Alternative titles; symbols
SNOMEDCT: 237983002; ORPHA: 24; DO: 0111261;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q43 | Fumarase deficiency | 606812 | Autosomal recessive | 3 | FH | 136850 |
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).
Fumarase deficiency (FMRD) 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).
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 mutations in the FH gene: a point mutation (P174R; 136850.0010) and a whole gene deletion (136850.0011). Prenatal diagnosis confirming the deficiency was performed on the subsequent pregnancy by genetic testing of amniocytes. Ultrasound at 20 weeks' gestation 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 one of the mutations, and neither showed cancer or abnormal cutaneous findings suggesting HLRCC.
Prasad et al. (2017) reported 2 sisters with an attenuated form of FMRD, including absence of encephalopathy and near-normal urine fumaric acid levels. At age 2.5 years, the older sib was evaluated for failure to thrive and developmental delays. She had a history of constipation and required a gastrostomy tube for feeding issues. She had facial dysmorphisms, including microcephaly, epicanthal folds, bilateral strabismus, low-set ears, a broad nasal bridge, and a tented upper lip. Neurologic examination showed mild ataxia and hypotonia. Before the age of 10 years, she developed focal seizures with secondary generalization. At age 10, she was reported to have appropriate development but unusual behaviors including putting objects in her mouth and causing self-injury. The younger sib was reported to have developmental delay, feeding issues, and dysmorphisms similar to her sister.
Grocott et al. (2020) reported a patient who was diagnosed with dysphagia, gastrointestinal reflux, and poor weight gain at 18 months of age. At 21 months of age she was nonverbal and could not sit or crawl. Urine organic acid analysis demonstrated increased fumaric acid. She developed myoclonic jerks at 3 years of age, and tonic-clonic seizures at 5 years of age. Seizures persisted despite treatment with multiple antiepileptics. At 12 years of age she had seizures, constipation, developmental delay, truncal hypotonia, joint pain, muscle contractures, and scoliosis. She was nonverbal and nonambulatory. Seizure frequency was decreased after lacosamide was added to her therapeutic regimen.
In the case reported by Petrova-Benedict et al. (1987), the parents of the affected child were first cousins, supporting autosomal recessive inheritance. 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.
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 FH 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).
In 2 sisters with an attenuated form of FMRD, Prasad et al. (2017) identified compound heterozygous mutations in the FH gene: a duplication (K477dup; 136850.0012) and a splice site mutation (136850.0013). The sibs had no encephalopathy and near-normal urine fumaric acid levels. The mutations segregated with the disorder in the family.
In a patient with FMRD, Grocott et al. (2020) identified compound heterozygous mutations in the FH gene (D65G, 136850.0014; c.1293delA, 136850.0015). Fumarase enzyme was purified from plasmids containing FH with each of the patient's mutations. Fumarase with the c.1293delA mutation had defective enzyme activity and oligomerization. Fumarase with the D65G mutation had a lower catalytic activity compared to wildtype. Urine organic acids in the patient demonstrated elevated fumaric acid, and cytosolic and mitochondrial fumarase enzyme activity were decreased in patient fibroblasts.
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, 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).
Bourgeron, T., Chretien, D., Poggi-Bach, J., Doonan, S., Rabier, D., Letouze, P., Munnich, A., Rotig, A., Landrieu, P., Rustin, P. Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. J. Clin. Invest. 93: 2514-2518, 1994. [PubMed: 8200987] [Full Text: https://doi.org/10.1172/JCI117261]
Bourgeron, T., Chretien, D., Rotig, A., Munnich, A., Landrieu, P., Rustin, P. Molecular characterization of fumarase deficiency in two children with progressive encephalopathy. (Abstract) Am. J. Hum. Genet. 53 (suppl.): A891 only, 1993.
Coughlin, E. M., Chalmers, R. A., Slaugenhaupt, S. A., Gusella, J. F., Shih, V. E., Ramesh, V. Identification of a molecular defect in a fumarase deficient patient and mapping of the fumarase gene. (Abstract) Am. J. Hum. Genet. 53 (suppl.): A896 only, 1993.
Dougherty, J. Forbidden fruit: inbreeding among polygamists along the Arizona-Utah border is producing a caste of severely retarded and deformed children. Phoenix New Times, December 29, 2005.
Gellera, C., Uziel, G., Rimoldi, M., Zeviani, M., Laverda, A., Carrara, F., DiDonato, S. Fumarase deficiency is an autosomal recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes. Neurology 40: 495-499, 1990. [PubMed: 2314594] [Full Text: https://doi.org/10.1212/wnl.40.3_part_1.495]
Grocott, O., Phanor, S. K., Fung, F., Thibert, R. L., Berkmen, M. B. Clinical report and biochemical analysis of a patient with fumarate hydratase deficiency. Am. J. Med. Genet. 182A: 504-507, 2020. [PubMed: 31746132] [Full Text: https://doi.org/10.1002/ajmg.a.61415]
Kerrigan, J. F., Aleck, K. A., Tarby, T. J., Bird, C. R., Heidenreich, R. A. Fumaric aciduria: clinical and imaging features. Ann. Neurol. 47: 583-588, 2000. [PubMed: 10805328]
Mroch, A. R., Laudenschlager, M., Flanagan, J. D. Detection of a novel FH whole gene deletion in the propositus leading to subsequent prenatal diagnosis in a sibship with fumarase deficiency. Am. J. Med. Genet. 158A: 155-158, 2012. [PubMed: 22069215] [Full Text: https://doi.org/10.1002/ajmg.a.34344]
Petrova-Benedict, R., Robinson, B. H., Stacey, T. E., Mistry, J., Chalmers, R. A. Deficient fumarase activity in an infant with fumaricacidemia and its distribution between the different forms of the enzyme seen on isoelectric focusing. Am. J. Hum. Genet. 40: 257-266, 1987. [PubMed: 3578275]
Prasad, C., Napier, M. P., Rupar, C. A., Prasad, C. Fumarase deficiency: a rare disorder on the crossroads of clinical and metabolic genetics, neurology and cancer. Clin. Dysmorph. 26: 117-120, 2017. [PubMed: 27541980] [Full Text: https://doi.org/10.1097/MCD.0000000000000148]
Snodgrass, P. J. Fumarase deficiency. (Letter) New Eng. J. Med. 316: 345 only, 1987. [PubMed: 3807970]
Whelan, D. T., Hill, R. E., McClorry, S. Fumaric aciduria: a new organic aciduria, associated with mental retardation and speech improvement. Clin. Chim. Acta 132: 301-308, 1983. [PubMed: 6616883] [Full Text: https://doi.org/10.1016/0009-8981(83)90008-6]
Zinn, A. B., Kerr, D. S., Hoppel, C. L. Fumarase deficiency: a new cause of mitochondrial encephalomyopathy. New Eng. J. Med. 315: 469-475, 1986. [PubMed: 3736629] [Full Text: https://doi.org/10.1056/NEJM198608213150801]