Original Title: Avis: Évaluation de la pertinence du dépistage néonatal sanguin par spectrométrie de masse en tandem de l’acidémie glutarique de type 1 (GA1)

Authors' objectives: Glutaric acidemia type 1 (GA1) is an inborn metabolic error caused by genetic variants in the GCDH gene, encoding the protein glutaryl-CoA-dehydrogenase (GCDH). GCDH is involved in the metabolism of lysine, tryptophan and hydroxylysine, and the reduction of its activity leads, among other things, to the accumulation of neurotoxic metabolites. Overall, the prevalence of GA1 is approximately 1 in 100,000 newborns and the disease can present in different forms (infantile, late, or asymptomatic) and biochemical profiles (low or high excretor) depending on the time of onset of signs and symptoms and residual enzyme activity. GA1 can cause acute encephalopathy and movement disorders, subdural hematomas, and renal problems. In the vast majority of cases, the first symptoms appear after three months of age, and the risk of acute encephalopathy decreases after six years of age. Patient prognosis depends primarily on the timing of diagnosis, either before or after the onset of symptoms, and on early management. Acute encephalopathies can cause progressive movement disorders resembling a dystonic/dyskinesic syndrome, as can exposure to neurotoxic metabolites. Acute encephalopathy would gradually affect the brain system, and the child may eventually develop difficulty swallowing and chewing, and possibly choking. Intellectual functions would not be affected during encephalopathy attacks, and the child may even remain alert. Although there has never been an GA1 screening relevance assessment in Québec, GA1 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 the relevance of maintaining, or not, newborn screening for GA1 in the Québec Neonatal Blood and Urine Screening Program.

Authors' results and conclusions: RESULTS: The integration of all scientific, contextual, and experiential data led to the following findings. (#1 Poor prognosis for untreated children): Brain damage from acute encephalopathy and accumulation of neurotoxic metabolites is irreversible. • Clinical identification of patients before the onset of symptoms is difficult: - 75% of patients will have macrocephaly, but it is not detected or will not lead to a GA1 diagnosis; - babies with GA1 may be confused with patients with shaken baby syndrome; - there are no warning signs of acute encephalopathy. (#2 Early treatment would improve patient prognosis): Maintenance treatment consists primarily of a lysine-free diet and carnitine supplementation. In addition, emergency treatment should be applied in case of metabolic stress (e.g., fasting, fever). • When treatment is initiated during the newborn period, prior to the onset of symptoms, 80-90% of patients would remain asymptomatic. • Treatment would be effective in preventing acute encephalopathy and movement disorders when started before their onset. • Treatment does not appear to be effective in preventing renal problems. • Adherence to maintenance and emergency treatment would be essential to achieve full benefit. (#3 A reliable and valid screening test exists, but it has certain limitations): GA1 screening specificity meets the standards suggested by the members of the advisory committee (≥ 99.75%) and the MSSS (≥ 99%). • Sensitivity does not always meet MSSS standards (≥ 99%), primarily because of the identification of false negatives. • Those with a false-negative result primarily have a low excretory profile. • For the vast majority of affected newborns, the newborn screening test result will be received in a timely manner. (#4 Newborn screening for GA1 would benefit patients): Screened patients appear to have better motor development than clinically identified patients. They also tend to have fewer movement disorders. • Newborn screening, adherence to treatment, and biochemical profile are factors that influence the development of cognitive functions. • Newborn screening for GA1, however, would not have an impact on the development of subdural hematomas and on mortality. (#5 The economic cost-effectiveness of newborn screening for GA1 remains unclear): The available data suggest that, compared with no screening, the efficience of newborn screening for GA1 is variable. • No study identified in the literature has assessed the cost of newborn blood screening for GA1 by MS/MS in Québec, and other studies identified were conducted under conditions that are difficult to apply to Québec.

Authors' recommendations: RESULTS: The integration of all scientific, contextual, and experiential data led to the following findings. (#1 Poor prognosis for untreated children): Brain damage from acute encephalopathy and accumulation of neurotoxic metabolites is irreversible. • Clinical identification of patients before the onset of symptoms is difficult: - 75% of patients will have macrocephaly, but it is not detected or will not lead to a GA1 diagnosis; - babies with GA1 may be confused with patients with shaken baby syndrome; - there are no warning signs of acute encephalopathy. (#2 Early treatment would improve patient prognosis): Maintenance treatment consists primarily of a lysine-free diet and carnitine supplementation. In addition, emergency treatment should be applied in case of metabolic stress (e.g., fasting, fever). • When treatment is initiated during the newborn period, prior to the onset of symptoms, 80-90% of patients would remain asymptomatic. • Treatment would be effective in preventing acute encephalopathy and movement disorders when started before their onset. • Treatment does not appear to be effective in preventing renal problems. • Adherence to maintenance and emergency treatment would be essential to achieve full benefit. (#3 A reliable and valid screening test exists, but it has certain limitations): GA1 screening specificity meets the standards suggested by the members of the advisory committee (≥ 99.75%) and the MSSS (≥ 99%). • Sensitivity does not always meet MSSS standards (≥ 99%), primarily because of the identification of false negatives. • Those with a false-negative result primarily have a low excretory profile. • For the vast majority of affected newborns, the newborn screening test result will be received in a timely manner. (#4 Newborn screening for GA1 would benefit patients): Screened patients appear to have better motor development than clinically identified patients. They also tend to have fewer movement disorders. • Newborn screening, adherence to treatment, and biochemical profile are factors that influence the development of cognitive functions. • Newborn screening for GA1, however, would not have an impact on the development of subdural hematomas and on mortality. (#5 The economic cost-effectiveness of newborn screening for GA1 remains unclear): The available data suggest that, compared with no screening, the efficience of newborn screening for GA1 is variable. • No study identified in the literature has assessed the cost of newborn blood screening for GA1 by MS/MS in Québec, and other studies identified were conducted under conditions that are difficult to apply 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, 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 the study designs for 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, biochemical physician, and nurses. Compilation of all 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)