Streamlined determination of 3-O-methyldopa in dried blood spots: Prospective screening for aromatic l-amino-acid decarboxylase deficiency

Pin-Wen Chen; Wuh-Liang Hwu; Ni-Chung Lee; Yin-Hsiu Chien

doi:10.1016/j.ymgme.2023.107687

Streamlined determination of 3-O-methyldopa in dried blood spots: Prospective screening for aromatic l-amino-acid decarboxylase deficiency

Mol Genet Metab. 2023 Sep-Oct;140(1-2):107687. doi: 10.1016/j.ymgme.2023.107687. Epub 2023 Aug 15.

Authors

Pin-Wen Chen¹, Wuh-Liang Hwu², Ni-Chung Lee³, Yin-Hsiu Chien⁴

Affiliations

¹ Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
² Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatric, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan; Center for Precision Medicine, China Medical University Hospital, Taichung City, Taiwan.
³ Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatric, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan.
⁴ Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatric, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: chienyh@ntu.edu.tw.

PMID: 37635029
DOI: 10.1016/j.ymgme.2023.107687

Abstract

Background: Aromatic L-amino-acid decarboxylase (AADC) deficiency diagnosis is often delayed by low disease awareness and specific laboratory examinations. We demonstrated that an elevated concentration of L-dopa metabolite 3-O-methyldopa (3-OMD) in dried blood spots could be integrated into a newborn screening program to detect AADC deficiency.

Methods: DBS samples for amino acid and acylcarnitine analysis using NeoBase™2 reagents were also analyzed for the 3-OMD concentration using ¹³C₆-phenylalanine as an internal standard. For samples exceeding the pre-defined cutoffs, an additional spot was punched from the original filter paper for second-tier 3-OMD measurement by high performance liquid chromatography (HPLC)-MS/MS assay. Newborns with a 3-OMD concentration exceeding 500 ng/mL were referred for confirmatory testing.

Results: From Feb. 2020 to Dec. 2022, 157,371 newborns were screened for AADC deficiency. Eight newborns exhibited an elevated 3-OMD concentration (839-5170 ng/mL). Among them, six newborns were confirmed to carry two pathogenic DDC variants, indicating an incidence of AADC deficiency of ∼1:26,000 (95% confidence interval: 1 in 12,021 to 1 in 57,228). During the follow-up period, all six patients developed typical symptoms of AADC deficiency.

Conclusion: The screening for 3-OMD, a target for AADC deficiency, could be easily integrated into the existing newborn screening programs and facilitate the future application for early diagnosis and effective treatment.

Keywords: 3-O-methyldopa; AADC deficiency; Aromatic L-amino-acid decarboxylase; Expanded newborn screening; High performance liquid chromatography; Tandem mass spectrometry.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Metabolism, Inborn Errors* / diagnosis
Aromatic-L-Amino-Acid Decarboxylases / deficiency
Humans
Infant, Newborn
Prospective Studies
Tandem Mass Spectrometry*
Tyrosine

Substances

3-methoxytyrosine
Tyrosine
Aromatic-L-Amino-Acid Decarboxylases

Supplementary concepts

Aromatic amino acid decarboxylase deficiency