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Genetic and Rare Diseases Information Center (GARD)

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Fumarase deficiency

Other Names for this Disease
  • Fumarate hydratase deficiency
  • Fumaric aciduria
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I'm looking to find information on fumaric aciduria. Is there anyone living with this disease anywhere in the world?

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What is fumarase deficiency?

Fumarase deficiency is an inherited condition that primarily affects the nervous system, especially the brain. Affected infants may have microcephaly, abnormal brain structure, severe developmental delay, weak muscle tone (hypotonia), failure to thrive, seizures, and/or distinctive facial features. Other signs and symptoms may include hepatosplenomegaly, an excess of red blood cells (polycythemia), and/or or deficiency of white blood cells (leukopenia). Affected individuals usually survive only a few months, but a few have lived into early adulthood. This condition is caused by mutations in the FH gene and is inherited in an autosomal recessive manner.[1] No effective treatment is currently available.[2]
Last updated: 11/6/2012

What are the signs and symptoms of fumarase deficiency?

Most newborns with fumarase deficiency show severe neurologic abnormalities, including poor feeding, failure to thrive, and poor muscle tone (hypotonia). Early-onset infantile encephalopathy (altered brain structure or function), seizures, and severe developmental delay with microcephaly are also common. Other signs and symptoms may include infantile spasms, abnormal posturing of the limbs, and autistic features. Distinctive facial features have been reported in some affected individuals and have included an unusually prominent forehead (frontal bossing); low-set ears; a small jaw (micrognathia); widely-spaced eyes (ocular hypertelorism); depressed nasal bridge; and high-arched palate.[2]

Other findings in affected individuals can include neonatal polycythemia (an excess of red blood cells); leukopenia (deficiency of white blood cells); neutropenia; enlarged liver and spleen (hepatosplenomegaly); and pancreatitis.[2]

Many children with this condition do not survive infancy or childhood. Those surviving beyond childhood have severe psychomotor deficits.[2]
Last updated: 11/6/2012

What causes fumarase deficiency?

Mutations in the FH gene cause fumarase deficiency. The FH gene provides instructions for making an enzyme called fumarase, which participates in a series of reactions allowing cells to use oxygen and generate energy. Mutations in the FH gene disrupt the enzyme's ability to do its job. Disruption of the process that generates energy for cells is particularly harmful to cells in the developing brain, thus resulting in the signs and symptoms of fumarase deficiency.
Last updated: 11/6/2012

How might fumarase deficiency be treated?

There is currently no effective treatment for fumarase deficiency. Nutritional intervention may be appropriate for children with feeding difficulties. Physical therapy and wheelchairs can also be useful for some individuals.[2]
Last updated: 11/6/2012

How many people have fumarase deficiency?

While there is overall consensus that fumarase deficiency is a rare disorder, there are conflicting reports of the exact number of affected individuals reported in the literature. Some authors have stated that approximately 100 affected individuals have been reported worldwide, while others have stated that as of 2010, only 40 cases have been reported.[2][3][4]

The condition does occur in individuals of different ethnic backgrounds; however, it appears there is a higher frequency of affected individuals in the southwestern United States (around the border of northern Arizona and southern Utah).[2][3][4] It has been speculated that this is probably due to a founder effect in closed, religious polygamist communities living in these regions, among which marriage between relatives seems to be frequent.[4]
Last updated: 11/7/2012

How can I find individuals or families affected by fumarase deficiency?

You may be able to connect with individuals and/or families affected by fumarase deficiency through Climb, the National Information Centre for Metabolic Diseases. This organization works on behalf of children, young people, adults and families affected by metabolic disease. They have a Climb Family Contacts Network, which aims to help reduce the sense of isolation felt by many families affected by a rare disease, giving families the opportunity to share experiences, information and advice.
Last updated: 11/7/2012