General Features of Hypotonia

Assessing tone in an infant involves both observation of the patient at rest and application of certain examination maneuvers designed to evaluate both axial and appendicular musculature. Beginning with observation, a normal infant lying supine on an examination table will demonstrate flexion of the hips and knees so that the lower extremities are clear of the examination table, flexion of the upper extremities at the elbows, and internal rotation at the shoulders (Fig. 27.1). A hypotonic infant lies with the lower extremities in external rotation, the lateral aspects of the thighs and knees touching the examination table, and the upper extremities either extended down by the sides of the trunk or abducted with slight flexion at the elbows, also lying against the examination table. Evaluation of the traction response is done with the infant in supine position; the hands are grasped and the infant pulled toward a sitting position. A normal response includes flexion at the elbows, knees, and ankles, and movement of the head in line with the trunk after no more than a brief head lag. The head should then remain erect in the midline for at least a few seconds. An infant with axial hypotonia demonstrates excessive head lag with this maneuver (Fig. 27.2), and once upright, the head may continue to lag or may fall forward relatively quickly. Absence of flexion of the limbs may also be seen and indicates either appendicular hypotonia or weakness. The traction response is normally present after 33 weeks postconceptional age. Vertical suspension is performed by placing hands under the infant’s axillae and lifting the infant without grasping the thorax. A normal infant has enough power in the shoulder muscles to remain suspended without falling through, with the head upright in the midline and the hips and knees flexed (Fig. 27.3, A). In contrast, a hypotonic infant held in this manner slips through the examiner’s hands, often with the head falling forward and the legs extended at the knees (see Fig. 27.3, B). Infants with axial hypotonia related to brain injury may also demonstrate crossing, or scissoring, of the legs in this position, which is an early manifestation of appendicular hypertonia. In horizontal suspension, the infant is held prone with the abdomen and chest against the palm of the examiner’s hand. A normal infant maintains the head above horizontal with the limbs flexed, while a hypotonic infant drapes over the examiner’s hand with the head and limbs hanging limply. Other examination findings in hypotonic infants include various deformities of the cranium, face, limbs, and thorax. Infants with reduced tone may develop occipital flattening, or positional plagiocephaly, as the result of prolonged periods of lying supine and motionless.

Fig. 27.1 Normal infant lying supine with legs flexed and arms adducted.

Fig. 27.2 Hypotonic infant demonstrating abnormal traction response, with excessive head lag and absence of flexion of arms and legs.

Fig. 27.3 A, Vertical suspension in a normal infant: arms adducted, upright position of head and shoulders maintained, flexion of legs. B, Ventral suspension in a hypotonic infant, with elevation of shoulders and arms (slip-through) and extension of legs.

Localization

Once the presence of hypotonia in an infant is established, the next step in determining causation is localization of the abnormality to the brain, spinal cord, motor unit, or to multiple sites. A motor unit is a single spinal motor neuron and all the muscle fibers it innervates and includes the motor neuron with its cell body, axon, and myelin covering; the neuromuscular junction; and muscle. The major “branch point” at this stage of the assessment is whether the lesion is likely to be in the brain, at a more distal site, or at multiple sites.

The key features of disorders of cerebral function, particularly the cerebral cortex, are encephalopathy and seizures. Encephalopathy manifesting as decreased level of consciousness may be difficult to ascertain, given the large proportion of time normal infants spend sleeping. However, full-term or near-term infants with normal brain function spend at least some portion of the day awake with eyes open, particularly with feeding. Encephalopathy also manifests with excessive irritability or poor feeding, although the latter problem is rarely the sole feature of cerebral hemispheric dysfunction and may occur with disorders at more distal sites. Infants with centrally mediated hypotonia of many different etiologies frequently have relatively normal power despite a hypotonic appearance. Power may not be observable under normal circumstances because of a paucity of spontaneous movement, but it may be observable with application of a noxious stimulus such as a blood draw or placement of a peripheral intravenous catheter. Other indicators of central rather than peripheral dysfunction include fisting (trapping of the thumbs in closed hands), normal or brisk tendon reflexes, and normal or exaggerated primitive reflexes. Tendon reflexes should be tested with the infant’s head in the midline and the limbs symmetrically positioned; deviations from this technique often result in spuriously asymmetrical reflexes. Primitive reflexes are involuntary responses to certain stimuli that normally appear in late fetal development and are supplanted within the first few months of life by voluntary movements. Abnormalities of these reflexes include absent or asymmetrical responses, obligatory responses (persistence of the reflex with continued application of the stimulus), or persistence of the reflexes beyond the normal age range. Two of the most sensitive primitive reflexes are the Moro and asymmetrical tonic neck reflexes. The Moro reflex is a startle response present from 28 weeks after conception to 6 months postnatal age (Gingold et al., 1998). Quickly dropping the infant’s head below the level of the body while holding the infant supine with the head supported in one hand and the body supported in the other readily elicits this reflex. The normal response consists of initial abduction and extension of the arms with opening of the hands, followed quickly by adduction and flexion with closure of the hands. The tonic neck reflex is a vestibular response and is present from term until approximately 3 months of age. The response is elicited by rotating the head to one side while the infant is lying supine. The normal response is extension of the ipsilateral limbs while the contralateral limbs remain flexed. Central disorders resulting in hypotonia may also be associated with dysmorphism of the face or limbs, or malformations of other organs. Various defects in O-linked glycosylation of α-dystroglycan, a protein associated with the dystrophin glycoprotein complex that stabilizes the sarcolemma, result in structural defects of the brain, eye, and skeletal muscle.

Disorders of the spinal cord leading to neonatal hypotonia are usually secondary to perinatal injury. Spinal cord injury may occur in the setting of a prolonged, difficult vaginal delivery with breech presentation, resulting in trauma to the spinal cord, or may result from hypoxic-ischemic injury to the cord concurrently with encephalopathy. In the latter case, hypotonia may initially be attributable to the encephalopathy. In cases of hypotonia resulting from spinal cord injury, diminished responsiveness to painful stimuli, sphincter dysfunction with continuous leakage of urine and abdominal distension, and priapism may provide clues to localization of the lesion.

The hallmark of disorders of the motor unit is weakness. Tendon reflexes are absent or reduced. Tendon reflexes reduced out of proportion to weakness usually indicate a neuropathy, often a demyelinating neuropathy, whereas tendon reflexes reduced in proportion to weakness are more likely to result from myopathy or axonal neuropathy. The motor unit is the final common pathway for all reflexes, and for this reason, primitive reflexes are depressed or absent in motor unit disorders. This phenomenon may hinder detection of central nervous system (CNS) abnormalities when lesions at both levels coexist. Other abnormalities related to motor unit disorders in infants include underdevelopment of the jaw (micrognathia), a high arched palate, and chest wall deformities, in particular pectus excavatum. Muscle atrophy may also occur but also occurs in cerebral disorders. Sensory function is not assessable in detail in a neonate or young infant, particularly in the presence of encephalopathy, although reduced responsiveness to pinprick may provide clues to the presence of a polyneuropathy or spinal cord lesion in the setting of normal mental status. Some motor unit disorders may result in perinatal distress due to weakness and may result in a superimposed encephalopathy that confounds the localization of hypotonia.

Hypotonic infants may have reduced movement during fetal development, leading to fibrosis of muscles or of structures associated with joints, as well as foreshortening of ligaments. This results in restricted joint range of motion, or contractures. The term arthrogryposis refers to joint contractures that develop prenatally. The most common form of arthrogryposis is unilateral or bilateral clubfoot. The most severe end of this clinical spectrum is arthrogryposis multiplex congenita, or multiple joint contractures. The causes of this condition may be abnormalities of the intrauterine environment, motor unit disorders, or disorders of the CNS. Hypotonia in utero may also result in congenital hip dysplasia.

Neuroimaging

Neuroimaging studies, in particular magnetic resonance imaging (MRI), are most useful when suspecting structural abnormalities of the CNS. T1-weighted images most readily detect congenital malformations of the brain and spinal cord, while T2-weighted images and various T2-based sequences reveal abnormalities of white matter and show evidence of ischemic injury. Specialized techniques such as MR spectroscopy may show evidence of mitochondrial disease (Matthews et al., 1993) or disorders of cerebral creatine metabolism (Frahm et al., 1994). When performing neuroimaging studies that require sedation on hypotonic infants, give particular consideration to airway management and other safety issues.

Electroencephalography

Electroencephalography may be informative when seizures are suspected either as a cause of unexplained encephalopathy or a result of a more global disturbance of brain function. EEG may also reveal evidence of underlying structural abnormalities and thus increase the pretest probability of a diagnostic finding on neuroimaging.

Creatine Kinase

Creatine Kinase catalyzes the conversion of creatine to phosphocreatine, which serves as a reservoir for the buffering and regeneration of adenosine triphosphate (ATP). It expresses in many human tissues, in particular smooth muscle, cardiac muscle, and skeletal muscle. The concentration of CK detectable in serum increases in any condition in which tissues expressing high levels of the enzyme undergo breakdown. Serum CK concentration may be elevated in congenital myopathies, congenital muscular dystrophies, or in spinal muscular atrophy, but levels may also be elevated transiently following normal vaginal deliveries or with perinatal distress. Conversely, serum CK is normal in some congenital myopathies and inherited neuropathies.

Metabolic Studies

Removal of low-molecular-weight toxic metabolites across the placenta typically prevents inborn errors of metabolism (e.g., amino acidopathies, organic acidurias, urea cycle defects, fatty acid oxidation defects, mitochondrial disorders) from causing in utero injury. More commonly, these disorders manifest in a previously healthy newborn who develops hypotonia, encephalopathy, or seizures within the first 24 to 72 hours after birth, after oral feeding begins and toxic intermediates begin to accumulate in the blood. Although detection of many disorders is by state-mandated newborn screens, these results may not be available before an affected infant becomes symptomatic. For this reason, newborns who develop hypotonia and encephalopathy after an unremarkable first few days of life should have enteral feedings held until metabolic studies such as blood ammonia level, plasma amino acid, acylcarnitine profile, and urine organic acids have definitively excluded an inborn error of metabolism. Because neonatal sepsis has a similar presentation, undertake investigation for infection with cultures of blood, urine, and cerebrospinal fluid in such cases; empirical antimicrobial therapy should be initiated while diagnostic studies are pending.

Nerve Conduction Studies and Electromyography

Nerve conduction studies and EMG are the studies of choice in a suspected motor unit disorder when other available clinical information does not suggest a specific diagnosis. The two techniques are complementary and always performed together. They allow distinction between primary disorders of muscle and peripheral nerve disorders when the two are indistinguishable on clinical grounds. Repetitive nerve stimulation (RNS) studies evaluate the integrity of the neuromuscular junction, abnormalities of which are not detectable with routine nerve conduction studies or EMG. The most commonly observed abnormality on low-rate (2-3 Hz) RNS studies of patients with various forms of myasthenia is a significant decrement, usually defined as 10% or greater, in the amplitude of the compound motor action potential (CMAP) between the first and fourth or fifth stimuli of a series. Single fiber EMG (SFEMG) is a highly specialized technique that evaluates the delay in depolarization between adjacent muscle fibers within a single motor unit, referred to as jitter. This modality is highly sensitive for neuromuscular junction abnormalities but has a low specificity and requires a cooperative patient. SFEMG with stimulation of the appropriate nerve has been described in pediatric patients (Tidwell and Pitt, 2007), but experience with this technique in infants is limited to a small number of centers. The utility of these neurophysiology studies is dependent on the skill and experience of the clinician performing the tests, as well as the precision of the question posed.

Muscle Biopsy

Muscle biopsy is integral to the diagnosis of certain inherited muscle disorders such as congenital myopathies, congenital muscular dystrophies, and metabolic myopathies and may also aid in the distinction between myopathies and motor neuron disorders. Give careful consideration to the site chosen for biopsy. Ideally, a muscle should be chosen that is moderately but not severely weak and that has not undergone needle EMG. Another important consideration is the quantity of tissue obtained. Obtain a sufficient quantity of tissue to rapidly freeze a portion for routine histochemical stains, submit additional tissue for specialized studies such as biochemical assays, electron microscopy, or genetic studies, and have additional tissue available to be stored for possible future studies. In practical terms, this usually entails obtaining at least three separate specimens weighing 1 to 1.5 g each. Although needle biopsy may procure an adequate sample in some cases, open biopsy is more likely to yield an appropriate amount of tissue, thereby avoiding the need for a second surgical procedure and its attendant risks. The value of muscle biopsy, as with neurophysiology studies, depends on the experience of the interpreting laboratory and the focus of the question asked by the referring clinician. In addition to these factors, proper handling of the tissue between the operating room and the receiving laboratory is a critical link in the chain of custody. This step is often the most difficult to control, but it requires attention equal to the other steps in the process in order to maximize the probability of obtaining a diagnostic sample and minimize the risk of subjecting the patient to a second procedure.

Nerve Biopsy

Nerve biopsy plays a more limited role in the diagnosis of hypotonia in infancy. It is nevertheless appropriate when a peripheral neuropathy is suspected on clinical grounds, but available testing fails to yield a diagnosis. The sural nerve is usually chosen because of its accessibility and the relatively minor deficit produced by its removal. Sural nerve biopsy is most likely to be informative in the setting of an abnormal response on nerve conduction studies. The limited choice of peripheral nerves available for biopsy confines use of this procedure to centers with considerable experience. Submit portions of the nerve for routine histochemical stains, paraffin-embedded sections, and thin plastic sections, the latter processed for light microscopy or electron microscopy.

Genetic Testing

In some cases of hypotonia in infancy, the combination of clinical history, examination, and ancillary testing points toward a specific genetic diagnosis. Genetic testing is commercially available for many conditions, and the number continues to expand rapidly. Consult one or more of the accessible resources such as the Internet-based Online Mendelian Inheritance in Man or GeneTests.org for the most current information on testing for specific disorders.

Serology

In cases of a suspected neuromuscular junction disorder such as myasthenia gravis, assays of antibodies directed against the sarcolemmal nicotinic acetylcholine receptor or muscle-specific kinase are commercially available. Autoimmune myasthenia gravis is rare in infancy, but absence of the antibodies is required for the diagnosis of a congenital myasthenic syndrome. Several forms of myasthenia gravis occur in infancy and are discussed in greater detail later in this chapter.

Chromosomal Disorders

Hypotonia is a prominent feature of many disorders associated with large- or small-scale chromosomal abnormalities. Such disorders also are frequently associated with a dysmorphic appearance of the face and hands. Among the most common of these disorders is Prader-Willi syndrome, which is caused by absence of the paternal PWS/Angelman syndrome region on chromosome 15 (Butler, Meaney, and Palmer, 1986). Affected individuals often have profound hypotonia and poor feeding in infancy, suggesting a disorder of the motor unit or a combined cerebral and motor unit disorder. However, serum CK, EMG, muscle biopsy, and brain MRI are normal. The commonly recognized morphological features of almond-shaped eyes, narrow biparietal diameter, and relatively small hands and feet may not be readily apparent in early infancy. Approximately 70% of patients have a detectable small-scale deletion on chromosome 15 on high-resolution chromosomal analysis; DNA methylation studies reveal a pattern suggestive of exclusive maternal inheritance of this locus in 99%. Failure to thrive in infancy gives way in early childhood to hyperphagia and a characteristic pattern of behavioral abnormalities, intellectual disability, and hypogonadism.

Chronic Nonprogressive Encephalopathy

Chronic nonprogressive encephalopathy describes a clinical syndrome with many potential causes, including cerebral dysgenesis related to a genetic disorder, in utero infection, toxic exposure, inborn error of metabolism, or vascular insult. Perinatal brain injury resulting in a chronic encephalopathy is readily diagnosable and typically associated with a reduced level of consciousness and seizures. Hypoxic-ischemic brain injury in the newborn manifests with low Apgar scores, and lactic acidosis along with other indicators of injury to other vital organs is often present. Hypotonia related to ischemic brain injury usually gives way to spasticity. In cases of remote in utero injury or cerebral dysgenesis, hypotonia may be the only manifestation of the problem in the perinatal period. Clues to the presence of cerebral dysgenesis include malformations of other organs and abnormalities of head size or shape. In such cases, obtain an MRI of the brain, and a chromosomal anomaly should be sought with karyotype and chromosomal microarray analysis. The onset of hypotonia in a previously healthy neonate or infant is almost always cerebral in origin and may also relate to infection, vascular injury, or an inborn error of metabolism.

Chronic Progressive Encephalopathy

Chronic progressive encephalopathy more commonly presents with developmental regression than with hypotonia. Inborn errors of metabolism involving small molecules may cause this clinical presentation, but more frequently the cause is a disorder of lysosomal or peroxisomal metabolism leading to progressive accumulation of storage material in various tissues. These disorders frequently manifest with progressive facial dysmorphism, organomegaly, or skeletal dysplasia in addition to neurological decline.

Benign Congenital Hypotonia

Benign congenital hypotonia refers to infants with early hypotonia who later develop normal tone. It is a diagnosis made only in retrospect and has become less common in the era of high-resolution neuroimaging and genetic testing. Nevertheless, there remains a subset of children, often with a family history of a similarly affected parent or sibling who was undiagnosed. Intellectual disability of varying degrees frequently becomes apparent in later life.

Acid Maltase Deficiency

Acid maltase deficiency, an autosomal recessive deficiency of the lysosomal enzyme acid α-1,4-glucosidase, presents with a severe skeletal myopathy and cardiomyopathy and may also be associated with encephalopathy. Routine histochemical stains show accumulation of glycogen in lysosomal vacuoles and within the sarcoplasm. The diagnosis is confirmed with biochemical assay of enzyme activity in muscle or in cultured skin fibroblasts. Recombinant human enzyme is approved by the U.S. Food and Drug Administration (FDA) for replacement therapy, which can prolong survival (Kishnani et al., 2006).

Congenital Myotonic Dystrophy

Congenital myotonic dystrophy is an autosomal dominant disorder that typically presents in adolescence or early adulthood, but in some instances may be associated with profound hypotonia and weakness of the face and limbs in infancy. Approximately 25% of infants born to mothers with myotonic dystrophy are affected in this way, although the diagnosis in the mother may be unrecognized (Rakocevic-Stojanovic et al., 2005). Survivors of perinatal distress often have global developmental delay, with both intellectual impairment and motor disability throughout childhood, then develop myotonia and other characteristic symptoms of the muscular dystrophy as they approach puberty. To date, only myotonic dystrophy type 1, caused by abnormal expansion of a trinucleotide repeat within the gene, DMPK, has been associated with a congenital presentation. Genetic testing is commercially available.

Infantile Facioscapulohumeral Dystrophy

Facioscapulohumeral dystrophy (FSHD) is another dominantly inherited muscular dystrophy presenting most frequently in early adulthood, but which may have a congenital presentation. The genetic abnormality is contraction of a 3.3 kb repeat array at the D4Z4 locus. Those with the smallest integral number of repeats may have diffuse hypotonia and weakness in infancy and account for less than 5% of cases (Klinge et al., 2006). Affected infants may have cognitive impairment, epilepsy, and progressive sensorineural hearing loss. Serum CK is normal or mildly elevated. Family history may include a mildly affected parent, although cases also result from de novo mutations. Genetic testing is commercially available.

Syndromic Congenital Muscular Dystrophies

A group of congenital muscular dystrophies due to defects of O-linked glycosylation of dystroglycan, a component of the dystrophin-glycoprotein complex spanning the plasma membrane of skeletal myocytes, are associated with severe myopathy, a cerebral cortical malformation referred to as cobblestone lissencephaly, and ocular defects such as retinal dysplasia. In addition to profound hypotonia and weakness, affected infants often have intractable epilepsy. These diagnoses are suspected based on the characteristic constellation of abnormalities and have been clinically categorized as Fukuyama congenital muscular dystrophy, Walker-Warburg syndrome, and muscle-eye-brain disease. Thus far, six different causative genes have been identified (Muntoni et al., 2008), and there appears to be a far greater degree of phenotypic overlap among the different genotypes than was previously appreciated.

Congenital Disorders of Glycosylation

Congenital disorders of glycosylation are a group of recessively inherited defects in 21 different enzymes that modify N-linked oligosaccharides. Many forms present with hypotonia in infancy. The most common form, type Ia, results from a deficiency of the phosphomannomutase enzyme. In addition to hypotonia, affected infants may have hyporeflexia, global developmental delay, failure to thrive, seizures, and evidence of hepatic dysfunction, coagulopathy, and elevated thyroid-stimulating hormone (TSH). Characteristic examination findings include inverted nipples and an abnormal distribution of subcutaneous fat. Facial dysmorphism occurs but is not present in all cases. Brain MRI shows cerebellar hypoplasia. Analysis of transferrin isoforms in serum by isoelectric focusing reveals a characteristic pattern indicative of a defect in the early steps of the N-linked oligosaccharide synthetic pathway. Commercially available genetic testing identifies pathogenic sequence variants in 95% of affected individuals. Although cerebral dysfunction dominates the early clinical picture, some patients develop a demyelinating peripheral neuropathy in the first or second decade of life (Gruenwald, 2009).

Lysosomal Disorders

Certain defects of lysosomal hydrolases, in particular Krabbe disease and metachromatic leukodystrophy, result in progressive degeneration of both central and peripheral myelin (Korn-Lubetzki et al., 2003), producing both an encephalopathy and motor unit dysfunction (Cameron et al., 2004). Both disorders are associated with characteristic white matter abnormalities on brain MRI, and biochemical assays on peripheral blood of β-galactocerebrosidase in the case of Krabbe, and of arylsulfatase A in the case of metachromatic leukodystrophy confirm the diagnosis.

Infantile Neuroaxonal Dystrophy

Neuroaxonal dystrophy is a rare autosomal recessive disorder caused by mutations in the PLA2G6 gene, which encodes a calcium-independent phospholipase (Gregory et al., 2008). The classic form may present as early as 6 months of age with hypotonia, although psychomotor regression is more common, and progressive spastic tetraparesis and optic atrophy with visual impairment follow. Brain MRI shows bilateral T2 hypointensity of the globus pallidus, indicative of progressive iron accumulation, as well as thinning of the corpus callosum and cerebellar cortical hyperintensities. Nerve conduction studies show evidence of an axonal sensorimotor polyneuropathy with active denervation on EMG. The characteristic pathological finding is of enlarged and dystrophic-appearing axons on biopsy of skin, peripheral nerve, or other tissue containing peripheral nerve. Commercially available genetic testing identifies abnormalities in approximately 95% of children with early symptom onset.

Acquired Spinal Cord Lesions

Acquired spinal cord lesions relate to trauma sustained during delivery or occur as a part of the spectrum of hypoxic-ischemic encephalopathy. As previously noted, the highest risk of spinal cord injury occurs in vaginal deliveries with breech presentation, particularly when the head is hyperextended in utero. Herniation of the brainstem through the foramen magnum, as well as injury to the cerebellum, may also occur. Cervical spine injury may also occur in cephalic presentations with midforceps delivery, especially in cases of prolonged rupture of membranes. In both traction injury and hypoxic-ischemic injury, encephalopathy often dominates the early clinical picture and may obscure the extent of spinal cord dysfunction. Potential indicators in the acute phase include bladder distention with dribbling of urine and impaired sweating below the level of the lesion. Signs of spasticity gradually supplant early flaccid paraparesis. As mental status improves, the level and extent of motor impairment becomes apparent. MRI of the spine in the acute stage may show cord edema or hemorrhage, whereas imaging obtained later in the course may reveal cord atrophy.

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is the most common inherited disorder of the spinal cord resulting in hypotonia in infancy, occurring with an incidence of approximately 1 in 10,000 live births per year. It is an autosomal recessive disorder in which the molecular defect leads to impaired regulation of programmed cell death in anterior horn cells and in motor nuclei of lower cranial nerves. Both populations of motor neurons are progressively lost, producing hypotonia and weakness of limb and truncal musculature, as well as bulbar dysfunction. In approximately 95% of cases, the genetic defect is homozygous deletion of the survival motor neuron 1 (SMN1) gene, which is located on the telomeric region of chromosome 5q13 (Ogino and Wilson, 2002). A virtually identical centromeric gene on 5q13, referred to as SMN2, encodes a similar but less biologically active product (Swoboda et al., 2005). While no more than two copies of SMN1 are present in the human genome, variable numbers of SMN2 copies are present. The protein product of SMN2 appears to partially rescue the SMA phenotype such that a larger SMN2 copy number generally results in a milder presentation and disease course.

Historically, SMA patients have been categorized into different phenotypes or syndromes based on age of presentation and maximum motor ability achieved. The disease results from a common genetic abnormality with a spectrum of phenotypic severity contingent upon modifying factors that include SMN2 copy number and other loci not yet identified. The classification of the most severely affected patients, with weakness and hypotonia evident at birth, is SMA type 0. These infants may have arthrogryposis multiplex congenita in addition to diffuse weakness of limb and trunk muscles, but facial weakness is usually mild if present. Perinatal respiratory failure causes death in early infancy. SMA type 1, also referred to as Werdnig-Hoffmann disease, is a designation given to infants who develop weakness within the first 6 months of life. These infants may appear normal at birth or may appear hypotonic. Facial expression is usually normal, and arthrogryposis is usually absent. Weakness is worse in proximal than in distal muscles and worse in the lower extremities, which may lead to suspicion of a congenital myopathy or muscular dystrophy. Further confounding the diagnosis is the presence of an elevated serum CK in a substantial portion of patients (Rudnick-Schoneborn et al., 1998), although CK rarely rises above 1000 U/L. In addition to limb weakness, affected infants demonstrate abdominal breathing due to relative preservation of diaphragm function as compared to abdominal and chest wall musculature. Needle EMG shows evidence of both acute and chronic denervation in the limbs and serves to distinguish this disorder from myopathies with a similar presentation.

Genetic testing is commercially available for SMN-related SMA. Among the 5% of patients without homozygous deletion of SMN1, most are compound heterozygotes with the characteristic deletion on one allele and a point mutation on the other. Parents of affected children are obligatory heterozygotes. The natural history of SMA is unique among anterior horn cell disorders in that the progression of weakness is most rapid early in the disease course and subsequently slows. Nevertheless, in the absence of supportive measures, median survival is 8 months, with death due to respiratory failure. Survivors have normal cognitive development. Several agents that act as histone deacetylase inhibitors increase the expression of SMN2 mRNA in vitro and in vivo, and among these agents, valproate, sodium phenylbutyrate, and hydroxyurea are currently or have recently been in clinical trials in SMA patients (Oskoui and Kaufmann, 2008).

Infantile Spinal Muscular Atrophy with Respiratory Distress Type 1

Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1), previously classified as a variant of SMA type 1, is a rare and distinct autosomal recessive anterior horn cell disorder. Unlike SMN-related SMA, affected infants develop early diaphragmatic paralysis and distal limb weakness that progresses to complete paralysis. Many have intrauterine growth restriction and are born with ankle contractures. Approximately one-third are born prematurely. Similar to SMN-related SMA, EMG and muscle biopsy reveal evidence of chronic active denervation. The causative gene encodes the immunoglobulin µ-binding protein 2 (IGHMBP2), for which testing is commercially available (Grohmann et al., 2001).

X-linked Spinal Muscular Atrophy

This rare X-linked anterior horn cell degenerative disorder shares a considerable degree of phenotypic overlap with SMN-related SMA. Distinctive features include polyhydramnios secondary to impaired fetal swallowing and arthrogryposis. Consider the diagnosis in any simplex case of a male infant with an SMA phenotype and normal SMN1 copy number. The only known causative gene encodes the ubiquitin-activating enzyme 1 (UBE1), for which testing is available on a research basis only (Ramser et al., 2008).

Juvenile Myasthenia Gravis

Approximately 10% to 15% of cases of autoimmune myasthenia gravis due to endogenous production of antibodies directed against sarcolemmal nicotinic acetylcholine receptors or muscle-specific kinase occur in individuals younger than 16 years of age. The disorder is particularly rare in the first year of life (Andrews, 2004). The small number of infantile cases reported in the literature limits the conclusions drawn with respect to the occurrence of measurable antibody titers, treatment, and outcomes in this age group.

Neonatal Myasthenia

In approximately 15% of infants born to mothers with autoimmune myasthenia gravis, transitory symptoms of myasthenia occur in the neonatal period related to transfer of acetylcholine receptor antibodies across the placenta. Because the fetal nicotinic acetylcholine receptor is different from the adult form, the expression of myasthenic symptoms in newborns depends on the maternal production of antibodies against the fetal receptor. These antibodies are not active against the adult form of the receptor and therefore do not contribute to maternal symptoms. Likewise, antibodies against the fetal receptor are not detectable by commercially available assays. For these reasons, neither maternal symptom severity nor the maternal antibody titer predicts the likelihood or severity of neonatal myasthenic symptoms. As with juvenile myasthenia gravis, the predominant symptoms are ocular or bulbar, although generalized hypotonia or weakness may occur. Rarely, affected infants have arthrogryposis due to prenatal exposure to fetal antibodies, leading to prolonged immobility in utero. Affected infants may require respiratory support temporarily or may require symptomatic therapy with subcutaneous neostigmine prior to oral feeds to prevent fatigue and premature discontinuation of feeding. In a majority of cases, the symptoms resolve within the first month of life (Papazian, 1992).

Congenital Myasthenic Syndromes

Several genetic disorders of neuromuscular transmission have been identified as causing hypotonia; fluctuating or persistent weakness of ocular, bulbar, or limb muscles; or arthrogryposis in infancy. The basis of one widely used classification scheme of congenital myasthenic syndromes (CMS) is whether the abnormality occurs in the presynaptic motor nerve terminal, the synaptic cleft, or the postsynaptic sarcolemma. The cause of the presynaptic disorder is a defect in the enzyme choline acetyltransferase, which synthesizes the neurotransmitter, whereas the synaptic defect results from deficiency of the end-plate cholinesterase. The causes of the postsynaptic disorders are various abnormalities of the structure, localization, or kinetics of the acetylcholine receptor. Inheritance of most CMS is autosomal recessive, except for the slow channel syndrome, which is autosomal dominant. The clinical presentation is similar to other forms of myasthenia occurring in infancy, although deficiencies of the presynaptic enzyme, choline acetyltransferase, and of the postsynaptic acetylcholine receptor–associated protein, rapsyn, are also associated with sudden episodes of apnea (Hantai et al., 2004). Infants with CMS have negative antibody studies and demonstrate a decremental response on RNS. Specialized electrophysiological testing on fresh muscle biopsy specimens has been useful as a diagnostic tool but is not widely available. Of the 10 different genes currently known to be associated with CMS, testing is commercially available for 7, while testing of the others is available on a research basis only. Most forms of CMS are treated with cholinesterase inhibitors and/or the potassium channel inhibitor, 3,4-diaminopyridine. However, cholinesterase inhibitors may exacerbate end-plate cholinesterase deficiency and slow-channel syndrome, while the latter may respond to fluoxetine (Harper et al., 2003). The natural history of CMS is highly variable even among patients with the same genotype.

Infant Botulism

Spores of the gram-positive anaerobe Clostridium botulinum, an organism found in soil and in some cases in contaminated foods, produce an exotoxin that prevents anchoring of acetylcholine-containing vesicles to the presynaptic nerve terminal of the neuromuscular junction, disrupting neuromuscular transmission and resulting in flaccid weakness. In adults, the cause of botulism is ingestion of the preformed toxin; the organism itself cannot survive in the acidic environment of the adult digestive tract. By contrast, infants who ingest spores may be colonized and develop botulism from in situ production of the toxin. Affected infants may present any time after 2 weeks of age and may have relatively greater involvement of bulbar than appendicular muscles. The characteristic finding on RNS is an increment in the CMAP with high-rate (50 Hz) stimulation (Cornblath et al., 1983). Diagnostic confirmation is obtained by testing a stool or enema specimen with a bioassay in mice inoculated against different strains of toxin. Aside from supportive measures, early administration of botulinum immune globulin shortens the course of the disease (Arnon et al., 2006). In most cases, treatment should be initiated based on the clinical suspicion and should not be delayed while awaiting results of the bioassay.

Congenital Myopathies

Nonsyndromic Congenital Muscular Dystrophies