title: Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation.
abstract: Lipoic acid is an essential prosthetic group of four mitochondrial enzymes involved in the oxidative decarboxylation of pyruvate, α-ketoglutarate, and branched chain amino acids and in the glycine cleavage. Lipoic acid is synthesized stepwise within mitochondria through a process that includes lipoic acid synthetase. We identified the homozygous mutation c.746G>A (p.Arg249His) in LIAS in an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine. Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate and decreased pyruvate dehydrogenase complex activity. A pronounced reduction of the prosthetic group lipoamide was found in lipoylated proteins.
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg 5020, Austria. h.mayr@salk.at
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.forename: Franz A
authors.initials: FA
authors.lastname: Zimmermann
authors.forename: Christine
authors.initials: C
authors.lastname: Fauth
authors.forename: Christa
authors.initials: C
authors.lastname: Bergheim
authors.forename: David
authors.initials: D
authors.lastname: Meierhofer
authors.forename: Doris
authors.initials: D
authors.lastname: Radmayr
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.forename: Johannes
authors.initials: J
authors.lastname: Koch
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D000140:Acidosis, Lactic / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D002894:Chromosomes, Human, Pair 4; D003241:Consanguinity; D004734:Energy Metabolism / Q000235:genetics*; D004827:Epilepsy / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics / Q000254:growth & development; D017809:Fatal Outcome; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D005998:Glycine / Q000097:blood* / Q000652:urine; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia / Q000235:genetics; D018482:Muscle, Skeletal / Q000201:enzymology; D020125:Mutation, Missense; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013466:Sulfurtransferases / Q000172:deficiency*
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D013466:Sulfurtransferases; C116435:lipoic acid synthase; D005998:Glycine