Fumarase deficiency

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Fumarase deficiency
Fumarate wpmp.png
Fumarate is converted to malate by fumarase
Classification and external resources
OMIM 606812
DiseasesDB 29835

Fumarase deficiency (or fumaric aciduria), also known as "Polygamist Down's",[1] is an autosomal recessive metabolic disorder characterized by a deficiency of the enzyme fumarate hydratase, which is indicated by a buildup of fumaric acid in the urine.


Fumarase deficiency is caused by a mutation in the fumarate hydratase (FH) gene in humans, which encodes the enzyme that converts fumarate to malate in the mitochondria. Other mutant alleles of the FH gene, located on human Chromosome 1 at position 1q42.1, cause multiple cutaneous and uterine leiomyomata, hereditary leiomyomatosis and renal cell cancer.[2] Fumarase deficiency is one of the few known deficiencies of the Krebs cycle or tricarboxylic acid cycle, the main enzymatic pathway of cellular aerobic respiration.[3]

Fumarase deficiency has an autosomal recessive pattern of inheritance.

The condition is an autosomal recessive disorder,[4] and it is therefore usually necessary for an affected individual to receive the mutant allele from both parents. A number of children diagnosed with the disorder have been born to parents who were first cousins.[5][6] It can also be associated with uniparental isodisomy.[7]


Fumarase deficiency causes encephalopathy,[8] severe mental retardation, unusual facial features, brain malformation, and epileptic seizures[9] due to an abnormally low amount of fumarase in cells. It can initially present with polyhydramnios on prenatal ultrasound. Affected neonates may demonstrate nonspecific signs of poor feeding and hypotonia. Laboratory findings in neonates may indicate polycythemia, leukopenia, or neutropenia. As they age, neurological deficits begin to manifest with seizures, dystonias, and severe developmental delay.[10]

Emergence in a polygamist settlement[edit]

Fumarase deficiency is extremely rare, with only thirteen diagnosed and identified cases worldwide until roughly 1990. Since then an additional twenty cases have been documented in the twin towns of Colorado City, Arizona (formerly known as Short Creek or the Short Creek Community), and Hildale, Utah, settled in the 1930s by the Fundamentalist Church of Jesus Christ of Latter Day Saints, a church whose members left The Church of Jesus Christ of Latter-day Saints (LDS Church) beginning in 1890,[11] when the LDS Church banned plural marriage. The condition has since been dubbed "Polygamist's Down's."[1]

Theodore Tarby, a pediatric neurologist who has treated some of the community's fumarase deficient residents, has been quoted as estimating the IQ of his patients as around 25.[12] While treating a child with a developmental disability Tarby sent off a urine sample for testing and learned the child had a disorder so rare that only 13 other current cases were known worldwide.[13] Tarby later learned the child he treated had a sibling who had been diagnosed with cerebral palsy, a disease commonly associated with developmental difficulties. This sibling also turned out to have fumarase deficiency.[11]

See also[edit]


  1. ^ a b "Mormon Sect's Polygamy Causes Most Of The World's Fumarase Deficiency Cases". Digital Journal. 
  2. ^ Online 'Mendelian Inheritance in Man' (OMIM) Fumarase Deficiency -606812
  3. ^ Devlin, Thomas M. (2006). Textbook of biochemistry: with clinical correlations. New York: John Wiley. p. 546. ISBN 0-471-67808-2. 
  4. ^ Gellera, C.; Uziel, G.; Rimoldi, M.; Zeviani, M.; Laverda, A.; Carrara, F.; DiDonato, S. (March 1990). "Fumarase deficiency is an autosomal recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes". Neurology 40 (3 Part 1): 495–499. doi:10.1212/wnl.40.3_part_1.495. PMID 2314594. 
  5. ^ Petrova-Benedict, R.; Robinson, B.H.; Stacey, T.E.; Mistry, J.; Chalmers, R.A. (1987). "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 (3): 257–266. PMC 1684096. PMID 3578275. 
  6. ^ Bourgeron, T.; Chretien, D.; Poggi-Bach, J.; Doonan, S.; Rabier, D.; Letouzé, P.; Munnich, A.; Rötig, A.; Landrieu, P.; Rustin, P. (June 1994). "Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency". J. Clin. Invest. 93 (6): 2514–2518. doi:10.1172/JCI117261. PMC 294471. PMID 8200987. 
  7. ^ Zeng, Wen-Qi; Gao, Hanlin; Brueton, Louise; Hutchin, Tim; Gray, George; Chakrapani, Anupam; Olpin, Simon; Shih, Vivian E. (1 May 2006) [30 March 2006]. "Fumarase deficiency caused by homozygous P131R mutation and paternal partial isodisomy of chromosome 1". Am. J. Med. Genet. A 140A (9): 1004–1009. doi:10.1002/ajmg.a.31186. PMID 16575891. 
  8. ^ Bayley, Jean-Pierre; Launonen, Virpi; Tomlinson, Ian P.M. (25 March 2008). "The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency". BMC Med. Genet. 9 (1): 20. doi:10.1186/1471-2350-9-20. PMC 2322961. PMID 18366737. 
  9. ^ Kerrigan, John F.; Aleck, Kirk A.; Tarby, Theodore J.; Bird, C. Roger; Heidenreich, Randall A. (May 2000) [3 May 2001]. "Fumaric aciduria: clinical and imaging features". Ann. Neurol. 47 (5): 583–8. doi:10.1002/1531-8249(200005)47:5<583::AID-ANA5>3.0.CO;2-Y. PMID 10805328. 
  10. ^ Ewbank, Clifton; Kerrigan, John F. (April 4, 2013) [July 5, 2006]. "Fumarate Hydratase Deficiency". GeneReviews. Seattle WA: University of Washington. PMID 20301679.  |first3= missing |last3= in Authors list (help)
  11. ^ a b Dougherty, John (December 29, 2005). "Forbidden Fruit:Inbreeding among polygamists along the Arizona-Utah border is producing a caste of severely retarded and deformed children". The Phoenix New Times News. p. 2. 
  12. ^ Hollenhorst, John (February 8, 2006). "Birth defect is plaguing children in FLDS towns: Fumarase Deficiency afflicts 20, is linked to marriages of close Kin". Deseret News. 
  13. ^ Szep, Jason (June 14, 2007). "Polygamist community faces rare genetic disorder". Reuters. 

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