Ontario Newborn Screening for Spinal Muscular Atrophy: The First Year

Spinal muscular atrophy (SMA) is a rare degenerative neuromuscular disorder. SMA is commonly subdivided into types I, II, and III based on the age of symptom onset and the motor milestones achieved ¹ . The most common and severe form, type I, presents in infancy with survival beyond the second birthday rare, making SMA the most common genetic cause of childhood mortality. ¹ The incidence of SMA is often cited as ∼1 in 10,000 births, ² but large-scale population studies are required to evaluate the disease prevalence in different populations.

SMA is caused by deficiency of the survival motor neuron (SMN) 1 protein due to disruption of the SMN1 gene. In addition to SMN1, there is also a homologous gene, SMN2 that originated as an inverted duplication centromeric to SMN1 and is normally present in 0–5 copies. SMN2 differs from SMN1 by five translationally silent base pair changes; however, one of these maps to an exonic splice enhancer which leads to exclusion of exon 7 in ∼90% of SMN2 mRNA and degradation of the resulting protein. ¹ SMN2 thus makes ∼10% full-length mRNA (compared to SMN1)³; disease severity (i.e. SMA type) correlates inversely with SMN2 copy number although the genotype–phenotype correlation is not absolute.

Recently a number of treatments have been developed which greatly improve motor strength, function, and survival of children with SMA. ⁴ In June 2017, Health Canada approved nusinersen (Spinraza®) and in December 2020, onasemnogene abeparvovec (Zolgensma®) was approved. A third treatment, risdiplam (Evrysdi®) is currently under review. Given the benefit demonstrated with presymptomatic treatment, ⁴ SMA was naturally considered for newborn screening (NBS) programs that aim to identify and treat diseases prior to symptom onset which is crucial for patient outcomes. SMA has now been added to NBS panels in more than 10 countries on a pilot or permanent basis. ⁵

In Ontario, the Newborn Screening Ontario (NSO) Advisory Council reviewed the evidence and recommended that SMA be added to the provincial NBS panel. ⁶ SMA was included on a pilot basis in January 2020 and on a permanent basis in July 2020. Ontario is the only jurisdiction in Canada screening for SMA at this time. Prior to screening initiation, Ontario newborn screening and pediatric neuromuscular experts recommended that children with biallelic disruption of SMN1 (deletion or conversion) and four or fewer SMN2 copies be reported as positive. ⁶ NSO performs a laboratory-developed first-tier MassARRAY test for the presence of SMN1, and a second-tier multiligand probe amplification (MLPA) test for both SMN1 and SMN2 copy number on screening dried blood spots (DBS). ⁵ It was recommended that screen-positive infants undergo confirmatory molecular genetic testing and, in the case of children with 2 or 3 copies of SMN2, begin treatment within 16–30 days. ⁶ Children with four copies of SMN2 are closely monitored for symptoms with treatment initiated at the first sign of disease. ⁶

In the first full year, NSO tested 139,800 infants. Five infants were identified as positive, representing a provincial birth prevalence of 1 in 27,960. This rate is lower than that reported in the literature ¹ however, since this data only captures cases over 1 year, a longer ascertainment period will be important. As more jurisdictions begin to include SMA on newborn screening programs, it will also be seen how Ontario’s birth prevalence data compares to similar data that will now be collected prospectively in other regions. Notably, no false-positive cases were identified. Additionally, no false negatives have been identified by pediatric neuromuscular specialists caring for children with SMA in the province. Although NSO only reports children with <4 SMN2 copies, no infants with 0xSMN1 and >5xSMN2 copies have been identified. Of the five infants, one had 2xSMN2, three had 3xSMN2, and one had 4xSMN2 copies. All infants were referred to a treatment center by a median of 9 days of age (range: 6–15 days) with clinical neuromuscular assessment and confirmatory diagnostic testing in a clinical laboratory completed by median of 13.5 days of age (range: 12–18 days) for children with <3 copies of SMN2, and 24 days for the 4 copy SMN2 case (Table 1). At the time of writing, three patients had received disease-modifying treatment at a median age of 24 days of age (range: 18–32 days). This is consistent with the target time window of treatment initiation within 16–30 days of life. ⁶ We note that case 5 had complicating factors unrelated to NBS which introduced a delay to treatment initiation and that three of the cases had intervening weekends which introduced a 2-day delay in the time from sample receipt to screening result. All three of the treated patients were documented to be clinically asymptomatic at the time of treatment initiation. The family of one patient (3xSMN2 copies) declined treatment and the sole 4xSMN2 copy patient remains asymptomatic and continues to be followed as per provincial guidelines. ⁶ Once the diagnosis of SMA has been confirmed on an independent sample by a diagnostic laboratory and a baseline functional assessment completed by a trained physiotherapist/kinesiologist, an application can be submitted for private insurance and/or to the Ontario Ministry of Health and Long-Term Care’s Exceptional Access Program (EAP) for coverage of nusinersen. Although onasemnogene abeparvovec is approved, there is currently no decision regarding reimbursement criteria. Overall, the workflow has been efficient and treatment initiated within the recommended time goals (Table 1).

Table 1: Case summary and timing of screening results through treatment

An analysis of NSO’s first year of SMA screening identified at least three modifications that could potentially reduce time to treatment initiation: (1) operation of NSO molecular laboratory on weekends; (2) reduction in time to transport sample from the collection site to the NSO laboratory; (3) reduction of time required for confirmatory testing; and (4) submission of preliminary paperwork for provincial EAP approval while awaiting the results of the confirmatory genetic testing. Overall, Ontario NBS for SMA has successfully identified infants with SMA, enabling more timely access to treatment.