Fumarase Deficiency: History
Please note this is an old version of this entry, which may differ significantly from the current revision.

Fumarase deficiency is a condition that primarily affects the nervous system, especially the brain.

  • genetic conditions


Fumarase deficiency is a very rare disorder. Approximately 100 affected individuals have been reported worldwide. Several were born in an isolated religious community in the southwestern United States.


Fumarase deficiency is caused by mutations in the FH gene. This gene provides instructions for making an enzyme called fumarase (also known as fumarate hydratase). Fumarase participates in an important series of reactions known as the citric acid cycle or Krebs cycle, which allows cells to use oxygen and generate energy. Specifically, fumarase helps convert a molecule called fumarate to a molecule called malate.

Mutations in the FH gene disrupt the enzyme's ability to help convert fumarate to malate, interfering with the function of this reaction in the citric acid cycle. Impairment of the process that generates energy for cells is particularly harmful to cells in the developing brain, and this impairment results in the signs and symptoms of fumarase deficiency.


This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. However, people with one mutated copy of the FH gene in each cell, including parents of individuals with fumarase deficiency, tend to develop benign tumors containing smooth muscle tissue (leiomyomas) in the skin and, in females, the uterus. They also have an increased risk of kidney cancer. This condition is called hereditary leiomyomatosis and renal cell cancer (HLRCC).

Other Names for This Condition

  • fumarate hydratase deficiency
  • fumaric aciduria

This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/fumarase-deficiency


  1. Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer JP, Barclay E,Calonje E, Manek S, Adams SJ, Bowers PW, Burrows NP, Charles-Holmes R, Cook LJ,Daly BM, Ford GP, Fuller LC, Hadfield-Jones SE, Hardwick N, Highet AS, Keefe M,MacDonald-Hull SP, Potts ED, Crone M, Wilkinson S, Camacho-Martinez F, Jablonska S, Ratnavel R, MacDonald A, Mann RJ, Grice K, Guillet G, Lewis-Jones MS, McGrath H, Seukeran DC, Morrison PJ, Fleming S, Rahman S, Kelsell D, Leigh I, Olpin S,Tomlinson IP. Genetic and functional analyses of FH mutations in multiplecutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer,and fumarate hydratase deficiency. Hum Mol Genet. 2003 Jun 1;12(11):1241-52.
  2. Allegri G, Fernandes MJ, Scalco FB, Correia P, Simoni RE, Llerena JC Jr, deOliveira ML. Fumaric aciduria: an overview and the first Brazilian case report. JInherit Metab Dis. 2010 Aug;33(4):411-9. doi: 10.1007/s10545-010-9134-2.
  3. Bayley JP, Launonen V, Tomlinson IP. The FH mutation database: an onlinedatabase of fumarate hydratase mutations involved in the MCUL (HLRCC) tumorsyndrome and congenital fumarase deficiency. BMC Med Genet. 2008 Mar 25;9:20.doi: 10.1186/1471-2350-9-20.
  4. Deschauer M, Gizatullina Z, Schulze A, Pritsch M, Knöppel C, Knape M, Zierz S,Gellerich FN. Molecular and biochemical investigations in fumarase deficiency.Mol Genet Metab. 2006 Jun;88(2):146-52.
  5. Ezgu F, Krejci P, Wilcox WR. Mild clinical presentation and prolonged survivalof a patient with fumarase deficiency due to the combination of a known and anovel mutation in FH gene. Gene. 2013 Jul 25;524(2):403-6. doi:10.1016/j.gene.2013.03.026.
  6. Kerrigan JF, Aleck KA, Tarby TJ, Bird CR, Heidenreich RA. Fumaric aciduria:clinical and imaging features. Ann Neurol. 2000 May;47(5):583-8.
  7. Ottolenghi C, Hubert L, Allanore Y, Brassier A, Altuzarra C, Mellot-Draznieks C, Bekri S, Goldenberg A, Veyrieres S, Boddaert N, Barbier V, Valayannopoulos V, Slama A, Chrétien D, Ricquier D, Marret S, Frebourg T, Rabier D, Munnich A, deKeyzer Y, Toulhoat H, de Lonlay P. Clinical and biochemical heterogeneityassociated with fumarase deficiency. Hum Mutat. 2011 Sep;32(9):1046-52. doi:10.1002/humu.21534.
  8. Picaud S, Kavanagh KL, Yue WW, Lee WH, Muller-Knapp S, Gileadi O, Sacchettini J, Oppermann U. Structural basis of fumarate hydratase deficiency. J InheritMetab Dis. 2011 Jun;34(3):671-6. doi: 10.1007/s10545-011-9294-8.
  9. Raimundo N, Ahtinen J, Fumić K, Barić I, Remes AM, Renkonen R, Lapatto R,Suomalainen A. Differential metabolic consequences of fumarate hydratase andrespiratory chain defects. Biochim Biophys Acta. 2008 May;1782(5):287-94. doi:10.1016/j.bbadis.2008.01.008.
This entry is offline, you can click here to edit this entry!
Video Production Service