Pyruvate carboxylase and pyruvate dehydrogenase deficiency are the most common disorders in pyruvate metabolism and almost always affect the central nervous system. The severity and the clinical phenotypes vary, with a range from overwhelming neonatal lactic acidosis and early death to milder presentations. In the differential diagnosis, there are always the respiratory chain defects (see Chap. 22 on mitochondrial disorders).
Diagnosis depends on biochemical analysis in plasma, urine, and CSF followed by enzymatic analysis in various tissues and confirmation by DNA analysis.
Pyruvate carboxylase (PC) deficiency constitutes a defect both in the Krebs cycle and in gluconeogenesis and generally presents with severe neurologic dysfunction and lactic acidosis more frequently than with fasting hypoglycemia. There are three different phenotypes with wide spectrum in severity.
Pyruvate dehydrogenase deficiency (PDH) is most common due to deficiency in the X-linked PDHE1alpha, but also defects in the other subunits of PDH complex have been described. The clinical picture is PDHE1alpha is usually different in boys and girls. Neonatal lactic acidosis and Leigh’s encephalopathy occur more frequently in boys; girls can present with severe seizures and microcephaly. The diagnosis is suspected when lactate and pyruvate are elevated, with a normal pyruvate to lactate ratio.
Further confirmation is done biochemically on fibroblasts, lymphocytes, or muscle, and the different genes can be investigated. A prenatal diagnosis is then possible. Ketogenic diet might help in some patients.
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