title: Association of cerebral dysgenesis and lactic acidemia with X-linked PDH E1 alpha subunit mutations in females.
abstract: We describe an infant girl who presented at age 4 1/2 months with developmental delay, infantile spasms, hypotonia, and elevated lactate levels in the blood and cerebrospinal fluid. She had minor dysmorphic features. Muscle phosphorus magnetic resonance spectroscopy demonstrated reduced phosphocreatine and increased inorganic phosphate, suggesting a defect in oxidative energy metabolism. Pyruvate dehydrogenase activity in cultured fibroblasts was reduced (0.35 nmol/mg mitochondrial protein/min; controls 0.7-1.1 nmol/mg mitochondrial protein/min). Immunoblotting demonstrated a reduced amount of pyruvate dehydrogenase (PDH) E1 alpha immunoreactive protein with normal amounts of E2 protein. Single-strand conformational polymorphism analysis of E1 alpha cDNA prepared from fibroblasts disclosed an abnormal migration pattern, suggesting heterozygosity for a mutant allele. Dideoxy-fingerprinting of PCR-amplified genomic DNA was used to localize the mutation to exon 10. Direct sequencing demonstrated a novel 13-bp insertion mutation that would lead to premature termination of the protein product. This study further extends the allelic heterogeneity underlying PDH deficiency. The demonstration of bioenergetic abnormalities in muscle emphasizes that hypotonia in PDH deficiency may have combined peripheral and central etiologies. The results further suggest that the association of cerebral dysgenesis with lactic acidemia in females may be a useful clue to PDH deficiency.
authors.affiliation: Department of Biochemistry, University of Oxford, UK.
authors.forename: L J
authors.initials: LJ
authors.lastname: Otero
authors.forename: G K
authors.initials: GK
authors.lastname: Brown
authors.forename: K
authors.initials: K
authors.lastname: Silver
authors.forename: D L
authors.initials: DL
authors.lastname: Arnold
authors.forename: P M
authors.initials: PM
authors.lastname: Matthews
mesh_terms: D000140:Acidosis, Lactic / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities*; D004247:DNA / Q000235:genetics; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics*; D010758:Phosphorus; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000097:blood / Q000235:genetics*; D014960:X Chromosome
chemical_list: D010446:Peptide Fragments; D010758:Phosphorus; D004247:DNA