Testing for spinal muscular atrophy in an Australian newborn screening program identified patients across socioeconomic and cultural demographics, mitigating inequity and providing patients with access to multidisciplinary treatment.
Early diagnosis and treatment initiation is key for patients with spinal muscular atrophy (SMA), an inherited degenerative neuromuscular disease characterized by muscle weakening, atrophy, and death in infants. A recent study published in Developmental Medicine & Child Neurology found that a pilot newborn screening program in Australia identified at-risk patients with high specificity and could be effectively incorporated into clinical practice.
SMA is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene, leading to a deficiency in SMN protein and the subsequent clinical manifestations of the disease. The SMN2 gene does not typically allow for sufficient production of SMN, but in recent years, the therapeutic landscape has evolved and continues to expand. Even so, early diagnosis and treatment initiation before permanent loss of existing neurons is paramount to positive outcomes.
The study authors stated that newborn bloodspot screening (NBS) in Australia “continues to be one of the most successful population health programs, yielding greatly improved health outcomes for identified cases achieved by a combination of very early diagnosis and expedient initiation of treatment and management.” They suggested adding SMA to newborn screening panels could enhance the quality, efficiency, and efficacy of NBS programs based on the pilot study results.
The New South Wales and the Australian Capital Territory NBS program, in which parents are urged but not required to enroll their newborns, offers screening for over 30 congenital conditions and typically screens approximately 100,000 newborns each year. For SMA, the absence of SMN1 exon 7 alleles was considered screen positive. The authors noted that this does not detect heterozygous deletions or point mutations on the SMN1 gene, which account for about 2%-5% of the SMA population. SMN2 copy number did not factor into screen positivity, to allow for proficiency testing in the pilot study.
A total of 252,081 newborns were screened in the NBS program over the study period (August 2018 to January 2021), and 22 had positive screenings for SMA. Of those infants, 21 had confirmed SMA with homozygous deletions in exon 7 of SMN1. Twelve of these infants had 2 copies of SMN2, 8 had 3 copies, and 1 infant had 4 copies. Greater SMN2 copy number generally correlates with milder phenotypes.
Participants received positive screening results a median of 3 days after birth, received diagnostic confirmation a median of 15 days after birth, and therapy initiation at a median of 25 days after birth. The overall incidence of SMA in the program during the study period was 1 in 11,458 newborns. Compound muscle action potentials (CMAPs) were recorded at diagnosis, and there were significant differences between infants with different SMA genotypes. One of 3 newborns included in longitudinal assessment of CMAPs showed significant reductions in amplitude at symptom onset. Overall, these findings suggest NBS is crucial for diagnosis prior to motor neuron degeneration.
More than 99.9% of all newborns in New South Wales were included in NBS, which had a sensitivity rate of 100%, specificity greater than 99.9%. The false-positive rate was less than 0.001%, and the positive predictive value was 95.5%.
Implementation challenges included shipping delays, which lengthened time to completing the diagnostic workups, including SMN2 copy number results. This was addressed by the NBS laboratory obtaining accreditation for SMN2 testing with digital droplet polymerase chain reaction on dried bloodspots. Another challenge was managing urgent referrals. NBS staff partnered with neuromuscular specialists to work the NBS SMA pilot into established pathways and neuromuscular models of care.
Multidisciplinary collaboration and communication between a neuromuscular team, families, and community health care providers also proved important. Study authors noted that a decision support analysis and national clinical guidelines for SMA are warranted.
Overall, the results of the pilot program suggest SMA testing within NBS provided opportunities for early intervention in newborn patients and gave all families — regardless of financial, geographic, cultural or linguistic barriers — access to appropriate diagnosis and care for SMA.
“The results from this study can be used as a blueprint for NBS programs globally, as they work to expand the number of disorders screened, alongside providing a personalized model of care for identified individuals,” the authors concluded.
D'Silva AM, Kariyawasam DST, Best S, et al. Integrating newborn screening for spinal muscular atrophy into health care systems: an Australian pilot programme. Dev Med Child Neurol. Published online November 28, 2021. doi:10.1111/dmcn.15117