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Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality and is characterized by proximal muscular weakness.
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Humans have 2 nearly identical inverted SMN genes (SMN1 and SMN2) on chromosome 5q13 and homozygous deletion of the SMN1 gene results in SMA.
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The SMN2 gene produces mostly a shortened, unstable SMN messenger RNA (mRNA) and, through alternative splicing, a relatively small amount of full-length, functional SMN mRNA.
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The SMN2 gene copy number is a good prognostic
Spinal Muscular Atrophy
Section snippets
Key points
Incidence
The incidence of SMA is 1 in 11,000 live births.1
Prevalence
The prevalence of the carrier state is approximately 1 in 54.1
Severity
The clinical severity of spinal muscular atrophy (SMA) correlates inversely with SMN2 gene copy number and varies from an extreme weakness and paraplegia of infancy to a mild proximal weakness of adulthood.
Natural history
The natural history of SMA is complex and variable. For this reason, clinical subgroups have been defined based upon best motor function attainment during development. Type 1 SMA infants never sit independently. Type 2 SMA children sit at some point during their childhood, but never walk independently. Type 3 SMA children and adults are able to walk independently at some point in their childhood.
Clinical features
The predominant clinical features of SMA are muscle weakness and atrophy. Weakness is usually symmetric, with proximal muscles more affected than distal groups as in NP7.14 Over the last 125 years, reports detailing the clinical manifestations and wide range of clinical severity have all recognized and emphasized the seminal pathology as anterior horn cell degeneration, as well as the pertinent clinical features of symmetric, proximal predominant extremity weakness that also affects axial,
Molecular genetics
Before the discovery of the genetic etiology, SMA presented a riddle with regard to severity: how can 1 gene defect result in such a wide range of clinical severity? The solution to this riddle began with the discovery by the Melki laboratory in 1995 that 95% of cases of SMA, irrespective of type, are caused by a homozygous deletion in the SMN1 gene on chromosome 5q13.26 In humans, 2 forms of the SMN gene exist on each allele: a telomeric form (SMN1) and a centromeric form (SMN2; Fig. 4).
Clinical management
Over the past decade, there has been a marked improvement in the ability of clinicians to manage the multiple respiratory, nutritional, orthopedic, rehabilitative, emotional, and social problems that develop in the majority of these patients. A notable achievement in this regard was the development of a comprehensive standard of care document by Wang and a collaborating panel of experts that was published in 20076 and is currently being updated. This document established guidelines for managing
Therapeutic development
Before the 1990s, there were relatively few clinical trials in SMA because there was no clear molecular target. Those studies that were undertaken usually involved pharmacologic agents that were repurposed and had shown encouraging results in other diseases characterized by muscle weakness, such as amyotrophic lateral sclerosis or muscular dystrophy. Within 5 years of the discovery of the SMN gene, however, animal models of SMA were developed that mimic many of the pathologic and
Summary
SMA is a motor neuron disease of infancy, childhood, and adulthood and the genetics and pathophysiology has received extensive study over the last 20 years. This increased focus has led to an improvement of our understanding of the natural history of the many subtypes of SMA and to the development and distribution of standard of care recommendations. The dramatic preclinical results in SMA models systems have also led to incredible cooperation between clinicians, scientists, government,
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S.J. Kolb has received compensation for consulting from Biogen, F. Hoffman-La Roche, Jeffries LLC, and the Deerfield Institute. He is supported by NIH Grant K08NS067282; U01NS079163.