The Hypotonic Infant

Tone is the resistance of muscle to stretch. Clinicians test two kinds of tone: phasic and postural. Phasic tone is a rapid contraction in response to a high-intensity stretch (deep tendon reflexes). Striking the patellar tendon briefly stretches the quadriceps muscle. The spindle apparatus, sensing the stretch, sends an impulse through the sensory nerve to the spinal cord. This information is transmitted to the alpha motor neuron, and the quadriceps muscle contracts (the monosynaptic reflex ). Postural tone is the prolonged contraction of antigravity muscles in response to the low-intensity stretch of gravity. When postural tone is depressed, the trunk and limbs cannot maintain themselves against gravity and the infant appears hypotonic.

The maintenance of normal tone requires intact central and peripheral nervous systems. Not surprisingly, hypotonia is a common symptom of neurological dysfunction and occurs in diseases of the brain, spinal cord, nerves, and muscles ( Box 6-1 ). One anterior horn cell and all the muscle fibers that it innervates make up a motor unit . The motor unit is the unit of force. Therefore, weakness is a symptom of all motor unit disorders. A primary disorder of the anterior horn cell body is a neuronopathy , a primary disorder of the axon or its myelin covering is a neuropathy , and a primary disorder of the muscle fiber is a myopathy . In infancy and childhood, cerebral disorders are far more common than motor unit disorders. The term cerebral hypotonia encompasses all causes of postural hypotonia caused by cerebral diseases or defects.

BOX 6-1

  • C erebral H ypotonia

    • Benign congenital hypotonia

      Denotes the most common conditions and the ones with disease modifying treatments

    • Chromosome disorders

      • Prader-Willi syndrome

      • Trisomy

    • Chronic nonprogressive encephalopathy

      • Cerebral malformation

      • Perinatal distress

      • Postnatal disorders

    • Peroxisomal disorders

      • Cerebrohepatorenal syndrome (Zellweger syndrome)

      • Neonatal adrenoleukodystrophy

    • Other genetic defects

      • Familial dysautonomia

      • Oculocerebrorenal syndrome (Lowe syndrome)

    • Other metabolic defects

      • Acid maltase deficiency (see Metabolic Myopathies)

      • Infantile GM 1 gangliosidosis (see Chapter 5 )

      • Pyruvate carboxylase deficiency

  • S pinal C ord D isorders

  • S pinal M uscular A trophies

    • Acute infantile

      • Autosomal dominant

      • Autosomal recessive

      • Cytochrome c oxidase deficiency

      • X-linked

    • Chronic infantile

      • Autosomal dominant

      • Autosomal recessive

      • Congenital cervical spinal muscular atrophy

      • Infantile neuronal degeneration

      • Neurogenic arthrogryposis

  • P olyneuropathies

    • Congenital hypomyelinating neuropathy

    • Giant axonal neuropathy (see Chapter 7 )

    • Hereditary motor-sensory neuropathies (see Chapter 7 )

  • D isorders of N euromuscular T ransmission

    • Familial infantile myasthenia

    • Infantile botulism

    • Transitory myasthenia gravis

  • F iber -T ype D isproportion M yopathies

    • Central core disease

    • Congenital fiber-type disproportion myopathy

    • Myotubular (centronuclear) myopathy

      • Acute

      • Chronic

    • Nemaline (rod) myopathy

      • Autosomal dominant

      • Autosomal recessive

  • M etabolic M yopathies

    • Acid maltase deficiency

    • Cytochrome c oxidase deficiency

  • M uscular D ystrophies

    • Bethlem myopathy (see Chapter 7 )

    • Congenital dystrophinopathy (see Chapter 7 )

    • Congenital muscular dystrophy

      • Merosin deficiency primary

      • Merosin deficiency secondary

      • Merosin positive

    • Congenital myotonic dystrophy

Differential Diagnosis of Infantile Hypotonia

The Appearance of Hypotonia

When lying supine, all hypotonic infants look much the same, regardless of the underlying cause or location of the abnormality within the nervous system. Spontaneous movement may be decreased, full abduction of the legs places the lateral surface of the thighs against the examining table, and the arms lie either extended at the sides of the body or flexed at the elbow with the hands beside the head. Pectus excavatum is present when the infant has long-standing weakness in the chest wall muscles. Infants who lie motionless eventually develop flattening of the occiput and loss of hair on the portion of the scalp that is in constant contact with the crib sheet. When placed in a sitting posture, the head falls forward, the shoulders droop, and the limbs hang limply.

Newborns that are hypotonic and weak in utero may be born with hip dislocation, multiple joint contractures ( arthrogryposis ), or both, due to lack of mobility. Hip dislocation is a common feature of intrauterine hypotonia. The forceful contraction of muscles pulling the femoral head into the acetabulum is a requirement of normal hip joint formation. Arthrogryposis varies in severity from isolated clubfoot, the most common manifestation, to symmetric flexion deformities of all limb joints. Joint contractures are a nonspecific consequence of intrauterine immobilization. However, among the several disorders that equally decrease fetal movement, some commonly produce arthrogryposis and others never do. Box 6-2 summarizes the differential diagnosis of arthrogryposis. As a rule, newborns with arthrogryposis who require respiratory assistance do not survive extubation unless the underlying disorder is myasthenia. The traction response, vertical suspension, and horizontal suspension further evaluate tone in infants who appear hypotonic at rest.

BOX 6-2

  • Cerebral malformations

  • Cerebrohepatorenal syndrome

  • Chromosomal disorders

  • Fetal, nonnervous system causes

  • Motor unit disorders

    • Congenital benign spinal muscular atrophy

    • Congenital cervical spinal muscular atrophy

    • Congenital fiber-type disproportion myopathy

    • Congenital hypomyelinating neuropathy

    • Congenital muscular dystrophy

    • Genetic myasthenic syndromes

    • Infantile neuronal degeneration

    • Myotonic dystrophy

    • Neurogenic arthrogryposis

    • Phosphofructokinase deficiency

    • Transitory neonatal myasthenia

  • Nonfetal causes

Differential Diagnosis of Arthrogryposis

The Traction Response

The traction response is the most sensitive measure of postural tone and is testable in premature newborns within an incubator. Grasping the hands and pulling the infant towards a sitting position initiates the response. A normal term infant lifts the head from the surface immediately with the body ( Figure 6-1 ). When attaining the sitting position, the head is erect in the midline for a few seconds. During traction, the examiner should feel the infant pulling back against traction and observe flexion at the elbow, knee, and ankle. The traction response is not present in premature newborns of less than 33 weeks’ gestation. After 33 weeks, the neck flexors show increasing success in lifting the head. At term, only minimal head lag is present; after attaining the sitting posture, the head may continue to lag or may erect briefly and then fall forward. The presence of more than minimal head lag and failure to counter traction by flexion of the limbs in the term newborn is abnormal and indicates weakness and hypotonia.


Normal traction response. The lift of the head is almost parallel to the body and there is flexion in all limb joints.

(Reprinted with permission from Fenichel GM. Neonatal Neurology , 4th ed. Philadelphia: Elsevier; 2007.)

Vertical Suspension

To perform vertical suspension, the examiner places both hands in the infant’s axillae and, without grasping the thorax, lifts straight up. The muscles of the shoulders should have sufficient strength to press down against the examiner’s hands and allow the infant to suspend vertically without falling through ( Figure 6-2 ). While in vertical suspension, the head is erect in the midline with flexion at the knee, hip, and ankle joints. When suspending a weak and hypotonic infant vertically, the head falls forward, the legs dangle, and the infant may slip through the examiner’s hands because of weakness in the shoulder muscles.


Normal vertical suspension. The head is in the midline and the legs flex against gravity.

(Reprinted with permission from Fenichel GM. Neonatal Neurology , 4th ed. Philadelphia: Elsevier; 2007.)

Horizontal Suspension

When suspended horizontally, a normal infant keeps the head erect, maintains the back straight, and flexes the elbow, hip, knee, and ankle joints ( Figure 6-3 ). A healthy full-term newborn makes intermittent efforts to maintain the head erect, the back straight, and the limbs flexed against gravity. Hypotonic and weak newborns and infants drape over the examiner’s hands, with the head and legs hanging limply.


Normal horizontal suspension. The head rises intermittently and the head and limbs resist gravity.

(Reprinted with permission from Fenichel GM. Neonatal Neurology , 4th ed. Philadelphia: Elsevier; 2007.)

Approach to Diagnosis

The first step in diagnosis is to determine whether the disease location is in the brain, spine, or motor unit. More than one site may be involved ( Box 6-3 ). The brain and the peripheral nerves are concomitantly involved in some lysosomal and mitochondrial disorders. Both brain and skeletal muscles are abnormal in infants with acid maltase deficiency and congenital myotonic dystrophy. Newborns with severe hypoxic-ischemic encephalopathy may have hypoxic injury to the spinal cord as well as the brain. Several motor unit disorders produce sufficient hypotonia at birth to impair respiration and cause perinatal asphyxia ( Box 6-4 ). Such infants may then have cerebral hypotonia as well. Newborns with spinal cord injuries are frequently the product of long, difficult deliveries in which brachial plexus injuries and hypoxic-ischemic encephalopathy are concomitant problems.

BOX 6-3

  • Acid maltase deficiency

    Denotes the most common conditions and the ones with disease modifying treatments

  • Familial dysautonomia

  • Giant axonal neuropathy

  • Hypoxic-ischemic encephalomyopathy

  • Infantile neuronal degeneration

  • Lipid storage diseases

  • Mitochondrial (respiratory chain) disorders

  • Neonatal myotonic dystrophy

  • Perinatal asphyxia secondary to motor unit disease

Combined Cerebral and Motor Unit Hypotonia

BOX 6-4

  • Acute infantile spinal muscular atrophy

  • Congenital hypomyelinating neuropathy

    Denotes the most common conditions and the ones with disease modifying treatments

  • Congenital myotonic dystrophy

  • Familial infantile myasthenia

  • Neurogenic arthrogryposis

  • X-linked myotubular myopathy

Motor Unit Disorders with Perinatal Respiratory Distress

The etiology of hypotonia in neonates may be obtained in 67–85 % of newborns. Central hypotonia (60–80 %) is more common than peripheral hypotonia (15–30 %). Sixty percent of the cases are due to genetic/metabolic disease ( ).

The assessment of the floppy infant should look into the following: three-generation pedigree, history of drug or teratogen exposure (alcohol, solvents, drugs), breech presentation, reduced fetal movements, history of polyhydramnios, family history of recurrent infantile deaths, parental age, consanguinity, history of neuromuscular disease, perinatal asphyxia, Apgar scores, dysmorphism, arthrogryposis, DTRs and fasciculations ( ).

Testing of the hypotonic infant may include brain imaging and karyotype. Array comparative genomic hybridization (CGH) shows abnormalities in 5–17 % of floppy infants with normal karyotype. Array CGH is a very sensitive technique that may reveal variants of unclear significance ( ).

Inborn errors of metabolism are divided into: (1) toxic encephalopathies due to accumulation of toxic metabolites; (2) energy-deficient encephalopathies due to lack of energy production or utilization; and (3) disorders affecting the intracellular processing of complex molecules. Testing may include ammonia (elevated in urea cycle defects, organic acidemias or fatty acid oxidation disorders), high lactate levels in blood and CSF (cerebrospinal fluid) or magnetic resonance spectroscopy in disorders of carbohydrate metabolism and mitochondrial disease. Other tests include quantitative analysis of amino acids in blood and urine (aminoacidopathies), urine organic acids, acylcarnitine profiles in the plasma (organic acidemias, fatty acid oxidation defects), very-long-chain fatty acids (VLCFAs) in plasma (peroxisomal disorders), uric acid (normal in sulfite oxidase deficiency and low in molybdenum cofactor deficiency), isoimmune electrophoresis for transferrin (abnormal pattern in disorders of congenital disorders of glycosylation) and 7-dehydrocholesterol (elevated in Smith-Lemli-Opitz syndrome) ( ).

Clues to the Diagnosis of Cerebral Hypotonia

Cerebral or central hypotonia in newborns usually does not pose diagnostic difficulty. The history and physical examination identifies the problem. Many clues to the diagnosis of cerebral hypotonia exist ( Box 6-5 ). Most important is the presence of other abnormal brain functions such as decreased consciousness and seizures. Cerebral malformation is the likely explanation for hypotonia in an infant with dysmorphic features or with malformations in other organs.

BOX 6-5

  • Abnormalities of other brain functions

  • Dysmorphic features

  • Fisting of the hands

  • Malformations of other organs

  • Movement through postural reflexes

  • Normal or brisk tendon reflexes

  • Scissoring on vertical suspension

Clues to Cerebral Hypotonia

A tightly fisted hand in which the thumb is constantly enclosed by the other fingers and does not open spontaneously ( fisting ), and adduction of the thigh so that the legs are crossed when the infant is suspended vertically ( scissoring ), are early signs of spasticity and indicate cerebral dysfunction. Eliciting postural reflexes in newborns and infants when spontaneous movement is lacking indicates cerebral hypotonia. In some acute encephalopathies, and especially in metabolic disorders, the Moro reflex may be exaggerated. The tonic neck reflex is an important indicator of cerebral abnormality if the responses are excessive, obligatory, or persist beyond 6 months of age. When hemispheric damage is severe but the brainstem is intact, turning the head produces full extension of both ipsilateral limbs and tight flexion on the contralateral side. An obligatory reflex is one in which these postures are maintained as long as the head is kept rotated. Tendon reflexes are generally normal or brisk, and clonus may be present.

Clues to Motor Unit Disorders

Disorders of the motor unit are not associated with malformations of other organs except for joint deformities and the maldevelopment of bony structures. The face sometimes looks dysmorphic when facial muscles are weak or when the jaw is underdeveloped.

Tendon reflexes are absent or depressed. Loss of deep tendon reflexes that is out of proportion to weakness is more likely caused by neuropathy than myopathy, whereas diminished reflexes that are consistent with the degree of weakness are more often caused by myopathy than neuropathy ( Box 6-6 ). Muscle atrophy suggests motor unit disease but does not exclude the possibility of cerebral hypotonia. Failure of growth and even atrophy can be considerable in infants with brain insults. The combination of atrophy and fasciculations is strong evidence of denervation. However, the observation of fasciculations in newborns and infants is often restricted to the tongue, and distinguishing fasciculations from normal random movements of an infant’s tongue is difficult unless atrophy is present.

BOX 6-6

  • Absent or depressed tendon reflexes

  • Failure of movement on postural reflexes

  • Fasciculations

  • Muscle atrophy

  • No abnormalities of other organs

Clues to Motor Unit Disorders

Postural reflexes, such as the tonic neck and Moro reflex, are not imposable on weak muscles. The motor unit is the final common pathway of tone; limbs that will not move voluntarily cannot move reflexively.

Cerebral Hypotonia

Hypotonia is a feature of almost every cerebral disorder in newborns and infants. This section does not deal with conditions in which the major symptoms are states of decreased consciousness, seizures, and progressive psychomotor retardation. Rather, the discussion focuses on conditions in which hypotonia is sufficiently prominent that the examining physician may consider the possibility of motor unit disease.

Benign Congenital Hypotonia

The term benign congenital hypotonia is retrospective and refers to infants who are hypotonic at birth or shortly thereafter and later have normal tone. This diagnosis should be reserved for patients that besides recovering normal tone exhibit no other evidence of cerebral dysfunction; however, the majority of children with cerebral hypotonia without clear etiology may later exhibit cognitive impairment, learning disabilities, and other sequelae of cerebral abnormality, despite the recovery of normal muscle tone.

Chromosomal Disorders

Despite considerable syndrome diversity, common characteristics of autosomal chromosome aberrations in the newborn are dysmorphic features of the hands and face and profound hypotonia. For this reason, any hypotonic newborn with dysmorphic features of the hands and face, with or without other organ malformation, requires chromosome studies.

MECP2 Duplication Syndrome

The MECP2 duplication syndrome occurs only in males; inheritance is as an X-linked trait. Occasionally females have been described with a MECP2 duplication and related clinical findings, often associated with concomitant X-chromosomal abnormalities that prevent inactivation of the duplicated region ( ).

Clinical Features

Characteristic of the syndrome is infantile hypotonia, severe cognitive impairment with absence of speech, progressive spasticity, recurrent respiratory infections, and seizures. During the first weeks of life, feeding difficulties resulting from hypotonia becomes evident. The child may exhibit difficulty with swallowing and extensive drooling. In some cases, nasogastric tube feeding is required. Dysmorphic features include brachycephaly, midfacial hypoplasia, large ears, and flat nasal bridge.

Generalized tonic-clonic, atonic and absence seizures are common (50 %). Almost 50 % die before age 25 years, presumably from complications of recurrent infection. Growth measurements at birth, including head circumference, are usually normal.

Because of hypotonia, delayed motor developmental is the rule. Walking is late, some individuals have an ataxic gait, and one-third never walk independently. Most never develop speech and some individuals who attained limited speech lose it in adolescence. Hypotonia gives way to spasticity in childhood. The spasticity is greatest in the legs; mild contractures may develop over time. Often the use of a wheelchair is necessary in adulthood.


Duplications of MECP2 ranging from 0.3 to 8 Mb are observable in all affected males and identified by commercially available genetic testing.


Treatment is symptomatic and genetic counseling. The vast majority of affected males inherit the MECP2 duplication from a carrier mother; however, spontaneous mutations have been reported. If the mother of the proband has an MECP2 duplication, the chance of transmitting it in each pregnancy is 50 %. Males who inherit the MECP2 duplication will be affected; females who inherit the MECP2 duplication are usually asymptomatic carriers

Prader-Willi Syndrome

Hypotonia, hypogonadism, cognitive impairment, short stature, and obesity characterize the Prader-Willi syndrome ( ). Approximately 70 % of children with this syndrome have an interstitial deletion of the paternally contributed proximal long arm of chromosome 15(q11-13). The basis for the syndrome in most patients who do not have a deletion is maternal disomy (both chromosomes 15 are from the mother). Paternal disomy of the same region of chromosome 15 causes Angelman syndrome .

Clinical Features

Decreased fetal movement occurs in 75 % of pregnancies, hip dislocation in 10 %, and clubfoot in 6 %. Hypotonia is profound at birth and tendon reflexes are absent or greatly depressed. Feeding problems are invariable, and prolonged nasogastric tube feeding is common ( Box 6-7 ). Cryptorchidism is present in 84 % and hypogenitalism in 100 %. However, some newborns lack the associated features and only show hypotonia ( ).

BOX 6-7

  • Congenital myotonic dystrophy

  • Familial dysautonomia

  • Genetic myasthenic syndromes

  • Hypoplasia of bulbar motor nuclei (see Chapter 17 )

  • Infantile neuronal degeneration

  • Myophosphorylase deficiency

  • Neurogenic arthrogryposis

  • Prader-Willi syndrome

  • Transitory neonatal myasthenia

    Denotes the most common conditions and the ones with disease modifying treatments

Difficulty of Feeding in the Alert Newborn

Both hypotonia and feeding difficulty persist until 8 to 11 months of age and are then replaced by relatively normal muscle tone and insatiable hunger. Delayed developmental milestones and later cognitive impairment are constant features. Minor abnormalities that become more obvious during infancy include a narrow bifrontal diameter of the skull, strabismus, almond-shaped eyes, enamel hypoplasia, and small hands and feet. Obesity is the rule during childhood. The combination of obesity and minor abnormalities of the face and limbs produces a resemblance among children with this syndrome.

Major and minor clinical criteria are established ( Box 6-8 ). Weighting of major criteria is one point each; minor criteria are one half-point each. For children under 3 years of age, five points are required for diagnosis, four of which must be major criteria. For individuals 3 years of age and older, eight points are required for diagnosis, at least five of which must be major criteria. Supportive findings only increase or decrease the level of suspicion of the diagnosis.

BOX 6-8

Major Criteria

  • Neonatal and infantile central hypotonia with poor suck and improvement with age

  • Feeding problems and/or failure to thrive in infancy, with need for gavage or other special feeding techniques

  • Onset of rapid weight gain between 12 months and 6 years of age, causing central obesity

  • Hyperphagia

  • Characteristic facial features: narrow bifrontal diameter, almond-shaped palpebral fissures, down-turned mouth

  • Hypogonadism

    • Genital hypoplasia: small labia minora and clitoris in females; hypoplastic scrotum and cryptorchidism in males

    • Incomplete and delayed puberty

    • Infertility

  • Developmental delay/mild to moderate cognitive impairment/multiple learning disabilities

Minor Criteria

  • Decreased fetal movement and infantile lethargy, improving with age

  • Typical behavior problems, including temper tantrums, obsessive-compulsive behavior, stubbornness, rigidity, stealing, and lying

  • Sleep disturbance/sleep apnea

  • Short stature for the family by 15 years of age

  • Hypopigmentation

  • Small hands and feet for height age

  • Narrow hands with straight ulnar border

  • Esotropia, myopia

  • Thick, viscous saliva

  • Speech articulation defects

  • Skin picking

Supportive Findings

  • High pain threshold

  • Decreased vomiting

  • Scoliosis and/or kyphosis

  • Early adrenarche

  • Osteoporosis

  • Unusual skill with jigsaw puzzles

  • Normal neuromuscular studies (e.g., muscle biopsy, electromyography, nerve conduction velocity)

Criteria for the Clinical Diagnosis of Prader-Willi Syndrome

(Data from: Cassidy SB, Schwartz S. Prader-Willi syndrome. In: GeneClinics. Medical Genetic Knowledge Base [database online]. Seattle: University of Washington. Available at . PMID: 20301505. Last updated September 3, 2009.)


The mainstay of diagnosis is DNA-based testing to detect abnormal parent-specific imprinting within the Prader-Willi critical region on chromosome 15. This testing determines whether the region is maternally inherited only (the paternally contributed region is absent) and detects more than 99 % of individuals.


In infancy, special nipples or gavage feeding assures adequate nutrition. Physical therapy may improve muscle strength. Strabismus and cryptorchidism require surgical treatment. Growth hormone replacement therapy normalizes height and increases lean body mass. Medication for behavior modification is a consideration. Replacement of sex hormones produces adequate secondary sexual characteristics.

Chronic Nonprogressive Encephalopathy

Cerebral dysgenesis may be due to known or unknown noxious environmental agents, chromosomal disorders, or genetic defects. In the absence of an acute encephalopathy, hypotonia may be the only symptom at birth or during early infancy. Hypotonia is usually worse at birth and improves with time. Suspect cerebral dysgenesis when hypotonia associates with malformations in other organs or abnormalities in head size and shape. Magnetic resonance imaging (MRI) of the brain is advisable when suspecting a cerebral malformation. The identification of a cerebral malformation provides useful information not only for prognosis but also on the feasibility of aggressive therapy to correct malformations in other organs.

Brain injuries occur in the perinatal period and, less commonly, throughout infancy secondary to anoxia, hemorrhage, infection, and trauma. The sudden onset of hypotonia in a previously well newborn or infant, with or without signs of encephalopathy, always suggests a cerebral cause. The premature newborn showing a decline in spontaneous movement and tone may have an intraventricular hemorrhage. Hypotonia is an early feature of meningitis in full-term and premature newborns. Tendon reflexes may be diminished or absent during the acute phase.

Genetic Disorders

Familial Dysautonomia

Familial dysautonomia, the Riley-Day syndrome , is a genetic disorder transmitted by autosomal recessive inheritance in Ashkenazi Jews ( ). The abnormality is in the IKBKAP gene, located on chromosome 9q31-q33, which encodes the elongator complex protein 1. Similar clinical syndromes also occur in non-Jewish infants that are often sporadic and with an unknown pattern of inheritance.

Clinical Features

In the newborn, the important clinical features are meconium aspiration, poor or no sucking reflex, and hypotonia. The causes of hypotonia are disturbances in the brain, the dorsal root ganglia, and the peripheral nerves. Tendon reflexes are hypoactive or absent. The feeding difficulty is usual and provides a diagnostic clue. Sucking and swallowing are normal separately but cannot be coordinated for effective feeding. Other noticeable clinical features of the newborn or infants are pallor, temperature instability, absence of fungiform papillae of the tongue, diarrhea, and abdominal distention. Poor weight gain and lethargy, episodic irritability, absent corneal reflexes, labile blood pressure, and failure to produce overflow tears completes the clinical picture.


Mutation analysis is diagnostic. Two mutations account for more than 99 % of mutant genes in individuals with familial dysautonomia of Ashkenazi descent. Ophthalmological examination is useful to detect the signs of postganglionic parasympathetic denervation: supersensitivity of the pupil, shown by a positive miotic response to 0.1 % pilocarpine or 2.5 % methacholine, corneal insensitivity, and absence of tears.


Treatment is symptomatic; improved treatment of symptoms has increased longevity.

Oculocerebrorenal Syndrome (Lowe Syndrome)

Lowe syndrome is caused by markedly reduced activity of the enzyme inositol polyphosphate 5-phosphatase OCRL-1. Transmission is by X-linked recessive inheritance. Female carriers show partial expression in the form of minor lenticular opacities ( ).

Clinical Features

Lowe syndrome involves the eyes, central nervous system (CNS), and kidneys. All affected boys have dense cataracts and half have glaucoma. Box 6-2 lists the differential diagnosis of cataracts in newborns and infants. Corrected acuity is rarely better than 20/100. Hypotonia is present at birth and the tendon reflexes are usually absent. Hypotonia may improve, but tone never is normal. Motor milestones are achieved slowly and all boys have some degree of intellectual impairment. All boys have some degrees of proximal renal tubular dysfunction of the Fanconi type, including bicarbonate wasting and renal tubular acidosis, phosphaturia with hypophosphatemia and renal rickets, aminoaciduria, low-molecular weight proteinuria, sodium and potassium wasting, and polyuria. Slowly progressive chronic renal failure is the rule, resulting in end-stage renal disease after age 10 to 20 years.


Diagnosis depends on recognition of the clinical constellation. MRI shows diffuse and irregular foci of increased signal consistent with demyelination. The diagnosis is established by demonstrating reduced (<10 % of normal) activity of inositol polyphosphate 5-phosphatase OCRL-1 in cultured skin fibroblasts. Such testing is available clinically.


Symptomatic treatment includes early removal of cataracts, nasogastric tube feedings or feeding gastrostomy to achieve appropriate nutrition, occupational or speech therapy to address feeding problems, standard measures for gastroesophageal reflux, and programs to promote optimal psychomotor development.

Peroxisomal Disorders

Peroxisomes are subcellular organelles that participate in the biosynthesis of ether phospholipids and bile acids, the oxidation of VLCFAs, prostaglandins, and unsaturated long-chain fatty acids, and the catabolism of phytanate, pipecolate, and glycolate. Hydrogen peroxide is a product of several oxidation reactions, and catabolized by the enzyme catalase. Mutations in eleven different PEX genes cause this spectrum of disorders. PEX genes encode the proteins required for peroxisomal assembly.

The infantile syndromes of peroxisomal dysfunction are all disorders of peroxisomal biogenesis; the intrinsic protein membrane is identifiable, but all matrix enzymes are missing. The clinical spectrum of disorders of peroxisomal biogenesis includes the prototype, cerebrohepatorenal or Zellweger syndrome, as well as neonatal adrenoleukodystrophy and infantile Refsum disease (see Chapter 16 ). The latter two disorders are milder variants. Infantile hypotonia is a prominent feature of peroxisomal biogenesis disorders ( ).

Clinical Features

Affected newborns are poorly responsive and have severe hypotonia, arthrogryposis, and dysmorphic features. Sucking and crying are weak. Tendon reflexes are hypoactive or absent. Characteristic craniofacial abnormalities include a pear-shaped head owing to a high forehead and an unusual fullness of the cheeks, widened sutures, micrognathia, a high-arched palate, flattening of the bridge of the nose, and hypertelorism. Organ abnormalities include biliary cirrhosis, polycystic kidneys, retinal degeneration, and cerebral malformations secondary to abnormalities of neuronal migration.

Limited extension of the fingers and flexion deformities of the knee and ankle characterize the arthrogryposis. Neonatal seizures are common. Bony stippling (chondrodysplasia punctata) of the patella and other long bones may occur. Older children have retinal dystrophy, sensorineural hearing loss, developmental delay with hypotonia, and liver dysfunction. Infants with Zellweger syndrome are significantly impaired and usually die during the first year of life, usually having made no developmental progress. The clinical courses of neonatal adrenoleukodystrophy and infantile Refsum disease are variable; while children can be very hypotonic, others learn to walk and talk. These conditions are often slowly progressive.

Difficult to control seizures often begin shortly after birth but may commence any time during infancy. Death from aspiration, gastrointestinal bleeding, or liver failure usually occurs within 6 months and usually within 1 year.


Biochemical assay definitively establishes the diagnosis. Confirm biochemical abnormalities detected in blood and/or urine with cultured fibroblasts. Measurement of plasma VLCFA levels is the most commonly used and most informative. Elevation of C26:0 and C26:1 and the ratios C24/C22 and C26/C22 are consistent with a defect in peroxisomal fatty acid metabolism.


Treatment is symptomatic, anticonvulsants for seizures, vitamin K for bleeding disorders, hearing aids, cataract removal in infancy, and other initiatives as needed.

Pyruvate Carboxylase Deficiency

The initial features of pyruvate carboxylase deficiency are neonatal hypotonia, tachypnea, and movement disorders ( ).

Clinical Features

All affected newborns are conscious, but hypotonic and tachypneic during the first hours after birth. High amplitude tremor of the limbs is the rule, and bizarre eye movements are present in some affected infants. Seizures are uncommon. A rapid fatal outcome is the rule.


Hypoglycemia, lactic acidosis, and hypercitrullinemia are constant findings. Brain MRI shows cystic periventricular leukomalacia.


Diet therapy, in the first hours postpartum, with triheptanoin and citrate reverses the biochemical errors. The long-term outcome is not established.

Other Metabolic Defects

Infantile hypotonia is rarely the only manifestation of inborn errors of metabolism. Acid maltase deficiency causes a severe myopathy and is discussed with other metabolic myopathies. Hypotonia may be the only initial feature of generalized GM 1 gangliosidosis (see Chapter 5 ).

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