Discrepancy in redetermination of SMN2 copy numbers in children with SMA

Spinal muscular atrophy (SMA) is a rare autosomal recessive inherited neuromuscular disease with an incidence of about 1:6,000 to 1:10,000 in newborns. The clinical spectrum of severity is broad and ranges from early and severe weakness with respiratory insufficiency (type 1) to milder phenotypes with onset during childhood or adolescence (types 2–3).¹ SMA is caused by deletions and less commonly by point mutations in SMN1 (survival of motor neuron) on chromosome 5q. The paralogous SMN2 gene is present in a variable copy number and differs from SMN1 by few nucleotides. A single nucleotide change disrupts an exonic splicing enhancer and creates a new exonic splicing silencer resulting in splice modification and exclusion of exon 7, so that a mainly truncated and unstable SMN∆7 protein is produced.² While being of no importance in healthy individuals, SMN2 is crucial in patients with SMA, where smaller amounts of functional SMN protein (estimated to be around 10%) can be produced by each SMN2 copy. Therefore, the number of SMN2 copies inversely correlates with disease severity.^3,4 SMN2 is also targeted by antisense-oligonucleotide therapy, which leads to higher amounts of functional SMN protein by modifying splicing of exon 7.⁵