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Brain, Vol. 117, No. 3, 435-443, 1994
© 1994 Guarantors of Brain

research-article

Pyruvate dehydrogenase deficiency. Clinical presentation and molecular genetic characterization of five new patients

P. M. Matthews1,2, R. M. Brown1, L. J. Otero1, D. R. Marchington1, M. LeGris1, R. Howes1, L. S. Meadows1, M. Shevell3, C. R. Scriver4 and G. K. Brown1,

1Genetics Laboratory, Department of Biochemistry Oxford, UK 2University Department of Clinical Neurology, University of Oxford Oxford, UK 3Divisions of Pediatric Neurology Montreal, Canada 4Medical Genetics (de Beulle Laboratory), Department of Pediatrics, Montreal Children's Hospital, McGill University Montreal, Canada

Correspondence to: Correspondence to: Dr G. K. Brown, Genetics Laboratory, Department of Biochemistry, University of Oxford, South Parks Road, Oxford 0X1 3QU, UK

Fibroblast cultures from five patients with early onset severe encephalopathy and lactic acidosis were studied for evidence of pyruvate dehydrogenase (PDH) deficiency. Three males had significantly reduced activity (0.29 – 0.45 nmol/mg protein/mi versus normal controls 0.7–1.1 nmol/mg protein/min); two females had PDH activity within the normal range. However, as the majority of cases of PDH deficiency result from defects in the X-linked El {alpha} subunit and both females had biased patterns of X-inactivation (making it impossible to rule out the possibility that they were heterozygous for an El {alpha} gene defect) molecular genetic studies were performed. cDNA from the male patients was sequenced and mis-sense mutations found: Y243N(T{uparrow}A) in exon 7, D315A (G{uparrow}A) in exon 10 and R378H (G{uparrow}A) in exon 11. Single-strand conformation polymorphism analysis of amplified genomic DNA fragments and sequencing revealed a mis-sense mutation M282L (A{uparrow}C) in one female and a frameshift mutation caused by insertion of T (R288ins) in the other. Adding to recent descriptions of new mutations, this report emphasizes the allelic heterogeneity of the condition. The identification of mutations in females with a suggestive clinical phenotype, even when peripheral fibroblasts do not show deficient PDH activity, deficient PDH activity, illustrates the importance of molecular analysis of this disease.

pyruvate dehydrogenase deficiency; lactic acidosisl; genetic disease; mitochondria; X-inactivation

Received October 22, 1993. Revised January 10, 1994. Accepted January 17, 1994.


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