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Ontario Newborn Screening for Spinal Muscular Atrophy: The First Year

Published online by Cambridge University Press:  08 October 2021

Kristin D. Kernohan*
Affiliation:
Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada Newborn Screening Ontario, Ottawa, ON, Canada
Hugh J. McMillan
Affiliation:
Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
Ed Yeh
Affiliation:
Newborn Screening Ontario, Ottawa, ON, Canada
Melanie Lacaria
Affiliation:
Newborn Screening Ontario, Ottawa, ON, Canada
Michael Kowalski
Affiliation:
Newborn Screening Ontario, Ottawa, ON, Canada
Craig Campbell
Affiliation:
Children’s Hospital Western Ontario, Department of Pediatrics, Epidemiology and Clinical Neurological Sciences, Schulich School of Medicine, University of Western Ontario, London, ON, Canada
James J. Dowling
Affiliation:
Children’s Hospital Western Ontario, Department of Pediatrics, Epidemiology and Clinical Neurological Sciences, Schulich School of Medicine, University of Western Ontario, London, ON, Canada
Hernan Gonorazky
Affiliation:
Children’s Hospital Western Ontario, Department of Pediatrics, Epidemiology and Clinical Neurological Sciences, Schulich School of Medicine, University of Western Ontario, London, ON, Canada
Janet Marcadier
Affiliation:
Newborn Screening Ontario, Ottawa, ON, Canada
Mark A. Tarnopolsky
Affiliation:
McMaster Children’s Hospital, McMaster University, Hamilton, ON, Canada
Jiri Vajsar
Affiliation:
Children’s Hospital Western Ontario, Department of Pediatrics, Epidemiology and Clinical Neurological Sciences, Schulich School of Medicine, University of Western Ontario, London, ON, Canada
Alex Mackenzie
Affiliation:
Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
Pranesh Chakraborty*
Affiliation:
Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada Newborn Screening Ontario, Ottawa, ON, Canada
*
Correspondence to: Pranesh Chakraborty and Kristin Kernohan, Children’s Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada. Email: pchakraborty@cheo.on.ca, kkernohan@cheo.on.ca
Correspondence to: Pranesh Chakraborty and Kristin Kernohan, Children’s Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada. Email: pchakraborty@cheo.on.ca, kkernohan@cheo.on.ca
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Abstract

Type
Letter to the Editor
Copyright
© The Author(s), 2021. Published by Cambridge University Press on behalf of Canadian Neurological Sciences Federation

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 Reference Verhaart and Robertson1 . 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. Reference Verhaart and Robertson1 The incidence of SMA is often cited as ∼1 in 10,000 births, Reference Finkel, McDermott and Kaufmann2 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. Reference Verhaart and Robertson1 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. Reference De Vivo, Bertini and Swoboda4 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, Reference De Vivo, Bertini and Swoboda4 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. Reference Jędrzejowska5

In Ontario, the Newborn Screening Ontario (NSO) Advisory Council reviewed the evidence and recommended that SMA be added to the provincial NBS panel. Reference McMillan, Kernohan and Yeh6 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. Reference McMillan, Kernohan and Yeh6 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). Reference Jędrzejowska5 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. Reference McMillan, Kernohan and Yeh6 Children with four copies of SMN2 are closely monitored for symptoms with treatment initiated at the first sign of disease. Reference McMillan, Kernohan and Yeh6

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 Reference Verhaart and Robertson1 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. Reference McMillan, Kernohan and Yeh6 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. Reference McMillan, Kernohan and Yeh6 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.

Acknowledgements

Biogen provided funding to Newborn Screening Ontario (NSO) for the pilot portion of this study.

Conflict of Interest

PC and AM were the recipients of a grant from Biogen which funded the first 6 months of SMA NBS in Ontario. AM has also been a consultant for Biogen and is a member of clinical trials for Biogen and Roche SMA studies. HM has received financial support for research endeavors from Roche and is on the advisory board for Novartis. All other authors have no declarations.

Statement of Authorship

KK and ML are responsible for laboratory supervision and reporting for SMA NBS. EY developed the assay and oversees regular performance. MK conducted data analysis for infants screened to date. HJM, CC, JJD, HG, MAT, JV, JM are involved in the retrieval and care for identified SMA infants. AM and PC lead implementation of SMA NBS, PC is Medical Director for NBS Ontario.

References

Verhaart, IEC, Robertson, A, Wilson. IJ, etal, Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy – a literature review. Orphanet J Rare Dis. 2017;12:124.CrossRefGoogle Scholar
Finkel, RS, McDermott, MP, Kaufmann, P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014;83:81017.CrossRefGoogle ScholarPubMed
Burghes, AHM, Beattie, CE. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat Rev Neurosci. 2009;10:597609.CrossRefGoogle ScholarPubMed
De Vivo, DC, Bertini, E, Swoboda, KJ, et al. Nusinersen initiated in infants during presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the phase 2 NURTURE study. Neuromuscul Disord. 2019;29:84256.CrossRefGoogle ScholarPubMed
Jędrzejowska, M. Advances in newborn screening and presymptomatic diagnsosis of spinal muscualr atrophy. Degener Neurol Neuromuscul Dis. 2020;10:3947.Google Scholar
McMillan, HJ, Kernohan, KD, Yeh, E, et al. Newborn screening for spinal muscular atrophy: Ontario testing & follow-up recommendations. Can J Neurol Sci. 2020;48:124.Google ScholarPubMed
Figure 0

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