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REVEAL-CP: Selective Screening of Pediatric Patients for Aromatic L-Amino Acid Decarboxylase Deficiency with a Guthrie Card and In Silico Structural Modeling of One Index Case

Lookup NU author(s): Dr Eugen-Matthias Strehle

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© The Author(s) 2025. Published by Mary Ann Liebert, Inc., publishers. Background: The main objective of this prospective, multicenter study (REVEAL-CP) was to test children with cerebral palsy-like signs and symptoms for raised 3-O-methyldopa (3-OMD) blood levels, a biomarker for aromatic L-amino acid decarboxylase deficiency (AADCd). A secondary objective was to characterize the molecular basis for the defective aromatic L-amino acid decarboxylase (AADC) gene product. Methods: Patients were identified in pediatric secondary and tertiary care hospitals through database searches and personal communication. 3-OMD concentrations from Guthrie card tests were determined using liquid chromatography/mass spectrometry. If 3-OMD was raised, cerebrospinal fluid analysis and dopa decarboxylase (DDC) gene sequencing were performed. An in-silico mutagenesis analysis was carried out to model altered AADC enzymes. Results: In total, 166 patients were enrolled in this study. The median age was 8 years. Sixty-six patients (39.8%) had a diagnosis of cerebral palsy, with the most common type being “mixed” (n = 42; 25.3%). One patient (0.6%), an 11-month-old boy from Italy, was diagnosed with AADCd caused by a homozygous, pathogenic DDC variant (c.749C>T; p.Ser250Phe). Three-dimensional modeling of the Ser250Phe AADC enzyme variant revealed its destabilization. Conclusions: A Guthrie card test for 3-OMD is a recognized screening technique for AADCd. If universal newborn screening for this metabolic disease is not available, children with signs and symptoms of a movement disorder should be investigated for AADCd.

Publication metadata

Author(s): Strehle E-M, Battini R, Gowda V, Kuster A, Amin S, Bertoldi M, Perduca M, Leuzzi V, Johnson S, Lupo P, Liu E, Fox E, Werner C

Publication type: Article

Publication status: Published

Journal: Genetic Testing and Molecular Biomarkers

Year: 2025

Volume: 29

Issue: 1

Pages: 12-18

Online publication date: 20/01/2025

Acceptance date: 02/04/2018

Date deposited: 10/02/2025

ISSN (print): 1945-0265

ISSN (electronic): 1945-0257

Publisher: Mary Ann Liebert Inc.

URL: https://doi.org/10.1089/gtmb.2024.0427

DOI: 10.1089/gtmb.2024.0427

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