Newborn screening for aromatic l-amino acid decarboxylase deficiency

• Verfasst von: Reischl-Hajiabadi, Anna Theresa [VerfasserIn]
• Verfasst von: Okun, Jürgen G. [VerfasserIn]
• Verfasst von: Kohlmüller, Dirk [VerfasserIn]
• Verfasst von: Manukjan, Georgi [VerfasserIn]
• Verfasst von: Hegert, Sebastian [VerfasserIn]
• Verfasst von: Durner, Jürgen [VerfasserIn]
• Verfasst von: Schuhmann, Elfriede [VerfasserIn]
• Verfasst von: Hörster, Friederike [VerfasserIn]
• Verfasst von: Mütze, Ulrike [VerfasserIn]
• Verfasst von: Feyh, Patrik [VerfasserIn]
• Verfasst von: Hoffmann, Georg F. [VerfasserIn]
• Verfasst von: Röschinger, Wulf [VerfasserIn]
• Verfasst von: Janzen, Nils [VerfasserIn]
• Verfasst von: Opladen, Thomas [VerfasserIn]
• Titel: Newborn screening for aromatic l-amino acid decarboxylase deficiency
• Titelzusatz: strategies, results, and implication for prevalence calculations
• Verf.angabe: Anna T. Reischl-Hajiabadi, Jürgen G. Okun, Dirk Kohlmüller, Georgi Manukjan, Sebastian Hegert, Jürgen Durner, Elfriede Schuhmann, Friederike Hörster, Ulrike Mütze, Patrik Feyh, Georg F. Hoffmann, Wulf Röschinger, Nils Janzen, Thomas Opladen
• E-Jahr: 2024
• Jahr: 31 January 2024
• Umfang: 7 S.
• Fussnoten: Gesehen am 28.10.2024
• Titel Quelle: Enthalten in: Molecular genetics and metabolism
• Ort Quelle: Orlando, Fla. : Academic Press, 1998
• Jahr Quelle: 2024
• Band/Heft Quelle: 141(2024), 3, Artikel-ID 108148, Seite 108148-1-108148-7
• ISSN Quelle: 1096-7206
• DOI: doi:10.1016/j.ymgme.2024.108148
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: 3;methyldopa
• Sach-SW: 3-OMD
• Sach-SW: AADC deficiency
• Sach-SW: Aromatic l-amino acid decarboxylase
• Sach-SW: Neonatal screening
• K10plus-PPN: 190703627X

Abstract

Background - Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal-recessive neurometabolic disorder caused by variants in dopa decarboxylase (DDC) gene, resulting in a severe combined deficiency of serotonin, dopamine, norepinephrine, and epinephrine. Birth prevalence of AADCD varies by population. In pilot studies, 3-O-methyldopa (3-OMD) was shown to be a reliable biomarker for AADCD in high-throughput newborn screening (NBS) allowing an early diagnosis and access to gene therapy. To evaluate the usefulness of this method for routine NBS, 3-OMD screening results from the largest three German NBS centers were analyzed. - Methods - A prospective, multicenter (n = 3) NBS pilot study evaluated screening for AADCD by quantifying 3-OMD in dried blood spots (DBS) using tandem mass spectrometry (MS/MS). - Results - In total, 766,660 neonates were screened from January 2021 until June 2023 with 766,647 with unremarkable AADCD NBS (766,443 by 1st-tier analysis and 204 by 2nd-tier analysis) and 13 with positive NBS result recalled for confirmatory diagnostics (recall-rate about 1:59,000). Molecular genetic analysis confirmed AADCD (c.79C > T p.[Arg27Cys] in Exon 2 und c.215 A > C p.[His72Pro] in Exon 3) in one infant. Another individual was highly suspected with AADCD but died before confirmation (overall positive predictive value 0.15). False-positive results were caused by maternal L-Dopa use (n = 2) and prematurity (30th and 36th week of gestation, n = 2). However, in 63% (n = 7) the underlying etiology for false positive results remained unexplained. Estimated birth prevalence (95% confidence interval) was 1:766,660 (95% CI 1:775,194; 1:769,231) to 1:383,330 (95% CI 1:384,615; 1:383,142). The identified child remained asymptomatic until last follow up at the age of 9 months. - Conclusions - The proposed screening strategy with 3-OMD detection in DBS is feasible and effective to identify individuals with AADCD. The estimated birth prevalence supports earlier estimations and confirms AADCD as a very rare disorder. Pre-symptomatic identification by NBS allows a disease severity adapted drug support to diminish clinical complications until individuals are old enough for the application of the gene therapy.