Spinal Muscular Atrophy Types I–IV

Spinal muscular atrophy types I–IV are allelic disorders of the survival motor neuron (SMN) gene 1 located on chromosome 5q12.2-q13.3. When there is more than one affected individual in a given family, the phenotype is typically homogeneous but may be disparate in some cases. In normal individuals, there are two copies each of the SMN1 and SMN2 genes. Both genes produce similar but not identical proteins; the SMN2 gene appears to produce an unstable and rapidly degrading protein that can partially compensate for the lack of the SMN1 protein. There are no known clinical consequences from mutations of the SMN2 gene alone.

It is estimated that 95% of SMA I–III patients are homozygous for deletion of exons 7 and 8 of the SMN1 gene. The remainder are thought to be compound heterozygotes with absence of exons 7 and 8 on one allele and a point mutation of the other SMN1 allele. The severity of the SMA phenotype appears to be related to the number of SMN2 copies available to compensate for deleted SMN1 gene. Homozygotes devoid of SMN1 who harbor two copies of SMN2 tend to manifest as an SMA I phenotype. An increasing number of SMN2 copies correlates with proportionately milder (SMA II-IV) forms of the disease. Individuals homozygous for the SMN1 mutation with five copies of the SMN2 gene have been reported to be asymptomatic. Why motor neurons remain selectively vulnerable to SMN deficiency remains unknown.

Of the multiple SMA phenotypes, the infantile and childhood forms are the most prevalent. SMA type I or Werdnig–Hoffman disease is the most severe form (Fig. 68-1). Clinical manifestations become evident within the first 6 months of life. In contrast to the latter three categories, afflicted children with SMA I never develop the capability of sitting independently. In some cases, recognition of reduced movement occurs in utero or within the first few days of life. Affected infants are hypotonic with a symmetric, generalized, or proximally predominant pattern of weakness. Like ALS, facial weakness is typically mild and extraocular muscles are spared. Fasciculations are seen in the tongue but rarely in limb muscles, presumably because of the ample subcutaneous tissue of neonates. Manual tremor, so characteristic of SMA types II and III, is rarely present. Deep tendon reflexes are typically absent. Abdominal breathing, a weak cry, and a poor suck are commonplace. Ventilation difficulties stem primarily from intercostal rather than diaphragmatic weakness. Pectus excavatum and a diminished anteroposterior diameter of the chest are seen. Mild contractures may occur but arthrogryposis is not part of the classic phenotype. Intellectual development is normal. Without mechanical ventilation, death is inevitable, almost always within a year or two. An earlier age of onset correlates with a shorter life expectancy.

Figure 68-1 Spinal Muscular Atrophy Type 1.

SMA type Ia refers to a severe form of neonatal SMA associated with arthrogryposis multiplex congenita and a paucity of movement. Prognosis is poor with ventilatory support required at birth.

The intermediate form or SMA II typically begins between 6 and 18 months of age. The disorder is clinically defined by a child who sits independently but never walks. Postural hand tremor is the only significant phenotypic variance from Werdnig–Hoffman disease. Tongue fasciculations, areflexia, and a generalized to proximally predominant and symmetric pattern of weakness mimic the SMA I phenotype. Approximately 98% of these individuals survive to age 5 and two thirds to age 25. In view of the more protracted course and of wheelchair dependency SMA II and SMA III patients commonly acquire kyphoscoliosis and joint contractures (Fig. 68-2).

Figure 68-2 Pathologic Anatomy of Scoliosis.

The SMA III or the Kugelberg–Welander syndrome differs from the intermediate form only in the age of onset, milestones achieved, and life expectancy. Affected individuals develop the ability to stand and walk. Onset age is typically 18 months or more. Certain authors have attempted to divide SMA III into type a and type b, based on age at onset of symptoms, with the intention of better defining the natural history in individual patients. In SMA type IIIa, defined as symptom onset before 3 years, it is estimated that 70% will remain ambulatory 10 years after symptom onset. Twenty percent will still ambulate in 30 years after symptom onset. In SMA type IIIb, defined as symptom onset after 3 years, virtually all patients will remain ambulatory in 10 years and 60% at 40 years after symptom onset. Life expectancy extends into the sixth decade and may be normal in many individuals. Initial symptoms are typically related to proximal weakness. Hand tremor, areflexia, and tongue fasciculations are commonplace. Fasciculations in limb muscles are more evident than in SMA types I and II.

Adult-onset SMA IV is a rare, genetically heterogeneous disorder. SMA IV children achieve motor milestones at normal ages. Onset of weakness is typically in the third or fourth decade in the recessively inherited cases. Initial symptoms are typically proximal weakness of the lower extremities, particularly the hip flexors, hip extensors, and knee extensors. Shoulder abductors and elbow extensors are the most frequently affected muscles of the arms. Tongue fasciculations, hand tremor, and in some cases, calf hypertrophy may occur. Life expectancy in SMA IV is normal. Parents with SMA IV have given birth to children with more severe SMA phenotypes.

Spinal Muscular Atrophy with Respiratory Distress (SMARD1)

This is a rare disorder in which infants develop diaphragmatic weakness and ventilatory weakness in addition to hypotonia.

X-Linked Bulbospinal Muscular Atrophy (SBMA)—Kennedy Disease

SBMA is an X-linked disorder associated with an androgen receptor gene mutation. Consequently, it has frequent endocrine as well as neuromuscular consequences, the latter providing the primary source of morbidity.

SBMA is an X-linked, adult-onset disorder that is depicted in the vignette at the beginning of this chapter. It is a disorder almost exclusively of males with a median age of onset of 44 years. Initial symptoms are usually attributable to weakness of bulbar or proximal limb muscles. Younger men, and rarely female carriers, may be symptomatic but may go undiagnosed unless there are other previously diagnosed family members.

As the name implies, the clinical manifestations are largely referable to degeneration of the lower cranial nerve motor nuclei and anterior horn cells of the spinal cord. The weakness progresses insidiously and is proximally predominant and symmetric in pattern. Typically, symptoms referable to the lower extremities have the greatest initial impact. Approximately 10% of the time, the initial symptoms pertain to difficulty with swallowing, chewing, or speaking. Facial weakness is common. Jaw drop due to muscles of mastication may occur as well. Perioral and tongue fasciculations are common and represent helpful clinical clues. Like ALS, ptosis and ophthalmoparesis should suggest an alternative diagnosis. Like other SMAs, postural tremor is common. There is an associated, but frequently asymptomatic, sensory neuropathy that may only be recognized by nerve conduction studies. Clinical heterogeneity exists. Asymmetry of muscle weakness at onset has been emphasized by some authors. Occasionally, rapidly progressive weakness occurs. The median age of wheelchair dependency is 61 years or approximately 15 years after onset of weakness. Women who are heterozygous for Kennedy disease mutation may rarely be symptomatic.

The effects of SBMA are not restricted to the neuromuscular system. Affected males suffer the consequences of androgen insensitivity, including gynecomastia, impotence, testicular atrophy, and potential infertility. There is also an increased incidence of diabetes mellitus.

Juvenile Segmental Spinal Muscular Atrophy—Benign Focal Amyotrophy—Hirayama Disease

Unlike other SMAs, Hirayama disease appears to be a sporadic disorder in the majority of cases. In 1963, Hirayama described a slowly progressive, focal motor neuron disease affecting one, and at times, both upper extremities. In this and subsequent descriptions, males are affected in 60% of cases. Hirayama disease is perhaps best considered as a segmental or regional form of spinal muscular atrophy. Onset is typically between ages 15 and 25 with a range of 2 to 30 years. Although most commonly reported in those of Asian origin, it may occur in any ethnic background.

The characteristic phenotype is the insidious development of atrophy and weakness in C8–T1 muscles of the hand and forearm. It begins unilaterally, typically in the dominant extremity. Over the course of months to years, the weakness may gradually spread to involve more proximal muscles. In a third of cases, there is clinical weakness of the opposite limb. An even higher percentage will have bilateral upper extremity involvement on electrodiagnostic studies. Tendon reflexes in the involved limb may be spared, although neither overt pyramidal or bulbar involvement occurs. Reflex preservation may reflect the restricted nature of the disease and the lack of a reliable C8–T1 muscle stretch reflex. Like many other SMAs, tremor may occur. In most cases, there is an arrest of further progression after 6 years or less. Although a significant decline in affected limb function in the cold is common with all motor neuron diseases, “cold paresis” is particularly emphasized in this population. Hyperhidrosis of the involved limb has been described.

Hirayama disease is less frequently seen in Western populations. Ischemic changes in the cervical spinal cord of a single autopsied case of Hirayama disease led to the hypothesis of a compressive mechanism. In 2000, Hirayama reported the results of dynamic imaging in 73 patients and 20 controls. Ninety-four percent of patients had significant forward displacement and flattening of the posterior surface of the cervical cord during neck flexion (Fig. 68-3). The presumption is that the blood supply to the spinal cord is compromised, with the anterior horn representing the watershed and the most susceptible to ischemia. Other observations that supported this potential mechanism are the frequent asymmetric nature of spinal cord flattening in keeping with the asymmetric disease onset, and the lesser degree to which distortion occurred in older patients in whom progression had arrested. Nonetheless, this pathogenetic hypothesis is not universally accepted.

Figure 68-3 Hirayama Disease.

Scapuloperoneal Form of SMA (Davidenkow Disease)

A scapuloperoneal pattern of weakness may result from either neurogenic or myopathic disorders. The neurogenic form of the scapuloperoneal syndrome has been referred to by the eponym Davidenkow disease. It has been considered to represent a SMA variant even though distal sensory loss was common in Davidenkow’s original series. Symptomatic onset typically occurs in late childhood related to asymmetric weakness of scapular fixators or foot dorsiflexors. Weakness typically progresses into a more generalized pattern. Some patients with a neurogenic scapuloperoneal syndrome have been found to have mutations within the PMP-22 gene. This suggests that the disorder might be more correctly characterized as a hereditary neuropathy.

Distal SMA (Hereditary Motor Neuronopathy, Spinal Forms of Charcot–Marie–Tooth Disease)

Distal SMA (dSMA) is usually inherited in a dominant fashion in one third of cases but may have recessive or X-linked pattern as well. There are numerous genetic loci (Table 68-1). Like hereditary spastic paraparesis, distal SMA can be either “pure” or “complicated” based upon other neurologic system involvement. Complicated phenotypes may include diaphragmatic paralysis, vocal cord paralysis, and arthrogryposis.

Table 68-1 Genetics of Spinal Muscular Atrophies

Harding and Thomas introduced the concept of dSMA in 1980. The dSMAs have been perceived as progressive, hereditary disorders producing distal symmetric weakness in the absence of either clinical or electrodiagnostic sensory loss. The dSMAs have also been referred to as hereditary motor neuropathies but are considered to be anterior horn cell disorders in view of their pure motor manifestations. Distal SMA strongly resembles Charcot–Marie–Tooth (CMT) disease without sensory involvement. In fact, at least three forms of dSMA are allelic to recessively inherited forms of CMT. Weakness in distal SMA typically predominates in ankle dorsiflexors and evertors and toe extensors. Foot deformities characteristic of CMT are also common. Hand muscles may eventually become involved. There are a number of recognized dSMA genotypes (see Table 68-1).

Poliomyelitis

Poliomyelitis is a viral infection with tropism for gray matter of the spinal cord and motor cranial nuclei. Poliomyelitis translates literally into inflammation of spinal cord gray matter. It is often used synonymously with paralytic polio caused by the polio virus. In this chapter, it will refer to any viral infection with a predilection for anterior horn cells or motor cranial nerve nuclei. Polio may be either a monophasic or biphasic disease. The initial symptoms are nonspecific, last 1–2 days, and are predominantly constitutional and/or gastrointestinal in nature. They consist of fever, malaise, pharyngitis, headache, nausea, vomiting, and abdominal cramping (Fig. 68-4). In the majority of infected individuals, the illness is self-limited and ends at this point. In individuals who fall victim to the “major” illness, symptoms of brain or spinal cord involvement develop 3 to 10 days subsequent to the initial symptoms. The major illness is defined by CNS involvement with meningoencephalitis, with or without an associated paralytic component. Stiff neck, back pain, and fever are prominent; encephalitis with altered mental status can also be seen.

Figure 68-4 Pathogenesis of Poliomyelitis.

In individuals destined to develop paralytic disease, myalgias and cramping rapidly evolve into muscle weakness. The progression reaches its nadir within 48 hours of onset. The paralysis is typically asymmetric. It is confined to the limbs and trunk in half of the cases. There is a predilection for lumbosacral segments and proximal more than distal muscles (Fig. 68-5). Ten percent of cases have bulbar weakness only. Children are particularly susceptible to bulbar polio. Motor functions of the 7th, 9th and 10th cranial nerves are most likely to be affected. Ten percent of patients will manifest both spinal and bulbar weakness; ventilatory failure is more common in this group. Affected limbs are flaccid and areflexic. Like virtually all motor neuron disorders, the 3rd, 4th, and 6th cranial nerves are spared. Sensory signs and symptoms are atypical. In keeping with the known pathological involvement of the brainstem tegmentum and hypothalamus in cases with encephalitic components, clinical dysautonomia including fluctuating blood pressure, cardiac arrhythmia, and hyperhydrosis may occur.

Figure 68-5 Poliomyelitis.

The natural history of paralytic polio is variable, dependent in large part on the severity and extent of the initial illness. As in GBS, less than 10% of individuals will die from the acute illness. Acute mortality typically results from ventilatory failure or the complications of immobility. Those who survive typically regain strength inversely proportionate to the severity of the initial illness. The majority of this recovery takes place over the course of weeks to months, presumably due to reinnervation from neighboring motor units not affected by the disease.

The postpolio syndrome (PPS) has been recognized since 1875 but received no more than cursory attention until 1981 when interest escalated in response to the large numbers of people affected by the epidemics of the early 1940s who were now experiencing new symptoms. Current evidence suggests that patients who develop postpolio muscular atrophy do so because of the loss of anterior horn cells that occur as a consequence of normal aging superimposed upon a depleted reserve. There is convincing evidence that some individuals with prior polio may develop slowly progressive weakness (average decline 1%/year) after a protracted period of stability. How frequently this postpolio muscular atrophy (PPMA) occurs as a manifestation of PPS is a matter of some controversy. In one study, 50 prior polio patients were selected from a cohort of 300 patients and followed for 5 years. Sixty percent of this group developed symptoms. Of this symptomatic group, only a third had symptoms attributed to musculoskeletal complaints and none of these had measurable evidence of progressive atrophy and weakness. When PPMA occurs, it typically manifests in the regions most severely afflicted by the initial illness. Ventilatory function may decline, with one study suggesting an approximate 2% loss of vital capacity a year in keeping with the slowly progressive nature of the illness. Criteria have been established to solidify a PPMA diagnosis. These include objective measures of declining strength, muscle atrophy, and fatigue following a documented polio-like illness. This must occur subsequent to a protracted period of stability in absence of an alternative explanation.

There is no “gold standard” to determine which polio victims have developed PPMA. Consequently, estimates of the prevalence of PPS have ranged from 22 to 85%. Signs and symptoms of PPS have been reported to begin as early as 8 years after the initial illness or as late as 71 years with an average of 35 years. The likelihood of developing PPS seems to correlate with both the age of the patient at the time of the initial illness, as well as its severity.

West Nile Virus

West Nile virus (WNV) is a mosquito-borne viral pathogen of the Flavivirus family. Like polio, most infected individuals develop a minor, nonspecific illness that often includes fever, gastrointestinal complaints, back pain, and rash in addition to potential neurologic manifestations. A number of reports have linked WNV to a poliomyelitis-like phenotype that may affect facial as well as limb muscles with or without an associated meningo-encephalitic component. Approximately half of patients will develop flaccid weakness over a 3- to 8-day period that tends to be proximal and asymmetric in distribution. Electrophysiological and pathologic observations have suggested that this weakness originates from anterior horn cell injury. Confounding these observations are reports that the West Nile virus may produce Guillain–Barré and transverse myelitis phenotypes. Like the poliovirus, varying degrees of irreversible paralysis may result. Other agents that have been reported to cause poliomyelitis include enterovirus 71, acute hemorrhagic conjunctivitis, Coxsackie virus group A type 7, echovirus type 6, and the Japanese encephalitis virus. Rabies may also present as a paralytic illness in 20% of cases, with paralysis typically beginning in the bitten extremity.

Multifocal Motor Neuropathy

The majority if not all of the evidence available to date suggests that multifocal motor neuropathy (MMN) is an immune-mediated neuropathy resulting from multifocal myelin loss in peripheral motor axons. This selective vulnerability hypothetically exists because of a glycolipid epitope that is unique to or predominantly found in the myelin of peripheral motor nerves. Although antiganglioside antibodies are found in the serum of 30–80% of individuals with the MMN phenotype, a pathogenetic role for these antibodies remains unproven. Reduction in antiganglioside antibody levels does not correlate with disease responsiveness in all patients. Conversely, patients with the MMN phenotype who are seronegative appear to respond equally well to immunomodulating treatments.

MMN is characterized as a multifocal, pure motor, acquired immune mediated motor neuropathy. Despite this anatomic localization, it is more likely to be considered in the differential diagnosis of a motor neuron disease than a peripheral neuropathy. Like ALS it presents with painless weakness in a single limb, often in distal muscles in the upper extremity. Cramps and fasciculations may occur providing an additional phenotypic overlap with ALS. Like ALS, muscle stretch reflexes may be lost in an affected extremity. The clinical features that are most useful in distinguishing MMN from ALS include slower progression, the absence of unequivocal upper motor neuron signs, weakness without atrophy, nerve rather than segmental pattern of muscle weakness, and absence of signs attributable to cranial nerve dysfunction. The latter have been only reported as a rare consequence of MMN. Unfortunately with disease progression, these diagnostic clues may become obscured. On average, untreated MMN progresses much more slowly than ALS.

Hereditary Spastic Paraplegia

There are in excess of 30 different gene mutations associated with the hereditary spastic paraplegia (HSP) phenotype. Autosomal dominant, recessive, and X-linked modes of transmission are recognized. The multiple genotypes underlying HSP suggest that there is a common mechanism by which mutations of different proteins translate into an identical or near-identical phenotype. A uniform final common pathway, however, is yet to be defined. Proposed mechanisms include disturbances in axon transport, impaired Golgi function, mitochondrial dysfunction, disordered myelin synthesis, and maturational disturbances of the corticospinal tracts. Some of these hypotheses are based upon the intracellular positioning of affected proteins. The pathology of HSP would support its conceptualization as a “dying back myelopathy.”

HSP is a slowly progressive upper motor neuron (UMN) disorder of the lower extremities. Like other heritable disorders, other affected family members may not be readily identifiable. The presenting symptoms of HSP occur as a consequence of lower extremity spasticity that is symmetric in its distribution. Patients lose the ability to run or hop early in the course because of increased lower extremity extensor tone and the inability to flex the hip or knee in a facile manner. As a result, stride length is reduced. The legs tend to “scissor,” that is, cross over each other because of increased tone of thigh adductor muscles. Circumduction, that is, advancing the leg in a circular rather than a linear motion, is done for compensatory reasons to avoid tripping on a foot that maintains an inverted and plantar flexed posture. Leg strength may be diminished; weakness occurs in an “upper motor neuron” pattern, with hip flexors, knee flexors, and foot dorsiflexors being affected to the greatest extent. Hyperreflexia of the lower extremities is a universal feature, almost always accompanied by extensor plantar responses. Hyperreflexia of the upper extremities with Hoffman’s signs and reflex spread are common as well. Weakness, increased tone, impaired coordination or loss of function of the upper extremities, and cranial nerve dysfunction occur infrequently in pure HSP and should lead to consideration of an alternative diagnosis. Posterior column involvement with loss of vibratory sense in a length-dependent pattern in the lower extremities may be seen. Urinary frequency, urgency, and urgency incontinence are common symptoms even within the “pure” forms of the disease. Rectal urgency and incontinence and sexual dysfunction are less common but do occur. High arched feet and hammer toe deformities, a feature of a number of chronic neurologic diseases, are a common feature of the illness. Onset and severity of HSP varies considerably both within and between families. Initial symptoms may be recognized in any decade of life. The reasons for variations of disease onset and severity of affliction, both within and between families of the same genotype, are not currently understood although other “disease-modifying” genes are hypothesized to have a role.

Miscellaneous Causes of Motor Neuron Disease

Motor neuron disease phenotypes have occurred in association with other disorders. Understandably, little is known of the pathogenesis of these disparate and relatively uncommon disorders. Postirradiation neuropathy is frequently a pure motor syndrome; current evidence, including reports of root enhancement on MR imaging in some patients, favors a polyradiculopathy as the proposed pathomechanism. Radiation injury of the peripheral nervous system is typically delayed in onset with an average latency between exposure and symptoms of 6 years. The range, however, is exceedingly broad, with onset latency varying between 4 months and 25 years. Radiation doses typically exceed 4000 cGY in these patients.

Motor neuron disease may rarely occur as a paraneoplastic disorder or as a potential complication in irradiated Hodgkin patients. The latter is referred to as subacute motor neuronopathy to emphasize the presumed anterior horn cell localization. Motor deficits predominate in most cases. In the lower extremity, where bilateral exposure to nerve elements is the norm, the deficits are typically bilateral and asymmetric. Monomelic presentations do occur.