6533b827fe1ef96bd12865a0
RESEARCH PRODUCT
Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation.
Jan A.m. SmeitinkAndrea Superti-furgaLambert P. Van Den HeuvelHans H. GoebelR.j.h. SmeetsBeat SteinmannFrans J.m. TrijbelsKonrad OexleNils U. BosshardOlga Grafakousubject
MaleHeterozygoteMutation MissensePyruvate Dehydrogenase ComplexGene mutationBiologyCompound heterozygosityLoss of heterozygositymedicineHumansLeigh diseaseMuscle SkeletalDihydrolipoamide DehydrogenaseGeneticsSplice site mutationDihydrolipoamide dehydrogenasePyruvate Dehydrogenase (Lipoamide)Fibroblastsmedicine.diseasePyruvate dehydrogenase complexRenal disorders [UMCN 5.4]Genetic defects of metabolism [UMCN 5.1]Child PreschoolPediatrics Perinatology and Child HealthRNA Splice SitesLeigh DiseaseCellular energy metabolism [UMCN 5.3]description
Item does not contain fulltext A boy with recurrent episodes of hypoglycaemia and ataxia, microcephaly, mental retardation, permanent lactic acidaemia, intermittent 2-oxoglutaric aciduria as well as elevation of serum branched chain amino acids was diagnosed with dihydrolipoamide dehydrogenase (E3) deficiency. Analysis of genomic DNA revealed compound heterozygosity for two novel mutations: I393T in exon 11, located at the interface domain of the protein and possibly interfering with its dimerisation, and IVS9+1G>A located at a consensus splice site. A heterozygous polymorphism was also detected. In the patient's cDNA the I393T mutation and the polymorphism appeared to be homozygous, indicating that the mRNA coming from the IVS9+1G>A mutant allele is not stable. CONCLUSION: as opposed to the non-neurological phenotype of patients with a homozygous G229C mutation, this patient developed Leigh syndrome. Dihydrolipoamide dehydrogenase and pyruvate dehydrogenase complex activities in muscle were 29% and 14% of the lowest control values, respectively. Pyruvate dehydrogenase complex activity in fibroblasts was normal, however, indicating that the biochemical examination of defects in energy metabolism should be performed in a more energy demanding tissue.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2003-01-01 |