Phenotypic heterogeneity in the syndromes of 3-methylglutaconic aciduria

The in-depth evaluation of suspected mitochondrial disease

“…Surprisingly, lactic acid elevation on urine organic acid analysis is not a good discriminator for mitochondrial cytopathies [6]. Increased excretion of tricarboxylic acid (TCA) cycle intermediates, ethylmalonic acid, and 3-methyl glutaconic acid commonly occur in mitochondrial disease, but are rarely diagnostic of a specific mitochondrial disorder [21][22][23]. Of note, renal immaturity is a common cause of TCA cycle intermediates elevation in the urine.…”

X‐linked cardioskeletal myopathy and neutropenia (Barth syndrome): Respiratory‐chain abnormalities in cultured fibroblasts

“…X-Linked cardioskeletal myopathy, neutropenia and abnormal mitochondria (McKusick 302060; 3-methylglutaconic aciduria type 2; Barth syndrome) represents a rare metabolic disorder with a distinct clinical phenotype, reported so far from Europe (Barth et al 1983), North-America (Gibson et al 1991;Kelley et al 1991) and Australia (Ad6s et al 1993;Christodoulou et al 1994). It has the following clinical and biochemical profile: dilated cardiomyopathy; neutropenia due to maturation arrest; neuromuscular weakness; absence of cerebral involvement; and diminished statural growth.…”

“…It has the following clinical and biochemical profile: dilated cardiomyopathy; neutropenia due to maturation arrest; neuromuscular weakness; absence of cerebral involvement; and diminished statural growth. Clinical biochemical features include variable lactic acidaemia and lactic aciduria (Barth et al 1983); increased urinary excretion of 3-methylglutaconic acid, 3-methylglutaric acid and 2-ethylhydracrylic acid (Kelley et al 1991;Gibson et al 1991); and low serum cholesterol (Kelley et al 1991). Linkage analysis assigned the disease to distal Xq28 (Bolhuis et al 1991;Adds et al 1993;Christodoulou et al 1994).…”

“…Previous studies on the respiratory chain in skeletal muscle showed impaired oxidative phosphorylation at the level of complexes III and IV (Barth et al 1983) and decreased activity of complex IV (Christodoulou et al 1994). Results of clinical experiments pertaining to the organic acid abnormality and the low serum cholesterol included absent effect of leucine loading on the excretion of 3-methylglutaconic acid (Kelley et al 1991;Christodoulou et al 1994); normal activities of enzymes in the leucine pathway (3-methylglutaconyl-CoA hydratase (EC 4.2.1.18), 3-hydroxy-3-methylglutaryl-CoA lyase (EC 4.1.3.4), 3-hydroxy-3-methylglutaryl-CoA reductase); and normal in vitro biosynthesis of [14C]cholesterol from [J4C]acetate (Gibson et al 1991).…”

Novel missense mutation (R94S) in the TAZ (G4.5) gene in a Japanese patient with Barth syndrome

“…The activity of 3-methylglutaconyl CoA hydratase of cultured fibroblasts was within normal range (subject No. 1 in Gibson et al 1991). He was diagnosed as 3-methylglutaconic aciduria, type 2 (BTHS).…”