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 or autosomal recessive.

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. (See also testing for suspected inherited disorders of metabolism.)

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 by catalyzing the conversion of pyruvate to oxaloacetate.

There are 3 types of pyruvate carboxylase deficiency: type A (infantile form), type B (severe neonatal form), and type C (intermittent/benign form).

Deficiency may be primary, or secondary to other inborn errors of metabolism; inheritance for all forms is autosomal recessive, and each results in lactic acidosis.

Primary deficiency incidence is < 1/250,000 births but may be higher in certain American Indian populations (1). Developmental delay with seizures and failure to thrive 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. Additional symptoms for type B include hepatomegaly, pyramidal tract signs, and abnormal movement. People with type C have normal or mildly delayed neurologic development and episodic metabolic acidosis.

Secondary deficiency may be 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 symptoms may be alleviated for some patients through dietary management and thiamin supplementation.

Most affected children with type A die in infancy or early childhood.

Affected infants with type B die within the first 3 months of life.

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

1. Online Mendelian Inheritance in Man (OMIM) database: Complete gene, molecular, and chromosomal location information