Pyruvate Metabolism Disorders

Pyruvate dehydrogenase is a multi-enzyme complex responsible for the generation of acetyl CoA from pyruvate for the Krebs cycle. Deficiency results in elevation of pyruvate and thus elevation of lactic acid levels. Inheritance is X-linked X-Linked Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more or autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more .

Clinical manifestations vary in severity but include lactic acidosis and central nervous system malformations and other postnatal changes, including cystic lesions of the cerebral cortex, brain stem, and basal ganglia; ataxia; and psychomotor retardation.

Diagnosis of pyruvate dehydrogenase deficiency is confirmed by enzyme analysis of skin fibroblasts, DNA testing, or both. (Also see testing for suspected inherited disorders of metabolism Initial testing Most inherited disorders of metabolism (inborn errors of metabolism) are rare, and therefore their diagnosis requires a high index of suspicion. Timely diagnosis leads to early treatment and... read more .)

There is no clearly effective treatment for pyruvate dehydrogenase deficiency, although a low-carbohydrate or ketogenic diet and dietary thiamin supplementation have been beneficial for some patients.

Pyruvate carboxylase is an enzyme important for gluconeogenesis from pyruvate and alanine generated in muscle. Deficiency may be primary, or secondary to deficiency of holocarboxylase synthetase, biotin, or biotinidase; inheritance for both is autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more , and both result in lactic acidosis.

Primary deficiency incidence is < 1/250,000 births but may be higher in certain American Indian populations. Psychomotor retardation with seizures and spasticity are the major clinical manifestations. Laboratory abnormalities include hyperammonemia; lactic acidosis; ketoacidosis; elevated levels of plasma lysine, citrulline, alanine, and proline; and increased excretion of alpha-ketoglutarate.

Secondary deficiency is clinically similar, with failure to thrive, seizures, and other organic aciduria.

Diagnosis of pyruvate carboxylase deficiency is confirmed by enzyme analysis of cultured skin fibroblasts or DNA analysis.

There is no effective treatment for pyruvate carboxylase deficiency, but some patients with primary deficiency and all those with secondary deficiencies should be given biotin supplementation 5 to 20 mg orally once a day.