Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation.
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.


CONCLUSIONS
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.
Grafakou
Olga
O
Nijmegen Centrer for Mitochondrial Disorders, University Medical Centre Nijmegen, Department of Paediatrics, Geert Grooteplein 10, 9101, 6500HB Nijmegen, The Netherlands.
Oexle
Konrad
K
van den Heuvel
Lambert
L
Smeets
Roel
R
Trijbels
Frans
F
Goebel
Hans H
HH
Bosshard
Nils
N
Superti-Furga
Andrea
A
Steinmann
Beat
B
Smeitink
Jan
J
D002675:Child, Preschool; D008058:Dihydrolipoamide Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D005347:Fibroblasts / Q000201:enzymology; D006579:Heterozygote; D006801:Humans; D007888:Leigh Disease / Q000235:genetics*; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology; D020125:Mutation, Missense; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics; D022821:RNA Splice Sites
D011768:Pyruvate Dehydrogenase Complex; D022821:RNA Splice Sites; D008058:Dihydrolipoamide Dehydrogenase