Multiple respiratory chain abnormalities associated with hypertrophic cardiomyopathy and 3-methylglutaconic aciduria

Abstract

In a 4.5-month-old boy presenting with marked muscular hypotonia in the neonatal period, hepatomegaly, cardiac hypertrophy, recurrent hypoglycemia, metabolic acidosis, and secondary carnitine deficiency, there was a considerable urinary excretion of 3-methylglutaconic and 3-methylglutaric acid. Estimation of 3-methylglutaconyl-CoA hydratase, 3-hydroxy-3-methylglutaryl-CoA lyase and initial enzymatic steps of cholesterol biosynthesis in cultured fibroblasts and in different tissues postmortem revealed no enzyme deficiency. Analyses of the respiratory chain in postmortem tissues demonstrated severe impairment of complex I (NADH ubiquinone oxidoreductase) and complex IV (cytochrome c oxidase) activities in skeletal muscle and reduced complex IV activity in heart.

The 3‐methylglutaconic acidurias: what's new?

“…The majority of patients described so far presented with CM (Holme et al 1992; Ibel et al 1993; Besley et al 1995; Ruesch et al 1996; De Kremer et al 2001; Morava et al 2004; Sperl et al 2006). A subgroup presented with a severe early-onset phenotype with hypertrophic CM, and the unique features of early cataract, hypotonia/developmental delay, and lactic acidosis (Di Rosa et al 2006).…”

Induction of oxidative stress by the metabolites accumulating in 3-methylglutaconic aciduria in cerebral cortex of young rats

“…Besides these well-defined forms of MGTA, an unclassified group known as type IV has been reported in many patients presenting variable psychomotor retardation, spasticity, hypertonicity and cardiomyopathy (Gibson et al, 1991Gunay-Aygun, 2005). Some MGTA patients have elevated lactic acid or citric acid cycle intermediates, as well as abnormalities of the mitochondrial electron transport chain (Ibel et al, 1993;Besley et al, 1995;Ruesch et al, 1996), including deficiency of the activities of respiratory chain complexes I, II, III, IV and V Sweetman and Williams, 2001;Gunay-Aygun, 2005;Wortmann et al, 2006), strongly indicating mitochondrial dysfunction.…”

Mitochondrial disease in superoxide dismutase 2 mutant mice

“…This enzyme is a critical enzyme in ketogenesis and is required in the last step of leucine catabolism, and mutations in the HMG-CoA gene have been associated with some forms of 3-MGC aciduria (18,19). In urine, 3-MGC is detectable by gas chromatography͞mass spectrometry (GC͞MS), and patients with 3-MGC aciduria show a marked clinical heterogeneity that can encompass cardiomyopathy, bilateral optic atrophy, movement disorders, disorders of the respiratory chain, and hepatomegaly (20)(21)(22)(23)(24).…”