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 longue (LCHADD) et du déficit en protéine trifonctionnelle mitochondriale (TFPD)

Authors' objectives: The mitochondrial trifunctional protein complex (TFP) is a complex comprised of three enzymes involved in the beta-oxidation of long-chain fatty acids. A deficiency of all three enzymes in the complex causes a metabolic disease called mitochondrial trifunctional protein deficiency (TFPD), while a deficiency of the enzyme long-chain acyl-CoA dehydrogenase (LCHAD), a member of the complex, causes a metabolic disease called LCHAD deficiency (LCHADD). Both diseases are inherited in an autosomal recessive fashion and caused by mutations in one or both of the HADHA and HADHB genes. LCHADD is a biochemically indistinguishable entity from TFPD, and only molecular biological confirmation can discriminate between them. The absence or malfunction of these enzymes can lead to the dysfunction of multiple energy-intensive organs such as the heart, liver, kidneys, and muscles, and cause various clinical symptoms. The prevalence of LCHADD/TFPD ranges from 1 in 60,000 to 1 in 500,000 births and varies around the world depending on how it is identified. In Québec, birth prevalence remains uncertain. LCHADD/TFPD can manifest as hypoketotic hypoglycemia that can cause metabolic decompensation. Rhabdomyolysis, severe cardiac, and hepatic disorders, often fatal, are also observed. Peripheral neuropathies, degenerative and progressive ophthalmic pathologies that can lead to blindness are also found in some patients. All individuals with LCHADD/TFPD will develop signs and symptoms during their lifetime, and more than half of children will develop them during the first six months of life. Although there has never been an LCHADD/TFPD screening relevance assessment in Quebec, it has been performed since 2018 by tandem mass spectrometry on a dried blood sample. The Ministère de la Santé et des Services sociaux (MSSS) mandated the Institut national d'excellence en santé et en services sociaux (INESSS) to assess the relevance of maintaining, or not, newborn screening for LCHADD/TFPD in 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 Poor prognosis for untreated children): Mortality rates ranging from 20% to 80% have been observed in absence of newborn screening. • LCHADD is responsible for a proportion of sudden infant death syndrome cases (#2 Early treatment would 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 and supplementing with medium-chain triglyceride (MCT) oil. • Early treatment would reduce mortality and morbidity when adherence to treatment is good. However, nutritional treatment would not prevent the development of neurological or ocular complications but could slow them down. (#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. • Very few false-positive or false-negative results were observed in various screening programs. • In Québec, LCHADD/TFPD have been screened since 2018 and no newborns have since received a positive LCHADD/TFPD diagnosis, while 17 have received a false positive result. • For the vast majority of affected newborns, the result of the newborn screening test is obtained in a timely manner. (#4 Newborn screening for LCHADD/TFPD appears to be effective): • Newborn screening appears to be more effective than identification by clinical signs in reducing mortality and cardiac problems in patients with LCHADD/TFPD. • Liver, vision, muscle problems, and hypoglycemic episodes may also be less common in screened or asymptomatic patients. • Newborn screening does not appear to have a positive effect on neurological problems. • Many limitations are present in studies included in the systematic review, requiring caution in interpreting the results. (#5 The economic impact of newborn LCHADD/TFPD screening remains unclear): The literature review does not allow us to determine screening efficiency because the results are contradictory. The results of studies available in the literature are difficult to compare and apply to Québec context. • Although difficult to estimate in the current context, the budgetary impact of maintaining or withdrawing newborn screening for LCHADD/TFPD would be very limited, given the very low prevalence, the high performance of the screening test, and the absence of additional costs on the MS/MS platform.

Authors' recommendations: RESULTS: The integration of all the scientific, contextual and experiential data led to the following findings. (#1 Poor prognosis for untreated children): Mortality rates ranging from 20% to 80% have been observed in absence of newborn screening. • LCHADD is responsible for a proportion of sudden infant death syndrome cases (#2 Early treatment would 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 and supplementing with medium-chain triglyceride (MCT) oil. • Early treatment would reduce mortality and morbidity when adherence to treatment is good. However, nutritional treatment would not prevent the development of neurological or ocular complications but could slow them down. (#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. • Very few false-positive or false-negative results were observed in various screening programs. • In Québec, LCHADD/TFPD have been screened since 2018 and no newborns have since received a positive LCHADD/TFPD diagnosis, while 17 have received a false positive result. • For the vast majority of affected newborns, the result of the newborn screening test is obtained in a timely manner. (#4 Newborn screening for LCHADD/TFPD appears to be effective): • Newborn screening appears to be more effective than identification by clinical signs in reducing mortality and cardiac problems in patients with LCHADD/TFPD. • Liver, vision, muscle problems, and hypoglycemic episodes may also be less common in screened or asymptomatic patients. • Newborn screening does not appear to have a positive effect on neurological problems. • Many limitations are present in studies included in the systematic review, requiring caution in interpreting the results. (#5 The economic impact of newborn LCHADD/TFPD screening remains unclear): The literature review does not allow us to determine screening efficiency because the results are contradictory. The results of studies available in the literature are difficult to compare and apply to Québec context. • Although difficult to estimate in the current context, the budgetary impact of maintaining or withdrawing newborn screening for LCHADD/TFPD would be very limited, given the very low prevalence, the high performance of the screening test, and the absence of additional costs on the MS/MS platform.

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)