Fumarase deficiency
Encyclopedia
Fumarase deficiency 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 build up of fumaric acid
in the urine
.
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 cousin
s. It can also be associated with uniparental isodisomy.
, 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 polyhydraminos 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.
(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.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
fumarate hydratase, which is indicated by a build up of fumaric acid
Fumaric acid
Fumaric acid or trans-butenedioic acid is the chemical compound with the formula HO2CCH=CHCO2H. This white crystalline compound is one of two isomeric unsaturated dicarboxylic acids, the other being maleic acid. In fumaric acid the carboxylic acid groups are trans and in maleic acid they are cis...
in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
.
Pathophysiology
Fumarase deficiency is caused by a mutation in the fumarate hydratase (FH) geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
in humans, which encodes the enzyme that converts fumarate to malate
Malate
Malate is the ionized form of malic acid. It is an important chemical compound in biochemistry. In the C4 carbon fixation process, malate is a source of CO2 in the Calvin cycle....
in the mitochondria. Other mutant alleles of the FH gene, located on human Chromosome 1 at position 1q42.1, cause multiple cutaneous
Multiple cutaneous leiomyoma
Multiple cutaneous leiomyomas arise from the arrectores pilorum muscles, and are made up of a poorly circumscribed proliferation of haphazardly arranged smooth muscle fibers located in the dermis that appear to infiltrate the surrounding tissue and may extend into the subcutis.- See also :*...
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
Cellular respiration
Cellular respiration is the set of the metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate , and then release waste products. The reactions involved in respiration are catabolic reactions that involve...
.
Cousin
In kinship terminology, a cousin is a relative with whom one shares one or more common ancestors. The term is rarely used when referring to a relative in one's immediate family where there is a more specific term . The term "blood relative" can be used synonymously and establishes the existence of...
s. It can also be associated with uniparental isodisomy.
Presentation
Fumarase deficiency causes encephalopathyEncephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
, severe mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, unusual facial features, brain malformation, and epileptic seizures due to an abnormally low amount of fumarase
Fumarase
Fumarase is an enzyme that catalyzes the reversible hydration/dehydration of Fumarate to malate. Fumarase comes in two forms: mitochondrial and cytosolic...
in cells. It can initially present with polyhydraminos 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 thirteen diagnosed and identified cases worldwide until roughly 1990. Since then an additional twenty cases have been documented in the twin towns of Colorado City, ArizonaColorado City, Arizona
Colorado City is a town in Mohave County, Arizona, United States, and is located in a region known as the Arizona Strip. According to 2006 Census Bureau estimates, the population of the town was 4,607...
(formerly known as Short Creek or the Short Creek Community
Short Creek Community
The Short Creek Community originally began in 1935 following the death of Joseph Leslie Broadbent, under the leadership of John Y. Barlow and Joseph W. Musser. Formerly located in Short Creek, Arizona , the group was notorious for the practice of polygamy due to media coverage during the "Short...
), and Hildale, Utah
Hildale, Utah
Hildale is a city in Washington County, Utah, United States. The population was 2,726 at the 2010 census.Hildale is a twin city to the more well-known Colorado City, Arizona, both of which straddle the border between Utah and Arizona. Hildale is the headquarters of the Fundamentalist Church of...
, settled in the 1930s by the Fundamentalist Church of Jesus Christ of Latter Day Saints
Fundamentalist Church of Jesus Christ of Latter Day Saints
The Fundamentalist Church of Jesus Christ of Latter-Day Saints is one of the largest Mormon fundamentalist denominations and one of the largest organizations in the United States whose members practice polygamy. The FLDS Church emerged in the early twentieth century when its founding members left...
, 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
1890 Manifesto
The "1890 Manifesto", sometimes simply called "The Manifesto", is a statement which officially disavowed the continuing practice of plural marriage in The Church of Jesus Christ of Latter-day Saints...
. The condition has since been dubbed "Polygamist's Down's
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
."
Theodore Tarby, a pediatric neurologist
Neurologist
A neurologist is a physician who specializes in neurology, and is trained to investigate, or diagnose and treat neurological disorders.Neurology is the medical specialty related to the human nervous system. The nervous system encompasses the brain, spinal cord, and peripheral nerves. A specialist...
who has treated some of the community's fumarase deficient residents, has been quoted as estimating the IQ
Intelligence quotient
An intelligence quotient, or IQ, is a score derived from one of several different standardized tests designed to assess intelligence. When modern IQ tests are constructed, the mean score within an age group is set to 100 and the standard deviation to 15...
of his patients as around 25. While treating a child with a developmental disability
Developmental disability
Developmental disability is a term used in the United States and Canada to describe lifelong disabilities attributable to mental or physical impairments, manifested prior to age 18. It is not synonymous with "developmental delay" which is often a consequence of a temporary illness or trauma during...
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
Cerebral palsy
Cerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....
, a disease commonly associated with developmental difficulties. This sibling also turned out to have fumarase deficiency.
External links
- Mitochondrial Disorders: Fumarase Deficiency at Washington University, St. Louis, Missouri