Levels Above Lower Motor Neuron to Neuromuscular Junction

Pathogenesis and Etiology

The acute, early-onset, type 1 form of SMA (Werdnig-Hoffmann disease) and the rare, very severe type 0 form and the later-onset, chronic forms (types 2 and 3) are all related to a genetic defect that involves the q13 region of chromosome 5. The SMA region consists of a large (500-kb) duplication containing two copies of the gene deleted (or mutated) in SMA (i.e., the survival motor neuron [ SMN ] gene; Fig. 36.1 ). Thus on each chromosome 5 there are two copies of SMN: telomeric ( SMN1 ) and centromeric ( SMN2 ) copies. The deletions involve the telomeric copy. Homozygous deletions involving exon 7 of the SMN1 gene occur in approximately 95% of cases of SMA, regardless of type with the remaining cases harboring a deletion in one allele and a heterozygous point mutation in the other allele (compound heterozygotes) ( Table 36.1 ). The nearly identical SMN2 gene, which contains a single nucleotide change in exon 7 (a C-to-T transition) that profoundly influences splicing, produces primarily 90% to 95% of a truncated nonfunctional SMN protein and only approximately 5% to 10% of the normal full-length protein. Because of the genomic instability of this duplicated region of chromosome 5, SMN2 copy number may increase or decrease in the presence of the deleted SMN1 gene. The importance of this phenomenon in this context is that abundant evidence in animal models and now in humans shows that the copy number of SMN2 is the most critical determinant of the severity of the SMA phenotype . Children with SMA carry various SMN2 copy numbers: of patients with SMA type 1, 80% to 96% carry one or two SMN2 copies (more than 70% carry two SMN2 copies) and 4% to 20% have three copies; of patients with SMA type 2, 82% have three copies of SMN2; and of patients with SMA type 3, 96% to 100% have three or four copies of SMN2 ( Fig. 36.2 ). However, SMN2 copy number is not always an accurate predictor of phenotype. Other contributing factors may include modifier genes affecting the motor neurons and mutations in the SMN2 gene that alter the amount of full-length SMN protein it produces. Even among family members who carry the same number of SMN2 copy numbers, variation is observed, suggesting that modulators of SMN2 splicing and other modifier genes may be involved.

The biological functions of SMN1 and its relationship with SMA have been elucidated. The SMN protein interacts with other proteins in a multimolecular complex and appears to be involved principally in messenger RNA (mRNA) metabolism. The most critical function of SMN is in the assembly of the ribonucleoproteins of the so-called spliceosome, which is critically involved in the removal of introns from pre-mRNA and splicing together of exons in mature mRNA, for many proteins. The biological functions potentially affected are many, but most recent work suggests that axonal growth and maintenance are key roles. Spinal cord motor neurons are selectively vulnerable to decreased SMN protein. These neurons (as well as others) have long axons and many targets, particularly in large muscles, and may heavily depend on axonal mRNA transport; SMN protein plays a role in axonal mRNA trafficking. Whether the pathogenesis of SMA is due to a splicing defect due to SMN protein deficiency, disruption of an additional axonal SMN function, an unknown function, or a combination of the above is still unknown. Absence of SMN protein in cells is embryonic lethal in mice and other organisms. Why partial SMN deficiency specifically affects motor neurons remains unclear.

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- to 2-week period postnatally.

Neurological Features

The neurological features are highly consistent and striking ( Box 36.4 ). Hypotonia is severe and generalized. Unlike the situation with disorders of the cerebrum and other central causes of hypotonia, weakness is similarly severe. Most infants exhibit generalized weakness, but when it is possible to make a distinction between proximal and distal muscles, a proximal more than distal distribution is discernible. Only minimal movements at hips and shoulders may be elicited in the presence of active movements of hands and feet. The lower extremities are affected more severely than the upper extremities. Involvement of the axial musculature of the trunk and neck is particularly severe, and the resulting deficits are obvious with vertical suspension and pull-to-sit maneuvers ( Figs. 36.3A, B, and C ). Muscle atrophy is also severe and generalized, although the severity may be difficult to appreciate fully in the newborn. Indeed, the replacement of atrophied muscle by connective tissue may further hinder the appreciation of atrophy. Fasciculations of limbs are observed rarely, but an analogous phenomenon may be the characteristic fine rhythmic “tremor” of the extended fingers ( polyminimyoclonus ) most commonly observed in SMA types 2 and 3. Total areflexia is the rule, although rarely some reflex response, albeit depressed, can be elicited.

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. 36.4 ). The chest is almost always anteriorly collapsed and bell shaped, with an associated distention of the abdomen and intercostal recession during inspiration (see Fig. 36.4 ), 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.

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 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 of 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 SMA type 1 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 33 ) (autosomal recessive), and (3) congenital arthrogryposis, both with and without bone fractures (autosomal recessive and X-linked, respectively). None of these disorders is linked to the genetic region on chromosome 5 involved in SMA type 1 (see later discussion).

Course

The course of SMA type 1 is a close function of the age of onset. Infants with clear prenatal onset of very severe disease with respiratory failure at birth, marked diffuse weakness, and early deficits of facial movement (i.e., SMA type 0) usually die by 3 months of age. Those infants with clinical onset in the first 2 months of life have a range of median age at death of 4 to 8 months, with maximum survival rarely exceeding 12 to 18 months. Infants with clinical onsets after 2 months of age have clearly longer median and maximum survival times. In a natural history study of 34 children with SMA type 1 conducted by the Pediatric Neuromuscular Clinical Research Network between 2005 and 2009, the median age at which the combined endpoint of death or permanent ventilation was reached was 13.5 months (interquartile range = 8.1–22 months), and it was 10.2 months in infants with two SMN2 copies ( Table 36.2 ). Authors use various methodologies to report survival in patients with SMA type 1, as seen in Table 36.2 . Survival has improved with aggressive pulmonary care and nutritional support and, of course, with disease-modifying treatments. The very high survival rates noted in certain groups of patients with SMA type 1 (see Table 36.2 ) may be related specifically to invasive ventilation via tracheostomy and aggressive “proactive” care; however, these rates may also be related to the small number of patients in the reports.

Although infants who ultimately prove to have SMA type 2 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 independently and standing or even walking with support, with prolonged survival. This portion of the SMA type 2 cases usually can be distinguished from SMA type 1 in the early stages of the disease because of a more insidious onset and slower initial deterioration. Death in SMA type 1 usually relates to intercurrent respiratory complications. These complications are caused by aspiration because of defective swallowing, hypoventilation because of impaired intercostal muscle function, and impaired clearing of tracheal secretions secondary to weak or absent cough because of weak abdominal muscles.

Serum Enzymes

The creatine kinase (CK) level is usually normal in SMA type 1 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 34.4 ). 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 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 SMA type 1 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 34 ). Characteristically, pronounced atrophy of all fibers of both types within entire fascicles of muscle (i.e., panfascicular atrophy ) or large group atrophy occurs ( Fig. 36.5 ). The early signs of denervation (i.e., loss of checkerboard appearance, type grouping, or small group atrophy; see Chapter 34 ), features of anterior horn cell disease later in childhood, are nearly absent ( Fig. 36.6 ). This virtual absence of signs of terminal axonal sprouting and reinnervation (see Chapter 34 ) 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. 36.6 ). 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 almost all cases (see later).

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, fasciculations). 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 36.5 ). 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. 36.7A,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.

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 SMA type 1.

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 overt 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

SMA type 1 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 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 (J.J.V.), 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. Most important, perhaps, the issues related to disease-modifying treatments are addressed (see next section).

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 36.4 ) 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 may demonstrate signs of denervation (see Chapter 34 ). Frequently, however, it becomes very difficult to interpret the EMG findings because of secondary nonspecifc changes related to muscle degeneration and fibrosis. The diagnostic yield of a muscle biopsy is also very low for similar reasons. 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 imaging studies. Once a structural lesion(s) has been excluded, given the high frequency of cases with genetic etiology, genetic testing in the form of an arthrogryposis gene panel and probably a non-5q SMA panel should be pursued. Nevertheless, if SMA type 0 is suspected clinically, 5q SMA/ SMN gene testing should be ordered first. Rapid exome sequencing might be an option also, if available.

Onset

Onset of 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 SMA type 1 is considered as the probable diagnosis. The concurrence of fasciculations of 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

Without enzyme replacement therapy (ERT), 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 usually related to a combination of cardiac involvement and respiratory complications caused by thoracic muscle weakness and bulbar paralysis.