Fumarase deficiency (or fumaric aciduria) is an exceedingly rare

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...

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 substrates, and the enzyme converts the substrates into different molecules known as products. A ...

fumarate hydratase, 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 fu ...

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 excretion, excreted from the body through the urethra. Cel ...

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 (L ...

. 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 cultu ...

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 r ...

, 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 signific ...

, 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 neural oscillation, synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much o ...

due to an abnormally low amount of

fumarase Fumarase (or fumarate hydratase) is an enzyme () that catalyzes the reversible hydration/dehydration of fumarate to malate. Fumarase comes in two forms: mitochondrial and cytosolic. The mitochondrial isoenzyme is involved in the Krebs cycle and ...

in cells. It can initially present with polyhydramnios on prenatal ultrasound. Affected neonates may demonstrate nonspecific signs of poor feeding and

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...

. Laboratory findings in neonates may indicate

polycythemia Polycythemia (also known as polycythaemia) is a laboratory finding in which the hematocrit (the volume percentage of red blood cells in the blood) and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called eryth ...

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 inf ...

, 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 bacteria ...

. As they age, neurological deficits begin to manifest with seizures,

dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often inten ...

s, 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 ba ...

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 A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

. 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, which ar ...

at position 1q42.1, cause multiple cutaneous and uterine

leiomyomata A leiomyoma, also known as a fibroid, is a benign smooth muscle tumor that very rarely becomes cancer (0.1%). They can occur in any organ, but the most common forms occur in the uterus, small bowel, and the esophagus. Polycythemia may occur due to ...

, hereditary

leiomyomatosis A leiomyoma, also known as a fibroid, is a benign smooth muscle tumor that very rarely becomes cancer (0.1%). They can occur in any organ, but the most common forms occur in the uterus, small bowel, and the esophagus. Polycythemia may occur due to ...

and

renal cell cancer Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, res ...

. Fumarase deficiency is one of the few known deficiencies of the

tricarboxylic acid 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 ...

, the main enzymatic pathway of cellular aerobic

respiration Respiration may refer to: Biology * Cellular respiration, the process in which nutrients are converted into useful energy in a cell ** Anaerobic respiration, cellular respiration without oxygen ** Maintenance respiration, the amount of cellul ...

. The condition is an

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 Hildale is a city in Washington County, Utah, United States. The population was 1,127 at the 2020 census. Hildale is located on the border of Utah and Arizona. History Hildale, formerly known as Short Creek Community, was founded in 1913 by ...

, 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 of ...

). The two towns combine to form a community of 10,000 members of the

Fundamentalist Church of Jesus Christ of Latter Day Saints The Fundamentalist Church of Jesus Christ of Latter-Day Saints (FLDS Church) is a religious sect of the fundamentalist Mormon denominations whose members practice polygamy. The fundamentalist Mormon movement emerged in the early 20th century, ...

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 toda ...

, but in a larger sense is related to the

reproductive isolation The mechanisms of reproductive isolation are a collection of evolutionary mechanisms, behaviors and physiological processes critical for speciation. They prevent members of different species from producing offspring, or ensure that any offspring ...

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 fundamentalism, Mormon fundamentalist leader in Short Creek, Arizona. Childhood Barlow was born in Panaca, Nevada, Panaca, Lincoln County, Nev ...

or Joseph Smith Jessop. 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

Presentation

Pathophysiology

Diagnosis

Treatment

Epidemiology

See also

References

Further reading

External links