Fumarase deficiency (or fumaric aciduria) is an exceedingly rare autosomal recessive metabolic disorder in the

Krebs cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...

, characterized by a deficiency of the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

fumarate hydratase Fumarase (or fumarate hydratase) is an enzyme () that catalyzes the reversible Hydration reaction, hydration/Dehydration reaction, dehydration of fumarate to malate. Fumarase comes in two forms: mitochondrial and cytosolic. The mitochondrial isoe ...

, which causes a buildup of

fumaric acid Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297. The salts and esters are known as fum ...

in the

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

and a deficiency of

malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms ...

. Only 13 cases were known worldwide in 1990, after which a cluster of 20 cases was documented in a community in Arizona that has practiced successive

endogamy Endogamy is the practice of marrying within a specific social group, religious denomination, caste, or ethnic group, rejecting those from others as unsuitable for marriage or other close personal relationships. Endogamy is common in many cu ...

Presentation

Fumarase deficiency causes

encephalopathy Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but ...

, severe

intellectual disabilities Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

, unusual facial features, brain malformation, and epileptic

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...

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 Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of i ...

, or

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...

. As they age, neurological deficits begin to manifest with seizures, dystonias, and severe developmental delay.

Pathophysiology

Fumarase deficiency is caused by a mutation in the fumarate hydratase (FH)

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

in humans, which encodes the enzyme that converts

fumarate Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297. The salts and esters are known as f ...

in the mitochondria. Other mutant alleles of the FH gene, located on human

Chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, whi ...

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

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 Most generally, in the lineal kinship system used in the English-speaking world, a cousin is a type of familial relationship in which two relatives are two or more familial generations away from their most recent common ancestor. Commonly, ...

s. It can also be associated with uniparental isodisomy.

Diagnosis

Treatment

Epidemiology

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 Colorado City is a town in Mohave County, Arizona, United States, and is located in a region known as the Arizona Strip. As of the 2020 census, the population of the town was 2,478, down from 4,821 in 2010. At least three Mormon fundamentalis ...

and Hildale, Utah, both of which were formerly known as "Short Creek" (or the

Short Creek Community The Short Creek Community (now Colorado City, Arizona, and Hildale, Utah), founded in 1913, began as a small ranching town in the Arizona Strip. In the 1930s it was settled by Mormon fundamentalists. History In May 1935, members of the Council ...

). The two towns combine to form a community of 10,000 members of the Fundamentalist Church of Jesus Christ of Latter Day Saints who have a history of practicing successive endogamy, or marriage within their own communities. Nicknamed "Polygamist's Down's", the syndrome has been blamed on

cousin marriage A cousin marriage is a marriage where the spouses are cousins (i.e. people with common grandparents or people who share other fairly recent ancestors). The practice was common in earlier times, and continues to be common in some societies to ...

, but in a larger sense is related to the reproductive isolation of a community among whom 85% are blood relatives of

John Y. Barlow John Yeates Barlow (also known as John Yates Barlow) (March 4, 1874 – December 29, 1949) was a Mormon fundamentalist leader in Short Creek, Arizona. Childhood Barlow was born in Panaca, Lincoln County, Nevada, to Israel Barlow and his English ...

Joseph Smith Jessop Joseph Smith Jessop (January 25, 1869 – September 1, 1953) was an early patriarch in the Mormon fundamentalist movement and, with John Y. Barlow, co-founder of Short Creek, Arizona (later Colorado City, Arizona, and Hildale, Utah), home to the ...

. Since the initial cluster from FLDS communities were reported, it is now estimated that there are 100 documented cases worldwide. Fumarase deficiency
MedlinePlus accessed via Internet June 20, 2022

References

External links

{{DEFAULTSORT:Fumarase Deficiency Amino acid metabolism disorders Autosomal recessive disorders Rare diseases TCA and ETC metabolism disorders Fundamentalist Church of Jesus Christ of Latter-Day Saints Disorders causing seizures