title: Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency.
abstract: We report an inborn error of the tricarboxylic acid cycle, fumarase deficiency, in two siblings born to first cousin parents. They presented with progressive encephalopathy, dystonia, leucopenia, and neutropenia. Elevation of lactate in the cerebrospinal fluid and high fumarate excretion in the urine led us to investigate the activities of the respiratory chain and of the Krebs cycle, and to finally identify fumarase deficiency in these two children. The deficiency was profound and present in all tissues investigated, affecting the cytosolic and the mitochondrial fumarase isoenzymes to the same degree. Analysis of fumarase cDNA demonstrated that both patients were homozygous for a missense mutation, a G-955-->C transversion, predicting a Glu-319-->Gln substitution. This substitution occurred in a highly conserved region of the fumarase cDNA. Both parents exhibited half the expected fumarase activity in their lymphocytes and were found to be heterozygous for this substitution. The present study is to our knowledge the first molecular characterization of tricarboxylic acid deficiency, a rare inherited inborn error of metabolism in childhood.
authors.affiliation: INSERM U393, Département de Pédiatrie, Hôpital des Enfants-Malades, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Bourgeron
authors.forename: D
authors.initials: D
authors.lastname: Chretien
authors.forename: J
authors.initials: J
authors.lastname: Poggi-Bach
authors.forename: S
authors.initials: S
authors.lastname: Doonan
authors.forename: D
authors.initials: D
authors.lastname: Rabier
authors.forename: P
authors.initials: P
authors.lastname: Letouzé
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: A
authors.initials: A
authors.lastname: Rötig
authors.forename: P
authors.initials: P
authors.lastname: Landrieu
authors.forename: P
authors.initials: P
authors.lastname: Rustin
mesh_terms: D000595:Amino Acid Sequence; D001927:Brain Diseases / Q000235:genetics*; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics*; D002952:Citric Acid Cycle; D018076:DNA, Complementary / Q000737:chemistry; D005260:Female; D005649:Fumarate Hydratase / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation
chemical_list: D018076:DNA, Complementary; D005649:Fumarate Hydratase