Refining the diagnosis of mitochondrial HMG-CoA synthase deficiency.

Mitochondrial HMG-CoA synthase deficiency is an inherited metabolic disorder caused by a defect in the enzyme that regulates the formation of ketone bodies. Patients present with hypoketotic hypoglycaemia, encephalopathy and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting. The diagnosis may easily be missed as previously reported results of routine metabolic investigations, urinary organic acids and plasma acylcarnitines may be nonspecific or normal, and a high index of suspicion is required to proceed to further confirmatory tests. We describe a further acute case in which the combination of urinary organic acids, low free carnitine and changes in the plasma acylcarnitine profile on carnitine supplementation were very suggestive of a defect in ketone synthesis. The diagnosis of mitochondrial HMG-CoA synthase deficiency was confirmed on genotyping, revealing two novel mutations: c.614G > A (R188H) and c.971T > C (M307T). A further sibling, in whom the diagnosis had not been made acutely, was also found to be affected. The possible effects of these mutations on enzyme activity are discussed.

The relationship between branched-chain amino acids and alpha-keto acids in blood in uremia.

Branched-chain alpha-keto acid (BCKA) supplements are used as a nitrogen-free source of branched-chain amino acids (BCAA) in patients with chronic renal failure. Their use is dependent on the freely reversible interconversion of BCKA and BCAA in muscle tissue. In a group of eight young adults on dialysis compared to 11 normal healthy adults, the ratios of the fasting plasma concentrations of leucine and isoleucine to their corresponding alpha-keto acids, alpha-keto isocaproic acid and alpha-keto-beta-methyl-eta-valeric acid, respectively, were significantly elevated. These ratios appear to be sensitive to changes in intracellular glutamate and pyruvate. The ratios increased in seven insulin-dependent diabetics following insulin withdrawal, a situation where intracellular glutamate is increased. The ratios decreased in six normal healthy adults in response to submaximal treadmill exercise, a situation where intracellular pyruvate is increased. The elevated BCAA/BCKA ratios in uremia could be a reflection of reduced peripheral glucose utilization. A consequence of this will be enhanced conversion of supplemented BCKA to their corresponding BCAA. The close association between muscle BCAA and glucose metabolism suggests that the timing of BCKA administration in relation to energy intake might prove important.