BIOCHEMICAL-STUDIES AND GENETIC-STUDIES OF 4 PATIENTS WITH PYRUVATE-DEHYDROGENASE-E1-ALPHA DEFICIENCY

We report studies of four patients with pyruvate dehydrogenase complex (PDH) deficiency caused by mutations in the E1 alpha subunit. Two unr elated male patients presented with Leigh syndrome and a R263G missens e mutation in exon 8. This mutation has previously been described in m ales with the same phenotype. The two other patients had different nov el mutations: (1) an 8-bp deletion at the C-terminus (exon 11) was fou nd in one allele of a young girl suffering from microcephaly and (2) a C88S missense mutation (exon 3) in a boy who only presented with moto r neuropathy. These mutations were not found in the mothers of any of the four cases. Immunoblot analysis revealed decreased immunoreactivit y for the E1 alpha and E1 beta subunits in three out of the four patie nts. These findings confirm that: (1) PDH deficiencies are genetically heterogeneous, (2) the R263G mutation is more frequent in male cases than are other mutations and this amino acid is a hot spot for gene mu tations, (3) the last eight amino acids may be important for the confo rmation of the tetrameric E1-PDH enzyme, and (4) the amino acids at po sitions 88, 263 and 382-387 are essential for the linking of the a sub unit with the beta subunit and for the activity of the holoenzyme.