Which cytogenic findings are characteristic of spinal muscular atrophy (SMA)?

Updated: Apr 28, 2014
  • Author: Hidehiro Takei, MD; Chief Editor: Adekunle M Adesina, MD, PhD  more...
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The classic form of spinal muscular atrophy (SMA) (types I, II, and III) is an autosomal recessive motor neuron disorder (MND). All forms of SMA are associated with a locus on chromosome 5q13 that harbors the survival motor neuron gene (SMN1), and they are all caused by loss-of-function mutations or deletions of SMN1.

The SMN gene product is ubiquitously expressed, but it is detected at especially high levels in neuronal cells. This entity is a part of nuclear germ structures rich in heterogeneous nuclear ribonucleoproteins (hnRNPs). Some researchers have suggested that the SMN protein, as part of a large complex, plays a role in the assembly and regeneration of spliceosomal complexes.

The SMN gene exists in 2 copies, SMN1 and SMN2, which differ by only a single nucleotide in exon 7. The vast majority of the functional SMN protein is produced by SMN1, whereas SMN2 undergoes an alternative splicing pathway, producing primarily a transcript lacking exon 7 (SMN∆7) as the consequence of a single nucleotide transition (ie, C to T transition at position +6 of exon 7; c.840C>T). SMN∆7 is an unstable protein and is not functionally equivalent to full-length SMA.

About 10% of the mRNA transcript from SMN2 is spliced into the full-length transcript that codes for the fully functional SMN protein. Thus, the major factor influencing the severity of SMA phenotype (ie, SMA types I-III) is the number of SMN2 copies, which usually ranges from 1 to 4 and rarely may be as high as 8. [62] The underlying mechanism generating an increase in SMN2 copies and a reduction in or absence of SMN1 copies is gene conversion. [62]

Among 5q13-linked SMA patients, 96% of those with types I-III show homozygous absence of SMN1 exons 7 and 8 or exon 7 only because of deletions of SMN1 or conversion of SMN1 into SMN2. [62] The relatively uniform mutational spectrum in types I-III SMA has led to the availability of fast, reliable polymerase chain reaction (PCR)-based testing. SMN1 -targeted mutation analysis is used diagnostically to detect deletion of exons 7 and 8. SMN gene dosage analysis, determining the number of SMN1 copies, yields highly accurate SMA carrier detection.

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