Fumarase defect

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]. 

In addition to assays for the OXPHOS enzymes, assays have been described for many other enzymes involved in the MEGS. For PDHc, various types of diagnostic assays have been described and are widely used (33). Also for the TCA cycle enzymes various assays have been described, although to date, pathogenic defects have only been found in a-ketoglutarate dehydrogenase (38), succinate-CoA ligase (12), and fumarase (39). 

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 ... 

Which would you expect to have a greater effect on the rate of urea biosynthesis, a defect in fumarase activity or a defect in alanine aminotransferase ... 

In addition two mentally retarded adults with fumaric aciduria have been described, but the abnormality was thought to be due to a renal fumaric acid resorption defect. Fumarase activity was not determined in these patients. 

---