Newborn Screening for Spinal Muscular Atrophy in New York State

Abstract

Background and Objectives:Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel (RUSP) in July 2018, largely on the basis of the availability and efficacy of newly-approved disease modifying therapies. New York State (NYS) started universal newborn screening for SMA in October 2018. The authors report the findings from the first 3 years of screening.Methods:Statewide neonatal screening was conducted using DNA extracted from dried blood spots using a real-time quantitative polymerase chain reaction (qPCR) assay. Retrospective follow-up data were collected from 9 referral centers across the state on 34 infants.Results:In the first three years since statewide implementation, nearly 650,000 infants have been screened for SMA. 34 babies screened positive and were referred to a neuromuscular specialty care center. The incidence remains lower than previously predicted. The majority (94%), including all infants with 2-3 copies of SMN2, have received treatment. Among treated infants, the overwhelming majority (97%; 29/30) have received gene replacement. All infants in this cohort with 3 copies of SMN2 are clinically asymptomatic post-treatment based on early clinical follow-up data. Infants with 2 copies of SMN2 are more variable in their outcomes. Electrodiagnostic outcomes data from a subgroup of patients (n=11) for whom pre- and post-treatment data demonstrated either improvement or no change in CMAP amplitude at last clinical follow-up compared to pre-treatment baseline. Most infants were treated before 6 weeks of age (median = 34.5 DOL; range 11-180). Delays and barriers to treatment identified by treating clinicians followed two broad themes: medical and non-medical. Medical delays most commonly reported were presence of AAV9 antibodies and elevated troponin I levels. Non-medical barriers included delays in obtaining insurance as well as insurance policies regarding specific treatment modalities.Discussion:The findings from the NYS cohort of newborn screen-identified infants are consistent with other reports of improved outcomes from early diagnosis and treatment. Additional biomarkers of motor neuron health including electromyography can potentially be helpful in detecting pre-clinical decline.

Newbornscreening SMA – From Pilot Project to Nationwide Screening in Germany

“…In our study, most parents of children with 2 or 3 copies of the SMN2 gene were in favor of treatment with onasemnogene abeparvovec. Similar experiences have been reported by other research groups [ 24, 27 ]. However, a proportion of parents prefer RNA-based therapy mainly because of what they perceive as the unclear risk of gene replacement therapy.…”

“…Depending on the structures in place in different countries, the time to notify families of the suspicious finding varied from 8 to 11 days after birth. The median start of treatment in patients with 2 or 3 SMN2 copies varied from 19 days after birth in our pilot study to 34 days [19,24]. Knowing that at the time of the first clinical examination, up to one third of patients already show the first symptoms of SMA [19,25], shortening this period is an important goal.…”

“…The lack of accepted reimbursement for therapy in presymptomatic children is one of the major obstacles in some countries [ 23 ]. Time to treatment is largely influenced by non-medical factors such as transport time for blood testing, time to obtain insurance, and time to approve required reimbursement for therapies, in addition to medical issues such as time for genetic confirmation of suspicious findings, elevated liver enzymes, or AAV antibodies [ 24 ]. Care must be taken to minimize the time necessary to complete the various steps before treatment can begin.…”

Recommendations for Interpreting and Reporting Silent Carrier and Disease-Modifying Variants in SMA Testing Workflows

“…Copy number analysis for SMN1 and SMN2 genes associated with SMA can be difficult, as the copy number of these varies much more than other regions within the genome. Furthermore, rapid turnaround time for SMA diagnostic testing is important for timely administration of therapies which halt neuron degeneration [ 15 , 16 ]. SMA genetic testing for SMN1 and SMN2 exon 7 copy numbers is accomplished using a variety of methods, including PCR followed by capillary electrophoresis (PCR/CE), quantitative PCR (qPCR), digital droplet PCR (ddPCR), multiplex ligation-dependent probe amplification (MLPA), and next-generation sequencing (NGS).…”

“…When positive screening results are identified, follow-up testing is performed to confirm diagnosis and obtain SMN2 copy number results to infer disease prognosis. However, recent studies have provided data supporting the reporting of SMN2 copy numbers along with initial screening results, as it is beneficial for SMA patients with two copies of SMN2 where treatment timing is most crucial [ 16 ]. Others have suggested that disease modifier variant testing is also important to further refine the likely prognosis for SMA patients identified through NBS with two or three copies of SMN2 [ 17 ].…”