Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain

An infant with a neurodegenerative disorder accompanied by lactic acidemia is described. In muscle homogenate, the activity of lipoamide dehydrogenase (LAD), the third catalytic subunit of pyruvate dehydrogenase complex (PDHc ), alpha-ketoglutarate dehydrogenase complex (KGDHc), and branched-chain ke to acid dehydrogenase complex was reduced to 15% of the control. The activi ty of PDHc was undetectable and the activity of KGDHc was 2% of the control mean. The immunoreactive LAD protein was reduced to about 10% of the contr ol. Direct sequencing of LAD cDNA revealed only one mutation, substituting Asp for Val at position 479 of the precursor form. The mutation resides wit hin the interface domain and likely perturbs stable dimerization, The pheno typic heterogeneity in LAD deficiency is not directly correlated with the r esidual LAD activity but rather with its impact on the multienzymatic compl ex activity. (C) 1999 Academic Press.