Fumarase Deficiency

A number sign (#) is used with this entry because fumarase deficiency (FMRD) is caused by homozygous or compound heterozygous mutation in the fumarate hydratase gene (FH; 136850) on chromosome 1q43.

Heterozygous mutation in the FH gene can cause hereditary leiomyomatosis and renal cell cancer (HLRCC; 150800).

Description

Fumarase deficiency is a severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy (summary by Kerrigan et al., 2000 and Mroch et al., 2012).

Clinical Features

Zinn et al. (1986) reported the case of a male infant with mitochondrial encephalopathy who presented at 1 month of age with failure to thrive, developmental delay, hypotonia, cerebral atrophy, lactic and pyruvic acidemia, and fumaric aciduria. The patient died at 8 months of age. Mitochondria isolated from skeletal muscle showed selective defects in the oxidation of glutamate and succinate, whereas isolated liver mitochondria oxidized these normally. Fumarase activity was virtually absent in mitochondria of both sources. Homogenates of liver and muscle also showed very much reduced fumarase activity, indicating that the cytosolic form of the enzyme was also deficient. Organ differences in intramitochondrial accumulation of fumarase were thought to account for the selective oxidative defects observed in skeletal muscle and not in liver mitochondria.

Whelan et al. (1983) reported isolated fumaric aciduria in 2 adult sibs with mental retardation and speech impairment. The authors attributed the increased urinary excretion to a defect in renal clearance; fumarase activity was not assessed. Petrova-Benedict et al. (1987) reported a case of fumarase deficiency in a mentally retarded child who presented at 6 months of age with hypotonia, microcephaly, and delayed development. Fumarase was deficient in both the mitochondrial and the cytosolic compartments, but the cytosolic enzyme appeared to be more severely affected. Snodgrass (1987) commented on the occurrence of mild hyperammonemia in fumarase deficiency. Gellera et al. (1990) described the clinical features of fumarase deficiency. A 7-month old boy died in a demented state after a clinical course characterized by generalized seizures, psychomotor deterioration, and fumaric aciduria. Marked deficiency of both mitochondrial and cytosolic fumarases was found in skeletal muscle, brain, cerebellum, heart, kidney, liver, and cultured fibroblasts. Anti-fumarase crossreacting material was present in negligible amounts in these tissues.

Kerrigan et al. (2000) reported the clinical features of 8 affected members of a large consanguineous family with fumarase deficiency living in an isolated community in the southwestern United States. The ages of the patients ranged from 20 months to 12 years. All patients were profoundly developmentally retarded and had no language development. Only 1 child had achieved independent walking; all the others were unable to sit. All patients had relative macrocephaly and ventricular enlargement. Other common features included hypotonia, seizures, and status epilepticus. Dysmorphic features included frontal bossing, hypertelorism, depressed nasal bridge, anteverted nares, and high-arched palate. Five of 8 had polycythemia at birth. Neuroimaging showed striking abnormalities of the brain, including polymicrogyria, angulation of the frontal horns, decreased periventricular white matter, and small brainstem. Four patients had optic nerve hypoplasia or pallor.

Mroch et al. (2012) reported 2 brothers, born of unrelated parents, with genetically confirmed FH deficiency resulting in death in infancy. The first boy was born prematurely from a pregnancy complicated by polyhydramnios, and showed hypotonia and respiratory insufficiency after birth. An ultrasound at 20 weeks' gestation had shown agenesis of the corpus callosum, ventriculomegaly, bilateral renal pyelectasis, and a ventriculoseptal defect. Postmortem imaging showed lissencephaly. He developed severe metabolic acidosis, necrotizing enterocolitis, liver failure associated with coagulopathy and hyperbilirubinemia, and encephalopathy, resulting in death at age 22 days. Biochemical studies showed increased urinary tyrosine metabolites, citric cycle intermediates, citrulline, fumaric, malic, and succinic acids, and skin biopsy showed fumarase deficiency. Postmortem examination showed a distended abdomen, and the liver showed intrahepatic bile stasis. Electron microscopy of the liver revealed multiple swollen mitochondria with flat, plate-like, haphazardly arranged cristae. Genetic analysis identified compound heterozygosity for a point mutation in the FH gene and a deletion of the FH gene (136850.0010 and 136850.0011). Prenatal diagnosis confirming the deficiency was performed on the subsequent pregnancy by genetic testing of amniocytes. Ultrasound at 20 weeks showed ventriculomegaly, dangling choroid plexus, and possible agenesis of the corpus callosum. The parents elected to continue with the pregnancy, but the infant died on day 26. Postmortem examination again showed hepatic involvement, with fibrosis, iron deposition, and bile stasis. Electron microscopy showed abnormal mitochondria similar to that observed in his affected brother. Each unaffected parent was heterozygous for 1 of the mutations, and neither showed cancer or abnormal cutaneous findings suggesting HLRCC.

Inheritance

In the case reported by Petrova-Benedict et al. (1987), the parents of the affected child were first cousins. In the case reported by Gellera et al. (1990), autosomal recessive inheritance was supported by the finding of fumarase activities 30 to 50% of normal in both mitochondria and cytosol from cultured fibroblasts of the parents.

Molecular Genetics

Coughlin et al. (1993) identified a homozygous mutation in the FH gene (136850.0001) in a patient with fumarase deficiency. Bourgeron et al. (1993, 1994) identified a homozygous mutation in the fumarase gene (136850.0002) in 2 patients with progressive encephalopathy associated with fumarase deficiency.

In 2 brothers with infantile-lethal fumarase deficiency, Mroch et al. (2012) identified compound heterozygous mutations in the FH gene (136850.0010-136850.0011).

Population Genetics

There is an unusually high incidence of fumarase deficiency in the southwestern United States among members of the Fundamentalist Church of Jesus Christ of Latter Day Saints (FLDS), a religious community that practices inbreeding and polygamy. The genetic defect was traced to one of the community's founding patriarchs, the late Joseph Smith Jessop, and the first of his plural wives, who had 14 children together (Dougherty, 2005).