Combined 3-Methylglutaconic and 3-Hydroxy- 3-Methylglutaric Aciduria with Endocardial Fibroelastosis and Dilatative Cardiomyopathy in Male and Female Siblings with Partial Deficiency of Complex ll/lll in Fibroblasts

Abstract

We report on 2 children, brother and sister, who presented with cardiomyopathy and muscular hypotonia at the age of 8 months. They both excreted significant amounts of 3-hydroxy-3-methylglutaric acid (3-HMG) and 3-methylglutaconic acid (3-MGC) but no 3-methylglutaric acid (3-MG). Enzyme analysis in fibroblasts revealed normal activities of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase and of 3-methylglutaconyl hydratase and other enzymes of 3-HMG metabolism. Loading tests with leucine did not affect the excretion of 3-HMG and 3-MGC. The girl died as a result of her cardiomyopathy. while the boy recovered and was treated with cardiac supportive therapy. He showed a steady improvement during his clinical course with biochemical normalization of the urinary excretion of 3-HMG, concomitant with marked improvement in the hypertrophic cardiomyopathy. In cultured fibroblasts from both patients a reduced activity of complex II/III of the respiratory chain was measured which may be the cause of this new type of 3-HMG uria. Analysis of mitochondrial DNA heart muscle, liver and fibroblast culture of the patient did not reveal any major mitochondrial DNA rearrangements (deletion, duplication) or any point mutation that had been described in association with mitochondrial cardiomyopathy.

Neurochemical evidence that 3‐methylglutaric acid inhibits synaptic Na+,K+‐ATPase activity probably through oxidative damage in brain cortex of young rats

“…Type III or Costeff syndrome is an autosomal recessive disorder caused by mutations in the OPA3 gene, leading to bilateral optic atrophy (Anikster et al, 2001; Arn and Funanage, 2006). Type IV or “unspecified” MGTA comprises a heterogeneous disorder with progressive mental and psychomotor retardation, spasticity, hypertonicity, and cardiomyopathy (Besley et al, 1995; Ibel et al, 1993; Ruesch et al, 1996). Interestingly, some patients with MGTA have elevated lactic acid or/and citric acid cycle intermediates, as well as abnormalities of the mitochondrial electron transport chain (Besley et al, 1995; Ibel et al, 1993; Ruesch et al, 1996), including deficiency of the activities of respiratory chain complexes I, II, III, IV and V (Gibson et al, 1993; Gunay‐Aygun, 2005; Sweetman and Williams, 2001; Wortmann et al, 2006), indicative of a mitochondrial dysfunction.…”

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.…”