Systematic review of newborn screening programmes for spinal muscular atrophy

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder causing the degeneration of motor neurons in the spinal cord. Recent studies suggest greater effectiveness of treatment in the presymptomatic stage. This systematic review synthesises findings from 37 studies (and 3 overviews) of newborn screening for SMA published up to November 2023 across 17 countries to understand the methodologies used; test accuracy performance; and timing, logistics and feasibility of screening. All studies screened for the homozygous deletion of SMN1 exon 7. Most (28 studies) used RT-PCR as the initial test on dried blood spots (DBSs), while nine studies also reported second-tier tests on DBSs for screen-positive cases. Babies testing positive on DBSs were referred for confirmatory testing via a range of methods. Observed SMA birth prevalence ranged from 1 in 4000 to 1 in 20,000. Most studies reported no false-negative or false-positive cases (therefore had a sensitivity and specificity of 100%). Five studies reported either one or two false-negative cases each (total of six cases; three compound heterozygotes and three due to system errors), although some false-negatives may have been missed due to lack of follow-up of negative results. Eleven studies reported false-positive cases, some being heterozygous carriers or potentially related to heparin use. Time to testing and treatment varied between studies. In conclusion, several countries have implemented newborn screening for SMA in the last 5 years using a variety of methods. Implementation considerations include processes for timely initial and confirmatory testing, partnerships between screening and neuromuscular centres, and timely treatment initiation.