Original Title: Avis: Évaluation de la pertinence du dépistage néonatal de l’amyotrophie spinale

Authors' objectives: Spinal muscular atrophy (SMA) is an autosomal recessive genetic neuromuscular disorder. Approximately seven to eight children are born with SMA each year in Québec. SMA is the leading genetic cause of death in newborns and is characterized by muscle weakness and atrophy due to progressive and irreversible loss of motor neurons in the spinal cord and brain stem. This muscle loss affects the ability to crawl, walk, control neck and head movements and, ultimately, swallow and breathe. Treatments have been available since 2017. The Ministère de la Santé et des Services sociaux (MSSS) gave a mandate to the Institut national d’excellence en santé et en services sociaux (INESSS) to assess the relevance of implementing neonatal SMA screening for all newborns in Québec. With this screening, affected infants could be identified before they develop symptoms and before the neuronal loss, which is irreversible, becomes too significant. These infants could therefore benefit from the optimal effects of the available treatments. This mandate did not involve assessing the relevance of prenatal screening.

Authors' results and conclusions: RESULTS: In all the screening programs identified in the literature, only a few false positives have been detected. These results were explained by poor test optimization, the fortuitous detection of patients with carrier status, or poor sample quality. As well, very few false- 3 negative results have been identified. All these patients had mutations that are not detected by the current screening test, which shows its limitations. Nevertheless, test performance remains very good in most of the programs identified, with a sensitivity, specificity and positive predictive value of 100%. Regarding therapies, there is no study available that compares the clinical course of screened and unscreened infants. Treatments administered early or before symptom onset appear to be more effective in preventing death or the need for permanent ventilation. A positive impact on motor function development seems to be observed when treatment is initiated early or before symptom onset. However, the studies have considerable limitations, given the number of participants recruited during the presymptomatic phase and the lack of knowledge regarding the long-term efficacy of therapies. If implemented, neonatal SMA screening would be the first newborn screening test in Québec to use genetic material. This type of test is recognized as having excellent sensitivity and specificity and sometimes gives a false sense of security. At the same time, extracting deoxyribonucleic acid (DNA) can raise concerns about sample and data storage and about the confidentiality of the results obtained. However, the test used in SMA screening does not involve genome sequencing and is very selective for the SMN1 and SMN2 genes. Collecting rare disease screening and follow-up data into a centralized database would ensure that all children who have been diagnosed have access to the care and treatment required for their condition. Some of the health professionals consulted mentioned the need for a rare disease registry that would provide a better picture of the situation specific to Québec. Adding SMA to the neonatal blood screening platform could result in additional expenditures of approximately $4 million over three years for Québec’s neonatal blood screening program (Programme québécois de dépistage néonatal sanguin), the referral centres and the facilities in the health and social services network that provide follow-up of these patients. However, this investment includes upgrading the screening platform for the possible addition of new diseases for which to screen. This budget impact estimate includes the earlier diagnosis and the required clinical management but not the treatment costs, given the uncertainty associated with their estimation. In varying the epidemiological and economic inputs, the results of the probabilistic budget impact analysis show that there is a 95% probability that net expenditures will be between $3.4 million and $4.8 million over three years. CONCLUSION: Integrating the scientific, contextual and experiential data permits the following conclusions to be drawn: • Between seven and eight children with SMA are born each year in Québec. • Currently, most individuals with SMA are identified after symptom onset in Québec, often when they are at an advanced stage of the disease, while a minority are reportedly identified through family screening. An increase in the prevalence of SMA is not anticipated as a result of the implementation of screening. • Approximately 85% of SMA patients have type I (two copies of the SMN2 gene) or type II (three copies of the SMN2 gene). • A diagnostic delay of two to four months is observed for patients with type I SMA. This delay appears to be several months for type II patients and more than a year for those with type III. - Neonatal SMA screening would permit early identification of affected newborns and a reduction in diagnostic delay. • New therapies that alter the natural history of the disease are now available in Québec for patients with spinal muscular atrophy. • A multidisciplinary approach is needed to prevent or alleviate certain complications of the disease and improve the patient’s quality of life. • The homozygous deletion of exon 7 of the SMN1 gene is detected by the first-tier test using various amplification methods. In most programs, the number of copies of the SMN2 gene is determined by second-tier testing. • The test sensitivity and specificity are close to 100% in the studies where they could be calculated. The few false positives found had various causes (optimization problems, poor sample quality or fortuitous carrier status). The false negatives found were of the clinical rather than technical type; they could not have been detected by the screening test. • Newborns with carrier status are not targeted by the different screening programs, and newborns with five or more copies of the SMN2 gene are not considered positive by the programs. • No study with a design comparing the clinical course of screened and unscreened infants is available. According to indirect data on the natural history of the disease and an assessment of the impact of early treatment, treatments administered early or before symptom onset seem to be more effective in preventing death or the need for permanent ventilation and have a positive effect on motor function development.

Authors' recommendations: INESSS recommends adding spinal muscular atrophy screening to the blood platform in Québec’s neonatal screening program. • The implementation of a screening program should be accompanied by prospective data collection to measure the impact of neonatal screening and early management on the clinical course of SMA patients. A subsequent re-evaluation of spinal muscular atrophy screening would be desirable when Québec data become available. • The implementation of neonatal screening for spinal muscular atrophy should not replace the screening of individuals with a family history, either to determine carrier status or to perform prenatal screening.

Authors' methods: We conducted a scientific literature search with no restrictions on study design and collected contextual and experiential data from experts and from previous consultations with parents of affected infants. In addition, an efficiency model and a budget impact analysis were performed. All of the data (scientific, contextual, and experiential) were submitted to the Comité d’excellence clinique (CEC) en dépistage des maladies chroniques for deliberation.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/evaluation-de-la-pertinence-du-depistage-neonatal-de-lamyotrophie-spinale.html

Year Published: 2021

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/evaluation-de-la-pertinence-du-depistage-neonatal-de-lamyotrophie-spinale.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: Gouvernement du Québec