACNA1A are associated, making this disorder allelic to familial hemiplegic migraine (136). There may be phenotypic overlap with SCA6 (129; 202). The type of mutation does not appear to predict phenotype. Some patients respond to acetazolamide. A Class II study suggests efficacy of 4-aminopyridine in reducing attack frequency and improving quality of life (377). Symptoms are largely nonprogressive.
Restless legs syndrome. Restless legs syndrome is a sensorimotor disorder characterized by an irresistible urge to move the limbs, especially in the evening or at night. This is usually accompanied by discomfort in the lower extremities, often alluded to as “creepy” or “crawly.” Insomnia and daytime fatigue may result. Polysomnography may show periodic limb movement disorder. Restless legs syndrome in children may be mistakenly identified as “growing pains” (366). The International Restless Legs Syndrome Study Group (IRLSSG) has formulated the following diagnostic criteria: (1) desire to move the limbs, usually associated with paresthesias/dysesthesias; (2) motor restlessness; (3) symptoms are worse or exclusively present at rest (ie, lying, sitting), with at least partial and temporary relief by activity; and (4) symptoms are worse in the evening or night. In addition, one or more of the following features, although not required for diagnosis, may be present: (1) sleep disturbance; (2) periodic limb movements in sleep (PLMS), which consist of repetitive flexions of the hip, knee, or ankle lasting 0.5 to 5 seconds; (3) chronic symptoms with exacerbations and remissions; (4) positive family history; and (5) dopamine responsiveness (419). In pediatric restless legs syndrome, all four essential features must be present, and the child should be able to use his/her own words to describe the leg discomfort, or there should be at least two of the following supportive features: (1) sleep disturbance inappropriate for age; (2) biological parent or sibling has definite restless legs syndrome; (3) a sleep study documents a periodic limb movement index of greater than 5 of sleep (326).
Idiopathic restless legs syndrome is an autosomal dominant, often familial condition. Seven susceptibility loci have been identified (RLS1-7) with candidate genes, including BTBD9, MEIS1, MAP2K5/LBXCOR, and PTPRD. RLS 6 (BTBD9) is also associated with periodic limb movements of sleep. Childhood-onset restless legs syndrome is more likely to be familial. In pediatric cases, symptom onset may be as early as 1 year of age (291). The most common complaints are sleep problems, often resulting in fatigue, and coexistent periodic limb movements are common as well. Dopaminergic therapy is often successful. Comorbidities occur in 20% and may include parasomnias, attention deficit hyperactivity disorder, oppositional defiant disorder, anxiety disorders, and depression (325).
There is evidence that implicates impaired iron acquisition by neuromelanin cells (84). The underlying mechanism may be a defect in regulation of the transferrin receptors. Functional neuroimaging studies show reduced binding at the D2 receptor, suggesting dysfunction within dopaminergic pathways. Dopaminergic hypoactivity in the brains of restless leg syndrome patients has also been demonstrated (71). The fact that iron is a cofactor needed for dopamine production, and that the response to dopaminergic medications is favorable, further support theories of dopaminergic dysfunction in restless legs syndrome. Serum ferritin is often low and can correlate with disease severity.
Secondary restless legs syndrome is clinically indistinguishable and can be related to certain medications (eg, SSRIs, antihistamines) or other medical factors (eg, peripheral neuropathy, renal failure). Similar to adults, there is increased restless legs syndrome prevalence in pediatric patients with chronic kidney disease.
More than one third of adult restless legs syndrome subjects have onset of symptoms before 20 years of age. Maternal factors may contribute to variable expression. In a population study, 1.9% of children aged 8 to 11 years and 2.0% of 12- to 17-year-olds met criteria for restless legs syndrome, and there was a family history in over 70% of cases (324). Restless legs syndrome occurs with higher frequency in patients with Tourette syndrome (243) and attention deficit hyperactivity disorder (420). Treatment strategies include oral iron supplementation (especially if serum ferritin is less than 50 mcg/L), ensuring good sleep hygiene, clonidine at bedtime, gabapentin, though no double-blind, placebo-controlled trials in pediatric restless legs syndrome have been performed (326). Levodopa and dopamine agonists should be avoided due to the potential for augmentation of restless legs syndrome symptoms.
Sandifer syndrome. Sandifer syndrome is characterized by abnormal posturing of the head, neck, and upper body in association with hiatal hernia or severe gastroesophageal reflux and esophageal dysmotility (99). Abdominal pain and vomiting are typically present. Symptoms may begin anywhere from the neonatal period to 3 years of age and may be mistaken for torticollis or seizures. Symptoms are thought to be a response to pain associated with gastroesophageal reflux. Hiatal hernia need not be present, but gastroesophageal reflux is a constant feature. Treatments for gastroesophageal reflux, including Nissen fundoplication, result in control of the abnormal movements.
Cerebral palsy
Cerebral palsy is loosely defined as a nonprogressive disorder of motor control with static encephalopathy and diverse causes. It occurs worldwide with a frequency of about 2 to 2.5 per 1000 live births. Debate exists as to what percentage represents an avoidable complication of labor and delivery, but overall, preventable birth injury is felt to explain only a small percentage. Many forms of cerebral palsy are a manifestation of abnormal fetal brain development (210). Although cerebral palsy can develop in term infants, the risk is higher in low-birthweight infants and in twin pregnancies. Improved neonatal intensive care and consequent improved survival rates in this population of patients have led to a decreased prevalence of children with cerebral palsy. Pre- and perinatal injuries (such as genetic diseases, cerebral dysgenesis, hypoxia-ischemia, stroke, or maternal infections during gestation) account for up to 85% of cases, whereas postnatal infection, trauma, and stroke account for the rest. Pathophysiologic mechanisms and epidemiology are different in premature infants when compared to term infants. These children have a higher incidence of periventricular leukomalacia and cerebellar insults (37). In term infants, on the other hand, any type of encephalopathy may predict development of cerebral palsy, though antepartum risk factors seem to be implicated most often. In a case-controlled study, 69% of the case subjects had only antepartum risk factors, 24% had both antepartum and intrapartum factors, 5% had only intrapartum factors, and 2% had no recognized antepartum or intrapartum factors (19; 20). Maternal age, parity, and socioeconomic status are among determinants of antepartum risk. Type of delivery (eg, required induction, emergency vs. elective C-section), intrapartum complications, and maternal fever are among determinants of intrapartum risk (19). Several genetic mimics of cerebral palsy exist and in the absence of risk factors should be thoroughly investigated (321).
Cerebral palsy can be divided into different subtypes based on the predominant motor disorder: spastic (50%), dyskinetic (20%), ataxic (10%), or mixed (20%).
• Spastic cerebral palsy can be further subdivided into hemiplegic, diplegic, and quadriplegic types. Hemiplegic and diplegic children often have normal intelligence and are more likely to develop orthopedic problems including contractures. In hemiplegic cerebral palsy, cases are often in term infants, the upper extremity is more affected than the lower, and seizures may be common. It is often due to a vascular insult or a dysgenesis syndrome. Diplegic cerebral palsy commonly affects preterm infants with periventricular leukomalacia, and the lower extremities are more affected. Quadriplegic cerebral palsy is often due to more severe and extensive cerebral injury and can be associated with severe mental retardation, epilepsy, dysarthria, microcephaly, and strabismus. | |
• Dyskinetic cerebral palsy is characterized by different abnormal movements, including dystonia and chorea, and in contrast to the other types of cerebral palsy, intelligence is often well preserved in comparison with the degree of motor impairment. Causes include hypoxic-ischemic injury, metabolic disorders (mitochondrial cytopathies, organic acidurias, creatine deficiency, and kernicterus. Dopa responsive dystonia may be misdiagnosed as this (see section on DYT5a, DYT5b above). Dyskinetic cerebral palsy is due to injury to basal ganglia structures (neostriatum and globus pallidus) and the thalamus (124). The term hypoxia is the most common cause and most classically presents with anterior thalamic and posterior putaminal injury stretching across the posterior limb of the internal capsule. If hypoxia is more severe, it then involves more of the motor strip and eventually brainstem and generalized white matter tracks. Neonatal kernicterus, in which bilirubin deposits within the basal ganglia and brainstem structures (85) has become rare in most countries but is still seen. The kernicterus form of cerebral palsy is characterized by associated vertical ophthalmoparesis, deafness and abnormal dental enamel. | |
• Ataxic cerebral palsy includes variable degrees of ataxia and chorea or dystonia. Many patients have global developmental delay all are likely to be microcephalic. Cerebellar malformations, especially of the inferior vermis and hemispheres, are seen on imaging studies, in addition to less severe cerebral abnormalities. | |
Although generally a nonprogressive condition, some patients may experience a worsening of their movement disorder during adulthood (357). The pathophysiology of this phenomenon is not known. |
Head trauma
The association between trauma and subsequent development of a movement disorder is still a matter of some controversy. The closer the temporal relationship between the two strengthens the possibility of an association. In the acute period, tremors or dystonia may occur transiently. In studies looking at long-term outcome in patients with severe head trauma, several movement disorders may persist, including tremor, dystonia, stereotypy, myoclonus, parkinsonism, paroxysmal dyskinesias, exaggerated startle, ballism, and tics/tourettism (227).
Most patients who develop a posttraumatic movement disorder have demonstrable abnormalities on brain imaging. Movement disorders may be a result of the primary insult (eg, hemorrhage, contusion, infarct, or axonal shear injuries, especially if the basal ganglia are involved) or secondary processes during recovery (eg, hypoxia, hypotension, or cerebral edema, again especially with focal insults to the basal ganglia) (309).
• Tremor can be rest, kinetic, and postural, often with high amplitude and proximal involvement, the so-called “rubral” or “Holmes” tremor. It results from diffuse axonal injury or involvement of dentatothalamic pathways. It may begin several years following initial injury. Treatment involves usual tremor medications, or in severe cases, deep-brain stimulation. | |
• Dystonia (often hemidystonia) occurs as a result of contralateral caudate/putamen injury. Dystonia is often refractory to medications, though it may improve in some cases with anticholinergic medications. Deep-brain stimulator placement can be considered; response to stimulation in these patients is often less robust than in those with genetic forms of dystonia. | |
• Ballism is a rapid, flinging, seemingly purposeless movement of an extremity, and classically is described as a result of injury to the contralateral subthalamic nucleus. | |
• Myoclonus is often a result of anoxia and not necessarily head trauma, but metabolic causes should be ruled out (eg, renal or hepatic disease). In cases of global anoxia, it can be referred to as the Lance-Adams syndrome and may be characterized by predominant negative myoclonus (asterixis). | |
• Paroxysmal dyskinesias may occur following head trauma, but the pathophysiology is unclear, as idiopathic forms are thought to be genetic. | |
• Posttraumatic tics or tourettism is only reliably diagnosed in an individual who had no such symptoms prior to the trauma. Age of onset is generally older than typical patients with tics or Tourette syndrome. Basal ganglia injury is often the cause, and they usually respond to typical tic medications. | |
• Posttraumatic parkinsonism is still a cause for debate, with few well-documented cases, and generally in the context of severe closed head injury. The akinetic-rigid form predominates. |
Functional (psychogenic) movement disorders
Functional movement disorders have largely been studied in adults (188). Case series have shed further light on the phenomenology, presentation, and clinical course of psychogenic movement disorders in children (07; 120; 356). Functional movement disorders are often characterized by the following features:
• abrupt onset |
Psychogenic movement disorders may occur in the context of the following:
• other psychogenic features |
Further, Ahmed and colleagues found that psychogenic movement disorders were characterized by disappearance of involuntary movements when the patients thought they were not being observed and recovery following psychotherapy or suggestion (07). Features such as distraction and variability of movements during relaxation, sleep, or stress could not reliably distinguish psychogenic movement disorders from organic movement disorders.
Mean age at onset is in the early teenage years, and females are predominantly affected. Multiple movement disorder phenomenologies are often observed. The most common manifestations are dystonia and tremor, but gait disorders and myoclonus are also common, and functional tics have become increasingly common (181). Ferrara and Jankovic reported that psychogenic movement disorders in children represented 3.1% of the pediatric population followed at their academic movement disorders center, and 5.7% of the total psychogenic movement disorders population (120).
A shorter time from symptom onset to diagnosis of a psychogenic movement disorder leads to greater efficacy of treatment, which can include psychotherapy and rehabilitation. Unfortunately, disability and morbidity can include prolonged school absences and unnecessary surgical procedures.
Drug-induced movement disorders
Dopamine receptor blocking drugs.
Tardive dyskinesia. This is one of the most common medication-induced movement disorders. It is a hyperkinetic condition in which involuntary, repetitive oro-bucco-lingual movements predominate, especially in adults. However, the movements may be more generalized, or involve stereotypies, dystonia, akathisia, chorea, or tremor. Tardive dyskinesia is most commonly associated with use of dopamine receptor blocking drugs. The reported frequency of tardive dyskinesia in such patients varies greatly, but an average of 25% of adults, and 12% of children exposed to dopamine receptor blocking drugs may develop it (371; 403; 270). Dopamine receptor blocking drugs associated with tardive dyskinesia include phenothiazines (eg, chlorpromazine, thioridazine, fluphenazine), thioxanthenes (eg, thiothixene), butyrophenones (eg, haloperidol), diphenylbutylpiperidines (eg, pimozide), dibenzazepines (eg, loxapine), dibenzodiazepines (eg, clozapine, quetiapine), thienobenzodiazepines (eg, olanzapine), pyrimidinones (eg, risperidone), benzisothiazoles, (eg, ziprasidone), benzisoxazoles, substituted benzamides (eg, metoclopramide), indolones (eg, molindone), quinolinone (eg, aripiprazole), tricyclics (eg, amoxapine), and calcium channel blockers (eg, flunarizine, cinnarizine) (270; 322). Of these, metoclopramide is the most likely offender (268). Risk factors include advanced age, female gender, and total cumulative drug exposure. Studies suggest that the risk for developing tardive dyskinesia is lower with the newer, atypical dopamine receptor blocking drugs. Although tardive dyskinesia is more common in adults, it can occur in children, with some reports in infants. Symptoms may persist for months to years. Animal models suggest a possible role for dopamine receptor hypersensitivity, excessive NMDA receptor activation, or decreased GABAergic transmission in certain nuclei. Both tardive dyskinesia and withdrawal emergent syndrome have a good chance of remitting spontaneously, so treatment other than maintaining discontinuation of the dopamine receptor blocking drugs is typically not required. If symptoms are severe, however, use of monoamine-depleting drugs such as reserpine or tetrabenazine can be considered. Although such drugs also have dopamine-blocking activities, they do not appear to harbor the same long-term risk of developing tardive dyskinesia.
Acute dystonic reaction, including oculogyric crisis. Two percent to 3% of patients treated with neuroleptics will experience an acute dystonic reaction in the first few days following initiation of the drug (Dressler and Beneck 2005). The risk is higher with higher-potency drugs. Symptoms may include oculogyric crisis, facial grimacing, jaw fixation, cervical dystonia (retrocollis or torticollis), or opisthotonic posturing. Oculogyric crisis is a slow, conjugate, usually upward deviation of the eyes lasting for 1 minute or longer. The disorder is especially prevalent in children, can be uncomfortable, and can be associated with altered mentation (240). Medications associated with oculogyric crisis include cetirizine, carbamazepine, ziprasidone, haloperidol, phenothiazines, and metoclopramide. Untreated symptoms may last hours or days. Treatment includes diphenhydramine or anticholinergic medications.
Neuroleptic malignant syndrome. Symptoms include hyperthermia, rigidity, reduced consciousness or agitation, and autonomic symptoms (tachycardia, sialorrhea, diaphoresis). Tremor, ataxia, nystagmus, and ocular movement abnormalities may occur. Creatine phosphokinase is elevated; myoglobinuria is possible. This syndrome is life threatening, but it is rare in children (299). Treatment includes hydration, correction of electrolyte abnormalities, cooling blankets, dantrolene, and bromocriptine. Treatment with bromocriptine may shorten duration of symptoms.
Withdrawal emergent syndrome. This is a self-limited choreic movement disorder and another variant of drug-induced movement disorder, most frequently observed in children in whom dopamine receptor blocking drugs are abruptly withdrawn (08). In contrast to the stereotypic, repetitive movements in tardive dyskinesia, withdrawal emergent syndrome movements are slower, more random, and fluid, flowing from one muscle to another. Symptoms often last for a few days to a few weeks and resolve on their own (328).
Tremor. Similar to drug-induced tremor in adults, this can be a mixed tremor type, with components of rest, postural tremor, and kinetic tremor.
Antiepileptic drugs. Chorea, dystonia, tremor.
Beta-adrenergic drugs. Tremor.
Amphetamines. Chorea, tremor.
Lithium. Chorea, tremor.
Steroids, most immunosuppression medications. Tremor.
Benign movement disorders of childhood
Benign neonatal sleep myoclonus. The main clinical manifestation is clusters of 1 to 5 Hz myoclonic nonepileptic jerks during sleep that tend to involve the upper lower extremities and distal proximal muscles. Episodes are generally brief but may last up to 20 or 30 minutes and may have lateralized features. They typically start during the first 2 to 3 weeks of life and resolve by 6 months (206; 318). There is no EEG correlate.
Benign myoclonus of early infancy. Clinical manifestations are episodes of myoclonic spasms resembling infantile spasms, including shuddering of the head and shoulders, though a variety of paroxysmal transient nonepileptic movements may occur, usually while the infant is awake (62). Symptoms begin at 3 to 9 months of age and typically resolve be 3 years. Similar to benign neonatal sleep myoclonus, symptoms should not be confused with epilepsy (265). There is no EEG correlate.
Jitteriness. Jitteriness is described as generalized, symmetric, rhythmic, oscillatory movements resembling tremor or clonus. It is highly stimulus-sensitive and suppressible by gentle passive flexion of the involved limb. If symptoms persist beyond the expected age, evaluation for hypoxic-ischemic encephalopathy, hypocalcemia, hypoglycemia, or drug withdrawal should be undertaken. Symptoms typically begin in the neonatal period and resolve soon after birth (225).
Shuddering attacks. (see prior description above)
Spasmus nutans. (see prior description above)
Head-nodding. Intermittent, discrete episodes of head nodding occur while sitting or standing (but not lying down) and resemble stereotypy. The movements may look volitional or playful. A family history of essential tremor may be present (103).
Benign paroxysmal torticollis. The main manifestation is a head tilt to one side lasting a few hours to a few days. It usually occurs without other symptoms, but occasionally, pallor, vomiting, irritability, or ataxia may be present. There is often a family history of migraines. Older children may complain of headache, develop migraine attacks, or experience paroxysmal vertigo, raising the possibility that this disorder is a migraine variant. Symptoms generally begin at a few months of age; most resolve by 2 to 3 years, all cases by 5 years. Some cases have been associated with CACNA1A mutations (143). There is some evidence to suggest that pathogenic variants in CACNA1A may be associated with benign paroxysmal torticollis (364).
Paroxysmal tonic upgaze of infancy. This relatively benign disorder is characterized by: (1) onset usually under 1 year of age, (2) episodes of variably sustained conjugate upward deviation of the eyes, with neck flexion (chin down) apparently compensating for the abnormal eye position, (3) downbeating saccades in attempted downgaze, (4) normal horizontal eye movements, (5) diurnal fluctuation of symptoms, (6) frequent relief by sleep, (7) exacerbation with febrile illnesses, (8) various degrees of ataxia, (9) neurologic examination usually otherwise normal, (10) absence of deterioration during long-term follow-up, (11) eventual improvement, and (12) usually negative investigations, including imaging, EEG and CSF neurotransmitters (310). The disorder may be familial; some cases are associated with fetal exposure to sodium valproate, and others with structural lesions, often of the brainstem. The pathophysiology is still not understood. Fifty percent resolve without sequelae, but ataxia (247), borderline cognitive abilities, and residual minor oculomotor disorders may occur in the rest (59).
Benign idiopathic dystonia of infancy. This is a rare segmental dystonia that usually involves one upper extremity. Dystonic postures may consist of shoulder abduction, pronation of forearm, and wrist flexion, occurring at rest and resolving with movement. The age at onset is often before 5 months of age, with complete resolution by the 1st year (97).
Self-stimulatory behavior (infantile gratification phenomenon). Clinical manifestations include stereotyped posturing of the lower extremities with pressure to pelvic area lasting from minutes to hours (297). The posturing may be associated with grunting, diaphoresis, and facial flushing, and the episodes occur without loss of awareness and stop with distraction (435). Videotape evaluations may be revealing and greatly assist diagnosis (66).
Provisional tic disorder (transient tic disorder). This diagnosis can only be made in retrospect, after tics have resolved. It may occur in up to 20% of children. In the DSM5, the name of the condition was changed from “transient” to “provisional” (10).
Table 1. ICD Codes and OMIM Numbers for Childhood Movement Disorders
Disorder |
ICD-9 |
ICD-10 |
OMIM | |
Abetalipoproteinemia |
272.5 |
E78.6 |
#200100 | |
Angelman syndrome |
759.89 |
Q93.5 |
#105830 | |
Antiphospholipid syndrome (Systemic lupus erythematosus) |
710.0 |
L93, M32 |
#152700, 107320 | |
Aromatic amino acid decarboxylase (AADC) deficiency |
270.2 |
E70.8 |
#608643 | |
Ataxia with CoQ10 deficiency |
334.3 |
G11.9 |
#607426 | |
Ataxia with hypogonadotropic hypogonadism (Marinesco-Sjogren syndrome) |
334.2 |
G11.9 |
#248800 | |
Ataxia with vitamin E deficiency |
269.1 |
E56.8 |
#277460 | |
Ataxia-telangiectasia |
334.8 |
G11.3 |
#208900 | |
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) |
334.2 |
G11.8 |
#270550 | |
Benign hereditary chorea |
333.5 |
G25.5 |
#118700, 215450 | |
Benign idiopathic dystonia of infancy |
333.9 |
G25.9 | ||
Benign myoclonus of early infancy |
333.2 |
G25.3 | ||
Benign neonatal sleep myoclonus |
333.9 |
G25.8 | ||
Benign paroxysmal torticollis |
333.83, 723.5 |
G24.3, M43.6 | ||
Blepharospasm |
333.81 |
G24.5 |
#606798 | |
Bobblehead doll syndrome |
307.3 |
F98.4 | ||
Cerebellitis |
334.3 |
G11.9 | ||
Cerebral palsy |
343 |
G80 |
#603513, %605388 | |
Dentatorubral pallidoluyisal atrophy |
334 |
G11.9 |
#125370 | |
Early-onset ataxia with oculomotor apraxia and hypoalbuminemia (EAOH) |
334.2 |
G11.1 |
#208920 | |
Episodic ataxia (EA-1 with myokymia, EA-2 with nystagmus) |
334.3 |
G11.0 |
#160120, #108500 | |
Essential tremor |
333.1 |
G25.0 |
#190300, %602134 | |
Focal limb dystonia |
333.84, 333.89 |
G25.8, G24.8 | ||
Friedrich ataxia |
334.0 |
G11.1 |
#229300, %601992 | |
Dopa-responsive dystonia, Segawa disease (GCH1) |
270.2, 333.89 |
E70.9, G24.8 |
#128230, #605407 | |
Generalized dystonia (all) |
333.6 |
G24 | ||
DYT1 (Oppenheimer dystonia) |
G24.1 |
#128100 | ||
DYT2 |
%224500 | |||
DYT4 |
%128101 | |||
DYT11 (myoclonus-dystonia) |
333.2 |
G24.1, G25.3 |
#159900 | |
DYT12 (rapid-onset dystonia-parkinsonism) |
#128235 | |||
DYT13 |
%607671 | |||
DYT14 |
%607195 | |||
DYT15 |
%607488 | |||
Geniospasm |
333.1 |
G25.0 |
%190100 | |
Glutaric aciduria |
270 |
E72.3 |
#231670 | |
Gluten-associated ataxia |
579.0 |
K90.0 | ||
GM1 gangliosidosis |
330.1 |
E75.1 |
+230500 | |
GM2 gangliosidosis (Tay-Sachs disease) |
330.1 |
E75.0 |
#272800 | |
Hartnup disease |
270.0 |
E72.0 |
#234500 | |
Haw River syndrome |
#140340 | |||
Huntington disease, Westphal variant |
333.4 |
G10 |
+143100 | |
Hyperekplexia |
759.89 |
Q89.8 |
#149400 | |
Infantile shuddering attacks |
333.93 |
G25.8 | ||
Juvenile myoclonic epilepsy |
345.1 |
G40.3 |
#606904 | |
Juvenile neuronal ceroid lipofuscinosis |
330.1 |
E75.4 |
#256730, #204500, #204200, *600722 | |
Juvenile parkinsonism |
332 |
G20 | ||
Autosomal dominant |
#605543 | |||
Autosomal recessive |
#600116 | |||
Lafora disease |
345.00 |
G40.3 |
#254780 | |
Leigh syndrome |
330.8 |
G31.8 |
#256000 | |
Lesch-Nyhan disease |
277.2 |
E79.1 |
#300322 | |
McLeod neuroacanthocytosis |
333.5 |
G25.5 |
+314850 | |
Methylmalonic academia |
270 |
E72.0 |
#251000, #251100, #251110, #277400, #277400, %277410, %277380, 606169 | |
Mohr-Tranebjaerg syndrome (Dystonia-deafness syndrome, dystonia-optic atrophy syndrome) |
#304700 | |||
Myoclonus |
333.2 |
G25.3 | ||
Neuroacanthocytosis |
333.5 |
G25.5 |
#200150 | |
Niemann-Pick disease type C |
330.2, 272.7 |
G32.8, E75.2 |
#257220 | |
Oculogyric crisis |
333.9 |
G25.9 | ||
Opsoclonus-myoclonus |
379.59 |
H55 | ||
Palatal myoclonus |
333.2 |
G25.3 | ||
Pantothenate kinase associated neurodegeneration (PKAN, NBIA) |
333.0 |
G23.8 |
#234200 | |
Paroxysmal exertional dyskinesia |
333.5 |
G25.5 | ||
Paroxysmal hypnogenic dyskinesia |
333.5 |
G25.5 | ||
Paroxysmal kinesigenic dyskinesia |
333.5 |
G25.5 |
%128200 | |
Paroxysmal nonkinesiogenic dyskinesia (PNKD, Mount-Reback type) |
333.5 |
G25.5 |
#118800 | |
Paroxysmal tonic upgaze of infancy |
333.9 |
G25.9 | ||
Phenylketonuria |
270.1 |
E70.0 |
+261600 | |
Postinfectious chorea |
333.5 |
G25.5 | ||
Post-pump chorea |
333.5 |
G25.5 | ||
Rasmussen encephalitis |
323.81 |
G04.8 |
*305915 | |
Refsum disease |
356.3 |
G60.1 |
#266500 | |
Restless legs syndrome |
333.99 |
G25.8 |
%102300, %608831 | |
Rett syndrome |
330.8 |
F84.2 |
#312750 | |
Sandifer syndrome |
530.81 |
K21.9 | ||
Spasmus nutans |
307.3 |
F98.4 | ||
Spinocerebellar ataxia (autosomal recessive) |
334.2 |
G11.9 | ||
SCA1 |
#164400 | |||
SCA11 |
%604432 | |||
SCA12 |
#604326 | |||
SCA13 |
#605259 | |||
SCA14 |
#605361 | |||
SCA15 |
%606658 | |||
SCA17 |
#607136 | |||
SCA18 |
%607458 | |||
SCA19, 22 |
%607346 | |||
SCA2 |
#183090 | |||
SCA21 |
%607454 | |||
SCA25 |
%608703 | |||
SCA3 (Machado-Joseph disease) |
#109150 | |||
SCA5 |
#600224 | |||
Stereotypies |
333.9 |
G25.9 | ||
Sydenham chorea |
392 |
I02 | ||
Tardive syndromes |
333.9 |
G25.9 | ||
Tics |
307.20 |
F95 | ||
Torticollis |
333.83, 723.5 |
G24.3, M43.6 | ||
Tourette syndrome |
307.23 |
F95.2 |
#137580 | |
Transient tic disorder |
307.21 |
F95.0 | ||
Tyrosine hydroxylase deficiency |
270.2 |
E70.8 |
#605407 | |
Wernicke encephalopathy |
265.1 |
E51.2 | ||
Wilson disease |
275.1 |
E83.0 |
277900 | |
Withdrawal emergent syndrome |
333.9 |
G25.9 | ||
# indicates that it is a descriptive entry, usually of a phenotype, and does not represent a unique locus. The reason for the use of the #-sign is given in the first paragraph of the entry. Discussion of any gene(s) related to the phenotype resides in another entry(ies) as described in the first paragraph. + indicates that the entry contains the description of a gene of known sequence and a phenotype. % indicates that the entry describes a confirmed mendelian phenotype or phenotypic locus for which the underlying molecular basis is not known. No symbol before an entry number generally indicates a description of a phenotype for which the mendelian basis, although suspected, has not been clearly established or that the separateness of this phenotype from that in another entry is unclear. |
Media
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