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Spinal muscular atrophy

Olaf A Bodamer, MD, PhD, FAAP, FACMG
Section Editors
Douglas R Nordli, Jr, MD
Helen V Firth, DM, FRCP, DCH
Richard Martin, MD
Deputy Editor
John F Dashe, MD, PhD


Neuromuscular disorders that present in the newborn period with hypotonia and weakness can be caused by a variety of conditions that affect the central nervous system (brain or spinal cord), peripheral nervous system, or skeletal muscle. Spinal muscular atrophy (SMA) is characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem, which results in progressive muscle weakness and atrophy. This topic will review clinical aspects of spinal muscular atrophy (SMA), with a focus on SMN1 gene-related SMA.


The inheritance pattern of chromosome 5q-related SMA is autosomal recessive [1]. The different forms of 5q-SMA are caused by biallelic deletions or mutations in the survival motor neuron 1 (SMN1) gene on chromosome 5q13.2, resulting in deficiency of the SMN1 protein [2-5]. The most common mutation of the SMN1 gene is a deletion of exon 7 [6]. Approximately 94 percent of patients with clinically typical SMA carry homozygous deletions of exon 7. SMN protein appears to play a role in mRNA synthesis in motor neurons and also may inhibit apoptosis [7,8].

The differences in SMN protein activity and phenotypic expression appear to be related in part to a modifying gene, called SMN2. The SMN1 and SMN2 genes are more than 99 percent identical and lie within an inverted duplication on chromosome 5q13.2 [5]. The SMN1 gene lies telomeric of the SMN2 gene. The main difference between them is a C to T transition in exon 7 of the SMN2 gene [9,10]. This change leads to production of a truncated, nonfunctional SMN protein from the majority of SMN2-derived mRNAs. However, about 10 to 15 percent of mRNAs from SMN2 contain exon 7 and can produce some functional, full-length SMN protein [11]. Thus, loss of the SMN1 protein is partially compensated by SMN2 protein synthesis (figure 1), a mechanism that explains some but not all of the phenotypic variability in patients with SMA [12]. Disease severity in SMA generally correlates inversely with SMN2 gene copy number, which varies from 0 to 8 in the normal population, and to a lesser degree with the level of SMN protein [11,13-16]. The presence of three or more copies of SMN2 is associated with a milder phenotype [1,14].

While the most common forms of SMA are caused by deletions or mutations in the SMN1 gene on chromosome 5q (ie, 5q SMAs), there are a number of rare non-5q spinal muscular atrophies [15,17,18]. The non-5q SMAs are genetically and clinically heterogeneous (table 1).


The incidence of spinal muscular atrophy ranges from 4 to 10 per 100,000 live births, and the carrier frequency of disease-causing SMN1 mutations ranges from 1/90 to 1/47 [1,19-22]. SMA is the most common monogenic cause of infant mortality [23].

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Literature review current through: Nov 2017. | This topic last updated: Nov 06, 2017.
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