Pyruvate Dehydrogenase Complex Deficiency

Abstract Pyruvate dehydrogenase complex (PDC) deficiencies are inborn errors of carbohydrate metabolism that can profoundly impact the nervous system. Though the presentation can range from fatal neonatal lactic acidosis to ataxia and peripheral neuropathy in otherwise healthy school-age children, global developmental delay, hypotonia, microcephaly, and seizures are common. These nonspecific features can mimic other disorders. Both congenital brain malformations and destructive lesions can be seen. Ventriculomegaly and abnormalities of the corpus callosum are frequently observed, and Leigh syndrome may occur. The biochemical hallmarks are lactic acidemia, elevated pyruvate with a normal lactate-to-pyruvate ratio, and hyperalaninemia. Nearly all cases can be confirmed with combined assaying of PDC activity (in lymphocytes or cultured skin fibroblasts) and PDHA1 sequencing; additional genetic testing may identify the cause of cases due to mutations in other genes. It is increasingly recognized that mutations in genes that do not encode PDC proteins but are related to this pathway can also be implicated in PDC deficiency. The X-linked PDHA1 gene is responsible for the majority of cases, and this inheritance pattern likely accounts for the observation that females tend to have better survival than males, but often at the cost of poorer neurological and cognitive outcomes. PDC is a multiple enzyme complex that catalyzes the production of acetyl-CoA from pyruvate produced by glycolysis. PDC contains three catalytic enzymes, two regulatory enzymes, and a binding protein. It also requires the cofactors thiamine pyrophosphate (TPP), lipoic acid, and flavin adenine dinucleotide. While there is no proven effective treatment for PDC deficiency, the ketogenic diet is frequently employed to bypass the block in carbohydrate metabolism. Thiamine (vitamin B1), from which the cofactor TPP is derived, is typically given. Other potential treatments, such as dichloroacetate or phenylbutyrate, are candidates for further study.