Central hypotonia in infancy and childhood …

General Child Neurology

Updated 05.28.2023
Released 07.12.2006
Expires For CME 05.28.2026

Central hypotonia in infancy and childhood

Authors: Anton Dietzen MD, Eric Chin MD

See Contributor Disclosures

Editor: Ann Tilton MD

Central hypotonia in infancy and childhood

In This Article

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Introduction

Overview

Hypotonia in childhood may occur secondary to disorders affecting any point in the central or peripheral nervous system. Central hypotonia implies a localization above the level of the lower motor neuron. Hypoxic-ischemic encephalopathy is the predominant attributed etiology for congenital hypotonia, but the differential diagnosis is broad and encompasses over 500 identified genetic disorders. A logical, stepwise approach to diagnosis is essential. For most of these entities, there is no cure, and prognosis is variable. Treatment is individualized and may include supportive therapies (such as physical and occupational therapy or symptomatic treatment) or diagnosis-specific management.

Key points

	• Hypotonia is reduced tension or resistance of passive range of motion and can occur with varying degrees of weakness.
	• The first step in the evaluation of a child with hypotonia is localization to the central or peripheral nervous system (or both).
	• Central hypotonia is more likely to be noted axially with normal strength and hyperactive to normal deep tendon reflexes.
	• Other features common in central hypotonia include dysmorphic facies, macro or microcephaly, developmental delay (global, motor, speech, or cognitive), seizures, malformations of other organs, altered level of consciousness, abnormal eye movements, abnormal breathing pattern, or other signs of central nervous system dysfunction.
	• History and physical exam provide crucial diagnostic clues, though neuroimaging, genetic testing, and other laboratory evaluations are also important parts of assessment.

Historical note and terminology

Literature since the 1960s describes cerebral influences on developmental tone and motor control. The monograph by Victor Dubowitz in the late 1960s entitled “The Floppy Infant” provided a practical approach to diagnosis and classification of children with hypotonia (10). He emphasized two main questions when confronted with a floppy baby or child:

(1) “Is this a paralyzed child with incidental hypotonia?” and

(2) “Is this a hypotonic child without significant muscle weakness?”

His categorization of the paralytic conditions of hypotonic children with weakness and “incidental” hypotonia was found to be most often lower motor neuron diseases: proximal spinal muscular atrophies, congenital myopathies, and other neuromuscular disorders. The infants with nonparalytic conditions who had hypotonia without significant weakness included disorders of the central nervous system, connective tissue disorders, metabolic, nutritional, and endocrine disorders, acute illness, and essential (or benign) hypotonia. This subdivision, central versus peripheral hypotonia, remains clinically useful and represents the starting point for modern diagnostic algorithms (19).

Currently, neonatal central hypotonia may occur as a part of a wider spectrum of neonatal encephalopathy, or “altered behavior in the newborn characteristic of a disturbance in central nervous functioning” (16). Most neonatal hypotonia is attributed to perinatal hypoxic-ischemic encephalopathy (08), though the remainder of cases continue to represent a wide spectrum of disorders. Increasingly sophisticated genetic, biochemical, and imaging studies are allowing increasingly specific etiologic diagnoses in these cases (27; 32; 01; 24).

Over time, once an individual’s etiology and clinical course become clear, additional functional (rather than etiologic) diagnostic labels may be applied. Individuals with persistently disordered movement or posture secondary to early nonprogressive injury or malformation of the developing brain fall under a diagnosis of cerebral palsy. Movement disorders in cerebral palsy are typically classified as spastic, dyskinetic, ataxic/hypotonic, or mixed; persistent central hypotonia (particularly axially) is common in dyskinetic, ataxic/hypotonic, and mixed subtypes. In individuals with less motor impairment, diagnoses of developmental coordination disorder (DSM-V) or specific developmental disorder of motor function (ICD-10) may be applied. Population-based prognostic data are lacking, and it is unclear when historical labels such as “benign congenital hypotonia” may be confidently applied.

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:

Prenatal history.
	(1) Age of mother at time of birth: increased odds of chromosomal disorders are associated with advanced maternal age.
	(2) Nature of baby’s intrauterine movements: neuromuscular disorders may have decreased movements, and acute events may cause a sudden change in movement patterns. Rhythmic movements in utero may represent intrauterine seizures.
	(3) History of infections or teratogens during pregnancy: TORCH infections and teratogens increase risk of cerebral abnormalities and hypotonia.
	(4) History of polyhydramnios, oligohydramnios, or maternal history of previous miscarriages and fetal demise: may represent heritable metabolic or genetic conditions.
	(5) Abnormalities on screening ultrasounds: congenital brain anomalies are more often linked to central causes of hypotonia, whereas arthrogryposis multiplex is often linked to peripheral/neuromuscular disorders.
	(6) Presentation at birth: breech presentation is associated with hypotonia or neuromuscular disorders.
	(7) Positive family history of neuromuscular disorders: eg, myotonic dystrophy in the mother.
Birth/perinatal history.
	(1) History of prematurity: increased risk for cerebral abnormality, complications, and cerebral palsy.
	(2) Mode of delivery, complications/difficult birth: hypoxic-ischemic encephalopathy may lead to CNS damage.
	(3) Difficulties sucking/swallowing: may be seen with hypoxic ischemic injury, cerebral palsy, cerebral disorders, and neuromuscular causes.
	(4) Poor respiratory effort: may be seen with hypoxic ischemic injury or with severe neuromuscular disorders.
	(5) Encephalopathy: if out of context of birth history, may reflect underlying metabolic disorder or severe cerebral dysgenesis.
	(6) Neonatal seizures: if out of context of birth history, may reflect underlying metabolic disorder or cerebral dysgenesis.
	(7) Unexplained metabolic “lab” abnormalities: consider metabolic disturbances and inborn errors of metabolism.
Developmental history.
	(1) Moderate to severe developmental delay or intellectual disability: genetic, cerebral dysgenesis.
	(2) Normal previous development and loss of previously acquired motor skills: consider muscular dystrophies, progressive/intermittent metabolic disorders, or neurodegenerative disorders.
	(3) Mild delay in motor development with normal IQ and social development: “benign hypotonia” or normal variation in development.
Medical history.
	(1) Seizure disorders: cerebral dysgenesis, genetic, metabolic, chromosomal disorders.
	(2) Learning disabilities and behavioral disorders such as attention deficit hyperactivity disorder: reflect overall abnormality of brain development often associated with mild hypotonia.
	(3) Recurrent respiratory infections: neuromuscular dysfunction, possible central dysfunction.
	(4) Detailed review of systems: determine other associated malformations or systemic involvement.
	(5) Diet history: honey or corn syrup consumption may suggest clostridium botulinum exposure.
Pertinent exam findings.
	(1) Vital sign disturbance: may reflect severe cerebral dysgenesis, neuropathy, effects from hypoxia, acute illness.
	(2) General: dysmorphic features point to possible genetic abnormality.
	(3) Skin: neurocutaneous abnormalities may reflect underlying genetic syndrome (neurofibromatosis, tuberous sclerosis).
	(4) Ocular exam: retinal findings, “cherry red spot,” optic nerve exam (atrophy, pale disc) may reflect underlying metabolic abnormality. Abnormal optic nerve may indicate “central causes,” septo-optic dysplasias, etc.
	(5) Hepatosplenomegaly: TORCH infections, glycogen storage diseases, inborn errors of metabolism.
	(6) Extremities: abnormal digits, etc., may be characteristic of genetic syndromes.
	(7) Other organ abnormalities (cardiovascular, genitourinary): genetic syndromes or associations.
Neurologic exam.
	(1) Head circumference:
		Microcephaly: more common in central causes such as TORCH infections, genetic syndromes.
		Macrocephaly: neurocutaneous genetic syndromes, possible CNS disturbance such as hydrocephalus.
	(2) Mental status: normal IQ points to neuromuscular causes.
	(3) Nystagmus, erratic eye movements, strabismus: more common in central causes.
	(4) Prominent facial weakness: congenital myopathies, myasthenia gravis. Possible brainstem effects from hypoxia or cerebral dysgenesis. “Hypotonic facies” typically describe a child with open, downturned mouth and eyelid lag (secondary to hypotonia of facial muscles).
	(5) Other dysfunctions of cranial nerves (ie, Mobius syndrome, hearing loss): more likely central nervous system causes, or genetic causes.
Motor system evaluation.
	(1) General observation:
		(a) Resting position: Frog-leg position indicates significant hypotonia, especially in neonates when baseline tone is flexor “W.” Sitting in an older child is indicative of proximal hypotonia.
		(b) Muscle atrophy or fasciculations: more common in neuromuscular disorders.
		(c) Extent of movement: hypotonia is often associated with a lack of spontaneous movement.
		(d) Distribution of movement: In certain conditions such as anterior horn disease, there may be only movement of the distal extremities. Wide-based gait and genu recurvatum are also indicative of hypotonia.
	(2) Ventral suspension: an infant is typically held in ventral suspension, in which the infant is supported by a hand under the chest. Head control, trunk curvature, and movement of the extremities can be readily assessed (10; 04). A normal newborn will hold the head about 45 degrees or less to the horizontal, the back will be straight or only slightly flexed, the arms flexed at the elbows and partially extended at the shoulder, and the knees partially flexed. An infant with hypotonia may look like a “rag doll” and slump forward and need more support. An infant with possible central cause of hypotonia may scissor in ventral suspension (04).
	(3) Traction of the hands in the supine position will typically result in some degree of flexion in full-term and premature infants, but a hypotonic infant may have prominent head lag.
	(4) Muscle strength: may be more difficult to assess. One method to gauge movement is the ability of the neonate to sustain the posture of a limb against gravity (04). In older children, strength may be more easily tested.
	(5) Reflexes: more typically diminished or absent in neuromuscular disorders; likely to be increased in central disorders.
	(6) Sensory disturbance: may reflect nutritional causes, neuropathies, patterns of abnormalities suggestive of central causes (previous stroke, etc.).
	(7) Coordination: a hypotonic patient may be more uncoordinated from muscle tone abnormalities, but frank ataxia would make one consider more prominently cerebellar disorders or central causes. General clinical characteristics associated with hypotonia include weakness with pull to site, frog posture, vertical suspension, motor delay, hypermobile joints, horizontal suspension, scarf sign, antigravity positions, and resistance of passive movement (09).

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.

Hypotonia (MRI)

MRI of child with septo-optic dysplasia and bilateral periventricular leukomalacia. (Contributed by Dr. Tonia Sabo.)

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).

Holoprosencephaly (MRI)

Patient with holoprosencephaly. (Contributed by Dr. Tonia Sabo.)
Joubert syndrome (MRI)

Patient with Joubert syndrome. (Contributed by Dr. Tonia Sabo.)
Midbrain disconnection syndrome (MRI)

T1-weighted MRI of patient with midbrain disconnection syndrome. (Contributed by Dr. Tonia Sabo.)

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).

Differential diagnosis

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

[Hypotonia] may be the presenting feature of a neuromuscular disorder; it may occur in mentally retarded children or in the early presenting phase of cerebral palsy; it may be a manifestation of a connective tissue disorder; it may be associated with various metabolic disturbances in infancy; it may be an incidental and nonspecific sign in an acutely ill child; it may be completely physiological in the premature infant; and it may occur as a completely isolated symptom in an otherwise normal child.

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

	“Central causes” of hypotonia	“Neuromuscular causes” of Hypotonia
Perinatal and birth history risk factors	++++ Risk for genetic disorders ++++ Intrauterine seizures ++++ Hypoxic ischemic injury ++++ Neonatal seizures ++++ Encephalopathy +++ Prematurity ++ Arthrogryposis multiplex ++ Abnormal brainstem/ autonomic features	+++ Poor feeding, swallowing, or breathing out of context of birth history +++ Arthrogryposis multiplex +++ History of ptosis +++ Breech presentation
Exam features	++++ No muscle weakness +++ Dysmorphic features +++ Fisting of hands “mixed tone” +++ Impaired cognition ++ Muscle reflexes present ++ Crossing of adductors in ventral suspension ++ Nystagmus, strabismus	++++ Muscle weakness ++++ Waxing and waning course of weakness (NMUSC) +++ Normal intelligence ++ Characteristic dysmorphic features ++ Typically decreased muscle reflexes ++ Ptosis
Evaluation features	++++ Abnormal neuroimaging ++++ Abnormal metabolic and serologic tests ++++ Abnormal genetic tests +++ Reversible with correction of identified problem (sepsis, hypoxia)	++++ Abnormal creatine phosphokinase +++ EMG/nerve conduction velocity/muscle biopsy generally more helpful +++ Typically not reversible (NMUSC JXN/drug effect: exception) ++ Abnormal genetic tests
Key: ++++=highly associated, +++=generally associated, ++=less strongly associated, +=possibly associated

Table 2. Differential Diagnosis of a Child With Central Hypotonia

• Central nervous system malformation
	- cerebral dysgenesis, neuronal migrational disorders
• Acute systemic disturbance
	- electrolyte disturbance
• Endocrine disorders
	-thyroid disturbance
• Infectious causes
	- sepsis
• Hypoxia
	- birth injury
• Chromosomal and genetic disorders
	- Down syndrome, Prader-Willi syndrome, fragile X syndrome
• Metabolic disorders
	- Cerebral folate deficiency, biopterin disorders
• Toxin exposure • Vascular
	- stroke, hemorrhage
• Inborn errors of metabolism
	- mitochondrial, respiratory chain
• Cyanotic congenital heart disease • Normal variation in tone • Connective tissue disorders • Rule out lower motor neuron cause
	- anterior horn cell, neuromuscular junction, neuropathy, myopathic processes
• Consider mixed disorders with both central and neuromuscular causes of hypotonia
	- hypoxic–ischemic encephalopathy, metabolic and storage disorders

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

Neuroimaging:	Brain MRI may be normal (29%) or may reveal cerebral dysgenesis (29%), or sequelae of a vascular/hypoxic event (24%). The “classical” white matter–predominant injury pattern associated with spastic cerebral palsy appears to be rare in children with hypotonic cerebral palsy (17).
Initial metabolic labs:	Complete metabolic profile, with liver panel, bilirubin, lipid profile, thyroid panel, calcium, magnesium, complete blood count with differential. Drug/toxin screen, infectious labs.
Muscle enzyme test:	Creatine phosphokinase.
Initial chromosomal / genetic testing:	Whole exome/whole genome sequencing. “Chromosomal microarray if other anomalies present, spinal muscular atrophy if not included in newborn screening, or type 1 myotonic dystrophy if evidence of myotonia in the mother” (24).
Secondary genetic testing to consider:	Prader-Willi, fragile X syndrome, mitochondrial genome sequencing. If nondiagnostic, reanalyze sequencing every 2 to 3 years (24).
Secondary metabolic labs or tests of inborn error of metabolism:	Depending on the clinical picture, tests to consider include plasma amino acids, urine organic acids, arterial blood gas, lactic acid, pyruvate, lactate/pyruvate ratio, CSF analysis for neurotransmitters and amino acids and glucose (along with other routine studies), white blood count enzymes, test for congenital disorders of glycosylation, urine mucopolysaccharides, ammonia, very long chain fatty acids.
May need evaluation to rule out or consider component of lower motor neuron disease

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

Serum creatine phosphokinase
Initial metabolic labs:	Complete metabolic profile, calcium, phosphorus, magnesium, complete blood count
EMG/nerve conduction velocity
Muscle biopsy
Genetic tests:	Tests will vary depending on clinical situation, for example
	• Anterior horn cell disease: SMA Werdnig-Hoffmann disease 5q 11-13.
	• Congenital myopathies: central core disease 19 q13, myotubular myopathy Xq28.
	• Muscular dystrophies: DMD Del/Dup/Sequencing, myotonic dystrophy DM1 and DM2, mitochondrial enzyme deficiency myopathy panel
	• Peripheral neuropathy panels: CMT panel
Neuromuscular consultation recommended
Consider neuroimaging
Consider further evaluations to rule out central causes of 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:

		Goal-directed active motor therapy (eg, directed toward sitting, standing, or toward mobility)
	• Within ages 0 to 12 months
		-supervised awake “tummy time” activities
		- infant massage (for bonding and for sleep)
	• Within ages 12+ months
		- postural management programs to support age-appropriate activities in lying, supported sitting, or standing positions and to avoid asymmetrical lying and frog-legged positions
		- gait-directed treadmill training
		- consideration of orthotics (trial or use in preambulatory children in whom ankle instability is preventing age-appropriate exploration; use to support foot alignment in ambulatory children)
		- adaptive equipment to support activity and participation (eg, adaptive seating, compression garments, a stander/walker/gait trainer, or power mobility devices)
		- hip surveillance to monitor hip displacement and prevent hip subluxation and dislocation

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.

Media

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Contributors

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Authors

Anton Dietzen MD

Dr. Dietzen of Kennedy Krieger Institute and Johns Hopkins Hospital has no relevant financial relationships to disclose.
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Eric Chin MD

Dr. Chin of the Kennedy Krieger Institute have no relevant financial relationships to disclose.
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Editor

Ann Tilton MD

Dr. Tilton has received honorariums from Allergan and Ipsen as an educator, advisor, and consultant.
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Former Authors

Michael V Johnston MD†
Tonia M Sabo MD (original author), Sarah Risen MD, and Mihee J Bay MD

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Central hypotonia in infancy and childhood

Differential Diagnosis

neuromuscular disorders
intellectual disability
cerebral palsy
connective tissue disorders
metabolic disturbances in infancy
- prematurity
- brachial plexus injury at birth
- broken clavicle
- early presentation of stroke
- severe congenital myopathies
- myotonic dystrophy
- central core disease
- Duchenne muscular dystrophy
- limb girdle muscular dystrophies
- Fukuyama congenital muscular dystrophy
- anterior horn cell disease
- Werdnig Hoffmann disease
- spinal cord disease
- spinal bifida
- congenital malformation of the spine
- neuropathies
- cerebral dysgenesis
- cerebral dysplasias
- lissencephaly
- holoprosencephaly
- Joubert syndrome
- pontocerebellar hypoplasias
- midbrain disconnection syndrome
- peroxisomal disorders
- mitochondrial disorders
- organic and amino acidurias
- pyruvate carboxylase deficiency
- disorders of potassium, calcium, magnesium
- orthopedic/joint laxity
- acute systemic disturbance (electrolyte disturbance)
- endocrine disorders (thyroid disturbance)
- infectious causes (Sepsis)
- cyanotic congenital heart disease
- normal variation in tone

Also Relevant

Cerebral folate deficiency
Cerebral palsy
Congenital disorders of glycosylation
Disorders of peroxisome assembly
Down syndrome
- Holoprosencephaly
- Intellectual disability
- Joubert syndrome

Central hypotonia in infancy and childhood

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Anatomic localization

Pathophysiology

Epidemiology

Differential diagnosis

Table 1. Central Versus Lower Motor Neuron Causes of Hypotonia

Table 2. Differential Diagnosis of a Child With Central Hypotonia

Diagnostic workup

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

Outcomes

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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