Lactic Acidosis in Three Sibs Due to Defects in Both Pyruvate Dehydrogenase and α-Ketoglutarate Dehydrogenase Complexes

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Abstract
A Canadian Indian family is described in which 3 of the children were mentally retarded, and had seizures and other neurological abnormalities. They had chronic metabolic acidosis associated with elevated blood levels of lactate, pyruvate and alanine. Two of the children excreted large amounts of pyruvic and .alpha.-ketoglutaric acids in the urine and had elevated plasma levels of glutamic acid and proline. Hypoglycemia occurred with fasting in 2 of the children. Treatment with pharmacological doses of thiamine, lipoic acid, biotin, riboflavin and various dietary regimes was without effect. One child died at 3 1/2 mo. and another at 4 1/2 mo.; the 3rd is still alive at 23 mo. Enzyme assays revealed a low level of activity of both the pyruvate and .alpha.-ketoglutarate dehydrogenase complexes in cultured fibroblasts of 1 of the sibs. These patients appeared to have partial defects in the oxidation of pyruvate, as well as of .alpha.-ketoglutarate within the tricarboxylic acid cycle.