Original Title: Avis: Évaluation de la pertinence du dépistage néonatal sanguin par spectrométrie de masse en tandem de l’acidurie argininosuccinique (ASA)

Authors' objectives: Argininosuccinic aciduria (ASA) is an inborn metabolic error caused by genetic variants in the ASL gene, encoding the argininosuccinate lyase protein (ASL). ASL is involved in the urea cycle, primarily in arginine metabolism. Overall, ASA prevalence is approximately 1 to 9 per 100,000 newborns, and the disease can present in different forms (neonatal, late, asymptomatic) depending on the timing of the onset of signs and symptoms. Complications associated with ASA can include episodes of hyperammonemia, developmental delays, mental retardation, trichorrhexis nodosum, epilepsy, liver disorders and hypertension. Among the diseases associated with the urea cycle, patients with ASA will have fewer episodes of hyperammonemia, but more neurological disorders related to their disease. Diagnostic delay may occur, primarily in patients with the late stage of the disease. It is also possible for patients to be treated for secondary conditions such as hypertension without having received an ASA diagnosis. Although there has never been a relevance assessment conducted, ASA has been screened in Québec since 2018 using 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 maintaining, or not, newborn screening for ASA as part of the in the Québec Neonatal Blood and Urine Screening Program.

Authors' results and conclusions: RESULTS: The integration of all scientific, contextual, and experiential data has led to the following findings. (#1 Poor prognosis for untreated children): Patients with the neonatal form (more than half) of ASA have a poor prognosis compared with patients with the late form. • All symptomatic patients may develop neurologic complications. • Between 6% and 15% of patients with ASA die from the disease. (#2 Treatment may partially improve prognosis): Treatment consists of a protein-restricted diet and arginine supplementation; some patients may also receive ammonia scavengers. • Treatment may reduce hyperammonia attacks and prevent cognitive impairment. • Treatment will not prevent all neurological complications (#3 A reliable and valid screening test exists, but it is not be performed in a timely manner for about half of patients): ASA sensitivity and specificity screening meet MSSS standards. • The baseline rate is low and meets PQDNSU standards, while the detection rate ranges from 0 to 1:177,000. • The majority of newborns with the neonatal form present with symptoms before their newborn screening result. (#4 Newborn screening effectiveness is mixed): Patients screened during the infantile period have a less severe initial hyperammonia attack than patients identified by clinical signs. • Newborn screening appears to provide an advantage for the risk of developing a neurological disorder, movement disorders, and trichorrhexis nodosum. • Newborn screening does not appear to have an effect on the annual number of hyperammonia attacks, risk of seizures, liver complications, hypokalemia, and severe diarrhea. • Newborn screening does not appear to have an effect on mortality risks, although a non-statistically significant trend appears to be observed in favour of newborn screening. (#5 The economic burden of ASA newborn screening remains unclear): The available data are inconclusive as to the efficience of ASA newborn screening. The results of studies available in the literature are difficult to compare and apply to Québec. A budget impact analysis could not be conducted because of uncertainties surrounding the prevalence and performance of the screening test and the absence of additional costs on the MS/MS platform related to the maintenance or savings associated with the withdrawal of ASA screening, as well as the impossibility of making a comparison before and after screening was introduced.

Authors' recommendations: RESULTS: The integration of all scientific, contextual, and experiential data has led to the following findings. (#1 Poor prognosis for untreated children): Patients with the neonatal form (more than half) of ASA have a poor prognosis compared with patients with the late form. • All symptomatic patients may develop neurologic complications. • Between 6% and 15% of patients with ASA die from the disease. (#2 Treatment may partially improve prognosis): Treatment consists of a protein-restricted diet and arginine supplementation; some patients may also receive ammonia scavengers. • Treatment may reduce hyperammonia attacks and prevent cognitive impairment. • Treatment will not prevent all neurological complications (#3 A reliable and valid screening test exists, but it is not be performed in a timely manner for about half of patients): ASA sensitivity and specificity screening meet MSSS standards. • The baseline rate is low and meets PQDNSU standards, while the detection rate ranges from 0 to 1:177,000. • The majority of newborns with the neonatal form present with symptoms before their newborn screening result. (#4 Newborn screening effectiveness is mixed): Patients screened during the infantile period have a less severe initial hyperammonia attack than patients identified by clinical signs. • Newborn screening appears to provide an advantage for the risk of developing a neurological disorder, movement disorders, and trichorrhexis nodosum. • Newborn screening does not appear to have an effect on the annual number of hyperammonia attacks, risk of seizures, liver complications, hypokalemia, and severe diarrhea. • Newborn screening does not appear to have an effect on mortality risks, although a non-statistically significant trend appears to be observed in favour of newborn screening. (#5 The economic burden of ASA newborn screening remains unclear): The available data are inconclusive as to the efficience of ASA newborn screening. The results of studies available in the literature are difficult to compare and apply to Québec. A budget impact analysis could not be conducted because of uncertainties surrounding the prevalence and performance of the screening test and the absence of additional costs on the MS/MS platform related to the maintenance or savings associated with the withdrawal of ASA screening, as well as the impossibility of making a comparison before and after screening was introduced.

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, screening efficacy and safety. In addition, an extensive search of the scientific literature as well as grey literature was conducted across limitless multiple databases to study designs for other aspects assessed. Contextual and experiential data were collected from an advisory committee of specialists in genetic diseases: clinical biochemist, nutritionist, geneticist, biochemist physician 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: 2022

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)