Spinal Muscular Atrophy



SPINAL MUSCULAR ATROPHY (SMA) is a neuromuscular disorder characterised by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMA is the second most common lethal autosomal recessive disorder in Caucasians, after cystic fibrosis. There are two (highly-similar) genes playing a pivotal role in SMA: SMN1 and SMN2. This SALSA MLPA probemix P060-B2 SMA will detect copy number changes of exon 7 and 8 of the SMN1 and SMN2 genes.


Most individuals have two copies each of SMN1 and SMN2. The SMN1 and SMN2 genes can only be distinguished by two single nucleotide differences: one in exon 7 and one in exon 8. Both genes are located close to each other in a complicated inverted repeat area on chromosome 5q13. The two genes encode the same protein. However, the single nucleotide difference in exon 7 affects the mRNA splicing. As a result, the SMN2 gene is only 10-15% as efficient in making functional SMN protein as compared to SMN1.


More than 95% of SMA patients show homozygous deletion of at least exon 7 of the telomeric SMN1 gene. The great majority of SMA carriers can be identified by the presence of only a single SMN1 exon 7 copy. The one copy frequency in the US is estimated to be 1:37 for Caucasians, 1:46 for Ashkenazi Jews, 1:56 for Asians, 1:91 for African-Americans and 1:125 for Hispanics (Hendrickson, B.G. et al, 2009: J.Med.Genet. 46:641-644). The SMN2 copy number is very variable with only 60-70% of individuals having two copies. Provided that at least one functional SMN1 copy is present, complete absence of the centromeric SMN2 gene seems to have no clinical consequences. Establishing the number of the SMN2 copy number is however important for SMA patients: the more SMN2 copies, the less severe the disease is expected to be. Absence of SMN1 combined with a SMN2 copy number of only 1 or 2 usually results in early onset severe disease. Healthy individuals lacking SMN1 but having 5 or more SMN2 copies have been described.


Four probes in this P060-B2 SMA probemix detect SMN1 or SMN2 sequences. All other probes are reference probes on other chromosomes. Most important is the probe at 183 nt which is specific for SMN1 exon 7. Heterozygous deletion of this probe indicates that the individual is a SMA carrier. The SMN1 exon 8 probe at 218 nt will confirm a copy number change of the exon 7 probe in approximately 95% of all cases. Please note that only the exon 7 nucleotide difference between SMN1 and SMN2 has an effect on the production of a functional SMN protein. Therefore, in case only the SMN1 exon 8 probe appears to be deleted, it is most likely that the individual is not a SMA carrier. This new P060-B2 version also contains probes for SMN2 exon 7 (282 nt) and exon 8 (301 nt). Results from these SMN2 probes have no effect on the SMA carrier status but are important for the prognosis of SMA patients.