Spinal muscular atrophy (SMA) is characterized by progressive muscle weakness resulting from degeneration and loss of the anterior horn cells in the spinal cord and the brain stem nuclei. Onset ranges from before birth to adolescence or young adulthood.
The diagnosis of SMA is based on molecular genetic testing. The two genes associated with SMA are SMN1 and SMN2. SMN1 (survival motor neuron 1) is the primary disease-causing gene. About 95%-98% of individuals with SMA are homozygous for a deletion or truncation typically determined by lack of exon 7 of SMN1 and about 2%-5% are compound heterozygotes for an SMN1 deletion or truncation and an SMN1 intragenic mutation. However, the genetics of the disease are complicated by the fact that not all unaffected individuals are carrying the two copies of the SMN1 gene on two chromosomes: some unaffected subjects are actually carrying both copies on one chromosome only.
The lack of exon 7 is easily detectable by large deletions/duplications screening techniques like MLPA. However MLPA cannot detect SMA carriers who have two copies of the SMN1 gene on one chromosome and no copy on the other chromosome or who have a SMN1 intragenic mutation (4% of cases). Therefore, after a negative MLPA in an unaffected individual who is not supposed to be an obligate carrier, the proband can be considered as ‘less likely’ to be a carrier of a SMN1 disease-causing mutation, even if this possibility cannot be completely excluded.
Further useful information is provided by the MLPA manufacturer's fact sheets (MRC Holland).
For references and additional information Genereviews and MRC-Holland.
