Fumarase deficiency

Fumarase deficiency
Classification and external resources
Fumarate is converted to malate by fumarase
OMIM	606812
DiseasesDB	29835

Fumarase deficiency (or fumaric aciduria), also known as "Polygamist Down's",^[1] 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.

Contents 1 Pathophysiology 2 Presentation 3 Emergence in a polygamist settlement 4 References 5 External links

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.^[2] 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.^[3]

The condition is an autosomal recessive disorder,^[4] 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.^[5][6] It can also be associated with uniparental isodisomy.^[7]

Presentation

Fumarase deficiency causes encephalopathy,^[8] severe mental retardation, unusual facial features, brain malformation, and epileptic seizures^[9] 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.^[10]

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, 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,^[11] when the LDS Church banned plural marriage. The condition has since been dubbed "Polygamist's Down's."^[1]

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.^[12] 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.^[13] 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.^[11]

References

External links

• Shih VE, Mandell R (2006). Fumarate Hydratase Deficiency. In Pagon RA, Bird TD, Dolan CR, Stephens K. . GeneReviews (Seattle WA: University of Washington). http://www.ncbi.nlm.nih.gov/books/NBK1506/. 
• Pithukpakorn M, Toro JR (2006). Hereditary Leiomyomatosis and Renal Cell Cancer. In Pagon RA, Bird TD, Dolan CR, Stephens K. . GeneReviews (Seattle WA: University of Washington). http://www.ncbi.nlm.nih.gov/books/NBK1252/. 
• Mitochondrial Disorders: Fumarase Deficiency at Washington University, St. Louis, Missouri

Inborn error of amino acid metabolism (E70–E72, 270) K→acetyl-CoA Lysine/straight chain Glutaric acidemia type 1 · type 2 · Hyperlysinemia · Pipecolic acidemia · Saccharopinuria Leucine Maple syrup urine disease · Isovaleric acidemia · 3-Methylcrotonyl-CoA carboxylase deficiency · 3-hydroxy-3-methylglutaryl-CoA lyase deficiency · 3-Methylglutaconic aciduria 1 Tryptophan Hypertryptophanemia G G→pyruvate→citrate Glycine Sarcosinemia · D-Glyceric acidemia · Glutathione synthetase deficiency Glycine→Creatine: GAMT deficiency · Glycine encephalopathy G→glutamate→ α-ketoglutarate Histidine Carnosinemia · Histidinemia · Urocanic aciduria Proline Hyperprolinemia · Prolidase deficiency Glutamate/glutamine SSADHD G→propionyl-CoA→ succinyl-CoA Valine Maple syrup urine disease · Hypervalinemia · Isobutyryl-CoA dehydrogenase deficiency Isoleucine Maple syrup urine disease · Beta-ketothiolase deficiency · 2-Methylbutyryl-CoA dehydrogenase deficiency Methionine Hypermethioninemia · Homocystinuria · Cystathioninuria General BC/OA Propionic acidemia · Methylmalonic acidemia · Methylmalonyl-CoA mutase deficiency G→fumarate Phenylalanine/tyrosine Phenylketonuria Tetrahydrobiopterin deficiency · 6-Pyruvoyltetrahydropterin synthase deficiency Tyrosinemia Type II tyrosinemia · Type III tyrosinemia/Hawkinsinuria · Alkaptonuria/Ochronosis · Type I tyrosinemia Tyrosine→Melanin Albinism: Ocular albinism (1) · Oculocutaneous albinism (Hermansky–Pudlak syndrome) · Waardenburg syndrome Tyrosine→Norepinephrine Dopamine beta hydroxylase deficiency · reverse: Brunner syndrome G→oxaloacetate Urea cycle/Hyperammonemia (arginine, aspartate) N-Acetylglutamate synthase deficiency · Carbamoyl phosphate synthetase I deficiency · Ornithine transcarbamylase deficiency/translocase deficiency · Citrullinemia · Argininosuccinic aciduria · Argininemia Transport/ IE of RTT Solute carrier family: Cystinuria · Hartnup disease · Lysinuric protein intolerance · Iminoglycinuria Fanconi syndrome: Oculocerebrorenal syndrome · Cystinosis Other Trimethylaminuria · 2-Hydroxyglutaric aciduria · Fumarase deficiency M: MET mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)

Disorders of TCA and ETC TCA PDHA · Fumarase deficiency ETC Coenzyme Q10 deficiency · Björnstad syndrome/GRACILE syndrome · Leigh's disease M: MET mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)