|Fumarate is converted to malate by fumarase|
Fumarase deficiency (or fumaric aciduria) is an exceedingly rare autosomal recessive metabolic disorder in Krebs cycle characterized by a deficiency of the enzyme fumarate hydratase, which causes a buildup of fumaric acid in the urine, and a deficiency of malate. Only 13 cases were known worldwide in 1990, after which a cluster of 20 cases was documented in an inbred community in Arizona.
Fumarase deficiency causes encephalopathy, severe mental retardation, unusual facial features, brain malformation, and epileptic seizures 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.
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. 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.
The condition is an autosomal recessive disorder, 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. It can also be associated with uniparental isodisomy.
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There is a deficiency of malate in patients because fumarase enzyme can't convert fumarate into it therefore treatment is with oral malic acid which will allow the krebs cycle to continue, and eventually make ATP.
Fumarase deficiency is extremely rare - until around 1990 there had only been 13 diagnosed and identified cases worldwide.
A cluster of 20 cases has since been documented in the twin towns of Colorado City, Arizona and Hildale, Utah among an inbred community of 10,000 members of the Fundamentalist Church of Jesus Christ of Latter Day Saints. Nicknamed "Polygamist's down's", the syndrome has been blamed on cousin marriage, but in a larger sense is related to the reproductive isolation of a community among whom 85% are blood relatives of John Y. Barlow or Joseph Smith Jessop. (see Founder effect)
- Hereditary leiomyomatosis and renal cell cancer, a syndrome caused by autosomal dominant mutations of the fumarate hydratase gene.
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