ASSOCIATION OF CEREBRAL DYSGENESIS AND LACTIC ACIDEMIA WITH X-LINKED PDH E1-ALPHA SUBUNIT MUTATIONS IN FEMALES

We describe an infant girl who presented at age 4 1/2 months with deve lopmental delay, infantile spasms, hypotonia, and elevated lactate lev els in the blood and cerebrospinal fluid, She had minor dysmorphic fea tures, Muscle phosphorus magnetic resonance spectroscopy demonstrated reduced phosphocreatine and increased inorganic phosphate, suggesting a defect in oxidative energy metabolism, Pyruvate dehydrogenase activi ty in cultured fibroblasts was reduced (0.35 nmol/mg mitochondrial pro tein/min; controls 0.7-1.1 nmol/mg mitochondrial protein/min), Immunob lotting demonstrated a reduced amount of pyruvate dehydrogenase (PDH) E1 alpha immunoreactive protein with normal amounts of E2 protein, Sin gle-strand conformational polymorphism analysis of E1 alpha cDNA prepa red from fibroblasts disclosed an abnormal migration pattern, suggesti ng heterozygosity for a mutant allele. Dideoxy-fingerprinting of PCR-a mplified genomic DNA was used to localize the mutation to exon 10, Dir ect sequencing demonstrated a novel 13-bp insertion mutation that woul d lead to premature termination of the protein product, This study fur ther 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 e tiologies. The results further suggest that the association of cerebra l dysgenesis with lactic acidemia in females may be a useful clue to P DH deficiency.