OMIM 606812 | DiseasesDB 29835 | |
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Fumarase deficiency (or fumaric aciduria), also known as "Polygamist Down's", is an autosomal recessive metabolic disorder characterized by a deficiency of the enzyme fumarate hydratase, which is indicated by a buildup of fumaric acid in the urine.
Contents
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. 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.
Presentation
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.
Emergence in a polygamist settlement
Fumarase deficiency is extremely rare, with only 13 diagnosed and identified cases worldwide until roughly 1990. Since then an additional 20 cases have been documented in the twin towns of Colorado City, Arizona (formerly known as Short Creek or the Short Creek Community), and Hildale, Utah, settled in the 1930s by the Fundamentalist Church of Jesus Christ of Latter Day Saints, a church whose members left The Church of Jesus Christ of Latter-day Saints (LDS Church) beginning in 1890, when the LDS Church banned plural marriage. The condition has since been dubbed "Polygamist's Down's."
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. 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. 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.