Fumarase deficiency (or fumaric aciduria) is an autosomal recessive metabolic disorder characterized by a deficiency of the enzyme fumarate hydratase, which is indicated by a build up of fumaric acid in the urine.

Pathophysiology

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. ^[1] 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.^[2]

PAGENAME has an autosomal recessive pattern of inheritance.

The condition is an autosomal recessive disorder,^[3] 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.^[4][5] It can also be associated with uniparental isodisomy.^[6]

Presentation

Fumarase deficiency causes encephalopathy,^[7] severe mental retardation, unusual facial features, brain malformation, and epileptic seizures^[8] due to an abnormally low amount of fumarase in cells.

Emergence in a polygamist settlement

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 Arizona/Utah border towns of Colorado City, Arizona, and Hildale, Utah, settled in the 1930s by the Fundamentalist Church of Jesus Christ of Latter Day Saints a church that gradually split from The Church of Jesus Christ of Latter-day Saints beginning in 1890.^[9] Persons living in the surrounding communities have referred to this disease as "Polygamist's Down's."^[10]

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.^[11]. 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.^[12] 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.^[9]

According to the Phoenix New Times, the rare disease appeared when Martha Jessop, the daughter of Joseph Smith Jessop, one of the founders of the community, married her second cousin, John Yeates Barlow, in 1923.^[9] Tarby and fellow researchers at Barrow Neurological Institute at St. Joseph's Hospital in Phoenix have found that the highest incidence of the disease recorded anywhere appears in the population of polygamists living in these two towns.^[9]

References

External links

• Mitochondrial Disorders: Fumarase Deficiency at Washington University, St. Louis, Missouri

it:Aciduria fumarica fr:Acidurie fumarique