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3‐Methylglutaconic aciduria—lessons from 50 genes and 977 patients
Author(s) -
Wortmann Saskia B.,
Kluijtmans Leo A. J.,
Rodenburg Richard J.,
Sass Jörn Oliver,
Nouws Jessica,
Kaauwen Edwin P.,
Kleefstra Tjitske,
Tranebjaerg Lisbeth,
Vries Maaike C.,
Isohanni Pirjo,
Walter Katharina,
Alkuraya Fowzan S.,
Smuts Izelle,
Reinecke Carolus J.,
Westhuizen Francois H.,
Thorburn David,
Smeitink Jan A. M.,
Morava Eva,
Wevers Ron A.
Publication year - 2013
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-012-9579-6
Subject(s) - mitochondrial disease , medicine , mitochondrial myopathy , methylmalonic aciduria , respiratory chain , metabolic disorder , urea cycle , endocrinology , mitochondrial dna , pediatrics , mitochondrion , pathology , genetics , biology , gene , amino acid , methylmalonic acid , homocysteine , arginine
Elevated urinary excretion of 3‐methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3‐methylglutaconyl‐CoA hydratase deficiency (mutations in AUH ), it derives from leucine degradation. In all other disorders with 3‐methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3‐methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3‐methylglutaconic aciduria. Three percent of all urine samples of the patients referred showed 3‐methylglutaconic aciduria, often in correlation with disorders not reported earlier in association with 3‐methylglutaconic aciduria (e.g. organic acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3‐methylglutaconic aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3‐methylglutaconic aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH , TAZ, SERAC1, OPA3, DNAJC19 TMEM70 . These conditions should therefore be referred to as inborn errors of metabolism with 3‐methylglutaconic aciduria as discriminative feature.