Skip Navigation
Genetics Home Reference: your guide to understanding genetic conditions
http://ghr.nlm.nih.gov/     A service of the U.S. National Library of Medicine®

Fumarase deficiency

Reviewed April 2008

What is fumarase deficiency?

Fumarase deficiency is a condition that primarily affects the nervous system, especially the brain. Affected infants may have an abnormally small head size (microcephaly), abnormal brain structure, severe developmental delay, weak muscle tone (hypotonia), and failure to gain weight and grow at the expected rate (failure to thrive). They may also experience seizures. Some people with this disorder have unusual facial features, including a prominent forehead (frontal bossing), low-set ears, a small jaw (micrognathia), widely spaced eyes (ocular hypertelorism), and a depressed nasal bridge. An enlarged liver and spleen (hepatosplenomegaly) may also be associated with this disorder, as well as an excess of red blood cells (polycythemia) or deficiency of white blood cells (leukopenia) in infancy. Affected individuals usually survive only a few months, but a few have lived into early adulthood.

How common is fumarase deficiency?

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.

What genes are related to fumarase deficiency?

The FH 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.

Related Gene(s)

Changes in this gene are associated with fumarase deficiency.

  • FH

How do people inherit 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.

Where can I find information about diagnosis or management of fumarase deficiency?

These resources address the diagnosis or management of fumarase deficiency and may include treatment providers.

  • Gene Review: Fumarate Hydratase Deficiency (http://www.ncbi.nlm.nih.gov/books/NBK1506)
  • Genetic Testing Registry: Fumarase deficiency (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0342770)

You might also find information on the diagnosis or management of fumarase deficiency in Educational resources and Patient support.

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about fumarase deficiency?

You may find the following resources about fumarase deficiency helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for fumarase deficiency?

  • fumarate hydratase deficiency
  • fumaric aciduria

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about fumarase deficiency?

Ask the Genetic and Rare Diseases Information Center (https://rarediseases.info.nih.gov/gard).

What glossary definitions help with understanding fumarase deficiency?

aciduria ; autosomal ; autosomal recessive ; cell ; deficiency ; developmental delay ; enzyme ; failure to thrive ; gene ; hepatosplenomegaly ; hypertelorism ; hypotonia ; inherited ; microcephaly ; micrognathia ; molecule ; muscle tone ; nervous system ; ocular hypertelorism ; oxygen ; recessive ; white blood cells

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

References

  • 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 multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet. 2003 Jun 1;12(11):1241-52. (http://www.ncbi.nlm.nih.gov/pubmed/12761039?dopt=Abstract)
  • 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. Epub 2006 Feb 28. (http://www.ncbi.nlm.nih.gov/pubmed/16510303?dopt=Abstract)
  • Kerrigan JF, Aleck KA, Tarby TJ, Bird CR, Heidenreich RA. Fumaric aciduria: clinical and imaging features. Ann Neurol. 2000 May;47(5):583-8. (http://www.ncbi.nlm.nih.gov/pubmed/10805328?dopt=Abstract)
  • Raimundo N, Ahtinen J, Fumić K, Barić I, Remes AM, Renkonen R, Lapatto R, Suomalainen A. Differential metabolic consequences of fumarate hydratase and respiratory chain defects. Biochim Biophys Acta. 2008 May;1782(5):287-94. doi: 10.1016/j.bbadis.2008.01.008. Epub 2008 Feb 14. (http://www.ncbi.nlm.nih.gov/pubmed/18313410?dopt=Abstract)
  • Zeman J, Krijt J, Stratilová L, Hansíková H, Wenchich L, Kmoch S, Chrastina P, Houstek J. Abnormalities in succinylpurines in fumarase deficiency: possible role in pathogenesis of CNS impairment. J Inherit Metab Dis. 2000 Jun;23(4):371-4. (http://www.ncbi.nlm.nih.gov/pubmed/10896297?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: April 2008
Published: August 24, 2015