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. 2023 Nov;46(6):1104-1113.
doi: 10.1002/jimd.12669. Epub 2023 Aug 10.

Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1

K van Vliet  1 , A M Dijkstra  1 , M J Bouva  2 , J van der Krogt  3 , K Bijsterveld  3 , F van der Sluijs  3 , M G de Sain-van der Velden  4 , K Koop  5 , A Rossi  6 , J A Thomas  7 , C A Patera  8 , M B G Kiewiet  2 , P J Waters  9 , D Cyr  9 ; Québec NTBC Study Group; A Boelen  10 , F J van Spronsen  1 , M R Heiner-Fokkema  3
Affiliations

Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1

K van Vliet et al. J Inherit Metab Dis. 2023 Nov.

Abstract

Dried blood spot succinylacetone (SA) is often used as a 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 nine referred newborns (2 TT1, 7 false-positive), eight genetically confirmed MAAI-D children, and 66 controls. Maleic acid was elevated in uOA of 5/7 false-positive newborns and in the three 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 to 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 two newborns with normal Q-uMA. No sample was available for genetic analysis of the last false-positive infant with elevated Q-uMA. Our study shows that 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.

Keywords: maleic acid; maleylacetoacetate isomerase deficiency; newborn screening; succinylacetone; tyrosinemia type 1.

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References

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