Disorders of the Pyruvate Metabolism and the Krebs Cycle

This chapter focuses on pyruvate metabolism disorders, two classic Krebs cycle disorders (2-oxoglutaric aciduria and fumarase deficiency) and two other disorders of the Krebs cycle, severely affecting mitochondrial function and mitochondrial maintenance (succinyl-CoA synthetase—SCS—deficiencies, caused by mutations in SUCLA2 and SUCLG1 genes). 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 severe neonatal lactic acidosis and early death to milder presentations. 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. Pyruvate dehydrogenase deficiency (PDH) is most common due to deficiency in the X-linked PDH E1 alpha, but defects in other subunits of the PDH complex have been described. Secondary PDH deficiency and profound neurodegeneration was described in LONP1 deficiency. Neonatal lactic acidosis and Leigh’s encephalopathy occur more frequently in boys; girls can present with severe seizures and microcephaly. Fumarase deficiency and 2-oxoglutaric aciduria are rare disorders with global developmental delay and severe neurologic problems in infants. Patients with oxoglutaric aciduria have a variable severity of neurological involvement and metabolic acidosis and develop severe microcephaly and intellectual disability. Some patients with oxoglutaric aciduria present with DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). New disorders, like LIPT1 deficiency are known in the lipoic pathway leading to combined oxoglutaric aciduria and PDHc deficiency. Patients with fumarase deficiency present with either a fulminant course associated with fatal outcome within the first 2 years of life or a subacute encephalopathy with profound speech delay without metabolic crises. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to heterozygous germline fumarate hydratase (FH) mutations is an autosomal dominant condition and presents in young adults with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma. SUCLA2 and SUCLG1 defects have the clinical presentation of mitochondrial depletion syndromes with profound hypotonia, progressive dystonia, and muscular atrophy, in addition to severe sensorineural hearing impairment, which has been specifically associated with SUCLA2 defect. SUCLG1 defect has been also associated with congenital malformations (El-Hattab and Scaglia 2009). In disorders of the pyruvate metabolism the diagnosis is suspected with lactic acidemia and hypoglycemia, in PDH deficiency, when lactate and pyruvate are elevated, with a normal pyruvate to lactate ratio. Further confirmation is done biochemically on fibroblasts, lymphocytes, muscle, and the different genes can be investigated. The most important clues for the diagnosis in all the Krebs cycle disorders rely on urine organic analysis. 2-Oxoglutaric aciduria leads to chronic metabolic acidosis and variable urinary excretion of 2-oxoglutarate, while fumarase deficiency occurs with an increased excretion of fumarate associated with succinate and lactate excretion with eventual 2-oxoglutaric aciduria. A normal excretion of fumaric acid and a relative high fumarase residual activity do not rule out fumarase deficiency. In questionable cases, mutation analysis is needed to confirm the diagnosis. In SCS defects, mild methylmalonic aciduria with abnormal urine carnitine-ester profile is associated with only subtle abnormalities of the Krebs cycle intermediates. Due to the recognizable pattern of dystonia/±deafness syndrome and mild methylmalonic aciduria in SCS defects, direct genetic testing is a possible approach in the diagnosis of SUCLA2 and SUCLG1 defects. Carrier screening in fumarase deficiency is important due to the possible increased risk for certain malignancies.