AUTHOR INFORMATION

Section 1 of 10

Authored by Bryan Tsao, MD, Staff Physician, Department of Neurology, Neuromuscular Section, The Cleveland Clinic Foundation

Coauthored by Andrey S Stojic, MD, PhD, Fellow, Department of Neurology, Cleveland Clinic Foundation; Carmel Armon, MD, MSc, MHS, Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center

Bryan Tsao, MD, is a member of the following medical societies: American Academy of Neurology

Edited by Robert Baumann, MD, Program Director, Professor, Departments of Neurology and Pediatrics, University of Kentucky; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Kenneth J Mack, MD, PhD, Visiting Associate Professor, Department of Neurology, University of Wisconsin at Madison; Associate Professor and Consultant, Department of Neurology, Division of Child and Adolescent Neurology, Mayo Medical School; Selim R Benbadis, MD, Professor of Neurology, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida College of Medicine, Tampa General Hospital; and Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author's Email:	Bryan Tsao, MD
Editor's Email:	Robert Baumann, MD

eMedicine Journal, November 2 2006, VOLUME 7, Number 11

INTRODUCTION

Section 2 of 10

Background: The spinal muscular atrophies (SMAs) comprise a group of autosomal-recessive disorders characterized by progressive weakness of the lower motor neurons.

Werdnig and Hoffman first independently described SMAs in the early 1890s. They 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 (Katirji, 2002).

Since then, several types SMAs have been described on the basis of the 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 Kugelberg-Welander 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 (Bradley, 1996; Brzustowicz, 1996; Burlet, 1996; Harding, 1993).

Many classification systems have been proposed and include variants based on inheritance, clinical, and genetic criteria. Among these are the Emery (1971), Pearn (1980), and International SMA Consortium (ISMAC, 1994) systems. The ISMAC system is most widely accepted and is used in this review.

Pathophysiology: SMA is anatomically characterized by the loss of lower (alpha) motor neurons in the entire spinal cord and in select brainstem motor nuclei (nuclei of cranial nerves V, VII, IX, and XII).

Molecular and genetic studies revealed mutations in the survival motor neuron, or SMN, gene in chromosome subbands 5q11.2-13.3. This gene codes for the SMN protein, which is part of a multiprotein complex involved in the assembly of the spliceosomal small nuclear ribonucleoproteins (snRNPs). These snRNPs play a critical role in the early stages of messenger RNA (mRNA) processing (Brahe, 1996).

Mutations in the SMN gene result in a loss of function of the SMN protein. This loss in turn causes decreased assembly of snRNPs and defective mRNA processing. Why this impairment in mRNA processing selectively affects lower motor neurons and results in progressive motor unit degeneration is unclear. However, these discoveries offer the potential for considerable advancement in the characterization and treatment of these disorders.

Frequency:

• In the US: The SMAs 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 (Harding, 1993).

• Internationally: The incidence of SMA is 7.8-10 cases per 100,000 live births. Reports of carrier frequency are variable, with low frequencies in the United Kingdom (1 case per 60-80 individuals), intermediate frequencies in Germany and Italy (1 case per 50-60 individuals), and high frequencies in the Karaite ethnic group in Israel (1 case per 20 individuals).

Mortality/Morbidity: The mortality and/or morbidity rates of SMA 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.

• See Prognosis for more information.

Sex: Male individuals are most frequently affected, especially with the early-onset forms of SMA, ie, types I and II (Hausmanova-Petrusewicz, 1984).

Age: The ISMAC classification system is based on the age of onset. For instance, type I is when the disease appears from birth to 6 months, whereas type IV is typically seen in adults (Munsat, 1992). (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 SMAs.)

According to the ISMAC system, the age of onset for SMAs 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).

CLINICAL

Section 3 of 10

History: The diagnosis of SMAs includes the following a detailed clinical history. Obtaining a complete family history facilitates genetic counseling.

Patients with SMA 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 SMA often have above-average intelligence quotients (IQs) and demonstrate high degrees of intelligence.

The clinical manifestations of each particular form of SMA are discussed below (Walton, 1957; Bradley, 1996; Rudnik-Schoneborn, 1996; Fenichel, 1997; Joynt, 1997):

• 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 SMA, and some experts believe that SMA type II may overlap types I and III.
  
  
  
  • Most children present between the ages of 6 to 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 SMA 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.
  
  
  
  • 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.




• SMA 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 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 (McShane, 1992).
  
  
  
  • Distal SMA (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: Inheritance with the distal SMAs is correlated with the age of onset. Juvenile forms are autosomal recessive, whereas the adult form is autosomal dominant. The disease is characterized by peroneal muscular atrophy, weakness, and wasting in the legs. High foot arches (pes cavus) are often present. Deep tendon reflexes tend to be normal or reduced to absent. No sensory loss is observed in distal SMA in contrast to CMT or HSMN. In distal SMA, electrodiagnostic examination shows sparing of sensory nerves and is useful in distinguishing it from CMT or HSMN (Harding, 1980).
  
  
  
  • X-lined recessive bulbospinal muscular atrophy (Kennedy disease): 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 SMA: 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 (Kaeser, 1965).

  • X-linked form scapuloperoneal SMA: 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 SMA: 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 SMA: 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 SMA: 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 (Kondo, 1970).
  
  
  
  • Other: Other variants have been described, including SMA 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. See the bibliography for references describing these variants (Young, 1980; de Leon, 1984; Bertini, 1989; Kamoshita, 1990).
  
  
  

Causes: Many hypotheses had been proposed to explain the motor neuron degeneration observed in SMAs. The hypotheses include (1) arrested development of spinal cord during fetal life with degeneration of surviving motor neurons, (2) prominent glial proliferation in the proximal portion of the anterior spinal roots with secondary neuronal degeneration, (3) abnormal neuronal RNA and oxidative enzyme metabolism, (4) lack or inhibition of muscle-derived neuronal growth factors, (5) impaired muscle maturation, (6) abnormal apoptosis (programmed cell death), and (7) various adverse environmental influences.

Developments in molecular genetics have added an exciting dimension to our understanding of the pathogenesis of SMAs. In 1995, the journal Nature published findings from 2 research groups linking the gene responsible for chronic childhood-onset SMA (type II-III) to the long arm of chromosome 5. Later that year, the same groups mapped the gene for the SMA type I to the same region and band (5q11.2-13.3), demonstrating the genetic homogeneity among these 3 forms of SMA. Since then, mutations in 3 genes in this region have been identified in patients with SMA.

• SMN gene


• • This was the first gene to be isolated. Mutations in SMN are seen in virtually all cases of autosomal recessive SMA. More than 95% of early-onset forms of SMA (I-III) have deletions or mutations in the SMN1 gene. In contrast, mutations in SMN1 are present in only 20-30% of patients with SMA type IV.
  
  
  
  • Two copies of the SMN gene have been identified on the 5q arm: a telomeric SMN 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 the SMN1 gene (Frugier, 2002).
  
  
  
  • Expression of SMN1 produces the full-length SMN protein. In contrasts, 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 (Frugier, 2002).
  
  
  
  • 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 (Anderson, 2003).
  
  
  
  • 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 (Hausmanowa-Petrusewicz, 2005).
  
  
  
• Neuronal apoptosis inhibitory protein (AIP), NAIP, gene


• • This 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 (Roy, 1995).
  
  
  
• BFT2p44 gene: Mutations in this gene have been found in 15% of patients with SMA.

DIFFERENTIALS

Section 4 of 10

Amyotrophic Lateral Sclerosis
Congenital Muscular Dystrophy
Congenital Myopathies
Disorders of Carbohydrate Metabolism
Myasthenia Gravis
Primary Lateral Sclerosis

Other Problems to be Considered:

Acid maltase deficiency (type II glycogenosis)
Adrenoleukodystrophy
Botulism
Congenital hypomyelination neuropathy
Congenital polyneuritis
Down syndrome
GM1 gangliosidosis
Hurler syndrome
Infantile Gaucher disease
Marfan or Prader-Willi syndrome
Metabolic disorders (including the organic acidurias and mitochondrial diseases)
Neonatal and congenital myasthenia gravis
Peripheral neuritis
Poliomyelitis
Spinal cord transection
Type II (Pompe) glycogen storage disease

WORKUP

Section 5 of 10

Lab 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) because these clinical variations may represent other pathogenic processes.
  
  
  

Other Tests:

• Most cases spare the cardiac system, and ECGs are normal.



• Electrophysiologic studies are useful in differentiating the SMAs from other neurogenic and myopathic diseases (Hausmanowa-Petrusewicz, 1986; Krivickas, 1998).


• • With the exception of Kennedy and Davidenkow syndromes, sensory nerve conduction is normal in SMA.
  
  
  
  • 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 resemble myopathic motor units but are not due to a primary muscle disease. Instead, axon loss and resprouting results in fragmented motor units. Therefore, the appearance of MUP is a result of early and ongoing motor-unit reinnervation.
  
  
  
  • Fibrillation potentials can be seen in limb and paraspinal muscles and are most striking in early or progressive SMA. In late-juvenile and adult-onset forms, ongoing denervation may be 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 is often necessary to differentiate SMAs from other neuromuscular disorders. 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.

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 (Buchthal, 1970; Dubowitz, 1995).

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.)

TREATMENT

Section 6 of 10

Medical Care: Treatment is generally supportive. The goals are to improve the patients' quality of life and to minimize disability, particularly in patients with slow progression.

• The treatment of patients with adult-onset SMA is similar to that for amyotrophic lateral sclerosis (ALS), except that the course and life span in SMAs 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 (Armon, 2000).

  • 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 SMAs. 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 (Birnkrant, 1998).

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.

FOLLOW-UP

Section 7 of 10

Deterrence/Prevention:

• Genetic counseling should be offered to all families of patient's with SMA. 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 adult-onset 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 SMAs 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 (Zerres, 1995). These patients were subdivided on the basis of ISMAC criteria (ie, developmental milestones and age of onset).


• • 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 type III SMA is close to that of the healthy population. Antibiotic treatment has not prolonged survival in SMA type I. Birnkrant et al (1998) examined the role of noninvasive positive-pressure 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.

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.

MISCELLANEOUS

Section 8 of 10

Medical/Legal Pitfalls:

• As weakness and disability progress, patients with SMA may reach a point when it is unsafe for them to operate a motor vehicle or other machinery that requires dexterity.



• The risk of falling may increase.



• In addition to advising patients about the matters listed above, the physician should instruct them to comply with state regulations and to apply common sense.



• A decision should be made about how patients wish to be treated when they develop ventilatory failure, preferably well before it occurs.


• • Advance directives are in order for adults.
  
  
  
  • Early discussions regarding end-of-life issues with parents of affected children and adolescents are highly recommended.
  
  
  

Special Concerns:

• Other diseases and disease processes can mimic SMA.



• In Walton's 1957 series of 107 floppy infants, SMAs accounted for 62% of cases, followed by the congenital myopathies (17%), which represented numerous unrelated disease processes that were histochemically distinct. Atonic cerebral palsy accounted for 14% (most with intellectual impairment), followed by congenital muscular dystrophy (3%). Polymyositis, myasthenia gravis, and scurvy represented the remaining cases.



• The terms benign maturation delay and dissociated motor development describe the floppy infant with delayed motor milestones but preserved fine motor development and speech without evidence of a muscular disorder. A spectrum of disorders characterized by abnormal muscle maturation has been termed syndrome of congenital fiber type disproportion. Afflicted infants are usually developmentally delayed.



• Other differential diagnoses in the infantile- and childhood-onset forms include the following:


• • Adrenoleukodystrophy

  • Congenital hypomyelination neuropathy

  • Congenital polyneuritis

  • Down syndrome

  • Infantile botulism

  • Marfan or Prader-Willi syndrome

  • Metabolic disorders (including the organic acidurias and mitochondrial diseases)

  • Neonatal and congenital myasthenia gravis

  • Peripheral neuritis

  • Poliomyelitis

  • Spinal-cord transection
  
  
  
• Degeneration of the motor neurons as a part of generalized storage diseases is rare, but it has been observed in the following conditions:


• • Acid maltase deficiency (type II glycogenosis)

  • GM1 gangliosidosis

  • Hurler syndrome

  • Infantile Gaucher disease

  • Type II (Pompe) glycogen storage disease
  
  
  
• A poliomyelitislike illness associated with acute asthma in childhood (asthmatic amyotrophy, Hopkins syndrome) has been described (Manson, 1980).



• Juvenile ALS with an autosomal recessive inheritance pattern can occur with a rapidly progressive flaccid paralysis of all 4 limbs, but patients later develop pyramidal signs.

• Bulbar palsy in familial ALS and hereditary progressive bulbar palsy may mimic adult-onset SMAs. In both cases, bulbar dysfunction may be the initial manifestation, though patients with ALS invariably develop limb and respiratory weakness in a short time.

• Alexander disease may cause bulbar paresis. The diagnosis is made by means of electromyelography (EMG), head imaging studies, and appropriate biochemical testing.



• The adult SMA forms (especially early in the disease course) can be difficult to distinguish from familial motor neuron disease (FMND). However, FMND, by definition, eventually affect both the upper and lower motor neuron systems, leading to pyramidal-tract signs and rapid progression.

TEST QUESTIONS

Section 9 of 10

CME Question 1: Which statement concerning the spinal muscular atrophies (SMAs) is true?

A: The SMAs together constitute acquired disorders of the corticospinal tracts and result in spasticity, pathologically increased deep tendon reflexes, and sensory loss.
B: All forms of SMA result in death before age 2 years.
C: The SMAs are inherited disorders characterized by degeneration of the anterior horn cells and predominant findings in the lower motor neurons.
D: Serum creatine kinase (CK) levels are elevated more than 100 normal times in all patients with SMA.
E: The SMAs are an extremely rare group of disorders with an incidence of 1 case per 1 million live births.

The correct answer is C: The SMAs are a clinically heterogenous group of disorders characterized by degeneration of the anterior horn cells. Predominant clinical findings in affected patients include flaccid weakness, hyporeflexia, and muscle atrophy.

CME Question 2: Which statement concerning the spinal muscular atrophies (SMAs) is false?

A: Homozygous deletions in the survival motor neuron, or SMN, gene are found in 98.6% of patients with childhood-onset SMA.
B: Several clinical variants have been described, including SMA associated with hexosaminidase A deficiency.
C: X-linked recessive bulbospinal muscular atrophy (ie, Kennedy syndrome) is characterized by increased cytosine-adenine-guanine (CAG) repeats.
D: Treatment for the SMAs is generally supportive; the goals are to improve and maintain the patient's quality of life while minimizing disability.
E: Patients with SMA typically have profound mental retardation.

The correct answer is E: Intelligence quotients (IQs) of patients with SMA are normal or above average.

Pearl Question 1 (T/F): Chromosome 21 is associated with the acute and chronic childhood forms of spinal muscular atrophy (SMA).

The correct answer is False: The gene for both the acute and chronic SMA forms is found on chromosome subbands 5q11.2-q13.3.

Pearl Question 2 (T/F): The genetic defect in autosomal recessive spinal muscular atrophy, similar to X-linked recessive bulbospinal muscular atrophy (Kennedy disease), is an expanded trinucleotide repeat.

The correct answer is False: X-linked recessive bulbospinal muscular atrophy (ie, Kennedy syndrome), not SMA, is associated with trinucleotide repeats. Affected patients have an increased number of polymorphic tandem cytosine-adenine-guanine (CAG) repeats.

Pearl Question 3 (T/F): A form of spinal muscular atrophy (SMA) can clinically resemble Charcot-Marie-Tooth (CMT) disease types 1 and 2 or hereditary motor and sensory neuropathy (HMSN) types I and II.

The correct answer is True: Distal hereditary motor neuronopathy (HMN) type II manifests with distal muscle atrophy, high foot arches, and large-fiber sensory loss. Although some forms of SMA also cause distal muscle atrophy and resultant foot deformities (mimicking those found in CMT disease and HMN), sensory loss is not present.

Pearl Question 4 (T/F): The most common form of spinal muscular atrophy (SMA) is type I.

The correct answer is False: The most common form is SMA type II. This form accounts for approximately one half of all cases.

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Section 10 of 10

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