title: Novel mutations in dihydrolipoamide dehydrogenase deficiency in two cousins with borderline-normal PDH complex activity.
abstract: We have diagnosed dihydrolipoamide dehydrogenase (DLD) deficiency in two male second cousins, who presented with markedly different clinical phenotypes. Patient 1 had a recurrent encephalopathy, and patient 2 had microcephaly and lactic acidosis. Their presentation is unusual, in that the DLD subunit deficiency had little effect on pyruvate dehydrogenase complex activity, but caused a severe reduction in the activities of other enzymes that utilize this subunit. We have identified two mutations in the DLD gene in each patient. The second cousins have one novel mutation in common resulting in a substitution of isoleucine for threonine (I47T), which has not been previously reported in the literature. Patient 1 has a second mutation that has been reported to be common in the Ashkenazi Jewish population, G229C. Patient 2 has a second mutation, E375K, which has also been previously reported in the literature. Enzyme kinetic measurements on patient fibroblasts show that under certain conditions, one heteroallelic mutation may have a higher K(m). This may account for the differing clinical phenotypes. These findings have important repercussions for other patients with similar clinical phenotypes, as DLD activity is not normally measured in cases with normal PDHc activity.
authors.affiliation: Metabolism Research Programme, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jessie M
authors.initials: JM
authors.lastname: Cameron
authors.forename: Valeriy
authors.initials: V
authors.lastname: Levandovskiy
authors.forename: Neviana
authors.initials: N
authors.lastname: Mackay
authors.forename: Julian
authors.initials: J
authors.lastname: Raiman
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Renaud
authors.forename: Joe T R
authors.initials: JT
authors.lastname: Clarke
authors.forename: Annette
authors.initials: A
authors.lastname: Feigenbaum
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.forename: Brian H
authors.initials: BH
authors.lastname: Robinson
mesh_terms: D000140:Acidosis, Lactic / Q000201:enzymology / Q000235:genetics; D019943:Amino Acid Substitution; D001483:Base Sequence; D001928:Brain Diseases, Metabolic / Q000201:enzymology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D008058:Dihydrolipoamide Dehydrogenase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006579:Heterozygote; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008831:Microcephaly / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D010641:Phenotype; D017354:Point Mutation; D021122:Protein Subunits; D011768:Pyruvate Dehydrogenase Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D021122:Protein Subunits; D011768:Pyruvate Dehydrogenase Complex; D004247:DNA; D008058:Dihydrolipoamide Dehydrogenase