Maleic acid is a biomarker for Maleylacetoacetate isomerase deficiency; implications for newborn screening of Tyrosinemia type 1

• Published in: Journal of inherited metabolic disease Vol. 46; no. 6; pp. 1104 - 1113
• Main Authors: van Vliet, K, Dijkstra, A M, Bouva, M J, van der Krogt, J, Bijsterveld, K, van der Sluijs, F, de Sain-van der Velden, M G, Koop, K, Rossi, A, Thomas, J A, Patera, C A, Kiewiet, M B G, Waters, P J, Cyr, D, Boelen, A, van Spronsen, F J, Heiner-Fokkema, M R
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.11.2023
• Subjects: Acids; Biomarkers; Children; Creatinine; Genetic analysis; Maleic acid; Maleylacetoacetate isomerase; Medical screening; Neonates; Urine; succinylacetone; Tyrosinemia type 1; newborn screening; maleic acid; Maleylacetoacetate isomerase deficiency
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1002/jimd.12669

Dried blood spot succinylacetone (SA) is often used as biomarker for newborn screening (NBS) for Tyrosinemia type 1 (TT1). However, false-positive SA results are often observed. Elevated SA may also be due to maleylacetoacetate isomerase deficiency (MAAI-D), which appears to be clinically insignificant. This study investigated whether urine organic acid (uOA) and quantitative urine maleic acid (Q-uMA) analyses can distinguish between TT1 and MAAI-D. We reevaluated/measured uOA (GC-MS) and/or Q-uMA (LC-MS/MS) in available urine samples of 9 referred newborns (2 TT1, 7 false-positive), 8 genetically confirmed MAAI-D children and 66 controls. Maleic acid was elevated in uOA of 5/7 false-positive newborns and in the 3 available samples of confirmed MAAI-D children, but not in TT1 patients. Q-uMA ranged from not detectable to 1.16 mmol/mol creatinine in controls (n=66), and from 0.95-192.06 mmol/mol creatinine in false-positive newborns and MAAI-D children (n=10). MAAI-D was genetically confirmed in 4/7 false-positive newborns, all with elevated Q-uMA, and rejected in the 2 newborns with normal Q-uMA. No sample was available for genetic analysis of the last false-positive infant with elevated Q-uMA. MAAI-D is a recognizable cause of false-positive TT1 NBS results. Elevated urine maleic acid excretion seems highly effective in discriminating MAAI-D from TT1. This article is protected by copyright. All rights reserved.