A fourth case of fumarase deficiency

Abstract

Fumarate hydratase (fumarase, EC 4.2.1.2) has a key role in cellular energy production: in the mitochondria it is a component of the tricarboxylic acid cycle; in the cytoplasm it is presumably a source of malate for the malate-aspartate shuttle, with an important source of fumarate being the urea cycle. Three cases of proven fumarase deficiency (McKusick 13686) have been reported (Zinn et al., 1986;Christensen et al., 1986;Petrova-Benedict et al., 1987).The second child of consanguineous Asian parents was delivered at 42 weeks, weight 3640 g. Hydramnios occurred in the third trimester. The female infant had dysmorphic facial features. On ultrasound and CT scans, the brain was malformed with agenesis of the corpus callosum, moderate communicating hydrocephalus affecting all four ventricles, and a small cyst in the right occipital horn. Chromosomes appeared normal. There was no apparent cardiomyopathy. She was clearly neurologically impaired from birth, fed poorly, and failed to thrive. She did not receive parenteral nutrition at any time. By 20weeks, vomiting, irritability and spasticity were problems. Her liver was consistently palpable to 2cm. She had conjugated hyperbilirubinaemia in the first 2months (plasma bilirubin t22-226~tmol/L) with a moderately raised plasma aspartate aminotransferase (AST) (63-87IU/L; normal 5-42) and ammonium (63~tmol/L). The jaundice abated, but AST remained elevated. Plasma and urinary amino acids, non-fasting plasma lactate and serum et-antitrypsin were normal. Blood pyruvate was raised (206 and 226 gmol/L). She did not have a metabolic acidosis.The bile duct and gall bladder appeared normal on ultrasound examination at 3 and 7 weeks. At open liver biopsy at 7 weeks, the liver was firm and green-tinged. Histology showed portal tract expansion by fibrosis, with focal degenerative changes in the bile ducts and peripheral bile ductular proliferation. Mild hepatocellular damage consistent with marked cholestasis was also present. Appearances were similar to changes associated with prolonged parenteral nutrition, but Kupffer cells only contained bile and lipochrome pigments. A quadriceps muscle biopsy appeared normal. She died aged 24weeks with an overwhelming varicella infection.Five urine samples, collected from 4 to 22weeks, analysed for organic acids showed grossly elevated fumaric acid at 2972-3829mmol/mol creatinine ~University

Neuropathology and pathogenesis of mitochondrial diseases

“…As this is the obligatory pathway for energy generation in the brain under normal circumstances, such defects represent a profound impairment of the energy-generating capacity of the brain and presumably this is the reason for the extensive pathological changes. Similar pathological changes have also been described in the much rarer condition of fumarase deficiency, a major defect in the citric acid cycle which would also be expected to have a profound effect on mitochondrial energy metabolism (Walker et al 1989).…”

Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency.

“…Facial dysmorphism and an unusual neonatal liver disorder have also been noted in one patient and were tentatively attributed to the deficiency (16). Fumaric aciduria is consistently observed, associated with increased excretion of one or more of the Krebs cycle intermediates, succinic acid, a-ketoglutaric acid, citric acid, or malic acid (5,15).…”

Magnetic resonance imaging in lactic acidosis

“…The cerebral atrophy is progressive during postnatal life. Agenesis of the corpus callosum has been described (Walker et al 1989). MRI and histopathological findings have not been reported.…”