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Neurodevelopmental abnormalities and lactic acidosis in a girl with a 20-bp deletion in the X-linked pyruvate dehydrogenase E1 subunit gene

From the Genetics Laboratory, Department of Biochemistry (Drs. Matthews, Marchington, and G.K. Brown, and Mrs Brown and Miss Otero) and the University Department of Clinical Neurology (Dr. Matthews), University of Oxford, Oxford, UK; and the Institute for Child Health (Dr. Leonard), University of London, London, UK.

We describe a girl with developmental abnormalities of the CNS and a lactic acidosis whose cultured fibroblasts showed a profound deficiency of pyruvate dehydrogenase complex (PDHC) activity (patient = 0.14 nmol/mg protein per minute, controls = 0.7 to 1.1 nmol/mg protein per minute). Immunocytochemistry demonstrated the fibroblast culture to be mosaic, with 14% of cells expressing the PDHC E1 subunit protein in normal amounts and the remaining 86% having no detectable immunoreactive activity. Direct sequencing of cDNA for the X-linked PDHC E1 subunit established that the patient was heterozygous for a 20-bp deletion beginning in the codon for Ser³⁰⁰ of the derived amino acid sequence. The pattern of methylation at the DXS255 locus suggested predominant expression of the X chromosome carrying the mutant allele in the fibroblast culture. There was a good correlation between the residual PDHC activity, the proportion of cells with immunoreactive E1 protein, and the X chromosome inactivation ratio, demonstrating the importance of X-inactivation for expression of this X-linked neurometabolic disease in females.

Address correspondence and reprint requests to Dr. G.K. Brown, Genetics Laboratory, Department of Biochemistry, South Parks Road, Oxford OX13QU, UK.

Supported by the Medical Research Council (Canada), NIH, and the Wellcome Trust (P.M.M. and G.K.B.).

Received October 20, 1992. Accepted for publication in final form February 10,1993.

This article has been cited by other articles:

				M. Y. Lib, R. M. Brown, G. K. Brown, M. F. Marusich, and R. A. Capaldi Detection of Pyruvate Dehydrogenase E1{alpha}-subunit Deficiencies in Females by Immunohistochemical Demonstration of Mosaicism in Cultured Fibroblasts J. Histochem. Cytochem., July 1, 2002; 50(7): 877 - 884. [Abstract] [Full Text] [PDF]

				K. J. Morten, P. Beattie, G. K. Brown, and P. M. Matthews Dichloroacetate stabilizes the mutant E1{alpha} subunit in pyruvate dehydrogenase deficiency Neurology, August 1, 1999; 53(3): 612 - 612. [Abstract] [Full Text]