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Disorder of pyruvate metabolism
Last reviewed: 07.07.2025
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Pyruvate dehydrogenase deficiency
Pyruvate dehydrogenase is a multienzyme complex responsible for the formation of acetyl CoA from pyruvate for the Krebs cycle. Deficiency of this enzyme leads to elevated pyruvate levels and therefore elevated lactic acid levels. The inheritance pattern is X-linked or autosomal recessive.
Symptoms vary in severity but always include lactic acidosis and structural CNS abnormalities and other postnatal changes, including cystic changes of the cerebral cortex, brainstem, and basal ganglia; ataxia; and psychomotor retardation. Diagnosis is confirmed by skin fibroblast enzyme testing, DNA testing, or a combination of both. There is no definitively effective treatment, although a low-carbohydrate diet and dietary thiamine supplementation have been effective in some patients.
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Pyruvate carboxylase deficiency
Pyruvate carboxylase is an enzyme important for gluconeogenesis from pyruvate and alanine formed in muscle. Deficiency may be primary or secondary to deficiency of holocarboxylase synthetase, biotin, or biotinidase; inheritance is autosomal recessive in both cases and lactic acidosis occurs.
The incidence of primary deficiency is less than 1/250,000 births but may be higher in certain American Indian populations. The main clinical manifestations are psychomotor retardation with seizures and spasticity. Laboratory abnormalities include hyperammonemia; lactic acidosis; ketoacidosis; elevated plasma lysine, citrulline, alanine, and proline; and increased excretion of alpha-ketoglutarate. Diagnosis is confirmed by enzyme testing in cultured skin fibroblasts.
Secondary deficiency is clinically similar to primary deficiency, with the development of hypotrophy, convulsions and other organic acidurias.
There is no effective treatment, but selected patients with primary deficiency, as well as all patients with secondary deficiency, should be given oral biotin 5-20 mg once daily.
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