Clinical manifestations

Presentation and course

Patients with juvenile Huntington disease present with a variety of motor and nonmotor symptoms and routinely appear quite different from those with the adult-onset form. In adult-onset Huntington disease, chorea is the most prominent movement disorder, which manifests early in the disease course and worsens over time and can plateau and even improve toward the later stages of the disease whereas dystonia and parkinsonism become more prominent (31). Chorea in juvenile Huntington disease is relatively rare, occurring in less than 10% of cases (12). Parkinsonism and dystonia are the most common presenting motor symptoms (seen in approximately 50%-60% of those with juvenile Huntington disease). Myoclonus and epilepsy are reported in approximately 30% to 50% of patients with juvenile Huntington disease (15; 05). Furthermore, epilepsy is much more common in childhood-onset than adolescent-onset Huntington disease (05). Other motor symptoms include tics, which have been described as a presenting symptom in patients lacking a family history of tics (13). Epilepsy may occur as generalized, focal, mixed, or as a progressive myoclonic epilepsy (20; 12). Median survival was also shorter in the more highly expanded patients (18).

Although the motor symptoms are more well-known, the most common early features of juvenile Huntington disease tend to be cognitive and behavioral (31; 05). This together with significant weight loss are the symptoms that tend to be most devastating to the patients and families (16; 42). Early on, parents may note speech and language problems as well as declining school performance and sometimes developmental regression (32). Later, progressive cognitive dysfunction becomes more prominent and there are more widespread symptoms including oropharyngeal dysfunction, weight loss and cachexia, poor oral hygiene, and behavioral changes (32). Cognitive changes commonly include impairments in executive functioning (43). Behavioral symptoms include impulsivity, aggression, opposition, and disinhibition whereas psychological symptoms commonly include depression, anxiety, obsessiveness, inattention/ADHD, aggression, apathy, impulsiveness, sleep problems, and irritability (43; 28). Psychotic symptoms such as hallucinations and delusions are rare but have been reported (11). Prevalence rates of up to 87% of ADHD prior to the diagnosis of juvenile Huntington disease have been reported (43). These symptoms may also predate the diagnosis by several years. One study found that when comparing to age and height comparable healthy controls, body mass index of patients with juvenile Huntington disease is at least 10% less than unaffected individuals (47).

In patients in whom symptoms begin prior to age 10, the developmental and neurobehavioral phenotype is often worse, including more severe epilepsy, cognitive deficits from early in life, behavioral difficulties, and spasticity (44; 02).

Prognosis and complications

Juvenile Huntington disease advances more rapidly than the adult-onset disease, with a shorter median survival (44; 18). Three main stages have been described. In the first stage the main symptoms are behavioral disruption, learning impairment, and gait changes. The second stage is manifested by more rapid cognitive changes, rigidity, seizures, and dysarthria. The last stage patients may become hypotonic and have worsened seizure frequency and worsened disability (12).

These symptoms progress over time and eventually leave the adolescent or young adult disabled, with some unable to ambulate. They become dependent on caregivers for all activities of daily living (42). When patients are hospitalized for respiratory infections, status epilepticus, malnutrition, or other complications, the hospital stays tend to be prolonged. Children with juvenile Huntington disease have been reported to be 8 times more likely to die during their hospitalizations, with cause of death attributed to pneumonia, sepsis, or status epilepticus (30).

These symptoms and the progressive nature of the disease, as well as having multiple family members affected, commonly leads to significant caregiver stress. Therefore, the involvement of a social worker to assist with services for the family is paramount.

There is no validated assessment to track the severity of symptoms specifically in juvenile Huntington disease. The Unified Huntington Disease Rating Scale continues to be the primary measure utilized; however, a number of factors limits the ability of the scale to adequately capture disease severity in this population (45). These include normal variations due to developmental age as well as the challenges related to differing symptomatology. As chorea occurs more rarely in juvenile Huntington disease, the scale can underestimate disease severity in the pediatric population (32).

Clinical vignette

A 15-year-old female presented to our institution with chief complaint of abnormal gait and abnormal movements. She had been typically developing until age 8 when her cognition no longer progressed and shortly thereafter her school performance declined. At age 12 she developed myoclonus involving mostly the axial musculature. CT head and EEG at age 12 were performed and found to be normal. Over the next few years, the myoclonus became more generalized, and her legs became stiff. Subsequently, she developed a shuffling gait and postural instability. There was no history of seizures. Her father recently passed away from Huntington disease. Exam was significant for slow, dysarthric speech, impaired upgaze, bradykinesia, and axial myoclonus. She had a shuffling gait and postural instability. She had Huntington repeat expansion testing and was found to have 80 repeat expansion of the Huntington 1 allele. In terms of management, she was started on clonazepam for myoclonus and baclofen for dystonia. Referrals were made for nutrition, palliative care, physical medicine and rehab, sleep medicine, neuropsychology, physical therapy, occupational therapy, speech therapy, and social work. Over time, her oral intake continued to worsen, with continued weight loss. She was admitted for management of an aspiration pneumonia and underwent gastrostomy tube placement, with complications of sepsis and persistent respiratory failure. Her family elected for only comfort care measures, and she passed.

Biological basis

Etiology and pathogenesis

The pathology involved in juvenile Huntington disease is thought to be similar and more severe than adult-onset cases. Huntington disease is inherited in an autosomal dominant manner and is due to an unstable expansion of a CAG repeat in the first exon of the HTT gene, resulting in an expanded glutamine in the huntingtin protein (39; 14). Huntingtin is a nuclear protein that is expressed ubiquitously and regulates transcription by binding to transcription factors. Although widespread and present in the brain and other parts of the body, its exact function is largely not known. Wild-type huntingtin upregulates transcript of brain-derived neurotrophic factor from neurons in the cortex, which promotes the survival of neurons in the striatum. It also is thought to regulate vesicular transport by interacting with several cytoplasmic proteins (09; 08). Mutant protein, however, leads to cleavage and protein fragments aggregate within the tissue (23). Studies have also shown formation of intranuclear inclusion bodies containing mutant protein fragments, which is thought to be a response to the toxic mutant protein (04).

The cortex and striatum seem to be particularly sensitive to the toxic accumulation of mutant huntingtin protein as prominent atrophy occurs with degeneration of the medium spiny neurons shown in autopsy of patients with Huntington disease (37). There are several mechanisms underlying the toxic effects of the protein aggregates and that have been identified using primarily animal models. The first mechanism relates to transcriptional interference by the aggregates directly entering the nucleus, which may affect neurotransmitter receptors, ion channels, and brain-derived neurotrophic factor. Mutant protein could also cause abnormalities in vesicle transport as well as disrupt the ability to tag and clear misfolded proteins within the cell (14). Mutant protein and aggregates may also lead to disruption of mitochondrial function as neurons affected show reduced ATP levels and oxidative stress (07). Lastly, mutant protein is shown to disrupt calcium signaling and leads to excitotoxicity by interacting with NMDA receptors and inositol triphosphate receptors eventually leading to excess influx of calcium within the cell leading to cell death (10; 50; 46).

There is also some thought that defects in energy metabolism also play a role in pathophysiology as skeletal muscle of these patients reveal an energy deficit that may account, at least partly, for patients with juvenile Huntington disease suffering from weight loss and lower BMIs. Given the growth and development that occurs during childhood the higher demand organs (brain and skeletal muscle) may be more vulnerable (48).

Greater than 40 CAG repeats is considered unequivocally pathologic for Huntington disease. Thirty-six to 39 repeats are also known to cause pathology but may have reduced penetrance. Twenty-seven to 35 repeats are considered intermediate range, with potential to expand to disease-causing length in future generations, and fewer than 27 repeats are considered normal (32).

Patients with over 60 repeats are likely to have juvenile onset. Nevertheless, approximately half of patients with juvenile Huntington disease will have repeat lengths under 60 and there have been case reports of patients with adult-onset disease who have more than 60 repeats (32).

Several studies have evaluated the effect of the total number of expansions on disease symptomatology. In general, large expansions are associated with an earlier onset and more rapid progression (18; 40). However, this appears not to be the only factor, as there have been reports of several patients with juvenile Huntington disease but with repeat lengths as low as 42.

Patients with juvenile Huntington disease and more than 80 repeats appear more likely to have a particularly aggressive form of the disease, with more frequent developmental delay, seizures, and earlier and more severe gait impairment (18).

In approximately 70% to 80% of cases of juvenile Huntington disease, the transmitting parent is a father when clinical onset is 11 to 20 years and 90% of those with childhood onset. The predominance of male transmission is due to instability in the CAG repeat length during spermatogenesis, which increases if the father already has longer CAG repeats (32).

Epidemiology

The prevalence of Huntington disease, irrespective of age of onset, is approximately 4 to 10 per 100,000. Estimates of juvenile Huntington disease prevalence vary but is in the realm of 1% to 10% of all Huntington disease cases (31; 01; 05).

Juvenile Huntington disease affects males and females equally. However, almost 80% of these patients inherit the disease-causing allele from the father, likely due to instability during spermatogenesis (32). It has also been found that total number of CAG repeat length is inversely correlated with the age of onset (44; 18).

Diagnostic workup

The broad range of symptoms seen in juvenile Huntington disease can make the presentation similar to that seen in a variety of other genetic and acquired conditions, including monoamine neurotransmitter synthesis disorders, epilepsies, mitochondrial cytopathies, neurodegeneration with brain iron accumulation, lysosomal disorders, neuronal ceroid lipofuscinosis, dentatorubral-pallidoluysian atrophy, Wilson disease, some spinocerebellar ataxias, juvenile-onset Parkinson disease, Niemann-Pick type C, the gangliosidoses, and cerebrotendinous xanthomatosis (21; 12).

Parkinsonism is relatively rare in children and is caused most often by exposure to dopamine receptor blocking medications or following an infectious or autoimmune encephalitis. Other less common causes include hydrocephalus, basal ganglia tumors, and hypoparathyroidism (21).

As some of these disorders are treatable, in cases where a family history of Huntington disease is absent, providers should keep other diagnoses in mind and patients would benefit from neuroimaging, neurotransmitter, and metabolic testing as directed by history and examination (22).

Diagnosis of Huntington disease is based on clinical evaluation and confirmed by a positive genetic test. In juvenile Huntington disease and in particular childhood-onset Huntington disease, this can be much more difficult, as the symptoms can mimic several other neurodevelopmental disorders.

Care must be taken in interpreting the results of Huntington disease repeat length testing. In children and teens in whom symptoms are not specific to Huntington disease, if there is no family history and repeat length is between 40 and 60, it may remain unclear whether Huntington disease is the cause of current symptoms or only that they will be affected in the future (32).

Per U.S. Huntington Disease Genetic Testing Group guidelines, genetic testing of asymptomatic children under 18 is not recommended, as they cannot consent to testing, there is not yet a disease-modifying treatment available, and positive results can have a significant psychological impact on affected persons and their family members. There can also be practical repercussions (eg, with regard to employment and insurability) (29).

Guidelines suggest that children under age 10 with genetically confirmed family history of Huntington disease and two or more of the following should be tested: declining school performance, gait disturbance, rigidity, seizures, and oral motor dysfunction.

Currently, patients presenting with tics, tremor, chorea, and spasticity in the absence of a genetically confirmed family history and lack of cognitive or behavioral symptoms need not be tested (29). The greatest challenge to clinicians is the older child or adolescent child who is presenting with only neuropsychiatric symptoms with a genetically confirmed family history. This becomes even more complicated when the families make the self-diagnosis of juvenile Huntington disease (26). In these cases, it has been advocated to follow imaging or institute a period of observation to monitor for a progressive course (29).

Prenatal testing is also available for at risk fetuses (32). This again has the potential for several consequences with premature testing. For example, one case reported a 3-year-old male with developmental delay and refractory epilepsy, hypotonia, ash leaf spots, and microcephaly of which there was a strong family history of Huntington disease who was found to have more than 80 CAG repeats and his symptoms were attributed to juvenile Huntington disease. Subsequently, imaging revealed subcortical tubers and the family history of tuberous sclerosis seemed to be neglected and was found over a year later. Another case was a 4-year-old patient who was tested prenatally and found to have more than 80 CAG repeats and presented for symptomatic treatment due to abnormal movements. The movements were found to be stereotypies (49). These cases further illustrate that testing should truly only be performed until the symptoms are noted to be progressive and consistent with juvenile Huntington disease and mimickers, as discussed earlier, are excluded, as many of them have disease-modifying therapy available.

Neuroimaging. Imaging in juvenile Huntington disease also reveals differing changes to the brain than in adult-onset Huntington disease. These patients will commonly have the atrophy of the caudate as with adult-onset Huntington disease and to a lesser extent the putamen (36; 03). Atrophy of the frontal and parietal lobes can be quite prominent in juvenile Huntington disease (whereas is only present approximately 20% of adult-onset) as well as the internal globus pallidus. Overall, there is 2.5 times more damage done to the basal ganglia than the rest of the brain (41). Magnetic resonance spectroscopy in juvenile Huntington disease may show widespread elevated glutamate and low striatal creatine (34).

Firstly, overall brain volume is lower in those with juvenile Huntington disease, and, in comparison, the cerebellum is proportionately enlarged. Also, the greater number of CAG repeats is predictive of a smaller putamen and larger cerebellar volumes (24). However, in children with symptom onset less than 6 years of age, cerebellar atrophy has also been reported. It is unclear if the enlarged cerebellum is compensatory or pathologic (24; 48). The effects to the striatum are thought to be responsible for the motor symptoms found in juvenile Huntington disease and the volume of the caudate and putamen are the strongest predictors of the level of motor symptoms present (24). Again, in children with short disease duration the volume of the putamen is still noted to be significantly less than healthy controls. Therefore, there is some thought that there is deviation from the normal development of these brain structures when the mutant huntingtin protein is present (48).

Management

There are currently no approved disease-modifying interventions for juvenile Huntington disease (27). Treatments are supportive and include medications for tone (eg, clonazepam, baclofen), antiepileptic medications, and physical therapy. There is little evidence for most interventions and polypharmacy occurs frequently, necessitating mindful medication reassessment periodically (35). Huntingtin-lowering technologies including antisense oligonucleotides show promise in studies of patients with adult-onset Huntington disease to reduce the expression of mutant huntingtin; however, these modalities have not been tried in children.

Motor symptoms that require treatment include spasticity, rigidity, dystonia, bradykinesia, tics, myoclonus, and tremor. Management of the spasticity mainly involves baclofen, tizanidine, or benzodiazepines. In the case of rigidity and bradykinesia, these are treated with carbidopa/levodopa or dopamine agonists (32). Tics can also be common presenting symptoms in juvenile Huntington disease, and these can be managed with VMAT2 inhibitors such as tetrabenazine as well as neuroleptics whereas the tremor and myoclonus tend to be responsive to benzodiazepines (35).

More invasive means of treatment have also been utilized with decent success including intrathecal baclofen pumps as well as botulinum toxin injections (25). Deep brain stimulation with electrode placement in bilateral globus pallidus has been used for management of motor symptoms; however, control of the dystonia and parkinsonism have been inconsistent in the cases reported thus far in juvenile Huntington disease (17). One case of impairing chorea was managed with unilateral pallidothalamic tractotomy, which led to transient worsening of dysarthria (19).

Mood disorders occur frequently in juvenile Huntington disease, with most common symptoms including depression, anxiety, obsessive compulsive disorder, and less commonly hallucinations and mania (33). Behavioral symptoms can be treated with antidepressants, mood stabilizers, and dopamine blocking agents (33). In patients with epilepsy, antiepileptics are commonly used to treat both mood stabilization and seizures, and the most commonly prescribed drug used as first line is valproic acid. Inattention is also common; however, stimulants may have adverse effects on motor symptoms. Therefore, nonstimulant options tend to be preferred (32). Management of neurocognitive symptoms can be difficult; however, yearly neuropsychiatric testing allows for areas of weakness to be identified and allows for school accommodations to be put in place early (43).

Anecdotally, there have been few case reports of cannabinoids used in early onset Huntington disease with improvements in weight gain, improved mood, and improved appetite; however, this has not been tested in a larger series as a randomized control trial (38).

Outcomes

The disease itself also has multisystem implications; therefore, a multidisciplinary approach is best, and the role of each discipline as the disease progresses will change (25). The median disease duration has been reported as approximately 20 years. School support is also important as cognitive decline is prominent and yearly neuropsychiatric evaluations may be helpful (43). The disease is progressive; therefore, at some stage end of life care should be discussed. Weight loss and dysphagia are common; therefore, discussion of a feeding tube should be discussed earlier rather than later in the disease course. Palliative physicians will also be crucial for other management including symptomatic treatment of pain involved in difficult to manage dystonic spasms (25). Other specialists commonly involved in the care of patients with juvenile Huntington disease include a pediatrician, child psychiatrist and psychologist, dietician, social worker, dentist, and speech, occupational, and physical therapists (32).

Special considerations

Social implications. In many of these families that are affected by juvenile Huntington disease, the transmitting parent may have already passed away or be in the end stages of the disease. Therefore, the care giver role in the family can be especially burdensome. In a UK study, families affected were interviewed about their experiences with being the parent of a child with juvenile Huntington disease. Many of the parents had a strong sense of something being wrong with their child even long before the diagnosis was made and many times the suspicions were difficult to articulate, with a vague sense of “a strange look in her eyes” or “she just isn’t like the other kids” (16).

Once the diagnosis is made, many families have described the diagnosis as a “sentence.” One parent described that the disease denied her child the chance to be a normal child even in the short time she had left. Not only this but many of the caregivers are left in a place of feeling completely hopeless and robbed of any happiness they may have had left (16).

Also, given the rarity of the disease, many families experienced frustration in their interactions with healthcare providers, especially when physicians are hesitant to admit their lack of knowledge of the disease. Parents continue to prefer responses such as “I don’t know the answer, let me get back to you” (16).

Lastly, respite care needs to be prioritized for these caregivers and families as well as support groups in which they can relate to others similarly. Many of the caregivers in the UK study endorse an overwhelming sense of isolation; therefore, having another person that understands the impact of the disease on the family can help alleviate some of these feelings (16).