Spinal Muscular Atrophies

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Key points

  • Spinal muscular atrophies (SMAs) are hereditary degenerative disorders of lower motor neurons associated with progressive muscle weakness and atrophy.

  • SMA subtypes are classified by severity of weakness: type I nonsitters, type II sitters, type III walkers, and type IV adult-onset patients with mild phenotype.

  • The survival of motor neuron (SMN) gene is present in 2 copies on each chromosome 5, designated SMN1 and SMN2. A majority of cases are caused by homozygous deletions of exon 7 of the

Epidemiology

The incidence of SMA has been estimated at 1 in 6000 to 11,000 live births4, 5, 6, 7 or approximately 7.8 to 10 per 100,000 live births8, 9, 10 and at 4.1 per 100,000 live births for type I SMA.8 The estimated panethnic disease frequency is approximately 1 in 11,000.7 The carrier frequency for mutations in the SMN1 gene has been estimated from 1:38 to 1:70. Despite the high carrier frequency, the incidence of SMA is lower than expected. It has been postulated that this may reflect that some

Clinical characteristics

Although most patients with SMA have deletions or mutations involving the SMN1 gene, a range of phenotypic severity permits division into 4 broad clinical subtypes. It is recognized that the subtypes represent a phenotypic continuum extending from the very severe, with onset in utero, to the very mild, with onset during adulthood; there is also a spectrum of severity within each of these groups (Table 1).12, 13 For the purposes of clinical classification or of guidelines developed for standards

The Survival of Motor Neuron Gene

In 1995, Lefebvre and colleagues58 identified the SMN gene within the SMA chromosomal region, which was absent or interrupted in 98.6% of the patients in their group. The structure of this region is complex, with a large inverted duplication of a 500-kb element. This contains the SMN1 gene, which is deleted or interrupted in patients with SMA and is evolutionarily older, in the telomeric portion of the region; and the SMN2 gene, a duplication of SMN1 that differs from it by only 5 nucleotides,

Other diagnostic tests

In patients with SMA, the serum creatine kinase may be 2- to 4-fold elevated but not more than 10 times normal.22 Nerve conduction studies demonstrate normal sensory potentials but may show diminished compound motor action potential amplitudes.72 Needle electromyography (EMG) in patients with type II/III SMA demonstrates a neurogenic pattern with high-amplitude, long-duration motor unit potentials with reduced recruitment pattern. Needle EMG in patients with type I SMA shows denervation changes

Differential diagnosis

The differential diagnosis of 5q SMA is listed in Box 1.

Treatment

Currently, there is no cure for SMA. Despite the presence of homozygous deletions of SMN1 in a majority of patients with SMA,74 however, the unique structure of the 5q11.1-13.3 inverted duplication provides potential therapeutic targets. There has been great interest in identifying agents that can increase the amount of full-length SMN protein by up-regulating the expression of the SMN2 gene or promoting inclusion of exon 7. Researchers are also actively exploring several other approaches to

Care of patients with spinal muscular atrophy

Patients with SMA and their families benefit greatly from a multidisciplinary approach to care. This approach involves members from neurology/neuromuscular medicine, orthopedics, physical and occupational therapy, pulmonology, nutrition and gastroenterology. For severely affected patients with type I SMA, early involvement of the pediatric advanced care or palliative care team can provide parents with support and assistance in making decisions that are consonant with their values and help to

Summary

SMA is a chronic, inherited motor neuron disease for which there is no established treatment. Yet there is cause for optimism, because it is an area of active research, and knowledge about the molecular genetics and pathogenesis of SMA is ever increasing. Several groups are actively exploring pharmacologic treatments, whether through the use of approved drugs, identification of new agents via high-throughput screens, or development of novel pharmaceutical compounds. Consortia of clinicians and

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    Disclosures: Dr. Darras receives research support from PTC Therapeutics and ISIS Pharmaceuticals.

    This article was funded in part by the SMA Foundation (New York, NY).

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