Disorders of the Krebs Cycle

Abstract

This chapter focuses on two classic Krebs cycle disorders (2-oxoglutaric aciduria and fumarase deficiency) and two recently discovered disorders of the Krebs cycle, severely affecting mitochondrial function and mitochondrial maintenance (succinyl-CoA synthetase –SCS – deficiencies, characterized by mutations in SUCLA2 and SUCLG1 genes). 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 mental retardation. A special form (DOOR syndrome) occurs with sensorineural deafness and osteodystrophy. 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. 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. The most important clues for the diagnosis in all these disorders rely in 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.