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

Abstract

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 alpha subunit protein in normal amounts and the remaining 86% having no detectable immunoreactive activity. Direct sequencing of cDNA for the X-linked PDHC E1 alpha 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 alpha protein, and the X chromosome inactivation ratio, demonstrating the importance of X-inactivation for expression of this X-linked neurometabolic disease in females.

• Authors: P M Matthews, R M Brown, L Otero, D Marchington, J V Leonard, G K Brown
• Journal: Neurology (Neurology) Vol. 43 Issue 10 Pg. 2025-30 (Oct 1993) ISSN: 0028-3878 [Print] United States
• PMID: 7692352 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA Primers
• Macromolecular Substances
• Pyruvate Dehydrogenase Complex

Topics

• Acidosis, Lactic (genetics, physiopathology)
• Base Sequence
• Cells, Cultured
• Child, Preschool
• DNA Primers
• Developmental Disabilities (genetics, physiopathology)
• Female
• Fibroblasts (enzymology)
• Humans
• Immunoblotting
• Macromolecular Substances
• Mitochondria (enzymology)
• Molecular Sequence Data
• Mosaicism
• Nervous System Diseases (genetics, physiopathology)
• Polymerase Chain Reaction
• Pyruvate Dehydrogenase Complex (genetics, metabolism)
• Pyruvate Dehydrogenase Complex Deficiency Disease (enzymology, genetics, physiopathology)
• Sequence Deletion
• Skin (enzymology)
• X Chromosome