DIHYDROLIPOYL DEHYDROGENASE DEFICIENCY - A CAUSE OF CONGENITAL LACTIC ACIDOSIS

Abstract

A male infant born of consanguineous parents (B.Wt. 3 kg) presented acutely at 2 months of age (wt. 4.8 kg) with lethargy, hypertonia, episodic irritability, optic atrophy, laryngeal stridor, irregular respirations and metabolic acidosis. He had elevated blood levels of pyruvate (0.38 mM, N<0.2 mM), lactate (5.3 mM, N<2 mM) and α-ketoglutarate (0.103 mM, N<0.054 mM). He also had elevated levels of branched chain amino acids (x2 upper limit of normal) and occasional alanine responsive hypoglycemia (30-35 mg%). A defect of oxidative decarboxylation was postulated. Neither high dose of thlamine therapy (1 g/day) nor a high fat diet, affected the persistent lactic acidosis (4-10 mM). He deteriorated neurologically and died at the age of 7 months. Autopsy revealed cavitation and demyelination in the basal ganglia, thalami, and brain stem. Key gluconeogenic enzyme activities were normal in liver, muscle, brain and kidney. Total pyruvate (PDH) and α-ketoglutarate (αKGDH) dehydrogenase complex activities were reduced in all tissues to 5-10% of control values. The pyruvate decarboxylase component of PDH (E₁) was normal but the dihydrolipoyl dehydrogenase component (E₃) was reduced in activity (5% of control value). Deficiency of E₃ compromizes both PDH and αKGDH activity. This compromizes both entry into and activity of the tricarboxylic acid cycle. Normal growth and development indicates a greater reliance on glycolytic than oxidative metabolism in the early months of life.

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