Spinal Muscular Atrophy

Background The spinal muscular atrophies (SMAs) comprise a group of autosomal-recessive disorders characterized by progressive weakness of the lower motor neurons. In the early 1980s, Werdnig and Hoffman described a disorder of progressive muscular weakness beginning in infancy that resulted in early death, though the age of death was variable. In pathologic terms, the disease was characterized by loss of anterior horn cells. The central role of lower motor neuron degeneration was confirmed in subsequent pathologic studies demonstrating a loss of anterior horn cells in the spinal cord and cranial nerve nuclei.[1] Since then, several types of spinal muscular atrophies have been described based on age when accompanying clinical features appear. The most common types are acute infantile (SMA type I, or Werdnig-Hoffman disease), chronic infantile (SMA type II), chronic juvenile (SMA type III or KugelbergWelander disease), and adult onset (SMA type IV) forms. The genetic defects associated with SMA types I-III are localized on chromosome 5q11.2-13.3.[2, 3, 4, 5] Many classification systems have been proposed and include variants based on inheritance, clinical, and genetic criteria. Among these are the Emery[6] , Pearn[7] , and International SMA Consortium system[8] . The ISMAC system is most widely accepted and is used in this review. Pathophysiology In 1995, the spinal muscular atrophy disease-causing gene, termed the survival motor neuron (SMN), was discovered.[9] Each individual has 2 SMN genes, SMN1 and SMN2. More than 95% of patients with spinal muscular atrophy have a homozygous disruption in the SMN1 gene on chromosome 5q, caused by mutation, deletion, or rearrangement. However, all patients with spinal muscular atrophy retain at least 1 copy of SMN2, which generates only 10% of the amount of full-length SMN protein versus SMN1. This genomic organization provides a therapeutic pathway to promote SMN2, existing in all patients, to function like the missing SMN1 gene.[10] Epidemiology Frequency United States The spinal muscular atrophies are the second most common autosomal-recessive inherited disorders after cystic fibrosis. The acute infantile-onset SMA (type I) affects approximately 1 per 10,000 live births; the chronic forms (types II and III) affect 1 per 24,000 births. SMA types I and III each account for about one fourth of cases, whereas SMA type II is the largest group and accounts for one half of all cases. [11] International The incidence of spinal muscular atrophy is about 1 in 10,000 live births with a carrier frequency of 1 in 50.[7, 12] Mortality/Morbidity The mortality and/or morbidity rates of spinal muscular atrophy are inversely correlated with the age at onset. High death rates are associated with early onset disease. In patients with SMA type I, the median survival is 7 months, with a mortality rate of 95% by age 18 months.

Respiratory infections account for most deaths. In type II SMA, the age of death varies, but death is most often due to respiratory complications. See Prognosis for more information. Sex Male individuals are most frequently affected, especially with the early-onset forms of spinal muscular atrophy, ie, types I and II.[13] 1

Age The ISMAC classification system is based on the age of onset.[8] See Background, History, and Physical for a review of the existing classification systems and a brief discussion of their relevancy to the role of age in spinal muscular atrophies. According to the ISMAC system, the age of onset for spinal muscular atrophies is as follows:

SMA type I (acute infantile or Werdnig Hoffman): Onset is from birth to 6 months. SMA type II (chronic infantile): Onset is between 6 and 18 months. SMA type III (chronic juvenile): Onset is after 18 months. SMA type IV (adult onset): Onset is in adulthood (mean onset, mid 30s). History The diagnosis of spinal muscular atrophies includes the following a detailed clinical history. Obtaining a complete family history facilitates genetic counseling. Patients with spinal muscular atrophy present with weakness and muscle wasting in the limbs, respiratory, and bulbar or brainstem muscles. They have no evidence of cerebral or other CNS dysfunction. Patients with spinal muscular atrophy often have above-average intelligence quotients (IQs) and demonstrate high degrees of intelligence. The clinical manifestations of each particular form of spinal muscular atrophy are discussed:[14, 2, 15, 16, 17] SMA type I - Acute infantile or Werdnig-Hoffman disease Patients present before 6 months of age, with 95% of patients having signs and symptoms by 3 months. They have severe, progressive muscle weakness and flaccid or reduced muscle tone (hypotonia). Bulbar dysfunction includes poor suck ability, reduced swallowing, and respiratory failure. Patients have no involvement of the extraocular muscles, and facial weakness is often minimal or absent. They have no evidence of cerebral involvement, and infants appear alert. Reports of impaired fetal movements are observed in 30% of cases, and 60% of infants with SMA type I are floppy babies at birth. Prolonged cyanosis may be noted at delivery. In some instances, the disease can cause fulminant weakness in the first few days of life. Such severe weakness and early bulbar dysfunction are associated with short life expectancy, with a mean survival of 5.9 months. In 95% of cases, infants die from complications of the disease by 18 months. SMA type II - Chronic infantile form This is the most common form of spinal muscular atrophy, and some experts believe that SMA type II may overlap types I and III. Most children present between the ages of 6 and 18 months. The most common manifestation that parents and physicians note is developmental motor delay. Infants with SMA type II often have difficulties with sitting independently or failure to stand by 1 year of age. An unusual feature of the disease is a postural tremor affecting the fingers. This is thought to be related to fasciculations in the skeletal muscles. Pseudohypertrophy of the gastrocnemius muscle, musculoskeletal deformities, and respiratory failure can occur. The lifespan of patients with SMA type II varies from 2 years to the third decade of life. Respiratory infections account for most deaths. SMA type III - Chronic juvenile or Kugelberg-Welander syndrome This is a mild form of autosomal recessive spinal muscular atrophy that appears after age 18 months. SMA type III is characterized by slowly progressive proximal weakness. Most children with SMA III can stand and walk but have trouble with motor skills, such as going up and down stairs. 2

Bulbar dysfunction occurs late in the disease. Patients may show evidence of pseudohypertrophy, as in patients with SMA type II. The disease progresses slowly, and the overall course is mild. Many patients have normal life expectancies. SMA type IV - Adult-onset form Onset is typically in the mid 30s. In many ways, the disease mimics the symptoms of type III. Overall, the course of the disease is benign, and patients have a normal life expectancy. Physical Patients with disease of the lower motor neurons present with flaccid weakness, hypotonia, decreased or absent deep tendon reflexes, fasciculations, and muscle atrophy. SMA type I - Acute infantile or Werdnig-Hoffman disease Diffuse muscle weakness and hypotonia can be demonstrated with a variety of bedside maneuvers, including the traction response, vertical suspension, and horizontal suspension tests. In general, infants with SMA type I cannot hold their heads up when pulled to the sitting position, and they will slip through the examiner's hands when held vertically. They lay limp in the physician's hand when held under the abdomen and facing down. Weakness is greater in proximal than distal muscles and may mimic muscle disease (myopathy). Findings on sensory examination are normal. Deep tendon reflexes are absent, as are long-tract signs and sphincteral abnormalities. Arthrogryposis, or deformities of the limbs and joints at birth, can be observed and results from in utero hypotonia. Skeletal deformities (scoliosis) may be present. In the infant or newborn, fasciculations are often restricted to the tongue, but tongue fasciculations can be difficult to distinguish from normal random movements unless atrophy is also present. SMA type II - Chronic infantile form Infants cannot get to a sitting position on their own, though they may stay upright if placed in that position. As with SMA type I, SMA type II cause notable, symmetric proximal weakness, hypotonia, and fasciculations. Findings on sensory examination are normal, and long-tract signs are absent. When the patient's hands are held out, a characteristic fine postural tremor may be observed. SMA type III - Chronic juvenile or Kugelberg-Welander syndrome Children can ambulate, but they have proximal muscle weakness and various degrees of muscle hypotonia and wasting. The lower extremities are often more severely affected than the upper extremities. SMA type IV - Adult-onset form Patients are similar to those with SMA type III in presentation and clinical findings, though the overall degree of motor weakness is less severe in type IV than in type III. Spinal muscular atrophy variants

Juvenile bulbar palsy, or bulbar hereditary motor neuronopathy (HMN) types I and II: Bulbar HMN I (Vialletto-van Laere syndrome) is an autosomal recessive syndrome that begins in the second decade of life. It is characterized by facial weakness, dysphagia and dysarthria followed by facial weakness and 3

compromised respiratory function. The distinguishing feature of this syndrome is the development of bilateral sensorineural hearing loss. Bulbar HMN II (Fazio-Londe disease): This is characterized by progressive bulbar paralysis in the first decade of life. Patients present with stridor, dysarthria, and dysphagia. Cranial-nerve involvement leads to facial diplegia, ptosis, and ophthalmoplegia. Generalized weakness of the lower motor neurons and rare corticospinal-tract signs are sometimes observed. Median survival for patients with bulbar HMN II is 18 months.[18] Distal spinal muscular atrophy (spinal CMT or HMN type II): This may clinically mimic Charcot-Marie-Tooth (CMT) disease, otherwise known as hereditary motor and sensory neuropathy (HMSN) types 1 and 2: CMT is characterized by peroneal muscular atrophy, weakness, and wasting in the legs. High foot arches (pes cavus) are often present. Deep tendon reflexes are reduced or absent. Distal large fiber sensory loss is found on examination, although patients do not usually present with complaints of subjective sensory loss. Compared with CMT, patients with distal spinal muscular atrophy do not have sensory loss and the electrodiagnostic examination shows sparing of sensory nerves.[4] X-lined recessive bulbospinal muscular atrophy (Kennedy disease):[19]Patients present with bulbar weakness, gynecomastia, and lower motor neuron weakness beginning at age 20-40 years. Muscles cramps often precede weakness, and facial and perioral fasciculations are seen in more than 90% of patients. Increased rates of type 2 diabetes, infertility, and hand tremor are associated with Kennedy disease. This condition results from a triple repeat mutation (cytosine-adenine-guanine [CAG]) in exon 1 of the androgen receptor gene on the X chromosome. Because of the X-linked nature of Kennedy disease, daughters of affected patients are obligated carriers; therefore, genetic counseling is indicated. Scapuloperoneal spinal muscular atrophy: Type 1 (AD form) appears at age 14-26, with weakness, distal leg atrophy, and absent tendon reflexes and sparing of intrinsic foot muscles. Facial, bulbar, and pectoral muscles are rarely affected. Progression is slow, with survival into the seventh or eight decade of life. Type 2 (AR form): Patients present between birth and age 5 years, with weakness and atrophy of the lower extremities and pectoral girdle. The course is variable, and patients can survive to the fourth decade.[20] X-linked form scapuloperoneal spinal muscular atrophy: This has been described with an onset before age 10 years. Patients present with weakness of the pectoral girdle and arms with contractures. Cardiac conduction defects and cardiomyopathy are noted. The syndrome is slowly progressive but stabilizes by age 20 years, and patients survive to the sixth decade. Davidenkow syndrome: This is a form of scapuloperoneal SMA characterized by weakness of the pectoral girdle and distal leg muscles, pes equinovarus, and distal sensory loss and fasciculations. Autosomal dominant (age of onset, 15-30 y) and autosomal recessive (age of onset, < 15 y) forms have been described. The clinical course is slow in the autosomal dominant form, whereas the course of the autosomal recessive form is unknown. Fascioscapulohumeral (FSH) SMA: Most reports of this disorder are from Japan. It is an autosomal dominant or sporadic disorder characterized by limb-girdle and facial weakness occurring before age 20 years. The phenotype of FSH SMA is similar to that of FSH dystrophy (FSHD), another unrelated muscular dystrophy. However, FSH SMA does not have the chromosome 4 gene deletion seen in FSHD. Progression is slow, and the overall prognosis is good. Scapulohumeral spinal muscular atrophy: Described initially in a Dutch family, this autosomal dominant disorder is characterized by the onset of scapulohumeral weakness and atrophy between the fourth and sixth decades of life. Progression is rapid, with death from respiratory failure occurring within 3 years. Oculopharyngeal spinal muscular atrophy: This disorder is seen mainly in people of French-Canadian descent and is characterized by bulbar and cranial-nerve weakness followed by myopathic weakness of the limbs. The pattern of inheritance is autosomal dominant with variable penetrance. The onset is usually in the fourth to fifth decades of life, and the disease is slowly progressive. Ryukyuan spinal muscular atrophy: This is an autosomal recessive disorder described in men who live in the Japanese community on Ryukyu Islands. The onset is before age 5 years, and the disease is characterized by weakness and atrophy of the lower extremities, skeletal abnormalities (eg, scoliosis), and foot deformities (eg, pes cavus). Deep tendon reflexes are diminished or absent. The course of disease is unknown.[21] Other: Other variants have been described, including spinal muscular atrophy with pontocerebellar hypoplasia (PCH), multiple long-bone fractures at birth, diaphragmatic paralysis with early respiratory failure, congenital heart defects, arthrogryposis, segmental amyotrophy, vocal-cord paralysis (distal HMN type VII), and disease of the anterior horn cell with agenesis of the corpus callosum.[22, 23, 24, 24] Causes 4

In 1995, the SMN gene, responsible for SMA types I-III, was mapped to the long arm of chromosome 5. (See Pathophysiology.) Two copies of the SMN gene have been identified on the 5q arm: a telomericSMN gene (SMNt, or SMN1) and a centromeric SMN gene (SMNc, or SMN2). These 2 genes are nearly identical except for base-pair changes in exons 7 and 8. About 95% of all cases of SMA involve a homozygous deletion of theSMN1 gene.[25] Expression of SMN1 produces the full-length SMN protein. In contrast, expression of SMN2 produces a truncated version of the SMN protein that is missing the 16 amino acids from the carboxy terminus. This truncated protein results from a base-pair switch in exon 7 of the SMN2 gene. This switch leads to alternative splicing of SMN2 mRNA, with removal of the exon 7 sequence. About 70-80% of the gene product is in the form of this truncated protein. Only about 10-25% of the protein produced is the full-length functioning form.[25] Deletions or mutations in the SMN1 gene substantially decrease expression of the SMN protein. Expression of SMN2 alone does not appear to produce sufficient amounts of SMN protein to permit normal mRNA processing in the lower motor neurons. Inefficient or abnormal mRNA processing appears to have a toxic effect on the lower motor neurons and results in cellular degeneration.[26] SMN protein is part of a multimeric protein complex that plays a critical role in the assembly of snRNPs. These snRNPs are essential for early pre-mRNA splicing. The hypothesis is that impaired or reduced formation of snRNPs impairs mRNA splicing, with a toxic effect on normal cellular function. Why this mutation results in such selective degeneration of lower motor neurons is unclear, though the SMN protein is expressed in many types of neurons and organ systems.[27] Neuronal apoptosis inhibitory protein (AIP), NAIP, gene was also identified in 1995. Homozygous deletions of this gene are found in 45% of patients with SMA type I and in 18% of patients with SMA types II or III. This gene belongs to a class of highly conserved AIPs that help to regulate programmed cell death. Deletion of this gene appears to be associated with severe phenotypes of SMA.[28] Mutations in BFT2p44 have been found in 15% of patients with SMA

Differentials Amyotrophic Lateral Sclerosis Congenital Muscular Dystrophy Congenital Myopathies Disorders of Carbohydrate Metabolism Myasthenia Gravis Primary Lateral Sclerosis Laboratory Studies Laboratory testing The creatine kinase (CK) level is typically normal in SMA type I and normal or slightly elevated in the other types. CSF findings are normal. Genetic testing Both prenatal and postnatal tests are now commercially available. Tests for chromosome arm 5q should be performed. The 1992 ISMAC found that the accuracy of prenatal prediction by means of chorionic villi sampling and amniocentesis was 88-99%. Caution should be exercised when prenatal prediction is done in the presence of atypical features (see SMA variants in Physical) because these clinical variations may represent other pathogenic processes. 5

Other Tests Most cases spare the cardiac system, and ECGs are normal. Electrophysiologic studies are useful in differentiating the spinal muscular atrophies from other neurogenic and myopathic diseases.[30, 31] With the exception of Kennedy and Davidenkow syndromes, sensory nerve conduction is normal in spinal muscular atrophy. Compound motor action potentials (CMAPs) are low normal or reduced, depending on the severity of disease. In chronically weak muscles, CMAPs may be in the near-normal because of reinnervation and collateral sprouting. Motor velocities are normal. Modest slowing of motor conduction, when present, may accompany severe motor axon loss because of the loss of the fastest-conducting motor fibers. In affected muscles, needle-electrode examination reveals widespread broad and polyphasic motor unit potentials (MUPs) firing in a reduced or rapid neurogenic recruitment pattern. Superimposed low-amplitude, short-duration, and polyphasic MUPs may be present. These configuration changes may resemble myopathic MUPs, but in the case of spinal muscular atrophy are instead due to early MUP reinnervation. Fibrillation potentials may be seen in limb and paraspinal muscles and are most striking in early or progressive spinal muscular atrophy. In late-juvenile and adult-onset forms, active motor axon loss is sparse. Fasciculation potentials are uncommon, but spontaneously firing motor unit action potentials (MUAPs) at 5-15 Hz have been described as a unique feature of SMA I and II. Mild pseudomyotonic discharges have been observed in patients older than 6 years. However, these discharges are not specific for etiology and may be seen in chronic neurogenic disorders.

Procedures Muscle biopsy may necessary to differentiate spinal muscular atrophies from other neuromuscular disorders if genetic analysis is unrevealing. Muscle selection should be centered on clinically affected muscles but not to such a degree that degeneration renders the tissue unrecognizable. Adequate results can be obtained with open or needle biopsy as long as the physician has adequate experience in the procedure and in processing of the tissue. Electron microscopy can be used to evaluate for storage diseases. Histologic Findings Histologic findings depend on the stage and progression of disease. Initial changes include atrophy of muscle fibers with compensatory hypertrophy. This results in groups of large and small fibers (fiber-type grouping). During the first 6-8 weeks of life, differentiating congenital fiber type disproportion and SMA may be difficult. In the chronic forms of SMA, secondary myopathic changes may be seen in addition to type grouping and may histologically resemble the muscular dystrophies.[32, 33] Classic histologic findings include the following:

Degeneration and loss of spinal motor neurons with a neurogenic pattern of muscle morphology Occasional neuronal chromatolysis with loss of myelinated axons in both anterior and posterior roots A disproportionate loss of myelin in the thoracic and lumbar segments (especially in the corticospinal tracts) with relative sparing of the cervical cord Motor neurons in the brainstem, notably in the hypoglossal nucleus. (Reactive gliosis and secondary degeneration in roots and nerves are seen. However, these findings are not necessarily pathognomic for the SMAs.) Medical Care The first report of in vivo activation of SMN2 by valproic acid in 2006 led to a clinical study of 7 patients with genetically-confirmed SMA type III/IV.[34, 35]The results of the clinical trial are summarized as follows:

This was an open-label retrospective trial with examiners blinded to prior strength testing. Patient age ranged from 17-45 years with a mean age of 33 years. Duration of treatment was 8 months at a dose of valproic acid 250 mg twice a day, which was then increased to 500 mg twice a day after 3 months, as tolerated. 6

Treated patients were found to have a mean increase in quantitative muscle strength of 16% compared with normal strength and 48% compared with pretreatment values. Functional benefit was present in 6 of 7 patients; only 1 did not experience any improvement. Follow-up at 1 year showed sustained benefit. The onset of improvement was surprisingly quick, reported within a few months in most with initiation of valproic acid. Common adverse effects included initial sedation and an average weight gain of 5 lb. Larger controlled studies are underway. A randomized, double-blind, placebo-controlled trial in male subjects with genetically confirmed spinobulbar muscular atrophy (Kennedy disease) using oral dutasteride (a 5-alpha-reductase inhibitor that reduces dihydrotestosterone) did not show a significant effect on the progression of muscle weakness.[36] Failure of this treatment trial in spinobulbar muscular atrophy may in part be attributed to the underpowered study and the relatively short period in which treatment effect can be accurately measured because of the slowly progressive nature of this disease. These results also suggest that the role of androgens in spinobulbar muscular atrophy is complex. Supportive treatment should be aimed at improving the patients' quality of life and minimizing disability, particularly in patients with slow progression. The treatment of patients with adult-onset spinal muscular atrophy is similar to that for amyotrophic lateral sclerosis (ALS), except that the course and life span in spinal muscular atrophies is considerably longer. A multidisciplinary approach is essential and encompasses physical, occupational, speech, and respiratory therapies. The use of splints, bracing, and spinal orthoses can be customized to each patient.[37] The goals are to maximize the patient's independence and quality of life at each stage of the disease. Specific pharmacologic therapy is not available. Gene-specific therapy is not yet available. Patients and families can also be directed to ongoing clinical trials for the treatment of spinal muscular atrophies. Descriptions of various trials can be found at the following Web sites:

National Institutes of Health Families of Spinal Muscular Atrophy Spinal Muscular Atrophy Foundation Surgical Care Surgical revision may provide stable correction of the spine, and early orthopedic intervention may be indicated in patients in whom prolonged survival is anticipated. Noninvasive ventilation and percutaneous gastrostomy reportedly improves the quality of life with no effect on survival. These modalities may be most effective in prolonging lifespan in patients with slowly progressive disease, whereas they may provide comfort care in rapidly progressive infantile forms.[38] Consultations Consultations for ancillary evaluations and treatments are appropriate. Consult the following specialists as needed: physical therapist, occupational therapist, speech therapist, dietary or nutritional therapist, social service staff, pulmonologist, and gastroenterologist. Diet Ensuring optimal caloric intake enables patients to use weak muscles to their maximum capacity without incurring obesity as a comorbid condition.

Activity Encourage mobility. The goal of active but nonfatiguing exercises is to maintain range of motion, increase muscle flexibility, and prevent contractures. These exercises should not produce pain or exhaustion. Preventing spinal deformities (eg, scoliosis) and joint contractures is important. This goal is accomplished by using range-of-motion exercises, knee-ankle-foot orthoses, specialized wheelchairs and seats at home and school, and home assistance devices 7

eterrence/Prevention Genetic counseling should be offered to all families of patients with spinal muscular atrophy. Obtaining a complete family history facilitates genetic counseling. Education on how the disease is inherited may avert conception of affected individuals. Furthermore, the role of prenatal diagnosis, particularly in pregnant carriers or those with juvenile or adultonset forms, should also be addressed. Complications Medical complications associated with the SMAs include pulmonary infections, spinal deformities (eg, scoliosis), joint contractures, and respiratory failure. Prognosis See Mortality/Morbidity for more information. Most patients with SMA type I die before 18 months of age. In contrast, outcomes of juvenile and adult spinal muscular atrophies are difficult to define because the progression of these diseases varies widely. Survival probabilities for types I and II and probabilities of being ambulatory for type III were derived for 445 patients. These patients were subdivided on the basis of ISMAC criteria (ie, developmental milestones and age of onset).[39]

SMA I: Survival probabilities at ages 2, 4, 10, and 20 years were 32%, 18%, 8%, and 0%, respectively. SMA II: Survival probabilities at ages 2, 4, 10, and 20 years were 100%, 100%, 98%, and 77%, respectively. SMA III: Results differed. Onset before age 3 years: Probabilities of being ambulatory at ages 2, 4, 10, 20, and 40 years were 98%, 94.5%, 73%, 44%, and 34%, respectively. Onset after age 3 years: Probabilities of being ambulatory at ages 2, 4, 10, 20, and 40 years were 100%, 100%, 97%, 89%, and 67%, respectively. The life expectancy of patients with SMA type III is close to that of the healthy population. Antibiotic treatment has not prolonged survival in SMA type I. Birnkrant examined the role of noninvasive positivepressure ventilation and gastrostomy in patients with SMA type I. Although these supportive measures can be effective in slowly progressive neuromuscular diseases, they did not alter survival in patients with SMA type I.[38] Patient Education Normal schooling in patients with SMA, especially types II and II or more indolent forms, is highly recommended because their intelligence is normal or even superior to that of other individuals.