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| {{short description|Rare disease}} | | {{Short description|A rare metabolic disorder}} |
| {{Infobox medical condition (new) | | {{Medical condition (new)}} |
| | name = Fumarase deficiency
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| | synonyms = Fumarate hydratase deficiency <ref>{{cite web |title=Fumarase deficiency {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |url=https://rarediseases.info.nih.gov/diseases/6476/index |website=rarediseases.info.nih.gov |accessdate=8 April 2019}}</ref>
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| | image = Fumaric acid wpmp.png
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| | caption = [[Fumarate]] is converted to [[malate]] by [[fumarase]]
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| '''Fumarase deficiency''' (or '''fumaric aciduria''') is an exceedingly rare [[autosomal recessive]] [[metabolic disorder]] in [[Krebs cycle]] characterized by a deficiency of the [[enzyme]] [[fumarate hydratase]], which causes a buildup of [[fumaric acid]] in the [[urine]], and a deficiency of [[malate]]. Only 13 cases were known worldwide in 1990, after which a cluster of 20 cases was documented in an inbred community in Arizona.
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| ==Presentation==
| | '''Fumarase deficiency''' is a rare [[metabolic disorder]] characterized by a deficiency of the enzyme [[fumarase]], which is crucial in the [[citric acid cycle]] (also known as the [[Krebs cycle]]). This enzyme deficiency leads to a buildup of fumaric acid and a deficiency of malate, disrupting the energy production process in cells. |
| Fumarase deficiency causes [[encephalopathy]],<ref name="pmid18366737">{{cite journal |last1 = Bayley | first1 = Jean-Pierre | last2 = Launonen | first2 = Virpi | last3 = Tomlinson | first3 = Ian P.M. |title=The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency |journal=[[BMC Medical Genetics|BMC Med. Genet.]] |volume=9 |issue=1 |pages=20 |date = 25 March 2008 |pmid=18366737 |doi=10.1186/1471-2350-9-20 |pmc=2322961}}</ref> severe [[intellectual disabilities]], unusual facial features, brain malformation, and epileptic [[seizures]]<ref name="pmid10805328">{{cite journal | last1 = Kerrigan | first1 = John F. | last2 = Aleck | first2 = Kirk A. | last3 = Tarby | first3 = Theodore J. | last4 = Bird | first4 = C. Roger | last5 = Heidenreich | first5 = Randall A. |title=Fumaric aciduria: clinical and imaging features |journal=[[Annals of Neurology|Ann. Neurol.]] |volume=47 |issue=5 |pages=583–8 |date=May 2000 |origyear = 3 May 2001|pmid=10805328 |doi= 10.1002/1531-8249(200005)47:5<583::AID-ANA5>3.0.CO;2-Y }}</ref> 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, [[dystonia]]s, and severe developmental delay.<ref>{{cite book | chapter = Fumarate Hydratase Deficiency | first1 = Clifton | last1 = Ewbank | first2 = John F. | last2 = Kerrigan | first3 = Kirk|last3 = Aleck | title = GeneReviews | origyear = July 5, 2006 | date = April 4, 2013 | pmid = 20301679 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK1506/ |publisher= [[University of Washington]] |location= Seattle WA | title-link = GeneReviews }}</ref> | |
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| ==Pathophysiology== | | ==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 leiomyoma|multiple cutaneous]] and uterine [[leiomyomata]], hereditary [[leiomyomatosis]] and [[renal cell cancer]].<ref>{{OMIM|606812|Fumarase Deficiency}}</ref> Fumarase deficiency is one of the few known deficiencies of the [[Krebs cycle]] or [[tricarboxylic acid cycle]], the main enzymatic pathway of cellular aerobic [[Cellular respiration|respiration]].<ref name="isbn0-471-67808-2">{{cite book |last=Devlin|first=Thomas M. |title=Textbook of biochemistry: with clinical correlations |publisher=John Wiley |location=New York |year=2006 |isbn=978-0-471-67808-3 |page=546}}</ref> | | Fumarase, also known as fumarate hydratase, is an enzyme that catalyzes the reversible hydration of [[fumarate]] to [[malate]] in the citric acid cycle. This cycle is a key component of [[cellular respiration]], which is the process by which cells produce energy in the form of [[adenosine triphosphate]] (ATP). In individuals with fumarase deficiency, the lack of functional enzyme impairs the cycle, leading to reduced ATP production and an accumulation of fumarate. |
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| [[Image:autorecessive.svg|thumb|right|Fumarase deficiency has an autosomal recessive pattern of [[Heredity|inheritance]].]]
| | ==Genetics== |
| | Fumarase deficiency is inherited in an [[autosomal recessive]] pattern, meaning that an individual must inherit two copies of the defective gene, one from each parent, to manifest the disorder. The gene responsible for encoding fumarase is located on chromosome 1, and mutations in this gene lead to the enzyme deficiency. |
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| | ==Clinical Features== |
| | The clinical presentation of fumarase deficiency can vary, but common features include severe [[neurological]] impairment, [[developmental delay]], [[hypotonia]] (reduced muscle tone), and [[seizures]]. Affected individuals may also exhibit [[microcephaly]] (a smaller than normal head size), [[encephalopathy]], and [[dystonia]]. |
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| The condition is an [[autosomal recessive]] disorder,<ref name="pmid2314594">{{cite journal |last1=Gellera|first1=C.|last2=Uziel|first2=G.|last3=Rimoldi|first3=M.|first4=M.|last4=Zeviani|first5=A.|last5=Laverda|first6=F.|last6=Carrara|first7=S. |last7=DiDonato |title=Fumarase deficiency is an autosomal recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes |journal=[[Neurology (journal)|Neurology]] |volume=40 |issue=3 Part 1 |pages=495–499 |date=March 1990 |pmid=2314594 |doi=10.1212/wnl.40.3_part_1.495}}</ref> 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.<ref name="pmid3578275">{{cite journal | last1 = Petrova-Benedict | first1 = R. | last2 = Robinson | first2 = B.H. | last3 = Stacey | first3 = T.E. | last4 = Mistry | first4 = J. | last5 = Chalmers | first5 = R.A. |title=Deficient fumarase activity in an infant with fumaricacidemia and its distribution between the different forms of the enzyme seen on isoelectric focusing |journal=[[American Journal of Human Genetics|Am. J. Hum. Genet.]] |volume=40 |issue=3 |pages=257–266 |year=1987 |pmid=3578275 |pmc=1684096}}</ref><ref name="pmid8200987">{{cite journal |last1 = Bourgeron | first1= T. | last2 = Chretien | first2 = D. | last3 = Poggi-Bach | first3 = J. | first4 = S. | last4 = Doonan | first5 = D. | last5 = Rabier | first6 = P. | last6 = Letouzé | first7 = A. | last7 = Munnich | first8 = A. | last8 = Rötig | first9 = P. | last9 = Landrieu | first10 = P. | last10 = Rustin|title=Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency |journal=[[Journal of Clinical Investigation|J. Clin. Invest.]] |volume=93 |issue=6 |pages=2514–2518 |date = June 1994 |pmid=8200987 |doi=10.1172/JCI117261 |pmc=294471}}</ref> It can also be associated with [[uniparental isodisomy]].<ref name="pmid16575891">{{cite journal | first1 = Wen-Qi | last1 = Zeng | first2 = Hanlin | last2 = Gao | first3 = Louise | last3 = Brueton | first4 = Tim | last4 = Hutchin | first5 = George | last5 = Gray | first6 = Anupam | last6 = Chakrapani | first7 = Simon | last7 = Olpin | first8 = Vivian E. | last8 = Shih | title = Fumarase deficiency caused by homozygous P131R mutation and paternal partial isodisomy of chromosome 1 |journal=[[American Journal of Medical Genetics|Am. J. Med. Genet. A]] |volume=140A |issue=9 |pages=1004–1009 |date = 1 May 2006 |origyear = 30 March 2006|pmid=16575891 |doi=10.1002/ajmg.a.31186}}</ref>
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| ==Diagnosis== | | ==Diagnosis== |
| Fumarate hydratase (FH) deficiency should be suspected in individuals with the following clinical, laboratory, and imaging findings.
| | Diagnosis of fumarase deficiency is typically based on clinical features, biochemical testing, and genetic analysis. Elevated levels of fumaric acid in the [[urine]] and [[blood]] are indicative of the disorder. Genetic testing can confirm mutations in the fumarase gene. |
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| '''Clinical findings'''
| | ==Management== |
| * Neonatal and early-infantile severe [[encephalopathy]], which may include poor feeding, [[hypotonia]], and decreased levels of consciousness ([[lethargy]], [[stupor]], and [[coma]])
| | There is currently no cure for fumarase deficiency, and treatment is primarily supportive. Management may include [[anticonvulsant]] medications to control seizures, [[physical therapy]] to address motor difficulties, and [[nutritional support]]. Early intervention and supportive care can improve quality of life for affected individuals. |
| * [[Seizures]], present in many but not all affected individuals
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| * Intellectual disability / [[developmental delay]]
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| * [[Dysmorphic syndrome|Dysmorphic]] facial features including frontal bossing, depressed nasal bridge, and widely spaced eyes
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| '''Laboratory findings'''
| | ==Prognosis== |
| * Finding of isolated increased [[fumaric acid]] and [[alpha-ketoglutarate]] on urine organic acid analysis combined with increased [[Succinyl adenosine|succinyladenosine]] on urine [[purines]] and [[pyrimidines]] is highly suggestive of FH deficiency.
| | The prognosis for individuals with fumarase deficiency is generally poor, with many experiencing significant developmental challenges and reduced life expectancy. However, the severity of the condition can vary, and some individuals may achieve limited developmental milestones. |
| * Reduced [[fumarate hydratase]] enzyme activity. Fumarate hydratase [[enzyme]] activity can be measured in [[fibroblasts]] or leukocytes. Fumarate hydratase enzyme activity in severely affected individuals is often less than 10% of the control mean; however, residual fumarate hydratase enzyme activity in some affected individuals can be 11%-35% of the control mean. FH deficiency is evident in both isozymes – the mitochondrial form and the cytosolic form (see Molecular Genetics).
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| '''Imaging findings.''' Abnormalities on brain [[MRI]] examination, including enlarged [[ventricles]] and [[polymicrogyria]], may not be present in mildly affected individuals.
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| The diagnosis of FH deficiency is established in a proband with reduced fumarate hydratase enzyme activity in [[fibroblasts]] or [[leukocytes]] and/or biallelic pathogenic variants in FH identified by molecular [[genetic testing]].
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| ==Treatment== | |
| There is a deficiency of malate in patients because fumarase enzyme can't convert fumarate into it therefore treatment is with oral malic acid which will allow the Krebs cycle to continue, and eventually make ATP.
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| The goal of management is to improve symptoms, prevent complications, and increase quality of life. Examples of management options include:
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| * Standard [[anticonvulsant]] medications for [[seizures]].
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| * Placement of a [[feeding tube]] (if needed) for optimal nutrition and to prevent [[aspiration]].
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| * Special needs services for support with motor, language, and social development.
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| ==Epidemiology== | | ==Epidemiology== |
| Fumarase deficiency is extremely rare - until around 1990 there had only been 13 diagnosed and identified cases worldwide. | | Fumarase deficiency is extremely rare, with only a few dozen cases reported in the medical literature. It has been observed more frequently in certain populations with higher rates of consanguinity, such as the [[Mormon]] community in the [[United States]]. |
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| A cluster of 20 cases has since been documented in the twin towns of [[Colorado City, Arizona]] and [[Hildale, Utah]] among an [[Inbreeding|inbred]] community of 10,000 members of the [[Fundamentalist Church of Jesus Christ of Latter Day Saints]].<ref name="Dougherty2005">{{cite news | url = http://www.phoenixnewtimes.com/2005-12-29/news/forbidden-fruit/ | title = Forbidden Fruit:Inbreeding among polygamists along the Arizona-Utah border is producing a caste of severely retarded and deformed children | first1 = John | last1 = Dougherty | newspaper = The Phoenix New Times News | date = December 29, 2005 | page = 2 }}</ref><ref name=digitaljournal>{{cite web | url = http://www.digitaljournal.com/article/195535 | title = Mormon Sect's Polygamy Causes Most Of The World's Fumarase Deficiency Cases | work = Digital Journal | date = 2007-06-14 }}</ref><ref>{{cite news | url = http://deseretnews.com/dn/view/0,1249,635182923,00.html | title = Birth defect is plaguing children in FLDS towns: Fumarase Deficiency afflicts 20, is linked to marriages of close Kin | first = John | last = Hollenhorst | newspaper = Deseret News | date = February 8, 2006 }}</ref><ref>{{cite news | url = https://www.reuters.com/article/domesticNews/idUSN0727298120070614?sp=true | title = Polygamist community faces rare genetic disorder | first = Jason | last = Szep | date = June 14, 2007 | agency = Reuters }}</ref> Nicknamed "Polygamist's Down's", the syndrome has been blamed on [[cousin marriage]], but in a larger sense is related to the [[reproductive isolation]] of a community among whom 85% are blood relatives of [[John Y. Barlow]] or [[Joseph Smith Jessop]].<ref name=digitaljournal />
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| ==See also==
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| * [[Hereditary leiomyomatosis and renal cell cancer]]
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| * [[Founder effect]]
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| ==References==
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| {{Reflist}}
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| ==Further reading==
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| *{{cite book | chapter = Hereditary Leiomyomatosis and Renal Cell Cancer | first1 = Manop | last1 = Pithukpakorn | first2 = Jorge R. | last2 = Toro | title = GeneReviews | origyear = July 31, 2006 | date = November 2, 2010 | pmid = 20301430 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK1252/ |publisher= [[University of Washington]] |location= Seattle WA | title-link = GeneReviews }}
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| == External links ==
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| {{Medical resources
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| | DiseasesDB = 29835
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| | ICD10 = E88.8
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| | OMIM = 606812
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| | Orphanet = 24
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| {{Amino acid metabolic pathology}}
| | ==Related pages== |
| {{Disorders of TCA and ETC}}
| | * [[Metabolic disorder]] |
| | * [[Citric acid cycle]] |
| | * [[Genetic disorder]] |
| | * [[Neurological disorder]] |
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| {{DEFAULTSORT:Fumarase Deficiency}}
| | [[Category:Metabolic disorders]] |
| [[Category:Amino acid metabolism disorders]] | | [[Category:Genetic disorders]] |
| [[Category:Autosomal recessive disorders]] | | [[Category:Neurological disorders]] |
| [[Category:Rare diseases]] | |
| [[Category:TCA and ETC metabolism disorders]]
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| [[Category:Fundamentalist Church of Jesus Christ of Latter-Day Saints]]
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| [[Category:Disorders causing seizures]]
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A rare metabolic disorder
Template:Medical condition (new)
Fumarase deficiency is a rare metabolic disorder characterized by a deficiency of the enzyme fumarase, which is crucial in the citric acid cycle (also known as the Krebs cycle). This enzyme deficiency leads to a buildup of fumaric acid and a deficiency of malate, disrupting the energy production process in cells.
Pathophysiology
Fumarase, also known as fumarate hydratase, is an enzyme that catalyzes the reversible hydration of fumarate to malate in the citric acid cycle. This cycle is a key component of cellular respiration, which is the process by which cells produce energy in the form of adenosine triphosphate (ATP). In individuals with fumarase deficiency, the lack of functional enzyme impairs the cycle, leading to reduced ATP production and an accumulation of fumarate.
Genetics
Fumarase deficiency is inherited in an autosomal recessive pattern, meaning that an individual must inherit two copies of the defective gene, one from each parent, to manifest the disorder. The gene responsible for encoding fumarase is located on chromosome 1, and mutations in this gene lead to the enzyme deficiency.
Clinical Features
The clinical presentation of fumarase deficiency can vary, but common features include severe neurological impairment, developmental delay, hypotonia (reduced muscle tone), and seizures. Affected individuals may also exhibit microcephaly (a smaller than normal head size), encephalopathy, and dystonia.
Diagnosis
Diagnosis of fumarase deficiency is typically based on clinical features, biochemical testing, and genetic analysis. Elevated levels of fumaric acid in the urine and blood are indicative of the disorder. Genetic testing can confirm mutations in the fumarase gene.
Management
There is currently no cure for fumarase deficiency, and treatment is primarily supportive. Management may include anticonvulsant medications to control seizures, physical therapy to address motor difficulties, and nutritional support. Early intervention and supportive care can improve quality of life for affected individuals.
Prognosis
The prognosis for individuals with fumarase deficiency is generally poor, with many experiencing significant developmental challenges and reduced life expectancy. However, the severity of the condition can vary, and some individuals may achieve limited developmental milestones.
Epidemiology
Fumarase deficiency is extremely rare, with only a few dozen cases reported in the medical literature. It has been observed more frequently in certain populations with higher rates of consanguinity, such as the Mormon community in the United States.
Related pages
