The influence of genotype on the natural history of types 1 - 3 spinal muscular atrophy

Abstract

The severity of spinal muscular atrophy (SMA) is inversely correlated with the number of survival of motor neuron 2 (SMN2) copies an individual has. This observational, retrospective analysis of natural history data included untreated individuals with a genetic diagnosis of types 1-3 SMA and stratified disease-related characteristics by SMN2 copy number. The outcomes investigated were time to: death, permanent ventilation, respiratory support, feeding support, scoliosis surgery, and achievement and loss of motor milestones. Of 134 individuals; 33 had two SMN2 copies and 101 had 3 or more copies. Survival was linked to increasing SMN2 copy number: mean age at death for individuals with two SMN2 copies was 8 months (standard deviation [SD]: 4 months) and 10 years (SD: 5 months) for individuals with three copies, and no deaths were reported in individuals with ≥4 SMN2 copies. Increasing SMN2 copy number was linked to a longer time to permanent ventilation, respiratory support, feeding support, and scoliosis, as well as loss of motor milestones. SMA disease-related endpoints showed distinct patterns between groups with differing SMN2 copy numbers. Prediction and assessment of disease progression may be stratified by SMN2 copy number, which will be important for evaluating the impact of treatment.

Keywords: Natural history; Outcomes; Rare genetic disease; SMA; SMN2 copy number; Spinal muscular atrophy.