Mitochondrial ATP-Synthase Deficiency in a Child with 3-Methylglutaconic Aciduria

Abstract

ABSTRACT. We report the finding of mitochondrial ATPsynthase deficiency in a child with persistent 3-methylglutaconic aciduria. The child presented in the neonatal period with severe lactic acidosis, which was controlled by Na-H C 0 3 and glucose infusions. During the 1st y of life, there were several episodes of lactic acidosis precipitated by infections or prolonged intervals between meals. The excretion of lactate in urine was variable, but there was a persistent high excretion of 3-methylglutaconic acid. The activity of 3-methylglutaconyl-CoA hydratase in fibroblasts was normal. The child had a hypertrophic cardiomyopathy and magnetic resonance images revealed hypoplasia of corpus callosum. The gross motor and mental development was retarded, but there were no other neurologic signs. Investigation of muscle mitochondrial function at 1 y of age revealed a severe mitochondrial ATP-synthase deficiency (oligomycin-sensitive, dinitrophenol-stimulated Mg2+ ATPase activity: 27 nmol x min-' x (mg protein)-', control range 223-673 nmol x min-' x (mg protein)-'.The mitochondrial respiratory rate was low and tightly coupled. The respiratory rate was normalized by the addition of an uncoupler. Low MgZ+ ATPase activity was also demonstrated by histochemical methods. Morphologic examination revealed ultrastructural abnormalities of mitochondria. There was no deletion of mitochondrial DNA. The sequences of the ATP synthase subunit genes of mitochondrial DNA were in accordance with published normal sequences. (Pediatr Res 32: 731-735,1992)

Reduced Respiratory Control with ADP and Changed Pattern of Respiratory Chain Enzymes as a Result of Selective Deficiency of the Mitochondrial ATP Synthase

“…The high ATPase threshold is likely to rescue the energy supply to some extent; however, it might differ in cells and tissues with different genetic background. From the three earlier reported patients with decreased ATPase and absence of mitochondrial mutations, two died within the first days of life (13,14) and one survived for several years (12). Similar to the previous two reported patients who lacked mutations of the mitochondrial genes ATP6 and ATP8 (12, 13), a clear reduction of the hydrolytic activity of mitochondrial ATPase (oligomycin sensitive) was found in investigated tissues.…”

3-Methylglutaconic Acidemia in Smith-Lemli-Opitz Syndrome

“…Lactic acidosis or other evidence of mitochondrial dysfunction occur in some patients with idiopathic 3MGC-aciduria (1, 2). Similarly, several patients with well-defined primary mitochondrial disorders, such as ATP-synthase deficiency and Pearson syndrome, have been found to excrete excessive amounts of 3MGC (5,6), suggesting that mitochondrial dysfunction may be primary in some patients with idiopathic 3MGC aciduria. In such patients, one mechanism for increased 3MGC-aciduria could be failure of mitochondrial uptake of peroxisomally or cytoplasmically synthesized 3MGC.…”

“…Except in several patients with mild neurologic abnormalities caused by a genetic deficiency of 3-methylglutaconyl-CoA hydratase (3,4), provocative testing including fasting, oral loading with i-leucine, and high protein diets have had little effect on the excretion of 3MGC, even in patients with 50-to 100-fold increased excretion of 3MGC. And whereas a few patients with excessive 3MGC aciduria have been found to have a primary defect of mitochondrial energy metabolism (5,6), most searches for a specific metabolic lesion in patients with 3MGC aciduria prove fruitless.…”

Cytoplasmic transfer of the mtDNA nt 8993 T-->G (ATP6) point mutation associated with Leigh syndrome into mtDNA-less cells demonstrates cosegregation with a decrease in state III respiration and ADP/O ratio.

“…ATP6 and subunit 9 (ATP9) are known to be major components of the proton channel Qf the ATP synthase (31,32), and it has been postulated that the leucine at position 156 in ATP6 sits adjacent to a glutamate in ATP9, creating a protonation site essential for proton translocation. Substitution of a positively charged arginine for the leucine would then neuttalize the negative charge of the glutamate and block the channel (30 (34,37,38), low F1 ATPase activity was also found, indicating a defective nuclear-encoded subunit of the complex. The patients described by Schotland et al (38) and Holme et al (37) sit at the ends of the clinical spectrum of oxidative phosphorylation disease, perhaps representing a mild tissue-specific mutant versus a severe mutant with systemic expression such as 8993 T-3 G. The similarity ofthe clinical picture of the patient described by Clark et al (34) to that of nt 8993 NARP patients (5-8, 10) also suggests that defects in different subunits of the H+-ATP synthase complex can lead to similar clinical pictures.…”