Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation
- 1 October 2003
- journal article
- case report
- Published by Springer Science and Business Media LLC in European Journal of Pediatrics
- Vol. 162 (10), 714-718
- https://doi.org/10.1007/s00431-003-1282-z
Abstract
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.Keywords
This publication has 19 references indexed in Scilit:
- Novel mutations in a boy with dihydrolipoamide dehydrogenase deficiency.2001
- Isolated complex I deficiency in children: Clinical, biochemical and genetic aspectsHuman Mutation, 2000
- Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews.1999
- Targeted disruption of the murine dihydrolipoamide dehydrogenase gene ( Dld ) results in perigastrulation lethalityProceedings of the National Academy of Sciences of the United States of America, 1997
- Liver Disease in the Ashkenazi-Jewish Lipoamide Dehydrogenase DeficiencyJournal of Pediatric Gastroenterology and Nutrition, 1997
- Lipoamide dehydrogenase deficiency in Ashkenazi Jews: An insertion mutation in the mitochondrial leader sequenceHuman Mutation, 1997
- Congenital lacticacidemia caused by lipoamide dehydrogenase deficiency with favorable outcomeThe Journal of Pediatrics, 1995
- Identification of two missense mutations in a dihydrolipoamide dehydrogenase-deficient patient.Proceedings of the National Academy of Sciences of the United States of America, 1993
- A structural model for human dihydrolipoamide dehydrogenaseProteins-Structure Function and Bioinformatics, 1992
- Recurrent, familial Reye-like syndrome with a new complex amino and organic aciduriaEuropean Journal of Pediatrics, 1990