Original Title: Avis: Évaluation de la pertinence du dépistage néonatal sanguin par spectrométrie de masse en tandem du déficit en déshydrogénase des acyl-CoA à chaîne très longue (VLCADD)

Authors' objectives: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a genetic disease associated with a defect in fatty acid beta-oxidation, transmitted in an autosomal recessive manner and caused by mutations in the gene encoding for the enzyme VLCAD. The absence or malfunction of VLCAD can lead to the dysfunction of multiple energy-intensive organs such as the heart, liver, muscles, and kidneys, and cause various clinical symptoms of varying severity depending on the age of presentation or the presence of triggering factors. The prevalence of VLCADD varies from 1 in 30,000 to 1 in 100,000 births and varies according to the region of the world and identification method. In Québec, the prevalence is estimated to be around 1 in 60,000 births. Very long chain acyl-CoA dehydrogenase deficiency can present in three clinical forms: early, intermediate, and late. The early form is the most common and severe. It usually presents in the first few weeks of life with less specific signs such as vomiting, hypoketotic hypoglycemia, irritability, and lethargy. Severe, often fatal, cardiac, and hepatic disorders are also characteristic of this form. The disease is also responsible for a number of cases of sudden infant death syndrome. In addition, individuals with any form of VLCADD may suffer from rhabdomyolysis. However, some patients with VLCADD may remain asymptomatic or present with symptoms only after a triggering event. Although there has never been a relevance assessment conducted, VLCADD has been screened in Québec since 2018 by tandem mass spectrometry on a dried blood sample. The Ministère de la Santé et des Services sociaux (MSSS) has mandated the Institut national d'excellence en santé et en services sociaux to assess maintaining, or not, VLCADD newborn screening as part of the Québec Neonatal Blood and Urine Screening Program.

Authors' results and conclusions: RESULTS: The integration of all the scientific, contextual and experiential data led to the following findings. (#1 VLCADD is a metabolic emergency): Newborn symptoms are subtle and very nonspecific at first and can progress very rapidly to death if no treatment is applied. • Mortality is very high in patients with the early form if there is no rapid diagnosis or newborn screening. • Diagnostic delay can last from several months to several years in people with VLCADD. (#2 Early treatment appears to improve prognosis): Treatment consists of preventing hypoglycemic episodes and rhabdomyolysis by avoiding prolonged periods of fasting and providing a frequent diet high in carbohydrates and very low in long-chain fatty acids. • Strict and prompt treatment may eliminate cardiac problems already present in some individuals. • Many patients may remain asymptomatic, especially those with intermediate or late forms, who adhere to nutritional therapy and a stricter management protocol on sick days (e.g., fever or vomiting). (#3 A reliable and valid screening test exists): The test performance calculated in various program studies meets MSSS standards for sensitivity and specificity values as well as reference rate. • In Québec, VLCADD has been screened since 2018. Less than 5 newborns had a positive diagnosis of this disease, 76 received a false positive result of which 44 had a carrier status. • In Québec, approximately two-thirds of newborns will receive their screening test result before developing symptoms. • Since C14:1 concentration is sensitive to feeding or metabolic stress, a newborn, especially if has affected by the late form, could obtain a false negative result on his/her screening test. (#4 Newborn screening for VLCADD appears to be effective): Newborn screening appears to be more effective than identification by clinical signs in reducing the number of hypoglycemic episodes, heart rhythm abnormalities, and muscle disorders in patients with VLCADD. • Many limitations are present in the studies included, which limit the interpretation of the results. (#5 The economic value of newborn VLCADD screening remains unclear): Only one study selected seems to indicate that screening would not be costeffective (would increase costs for minimal clinical gains), but it was not considered applicable to Québec.

Authors' recommendations: RESULTS: The integration of all the scientific, contextual and experiential data led to the following findings. (#1 VLCADD is a metabolic emergency): Newborn symptoms are subtle and very nonspecific at first and can progress very rapidly to death if no treatment is applied. • Mortality is very high in patients with the early form if there is no rapid diagnosis or newborn screening. • Diagnostic delay can last from several months to several years in people with VLCADD. (#2 Early treatment appears to improve prognosis): Treatment consists of preventing hypoglycemic episodes and rhabdomyolysis by avoiding prolonged periods of fasting and providing a frequent diet high in carbohydrates and very low in long-chain fatty acids. • Strict and prompt treatment may eliminate cardiac problems already present in some individuals. • Many patients may remain asymptomatic, especially those with intermediate or late forms, who adhere to nutritional therapy and a stricter management protocol on sick days (e.g., fever or vomiting). (#3 A reliable and valid screening test exists): The test performance calculated in various program studies meets MSSS standards for sensitivity and specificity values as well as reference rate. • In Québec, VLCADD has been screened since 2018. Less than 5 newborns had a positive diagnosis of this disease, 76 received a false positive result of which 44 had a carrier status. • In Québec, approximately two-thirds of newborns will receive their screening test result before developing symptoms. • Since C14:1 concentration is sensitive to feeding or metabolic stress, a newborn, especially if has affected by the late form, could obtain a false negative result on his/her screening test. (#4 Newborn screening for VLCADD appears to be effective): Newborn screening appears to be more effective than identification by clinical signs in reducing the number of hypoglycemic episodes, heart rhythm abnormalities, and muscle disorders in patients with VLCADD. • Many limitations are present in the studies included, which limit the interpretation of the results. (#5 The economic value of newborn VLCADD screening remains unclear): Only one study selected seems to indicate that screening would not be costeffective (would increase costs for minimal clinical gains), but it was not considered applicable to Québec.

Authors' methods: A rigorous and transparent synthesis of the literature, in the form of a quick review, was conducted to document the parameters under study, including test performance, and screening efficacy and safety. In addition, an extensive search of the scientific literature as well as grey literature was conducted across multiple databases without limitation to study designs for the other aspects assessed. Contextual and experiential data were collected from an advisory committee with members practicing in the field of genetic diseases - clinical biochemist, nutritionist, geneticist, medical biochemist, and nurses. The compilation of this information allowed us to identify findings on the various parameters under study. After reviewing these findings, the Comité délibératif permanent – Approches diagnostiques et dépistage, held discussions to formulate the final recommendation.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/depistage-neonatal-sanguin-par-spectrometrie-de-masse-en-tandem-derreurs-innees-du-metabolisme-asa-ga1-lchadd-tfpd-vlcadd.html

Year Published: 2023

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/depistage-neonatal-sanguin-par-spectrometrie-de-masse-en-tandem-derreurs-innees-du-metabolisme-asa-ga1-lchadd-tfpd-vlcadd.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: L'Institut national d'excellence en sante et en services sociaux (INESSS)