Spinal Muscular Atrophies (SMA) include a group of neuromuscular disorders characterized by degeneration of alpha motor neurons in the spinal cord with progressive muscle atrophy, weakness and paralysis.
The phenotypes are grouped on the basis of the classical age of the onset and maximum motor function achieved: very weak infants unable to sit unsupported (type 1), non-ambulant patients able to sit independently (type 2), up to ambulant patients with childhood (type 3) and adult-onset SMA (type 4).
More than 90% of cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene, usually homozygous absence of exons 7 and 8 of the SMN1 gene, or only of exon 7. The majority of patients inherit the SMN1 deletion from their parents. The SMN locus is part of a genomic inverted duplication region on human chromosome 5, which contains a paralogue gene, SMN2. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1 due to the predominant skipping of exon 7.
The diagnosis of SMA is based on molecular genetic testing. Genetic testing of SMN1/SMN2 is highly reliable and it is the first-line investigation when the condition is suspected in a typical case, then there is no need for a muscle biopsy.
A standard of SMA genetic testing is a quantitative analysis of both SMN1 and SMN2 using multiplex ligation-dependent probe amplification (MLPA), quantitative polymerase chain reaction (qPCR) or next-generation sequencing (NGS).
The incidence is approximately 10 in 100,000 live births.
A correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The approved drug for SMA is an antisense oligonucleotide that corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7.