Onset.

SMA type 1 is clinically apparent at birth or in the first several months of life. In one large series, clinical onset was at birth in 35%, in the first month in 16%, in the second month in 23%, and from the end of the second month to the sixth month in 26%. The finding of onset before 6 months with a median age of onset of 1 to 2 months is consistent. Onset in utero is supported by the observation that in most patients with SMA type 1 presenting at birth or in the early neonatal period, decreased and weak fetal movements in the last trimester are reported by the patients’ mothers. Neuropathological data (see later) have documented prenatal onset. In particularly severely affected infants, neonatal asphyxia or respiratory distress may occur. As just noted, some particularly severely affected infants (type 0) also may exhibit early deficits of facial movement, arthrogryposis, severe diffuse weakness, and early death. In those infants whose disease is not apparent at birth, onset in the first weeks is often acute. Indeed, clinical progression to severe disability characteristically occurs over a time course measured in days to a week or so. These clinical findings have a correlate from electrophysiological studies that show marked deterioration of motor function over a 1-week to 2-week period postnatally.

Neurological Features.

The neurological features are highly consistent and striking ( Box 32.4 ). ^a

a References .

Type I spinal muscular atrophy (Werdnig-Hoffmann disease): clinical manifestations of weakness of limb and axial musculature in a 4-month-old infant with severe weakness and hypotonia. With vertical suspension (A), note the dangling lower limbs with lack of hip flexion, tendency of upper limbs to slip through the examiner’s hands, and lack of neck flexion with resulting head lag. When subject is supine, note the frog-leg positioning of the legs and the lack of traction response (B) and the lag of head (C), with attempts by the examiner to pull the infant to a sitting position.

(Reprinted with permission from Oskoui M, Darras BT, De Vivo DC. Spinal muscular atrophy: 125 years later and on the verge of a cure. In: Sumner CJ, Paushkin S, Ko C-P, eds. Spinal Muscular Atrophy: Disease Mechanisms and Therapy . San Diego: Academic Press; 2017:chap 1, 3–19.)

The pattern of weakness of limbs leads to a characteristic posture, characterized particularly by a frog-leg posture with the upper extremities abducted and either externally rotated or internally rotated ( jug handle ) at the shoulders ( Fig. 32.4 ). The chest is almost always anteriorly collapsed and bell shaped, with an associated distention of the abdomen and intercostal recession during inspiration (see Fig. 32.4 ), known as paradoxical breathing. These features relate to weakness of the intercostal muscles and the relatively preserved diaphragmatic function. Contractures of the limbs, usually only at wrists and ankles, are evident in 10% to 20% of infants with onset in utero or in the first month of life.

Type I spinal muscular atrophy (Werdnig-Hoffmann disease): characteristic posture.

Ten-month-old girl with SMA Type I, who became symptomatic at about 1.5 to 2 months of age. Note the floppy appearance with frog-leg positioning of the legs. As is the case with the majority of infants with SMA Type I, this infant had no antigravity movement in her legs, only limited distal movement in the arms, and was areflexic throughout. She had two copies of SMN2. She did not receive noninvasive ventilator support (BiPAP) and passed away at 16.5 months of age. SMA , Spinal muscular atrophy; SMN , survival motor neuron.

(Reprinted with permission from Oskoui M, Darras BT, De Vivo DC. Spinal muscular atrophy: 125 years later and on the verge of a cure. In: Sumner CJ, Paushkin S, Ko C-P, eds. Spinal Muscular Atrophy: Disease Mechanisms and Therapy . San Diego: Academic Press; 2017:chap 1, 3–19.)

Involvement of cranial nerve nuclei is less striking than of anterior horn cells, at least early in the clinical course. Thus extraocular movements are normal, and facial motility is relatively well preserved. Indeed, the pathetic picture of a bright-eyed, nearly totally paralyzed infant is characteristic of Werdnig-Hoffmann disease. Sucking and swallowing are affected early in the course in approximately half of cases. Fasciculations and atrophy of the tongue, clinical signs in anterior horn cell disorders of slightly later onset, are apparent in only about one-third to one-half of patients, with the disease occurring at birth or in the first month.

Particularly noteworthy differential diagnostic features in the neurological examination include the presence of normal sphincter and sensory functions. Both these functions would be expected to be affected with major spinal cord disease, and sensory function with peripheral nerve disease. The patient’s alert state with normal visual and auditory responses rules against a central disorder. Total areflexia and absence of ptosis, ophthalmoplegia, and facial weakness rule against a variety of primary diseases of muscle. Distinction from type II glycogen storage disease (Pompe disease) can be most difficult, but this much less common disease is usually accompanied by prominent involvement of the heart and enlargement of the tongue.

Several rare genetic variants of infantile SMA should be distinguished from the type 1 SMA just described. These SMA variants and their mode of inheritance include the association of SMA with (1) diaphragmatic SMA or SMA with respiratory distress 1 (SMARD1; autosomal recessive), (2) pontocerebellar atrophy (type 1 pontocerebellar atrophy; see Chapter 29 ) (autosomal recessive), and (3) congenital arthrogryposis, both with and without bone fractures (autosomal recessive and X-linked, respectively). None of these disorders are linked to the genetic region on chromosome 5 involved in type 1 SMA (see later discussion).

Course.

The course of type 1 SMA is a close function of the age of onset. ^a

a References .

Although infants who ultimately prove to have type 2 SMA have a peak age at onset between 8 and 14 months, an occasional infant exhibits onset before 6 months and has a chronic course, including attainment of sitting or even walking, with prolonged survival. ^a

a References .

Serum Enzymes.

The creatine kinase (CK) level is usually normal in type 1 SMA or slightly elevated.

Electromyography.

The electromyogram (EMG) may be difficult to perform in the young infant, but with patience the major features of anterior horn cell disease are usually observed (see Table 30.4 ). Thus, at rest, fibrillation potentials are apparent. With muscle contraction, one sees a reduced number of fast-firing motor unit potentials that are usually of normal amplitude and duration because of failure to reinnervate efficiently in SMA type 1. In general, although no simple relationship exists between features on the EMG and outcome, one study showed a strong correlation between the degree of depression of the compound muscle action potential and functional outcome.

Nerve Conduction Studies.

Motor nerve conduction velocities are usually normal, although in particularly severe disease, a slight reduction may be observed. This finding suggests a disproportionate loss of anterior horn cells that give rise to the largest, fastest conducting fibers. The compound muscle action potentials (CMAPs) have very low amplitude because of significant loss of anterior horn neurons and/or axons. In contrast, the sensory nerve action potentials are normal, which underscores the motor neuron nature of the disease. Nevertheless, some patients with particularly severe cases of type 1 SMA have exhibited signs of severe motor and sensory neuropathy.

Muscle Biopsy.

The muscle biopsy of a patient with Werdnig-Hoffmann disease, with clinically apparent findings at birth or in the first month, usually exhibits advanced changes of denervation (see Chapter 30 ). Characteristically, pronounced atrophy of all fibers of both types within entire fascicles of muscle (i.e., panfascicular atrophy ) or large group atrophy occurs ( Fig. 32.5 ). The early signs of denervation (i.e., loss of checkerboard appearance, type grouping, or small group atrophy; see Chapter 30 ), features of anterior horn cell disease later in childhood, are nearly absent ( Fig. 32.6 ). This virtual absence of signs of terminal axonal sprouting and reinnervation (see Chapter 30 ) is probably indicative of the severe, fulminating process involving anterior horn cells that causes widespread elimination before such compensatory attempts can occur. A consistent increase in connective tissue is associated with the marked atrophy of muscle (see Fig. 32.6 ). Hypertrophy of predominantly type I fibers, often in clusters, is an additional characteristic feature. The finding that these hypertrophic fibers often occur in clusters suggests the possibility of reinnervation. The distribution of the histopathological findings parallels the generalized pattern of muscle weakness; the diaphragm is conspicuously less affected. Diagnosis by genetic testing has obviated the need for muscle biopsy in most cases (see later).

Type I spinal muscular atrophy (Werdnig-Hoffmann disease): muscle biopsy showing diffuse, panfascicular atrophy in an affected infant.

Skeletal muscle biopsy from a patient with SMA type I showing large group atrophy. The small fibers have staining characteristics of both types (I and II), whereas the large hypertrophic fibers all stain as type I (ATPase stain, pH 9.4). A control muscle biopsy is shown on the left for comparison. SMA , Spinal muscular atrophy.

Type I spinal muscular atrophy (Werdnig-Hoffmann disease): muscle biopsy showing grouped atrophy.

Note the clear neurogenic pattern of grouped atrophy and hypertrophic fibers, with modest increase in endomysial connective tissue.

(Reprinted with permission from Oskoui M, Darras BT, De Vivo DC. Spinal muscular atrophy: 125 years later and on the verge of a cure. In: Sumner CJ, Paushkin S, Ko C-P, eds. Spinal Muscular Atrophy: Disease Mechanisms and Therapy . San Diego: Academic Press; 2017:chap 1, 3–19.)

Other Studies.

The identification of the q11.2–13.3 region of chromosome 5 as the site of the genetic defect in Werdnig-Hoffmann disease led to the development of molecular diagnostic techniques (see “ Pathogenesis and Etiology ” earlier). Radiographs of the chest are useful in demonstrating the chest deformity, the thin ribs characteristic of severe congenital neuromuscular disease, and the marked atrophy of muscle. In the rare, very severe type 0 disease, long bone fractures may be observed.

Studies with real-time ultrasonography of limbs have demonstrated several types of changes (i.e., an increase in the intensity of echoes from muscle and the degree of muscle atrophy). The echogenicity of muscle correlates well with the severity of histopathological changes observed in biopsy specimens.

Essential Cellular Changes.

The major neuropathological changes are confined to the anterior horn cells of the spinal cord and the motor nuclei of cranial nerves ( Box 32.5 ). The essential cellular changes in infantile cases are (1) depletion of the number of neurons, (2) degenerative changes of neurons, (3) neuronophagia, and (4) infiltration with microglia and astrocytes ( Fig. 32.7A and B ). Enhanced apoptosis of anterior horn cell neurons is the most prominent feature during fetal life. Some workers also described cytological findings indicative of immaturity of neurons and suggested impaired development, as well as degeneration, of neurons. The depletion of neurons may be so marked that few, if any, remain in an anterior horn or cranial nerve nucleus. The degenerative changes consist particularly of central chromatolysis, characterized by rounded and distended neuronal cell bodies with eccentric nuclei and Nissl substance displaced to the periphery. Neuronophagia is not prominent, although it is readily demonstrated. The glial response consists of both microglia and astrocytes and is particularly prominent in the ventral aspect of the anterior horns.

The neuropathology of spinal muscular atrophy.

(A) Spinal cord. Loss of large motor neurons (arrows) in the anterior horns of the spinal cord in tissue obtained from autopsy material from a patient with SMA type I (stained with cresyl echt violet). A control spinal cord section is shown on the left for comparison. Small arrows indicate motor neurons. (B) Motor neuron undergoing chromatolysis appears swollen at lower and higher magnification (arrows) .

(Reprinted with permission from Darras BT, Markowitz JA, Monani UR, De Vivo DC. Spinal muscular atrophies. In: Darras BT, Jones HR Jr, Ryan MM, De Vivo DC eds. Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician’s Approach . 2nd ed. San Diego: Academic Press; 2015:chap 8, 117–145.)

Topography.

In severe Werdnig-Hoffmann disease, anterior horn cells are affected diffusely, with a particularly prominent affection of the ventromedial group. Cranial nerve nuclei involved invariably and markedly are of cranial nerves VII, IX, X, XI, and XII. The motor nucleus of nerve V is affected in approximately 70% of cases, and the abducens nucleus is involved in fewer than 50% of cases.

Other areas of the motor system are not consistently involved. Hypoxic changes are occasionally observed in hippocampal neurons and Purkinje cells of cerebellum. As noted later, associated degenerative changes in pontocerebellar structures are a feature of an SMA variant that is genetically distinct from type 1 SMA.

The motor nerves exhibit the changes expected from a loss of anterior horn cells (i.e., a decrease in number of myelinated fibers particularly and an increase in connective tissue). Striking atrophy with glial proliferation may be apparent in the proximal anterior roots. Indeed, the glial proliferation may be so conspicuous that some workers have attributed to it a pathogenetic role. The view that the glial infiltration is a secondary event is more widely accepted. Perhaps of greater interest is the demonstration of changes typical of axonal neuropathy in some severe cases. Such changes have led to the suggestion that the anterior horn cell degeneration is a secondary phenomenon, although the most prevalent view is that the neuropathic abnormalities are secondary. Kariya et al. also demonstrated structural and functional abnormalities at the level of the neuromuscular junction that precede symptoms in mice, as well as structural abnormalities in the neuromuscular junctions of humans with SMA, and hence proposed that SMA may be a synaptopathy .

Management.

Type 1 SMA that is apparent at birth or in the first month of life is usually accompanied by serious disturbances of sucking and swallowing early in infancy. Frequent aspiration of the oropharynx is needed, and usually cessation of oral feedings and institution of tube feeding are required before long to ensure adequate nutrition. Indeed, when dysphagia becomes severe enough to preclude reasonable nutrition and is complicated by frequent aspirations, many clinicians recommend gastrostomy or gastrojejunostomy feeding. This maneuver is carried out not to prolong life but to improve the patient’s quality of life and particularly to reduce parental anxiety associated with attempts at oral feeding. Surveillance for respiratory infection must be diligent, because this complication is the usual mode of demise for these unfortunate babies. The intensity of therapy (e.g., antibiotics, chest physical therapy, postural drainage, noninvasive positive pressure ventilation, and even tracheostomy and long-term mechanical ventilation) sometimes is difficult to determine decisively. Tracheostomy and mechanical ventilation have been associated with survival into childhood, although longer survival occurs, albeit rarely, without such invasive intervention. The quality of life in such bedridden infants and children is a grave concern. More important, range-of-motion exercises are used to prevent contractures and, I feel (JJV), to help the parents “do something” for their infant. In severe Werdnig-Hoffmann disease, my approach is foremost to provide emotional support to the parents and to ensure as much comfort as possible for the infant. I indicate to the family our current understanding of the dire outcome and recommend careful attention to oral-pharyngeal secretions, measures to ensure adequate nutrition, and diligent therapy of respiratory infections. I discuss the complex issues related to long-term mechanical ventilation.

The clinical trials pipeline for SMA over the past 15 years has been developing several therapeutic agents. With the goal of increasing SMN transcript, histone deacetylase inhibitors (such as valproic acid and sodium phenylbutyrate) were tested in randomized trials, but neither was effective ; nonhistone deacetylase inhibitors (such as hydroxyurea) were ineffective in a randomized trial; albuterol showed promise in two pilot studies; however, the mechanism of action remains unknown. Ionis Pharmaceuticals has conducted phase 3 clinical trials of an intrathecally delivered antisense oligonucleotide (SMNRx, or Nusinersen) targeting SMN2 exon 7 inclusion. Interim analysis of a phase 3 Nusinersen SMA type 1 study (ENDEAR) showed that infants receiving the medication intrathecally experienced a statistically significant improvement in the acquisition of motor milestones, compared with a control cohort, and led to the approval of nusinersen (Spinraza) by the FDA in December 2016. Early phase clinical trials are testing other orally administered small molecules that modulate SMN2 alternative splicing. Roche-PTC-SMA Foundation partnership put on hold clinical studies of RG7800, an orally administered molecule, after an unexpected safety finding at higher long-term doses in an animal study. They have recently announced phase 1 trials for a new molecule, RG7916. Novartis has entered phase 2 of a clinical trial for the orally administered molecule LM1070. The goal of stabilizing the SMN protein has led to preclinical studies of aminoglycosides, proteasome inhibitors, and indoprofen. Among neuroprotectors, olesoxime, a mitochondrial pore modulator that enhances motor neuron survival in culture, may be effective in stabilizing the disease, but riluzole and gabapentin have shown mixed results. Cell therapy through stem cells is under development; gene replacement therapy with a scAAV9/SMN1 gene construct in type 1 infants is in progress, and preliminary results seem promising. The goal of enhancing muscle function is on the horizon, with new potential therapeutic targets such as myostatin, follistatin, and other molecules.

Cervical Form.

A group of infants with a cervical form of anterior horn cell disease and arthrogryposis was described. The striking findings in the neonatal period were signs of severe symmetrical lower motor neuron deficit in the upper extremities in the absence of a history suggestive of traumatic injury of spinal cord or brachial plexus. Atrophy and flaccid weakness of upper extremities and the proximal and distal muscle groups were marked, and flexor contractures at the elbow and interphalangeal joints were apparent. Bulbar muscles were not affected. Lower extremities were normal. The course was nonprogressive. Onset in utero was suggested by the presence of flexion contractures, and onset in the first trimester was suggested by the presence of poorly formed palmar creases. The nature of the intrauterine insult to cervical anterior horn cells was not clear. One patient with a clinically similar case had intramedullary telangiectasia.

Caudal Form.

A caudal form of anterior horn cell disease with arthrogryposis was described as an apparently sporadic disorder with involvement localized to the lower extremities. Weakness, hypotonia, areflexia, and multiple joint contractures were the major features. A few patients later developed signs in the upper extremities and fasciculations of the tongue after several years. Whether these cases represent a different disorder from the SMA variant with predominant lower limb weakness described earlier (see Table 32.3 ), or are related to intrauterine infections of the anterior horn cells, is unknown.

Laboratory Studies.

EMG and muscle biopsy in both the generalized and local forms of neurogenic arthrogryposis multiplex congenita usually demonstrate signs of denervation (see Chapter 30 ). In the localized forms, the possibility of a correctable structural lesion of the cervical cord or the lumbosacral cord and cauda equina should be ruled out by appropriate studies.

Onset.

Onset of the Pompe disease may be apparent in the first days of life, although the median age at symptom onset in the largest series ( n = 168) was 2.0 months.

Neurological Features.

Initially, the weakness and hypotonia may be so severe that type 1 SMA is considered the probable diagnosis. The concurrence of fasciculations of the tongue and difficulty sucking, crying, and swallowing further mimics this primary anterior horn cell degeneration. However, several clinical features help distinguish Pompe disease from Werdnig-Hoffmann disease. First, cardiac involvement, resulting from accumulation of glycogen, is prominent in Pompe disease; radiographs demonstrate an enlarged globular heart, and electrocardiograms demonstrate evidence of myocardiopathy with shortened PR interval, giant QRS complexes, and inverted T waves. Second, the tongue, although weak and perhaps even fasciculating, is usually large in Pompe disease because of the glycogen accumulation, unlike the small, atrophic tongue of Werdnig-Hoffmann disease. Third, the skeletal muscles, although weak, are usually prominent in Pompe disease, because of glycogen accumulation (i.e., a true hypertrophy), and they have a characteristic rubbery feel. This finding is unlike the atrophy of Werdnig-Hoffmann disease. Fourth, the liver usually is enlarged and readily palpable in Pompe disease. Tendon reflexes are variable in glycogen storage disease. Most patients have preserved tendon reflexes early in the clinical course and later have total areflexia.

A recent report described a delay in myelination, determined by MRI, in five patients with infantile-onset Pompe disease. The clinical correlates of this disturbance remain to be clarified. Deposition of glycogen is a feature of human oligodendroglial development.

Clinical Course.

The clinical course is malignant. Infants require ventilatory support at a median age of 6 months, and death in one large series ( n = 168) occurred at a median age of approximately 9 months. In another series ( n = 153), the median age at death was 6 months. Survival rates at 12 months of age are approximately 25%, with only 17% ventilator free; at 18 months, the respective values are 12% and 7%. Death is related usually to a combination of cardiac involvement and respiratory complications caused by thoracic muscle weakness and bulbar paralysis.

Laboratory Studies.

The serum CK level is elevated because of cardiac and skeletal muscle involvement, and the serum transaminases also are usually elevated because of the combination of muscle and hepatic disease, with the former predominating. Muscle biopsy reveals large amounts of periodic acid–Schiff–positive material. Large vacuoles, often confluent, are apparent when standard fixation procedures are used. The confluent vacuoles, often resulting in a lacework appearance, are lysosomes filled with PAS-positive diastase-digestible material; they stain positively for acid-phosphatase. Also, free glycogen can be seen in the cytoplasm with electron microscopy ( Figs. 32.8A and B and 32.9 ). The EMG reveals fibrillations but often also signs of myopathic disorder because of prominent muscle involvement (see Chapter 33 ). An additional characteristic feature is irritability of muscle with the occurrence of pseudomyotonic bursts of discharges. The large R waves on electrocardiography are particularly helpful signs in diagnosis.

Muscle biopsy from an infant with acid maltase (GAA) deficiency (Pompe disease, GSD II).

H&E shows large vacuoles in all fibers (A, arrows ) that stain intensely with the acid phosphatase reaction (B).

(Reprinted with permission from Akman HO, Oldfors A, DiMauro S. Glycogen storage diseases of muscle. In: Darras BT, Jones HR Jr, Ryan MM, De Vivo DC eds. Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician’s Approach . 2nd ed. San Diego: Academic Press; 2015:chap 39, 735–760.)

Electron microscopy of muscle in infantile Pompe disease, showing large accumulation of free cytoplasmic glycogen (arrows) together with intralysosomal glycogen (inset) .

(Reprinted with permission from Akman HO, Oldfors A, DiMauro S. Glycogen storage diseases of muscle. In: Darras BT, Jones HR Jr, Ryan MM, De Vivo DC eds. Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician’s Approach . 2nd ed. San Diego: Academic Press; 2015:chap 39, 735–760.)

Neuropathology.

The neuropathology of Pompe disease is characterized by a striking increase in glycogen throughout the central and peripheral nervous systems (including the myenteric plexus of rectal mucosa). The accumulation of glycogen in the anterior horn cells is the most striking change.

Pathogenesis and Etiology.

The biochemical defect involves acid alpha-glucosidase (GAA; acid maltase) activity ( Fig. 32.10 ). This enzyme catalyzes the lysosomal pathway of glycogen degradation, presumably used during normal turnover of cellular constituents. (The major pathway of glycogen degradation, used for glucose-6-phosphate production, occurs in the cytosol and is catalyzed by phosphorylase.) Thus, in Pompe disease, the largest accumulation of glycogen is apparent in lysosomal structures. The enzymatic defect is demonstrable in muscle or cultured fibroblasts. Moreover, the enzyme is also present in fibroblasts grown from amniotic fluid cells, and this procedure can be used for prenatal diagnosis.

Scheme of glycogen metabolism and glycolysis.

Roman numerals indicate enzymes whose deficiencies are associated with muscle glycogenosis: II, acid maltase (GAA, Pompe disease); III, debrancher (GDE, Cori-Forbes disease); IV, brancher (GBE, Andersen disease); V, myophosphorylase (PYGM, McArdle disease); VII, phosphofructokinase (PFK, Tarui disease); VIII, phosphorylase kinase (PHK); IX, phosphoglycerate kinase (PGK); X, phosphoglycerate mutase (PGAM); XI, lactate dehydrogenase (LDH); XII, aldolase A; XIII, beta-enolase (ENO3); XIV, phosphoglucomutase (PGM); XV, glycogenin (GYG1); 0, glycogen synthase (GYS1). AMP , Adenosine monophosphate; ATP , adenosine trisphosphate; P , inorganic phosphate; PLD , phosphorylase-limit dextrin; UDPG , iridine diphosphate glucose.

(Reprinted with permission from Oldfors A, DiMauro S. New insights in the field of muscle glycogenoses. Curr Opin Neurol . 2013;26:544–553.)

There is good correlation between GAA gene mutations and severity of the phenotype. Infants tend to have deletion or nonsense mutations in the GAA gene, leading to significant enzyme deficiency, whereas older children and adults have milder, leaky mutations.

Management.

Attempts to replenish alpha-glucosidase by bone marrow transplantation have been unsuccessful. Very promising results are available for the use of enzyme replacement therapy (ERT), involving recombinant human alpha-glucosidase, at least for survival and cardiac and skeletal muscle function. In addition, a study of five infants treated from a median age of 6 months showed improvement in myelination by MRI in four of the patients. However, the response of infants with Pompe disease has been variable, with some infants surviving for more than 11 years but being paralyzed and ventilator-dependent; early treatment seems to improve the outcome. In a series of 20 infants treated in the UK between 2000 and 2009, the overall ventilator-free survival was 35%; 30% were alive and ventilator-dependent, and 35% died at a median age of 10 months. Further, questions regarding cognitive outcome have been raised in surviving infants because the recombinant GAA does not cross the blood-brain barrier.

Onset.

The disorder may be apparent at birth or may develop in the first weeks of life. Because the incubation period of the disease is approximately 10 days, infants affected at birth or in the first week presumably were affected in utero.

Neurological Features.

Most patients present with diffuse flaccid paralysis that is usually asymmetrical. Apnea may be the initial clinical feature. Not uncommonly, encephalitic involvement results in cerebral signs, including seizures. Respiratory failure may ensue promptly. Moreover, contractures can evolve rapidly, and care must be taken to avoid the postnatal development of arthrogryposis multiplex. Asymmetrical paresis is a common sequel.

Laboratory Studies.

The diagnosis is established by viral isolation from the stool. CSF pleocytosis with elevated protein content occurs.

Neuropathology.

The neuropathological features in the newborn are often more severe than in the adult. The qualitative features are similar. Neuronal necrosis, neuronophagia, and perivascular cuffing with inflammatory cells involve neurons of the anterior horns, motor nuclei of the brain stem, roof nuclei of the cerebellum, diencephalon, and motor cortex of the cerebrum.

Pathogenesis and Etiology.

Neonatal poliomyelitis is caused by infection of neurons by poliovirus, a classic neurotropic virus. The acquisition of virus may occur prenatally or early postnatally. The demonstration of maternal viremia and placental infection and the recovery of virus from meconium of stillborn infants of diseased mothers support the concept of intrauterine infection by transplacental mechanisms. Because of the incubation period for poliomyelitis, infants affected after approximately 10 days of age presumably were infected during delivery by contamination with infected stool or by postnatal exposure.

Management.

Management is entirely supportive.

Serum Enzymes.

The CK level is normal.

Electromyography.

The EMG indicates changes of denervation, as outlined in Table 30.4 .

Nerve Conduction Velocity.

Determination of nerve conduction velocity is critical and is too frequently overlooked in the evaluation of the hypotonic and weak newborn. In most severely affected infants, a drastic reduction in motor nerve conduction velocity has been demonstrated, and values of less than 10 to 12 m/second are recorded in nearly all cases (see Table 32.4 ). In many infants (including several of my patients), impulse transmission could not be detected. The absence of sensory nerve action potentials is also common.

Muscle Biopsy.

Muscle biopsy usually shows evidence of denervation (see Box 30.4 ), but the muscle histology occasionally may appear remarkably preserved in the presence of severe disease of nerve. The correct diagnosis may be suggested by examination of intramuscular nerves within the biopsy specimen of muscle. Changes seen in full form on nerve biopsy (see later discussion) may be suggested from such examination.

Other Studies.

The CSF protein concentration is a valuable adjunct to the diagnosis of infantile polyneuropathy. The CSF protein concentration is almost always elevated, even in the first weeks of life. The elevation usually becomes more marked with age, and occasionally a CSF protein concentration that is only marginally elevated in the first weeks of life becomes markedly elevated later in infancy.

Hypomyelination.

In the congenital hypomyelinative neuropathies, the essential feature has been the virtual absence of myelin sheaths ( Fig. 32.11 ). If any myelin is present, large-diameter nerve fibers, which normally are heavily myelinated, are conspicuous by the paucity of myelination. The normal proportion between diameter size and thickness of myelin sheath thus is lost. No signs of myelin destruction can be discerned; the lack of a demyelinating process is supported by biochemical studies, which showed no accumulation of cholesterol ester, the chemical hallmark of demyelination. Accompanying these changes may be a modest proliferation of Schwann cells and endoneurial fibroblasts.

Hypomyelination polyneuropathy.

This infant had severe, generalized hypotonia and weakness of facial movement, sucking, swallowing, and limb movement from the first days of life. The CSF protein level was slightly elevated on several occasions, and motor nerve conduction velocities were markedly reduced to 2 to 3 m/second. The infant died at months of age. The electron micrograph shows several axons (arrows) , each surrounded by a Schwann cell, one of which is sectioned through its nucleus (N). Note the marked paucity of myelin lamellae. No onion bulb formation is present. CSF , Cerebrospinal fluid.

(Courtesy Dr. Andrew W. Zimmerman.)

Onion Bulb Formation.

In many cases, so-called onion bulb formation has been detected. This morphological change is associated with the proliferation of Schwann cells and, to a lesser extent, endoneurial fibroblasts. Individual axons become invested by multiple Schwann cells. The multiple concentric lamellae of Schwann cell processes and, to a lesser extent, collagen fibers render the onion bulb appearance ( Fig. 32.12A–D ). In the youngest and most severely affected patients, the concentric lamellae consist principally of basement membrane of Schwann cells, there remaining little of Schwann cell plasma membrane. In older and usually less severely affected patients, the proliferative changes cause considerable separation of nerve fibers and an increase in the transverse diameter of the nerve; hence the term interstitial hypertrophy . In such patients, nerves may be palpable, particularly the posterior auricular in the neck, the ulnar at the elbow, and the peroneal at the fibular head.

Chronic polyneuropathy with onion bulb formation.

(A) From an infant with hypotonia and weakness from birth, elevated CSF protein level, and motor nerve conduction velocities markedly reduced to approximately 2 m/second. The sural nerve (which underwent biopsy when the child was years of age) shows total lack of myelin sheaths and, around individual axons, an increase in the number of Schwann cells arranged concentrically, assuming an onion bulb pattern (toluidine blue–O stain, ×500). (B) Sural nerve biopsy of year old girl with a DSD phenotype due to a PMP22 missense mutation. Large onion bulbs are seen around demyelinated and remyelinated (arrow) fibers. Marked increase in endoneural collagen. Bar = 5 µm. (C) From an infant with delayed motor development, areflexia, and distal muscular atrophy. This electron micrograph of the sural nerve, which underwent biopsy in the child at years of age, shows nerve fibers separated by an increased amount of collagen. Note particularly the three poorly myelinated nerve fibers with onion bulb formations. (D) Uncompacted myelin lamellae in sural nerve biopsy of 12-year-old girl with a missense mutation in the extracellular domain of MPZ . Bar = 1 µm.

(A From Kennedy WR, Sung JH, Berry JF. A case of congenital hypomyelination neuropathy. Arch Neurol . 1977;34:337–345. B and D, From Yiu EM, Baets J, Congenital and early infantile neuropathies. In: Darras BT, Jones HR Jr, Ryan MM, De Vivo DC eds. Neuromuscular Disorders of Infancy, Childhood and Adolescence: A Clinician’s Approach . 2nd ed. San Diego: Academic Press; 2015:chap 16, 289–318. C From Anderson RM, Dennett X, Hopkins IJ, Shield LK. Hypertrophic interstitial polyneuropathy in infancy. J Pediatr . 1973;82:619–624.)