Clinical manifestations

Presentation and course

Hypotonia may be readily apparent at birth or may be noted in childhood as a child fails to make expected developmental progress.

Clinical signs of low tone in infancy include excessive drooling, breathing difficulties, hip abduction with legs externally rotated in the supine infant (“frog-leg posture”), poor weight bearing through legs, arms extended at rest, head lag greater than expected for age when arm traction applied, increased distance of arm pull with the anterior scarf sign, and low tone notes on both vertical (“slip through” at the shoulders) and horizontal (C-curve over hand) suspension. Central hypotonia is typically more prominent axially in distribution. Mild weakness (with paucity of antigravity movements) can accompany central hypotonia, but severe weakness should prompt evaluation for peripheral nervous system abnormalities. Deep tendon reflexes are typically preserved but may not be exaggerated, particularly in the first months of life (08).

The clinical significance of central hypotonia later in childhood must be interpreted with respect to age and motor development. Central motor delay typically manifests in delayed motor milestones, and the degree of delay is a useful predictor (07). On examination, motor delays are mirrored by persistence of primitive reflexes (06) and delayed or atypical profiles of postural responses (20). Structured evaluations such as the Hammersmith Infant Neurological Examination incorporate assessments of tone and postural responses into age-based norms (15). However, validated standardized assessments of tone remain limited, particularly for older children (14).

Central hypotonia itself can impact functioning and causative brain dysfunction may produce additional coexisting diagnoses and deficits. Beyond gross and fine motor functioning, central hypotonia can contribute to oral motor symptoms including poor feeding, drooling, swallowing problems, or speech difficulty. Abnormal posture can impact feeding and seating. Joint laxity places the child at increased risk for dislocations or other skeletal abnormalities. Coexisting effects of cerebral dysfunction can range from encephalopathy to epilepsy or visual or hearing impairment.

Other clinical signs will vary by specific etiology. Examples include dysmorphic features associated with specific genetic disorders or multiorgan involvement in many metabolic disorders.

Clinical history. When evaluating a patient with hypotonia, important questions may include:

Prognosis and complications

The prognosis of central hypotonia varies significantly by etiology (eg, in MedLink Neurology article on Perinatal hypoxic-ischemic encephalopathy) (21; 23). In general, the causative process may be time-limited (as in hypotonic cerebral palsy; see MedLink Neurology article on Cerebral palsy for detailed discussion) or progressive (as occurs in some metabolic or degenerative disorders).

In cases of idiopathic congenital hypotonia, some individuals improve or recover completely, but many demonstrate persistent problems in motor coordination, language, and learning difficulties later in life (33).

In a high-risk neonatal neurology clinic, central hypotonia was associated with delay in motor development (30), and in follow-up of infants with hypotonia presenting before 1 year of age (03), 62% were found to be globally delayed.

For individuals who are diagnosed with predominantly hypotonic/ataxic cerebral palsy, impaired communication is particularly prominent (88%); cognitive impairment (31%) and seizures (46%) are also common. A majority of these individuals are ambulatory (17).

Persistently hypotonic patients may be at risk for musculoskeletal problems such as contractures, joint dislocation, respiratory compromise, and orthopedic complications based on abnormal postures and positions (34; 28).

Clinical vignette

A 4-month-old female presented with hypotonia, poor ocular fixation, and a history of “spasms” at 3 months of age. Her prenatal history was relevant for premature birth at 32 weeks’ gestation, with postnatal hospitalization only relevant for poor sucking/swallowing that resolved within the expected timeframe. There were no perinatal seizures or known intraventricular hemorrhage from prematurity.

At age 3 months, the patient then started developing clusters of spasms on awakening from sleep that got progressively more intense, sometimes lasting almost 10 minutes.

EEG confirmed hypsarrhythmia consistent with infantile spasms. She was started on adrenocorticotropic hormone injections after a short course of phenobarbital. Her flexor spasm seizures subsided, and seizures remained well controlled on maintenance zonisamide and phenobarbital.

On diagnostic testing, it was revealed she had septo-optic dysplasia as well as bilateral periventricular leukomalacia. Because of the seizures and this midline defect, she was referred to the genetics clinic. No metabolic or genetic etiology was identified after extensive evaluation. She had endocrine testing done because of this midline defect; despite concern for failure to thrive, no endocrine abnormalities have been found to date.

At age 17 months, she demonstrates severe developmental delay. She cannot sit without support and has head lag when pulled from prone. She has strabismus with prominent right esotropia. She does have a social smile and is babbling some.

She demonstrates mixed tone with prominent truncal hypotonia and high extensor tone of the legs at times. Reflexes are present and slightly brisk at the knees.

Overall, this patient’s hypotonia is attributed to cerebral palsy secondary to her brain dysmorphology (septo-optic dysplasia) and periventricular leukomalacia. She has guarded long-term developmental outcome and has been involved with physical, occupational, and visual therapies.

Biological basis

Anatomic localization

The entity of central hypotonia admits multiple localizations (from the lower motor neuron to the cortex), and some disorders impact multiple areas of the neuroaxis. Purely peripheral neuromotor disorders will be discussed under Differential diagnosis.

Maldevelopment or damage to the brain. Disorders affecting the brain structure account for a majority of cases with central hypotonia. These disorders are typically classified into the cerebral dysgenesis or dysplasias and conditions in which the developing brain may have been damaged, such as in prematurity.

Central hypotonia does not imply a specific localization within the brain, though some rules of thumb are noted: lesions of primary motor cortex or cerebellum will often decrease tone, and lesions of the basal ganglia or red nucleus will often increase tone (05). Lissencephaly, holoprosencephaly, and Joubert syndrome, and pontocerebellar hypoplasias as well as rare entities such as midbrain disconnection syndrome (02) have all been associated with central hypotonia (with varying degrees of specificity).

Anterior horn cell disease. Anterior horn cell disease, such as the spinal muscular atrophies, can present with a prominent hypotonia and can be a progressively fatal disease, which can be rapid in early infancy and childhood.

Spinal cord disease. “Spinal shock” may acutely present as hypotonia from an injury. A child may be born with congenital abnormalities of the spinal cord that may present with hypotonia affecting the legs more than the arms. Higher spinal cord defects may affect the arms and chest. Typically, below the area of the “lesion” there are decreased reflexes and hypotonia accompanied by motor paresis or paralysis. There may be accompanying bowel and bladder dysfunction.

Examples of spinal cord disorders are spina bifida, congenital maldevelopment, or damage to the spinal cord.

Conditions affecting both the lower and the upper motor neuron (combined peripheral and central hypotonia). When the underlying cause of hypotonia is a combined lower and upper motor neuron problem, it may present with developmental delay and cognitive impairment in addition to muscle weakness or increased creatine kinase level. Examples of such conditions are dystroglycanopathies (Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama-type congenital muscular dystrophy), congenital disorders of glycosylation, mitochondrial encephalomyopathies, Pelizaeus-Merzbacher disease, Marinesco-Sjögren syndrome, and Canavan disease (19).

The condition Fukuyama-type congenital muscular dystrophy is characterized by both dystrophic changes in the skeletal muscle and CNS migration disturbances. This disorder is characterized by severe infantile hypotonia, symmetrical generalized weakness, and mental retardation. The cerebral migrational disturbances normally seen are cobblestone lissencephaly along with other cerebral and cerebellar dysgenesis. A genetic test is available for this disorder located at the Fukuyama congenital muscular dystrophy gene at chromosome 9q31-q33 by genetic linkage analysis (29).

Amyotrophic lateral sclerosis is an example of adult-onset combined upper- and lower-motor neuron degeneration.

Pathophysiology

Tone (physiologically or pathologically) can be influenced by many factors such as sleep, hypoxia, metabolic factors, and position at the time of testing. Physiologically, tone is thought to be cortically driven with multiple hierarchical, recurrent intervening control mechanisms in the basal ganglia, cerebellum, brainstem reticular pathways, and spinal interneurons, though these processes are incompletely understood (11), as well as muscle spindles. Hypotonia then can reflect failure of signal generation, transmission, or modulation at any level of the motor neuroaxis. Molecular/genetic factors may also directly affect transmission and modulation at multiple anatomical levels (12).

Epidemiology

Central hypotonia is more common than peripheral hypotonia in neonates, accounting for 60% to 80% of cases (26; 37), though mortality appears to be higher for infants with peripheral hypotonia (22). Population-based studies have not been performed, but case series have reported identifiable genetic and metabolic diagnoses in as many as 60% of neonates presenting to tertiary care settings (27).

Differential diagnosis

Hypotonia as a clinical sign is highly nonspecific. As Dubowitz, in 1980, related:

Usually, symptoms of a patient with central hypotonia have a generalized hypotonic pattern. The symptoms are usually present in infancy or noted in early development with delayed acquisition of developmental milestones.

Unilateral weakness in an infant or child would typically make this diagnosis more unlikely and would suggest etiologies of unilateral weakness, such as brachial plexus injury at birth, broken clavicle, or an early presentation of stroke.

Peripheral localization patterns include:

Myopathic diseases. Severe congenital myopathies may present in the newborn period, with decreased movements of the face and body, hypotonia, ptosis, and decreased deep tendon reflexes. The mother may have reported decreased intrauterine movements.

Myopathies or muscular dystrophies presenting later in childhood or adulthood may present with delayed acquisition of typical motor milestones or loss of previously acquired motor milestones.

Often patients with a primary myopathic process have an abnormal creatine phosphokinase, possibly abnormal transaminases, abnormal EMGs, and may have characteristic patterns seen on muscle biopsy.

Examples of myopathies and or muscular dystrophies include: nemaline myopathy, metabolic myopathies, myotonic dystrophy, central core disease, Duchenne muscular dystrophy, and limb girdle muscular dystrophies. Infectious (postviral) metabolic disturbances (potassium, calcium abnormalities) and medications (prednisone) may affect muscle function but are generally reversible and are preceded by normal muscle function.

Neuromuscular junction disease. These patients may have a waxing and waning weakness. Ptosis may be involved in an infant with this condition. Weakness may be more prominent at the end of the day or after feeding. Weakness can generally be improved by administration of medications such as edrophonium. Genetic testing is commercially available for the acetylcholine receptor antibody binding, transmission, and uptake. EMG/nerve conduction velocity may show characteristic findings.

Neuropathies. Abnormal nerve function may be distinguished by abnormal sensory patterns and response of the infant or child. There may be accompanying autonomic dysfunction. Reflexes are typically diminished. Neuropathies may also present as a “stocking/glove” pattern of motor weakness.

Orthopedic or joint laxity. Abnormally free moving joints and flexibility may be confused with hypotonia but can usually be distinguished by proper assessment of the joints and flexibility of the patient. Hyperflexibilty or hypermobility is usually secondary to “joint laxity.” Hypermobile people are stated to be at one extreme of the normal distribution curve, but this can rarely be due to pathological conditions such as Ehlers Danlos syndrome. Typically, those conditions are associated with other abnormalities. Interestingly, hypermobility is twice as common in females as males. Hypermobile people are prone to a variety of musculoskeletal complaints such as patella dislocations and joint effusions. Some clinical tests that may indicate a patient is hypermobile include whether a patient is able to press the thumb to the forearm, hyperextend the fingers almost completely backwards, touch the floor with the palms of the hands, and whether or not the knees hyperextend (36).

Table 1. Central Versus Lower Motor Neuron Causes of Hypotonia

Table 2. Differential Diagnosis of a Child With Central Hypotonia

Diagnostic workup

Exclude critical/multisystemic illness. Critical neurologic (eg, hypoxic-ischemic encephalopathy) or systemic illnesses (eg, sepsis, metabolic crisis, hypoglycemia, or congenital heart disease) are common causes of hypotonia in the neonate and should be excluded in the initial evaluation (24).

Some inheritable recognized disorders of inborn errors of metabolism may present with hypotonia. Some typical disorders include peroxisomal disorders, mitochondrial disorders, and organic and amino acidurias. Some of these disorders may cause reversible severe hypotonia in the newborn period and need to be recognized in the first 1 to 3 days of life. Infants with pyruvate carboxylase deficiency may present with axial hypotonia and tachypnea (13). Bizarre ocular movements may be described as well as abnormal movements to the limbs (high amplitude tremor and hypokinesia). This complex of movements may be called hypokinetic rigid syndrome. Laboratory tests typically reveal lactic acidosis, hypercitrullinemia, and hyperammonemia. Treating these patients with triheptanoin and citrate may be lifesaving.

Genetic central hypotonia evaluations. Six academic institutions have reported that the diagnostic yield of genetic testing in infants with hypotonia is 50% or greater (31; 24). Over 500 genetic causes of hypotonia have been identified, so a broad-spectrum testing approach is often indicated. Whole exome/whole genome sequencing currently appear to have the highest diagnostic yield, though targeted single-disorder testing and microarrays have a role in initial evaluation when rapid turnaround can influence treatment decisions (eg, for spinal muscular atrophy in which presymptomatic initiation of treatment outcomes are dramatically better than post symptomatic initiation outcomes). Targeted phenotyping (including brain MRI and ophthalmologic examination) should accompany first-line testing, if not already performed. Second-line testing should target limitations in first-line testing (eg, mitochondrial genome sequencing, if not included). Nondiagnostic sequencing studies should be reanalyzed every 2 to 3 years as the annotation of clinical associations advances (24).

Less evidence is available regarding the yield of next-generation sequencing in older cohorts of children with hypotonia. One center has reported a 39% diagnostic yield in a mixed cohort of children referred for hypotonia, weakness, or gait disturbance (35).

Table 3. Diagnostic Testing to Consider in Evaluation of a Patient Thought to Have Central Hypotonia

Table 4. Diagnostic Testing to Consider in Evaluation of a Patient Thought to Have Lower Motor Neuron Hypotonia

Management

The American Academy for Cerebral Palsy and Development (AACPDM) Central Hypotonia Care Pathway Team maintains expert recommendations on care for children 0 to 6 years of age with hypotonia (including central hypotonia) (25).

Diagnostic evaluation (as reviewed above) is the first recommended step in developing a treatment plan. Potentially reversible metabolic conditions may present with hypotonia; these, and targeted treatments, are available for entities such as spinal muscular atrophy. These disorders need to be identified as soon as possible to minimize accrual of injury (25).

In addition, formal assessment of gross motor functioning using norm-referenced instruments can also help develop specific goals and goal-aligned treatment plans (25).

Interventions can include therapies, adaptive equipment, activity and environmental accommodations, and medical surveillance and interventions. Evidence for most interventions is considered "low" or "very low" (25). Recommended interventions include consideration of:

For many central disorders, coexisting deficits in cognition or communication or medical complexity can significantly impact ability to benefit from therapy programs as well as daily functioning. Careful evaluation and management of nonmotor manifestations are often crucial to successful management. When present, oromotor dysfunction may require evaluation and management due to the risk of aspiration and reflux (18).

Outcomes

Outcomes of treatment are variable based on underlying diagnosis, age of intervention, and associated comorbidities. Treatment-related complications are rare.