Newborn Screening for Spinal Muscular Atrophy: Ontario Testing and Follow-up Recommendations

Abstract

Background: Spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons causing muscle atrophy and weakness. Nusinersen, the first effective SMA therapy was approved by Health Canada in June 2017 and has been added to the provincial formulary of all but one Canadian province. Access to this effective therapy has triggered the inclusion of SMA in an increasing number of Newborn Screening (NBS) programs. However, the range of disease-modifying SMN2 gene copy numbers encountered in survival motor neuron 1 (SMN1)-null individuals means that neither screen-positive definition nor resulting treatment decisions can be determined by SMN1 genotype alone. We outline an approach to this challenge, one that specifically addresses the case of SMA newborns with four copies of SMN2. Objectives: To develop a standardized post-referral evaluation pathway for babies with a positive SMA NBS screen result. Methods: An SMA NBS pilot trial in Ontario using first-tier MassARRAY and second-tier multi-ligand probe amplification (MLPA) was launched in January 2020. Prior to this, Ontario pediatric neuromuscular disease and NBS experts met to review the evidence regarding the diagnosis and treatment of children with SMA as it pertained to NBS. A post-referral evaluation algorithm was developed, outlining timelines for patient retrieval and management. Conclusions: Ontario’s pilot NBS program has created a standardized path to facilitate early diagnosis of SMA and initiation of treatment. The goal is to provide timely access to those SMA infants in need of therapy to optimize motor function and prolong survival.

Newborn Screening for 5q Spinal Muscular Atrophy: Comparisons between Real-Time PCR Methodologies and Cost Estimations for Future Implementation Programs

“…According to Kellar-Guenther et al [39], seventeen USA states took 20 months to reach statewide implementations for SMA, and nowadays, 37 states are currently screening for SMA, representing 85% of newborn babies screened in the USA (Cure SMA, available online After establishing the strategy for implementation, centers have to determine the workflow and path of positive screened patients. Ontario's pilot program has reported to have a preliminary diagnosis 7-10 days after birth (considering the samples arriving from remote sites) and a definitive diagnosis between 16 and 27 days after birth [29]. When a positive patient is identified, some NBS centers have made contact with the pediatrician listed at the time of birth to formulate a disclosure plan and, after that, brought the family to the NBS center for an evaluation, confirmatory test, and information about the SMA treatments available.…”

“…We considered it feasible to use automated or semiautomated systems, as demonstrated by Czibere et al [22], and the use a 384-well reaction plate, enabling the screening of up to 2000 samples per day. A possible workflow for the screening step is shown in Figure 2, along with a real example of the time to treatment [29].…”

“…The protocol modifications include the targeted pre-amplification of the SMN gene before the real-time PCR and the use of SMN2 blocker primers, locked nucleic acid (LNA) SMN1 primers/probes, and minor groove binder (MGB) probes [20,[24][25][26][27][28]. Moreover, others have developed different strategies, as is the case of Ontario Province with the multiplex MassARRAY of SMA along with the genes for hearing loss and severe combined immunodeficiency [29].…”

“…Days 1−3 of the laboratory work were based on a calculation of the time for the preparation of 7 to 8 plates (384-well plates) a day (about 1500 samples/day) and our current assay experience; about 2 laboratory specialists would be needed during this workflow. * Based on McMillan et al[29]. ** International guidelines refer to treating all confirmed SMA infants with 4 SMN2 copies or less.…”

Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy

“…33 To expedite treatment initiation, the United States, Europe, Taiwan, Japan, and Australia, among other countries and regions, have introduced newborn screening programs or pilot studies (Figure 2). [34][35][36][37][38][39] Current guidelines recommend immediate treatment for all infants with two, three, or four copies of SMN2. [40][41][42] Recommendation: Treating physicians should discuss timing of therapeutic initiation with families, highlighting treatment urgency given that motor neuron degeneration largely occurs in the first few months and rapid decreases in motor unit number estimation and maximum compound motor action potential amplitude occur within 2 postnatal months, demonstrating irreversible loss of motor units.…”