Fumarase deficiency

Defects of the Krebs cycle. Fumarase deficiency was reported in children with mitochondrial encephalomyop-athy. Usually, there is developmental delay since early infancy, microcephaly, hypotonia and cerebral atrophy, with death in infancy or early childhood. The laboratory hallmark of the disease is the excretion of large amounts of fumaric acid and, to a lesser extent, succinic acid in the urine. The enzyme defect has been found in muscle, liver and cultured skin fibroblasts [16]. 

Gellera C, Uziel G, Rimoldi M, Zeviani M, Laverda A, Carrara 28. F, DiDonato S. Fumarase deficiency is an autosomal recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes. Neurology 1990 40 495-499. 

C-IO) Fumarase deficiency. There is a deficit in the transformation of fumarate to malate. The infant has developmental retardation, with abnormal neuromuscular function, lactic acidemia, and fumarate aciduria. The lactic acidosis may result from a backup of Krebs cycle function, all the way to lactate. Lactic acidosis may also be present in rare disorders of cytochrome oxidase activity. Diagnostically, there is a deficit in fumarase activity in assay of liver and skeletal muscle mitochondria. 

A one-month-old baby boy was brought to the hospital showing severely delayed development and cerebral atrophy. Blood tests showed high levels of lactate and pyruvate. By three months of age, very high levels of succinate and fumarate were found in the urine. Fumarase activity was absent in the liver and muscle tissue. The baby died at five months of age. This was the first reported case of fumarase deficiency and the defect was recognized too late for effective therapy to be administered. What reaction is catalyzed by fumarase How would a deficiency of this mitochondrial enzyme account for the baby s symptoms and test results ... 

Remes AM, Rantala H, Hiltunen JK, Leisti J, Ruokonen A. Fumarase deficiency two siblings with enlarged cerebral ventricles and polyhydramnios in utero. Pediatr 1992 89 730-734... 

Bourgeron T, Chretien D, Poggi-Bach J et al. Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. / Clin Invest 1994 93 2514-2518... 

Coughlin EM, Christen E, Kunze PL et al. Molecular analysis and prenatal diagnosis of human fumarase deficiency. Mol Genet Metab 1998 63 254-262... 

Saccharomyces cerevisiae Mitochondrial fumarase-deficient mutant 0.5 Kaclikova et al. (1992)... 

In contrast with the fall in the activity of muscle glycolytic enzymes in human muscular dystrophy, Dreyfus and his colleagues (DIO) found little or no decrease in the concentrations of certain enzymes involved in oxidative breakdown of fuel, notably succinate dehydrogenase, cytochrome oxidase, fumarase, and aconitase. In the mouse myopathy, the concentration of cytochrome oxidase is increased (W12) elevated levels of respiratory enzymes have been reported also in myopathy resulting from vitamin E deficiency (D6) and in genetically dystrophic chickens... 

Deficiency of fumarase causes marked elevations of fumaric acid and often other Krebs cycle intermediates in the urinary organic acids profile. The diagnosis is confirmed by measurement of fumarase activity in cultured skin fibroblasts, leukocytes or affected organs. For defining the carrier status of family members, fumarase activity measurement in blood mononuclear cells appears to be a good, easy screening tool [7-9]. Mutation analysis can confirm the results of enzyme studies [11]. 

S. cerevisiae is studied in regard to the biochemical regulation of malic acid production (Pines et al., 1996). Under environmentally stressed conditions, a small amoxmt of fumaric acid and malic acid (less than lOg/L) was produced by this common yeast. Similar to the malic acid production pathway of Aspergillus, the cytosolic reductive pathway of acid synthesis and accumulation has been shown in S. cerevisiae. A NMR study involving glucose conversions to malic acid indicates that the following reactions lead to malic acid accumulation pyruvate oxaloacetate->fumarate malate. The involvement of cytosolic fumarase in the conversion of fumaric acid to malic acid has been corroborated. Wang et al. (1988) have shown the ability of a cytoplasmic respiratory deficient mutant of S. cerevisiae to convert fumarate to malate without the participation of mitochondrial fumarase. 

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