Abstract:
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.
