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Fumarate Hydratase Deficiency

Synonyms: Fumarase Deficiency, Fumaric Aciduria

, MD, , MD, and , MD.

Author Information

Initial Posting: ; Last Update: April 4, 2013.

Summary

Clinical characteristics.

Fumarate hydratase deficiency results in severe neonatal and early infantile encephalopathy that is characterized by poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Dysmorphic facial features include frontal bossing, depressed nasal bridge, and widely spaced eyes. Many affected individuals are microcephalic. A spectrum of brain abnormalities are seen on magnetic resonance imaging, including cerebral atrophy, enlarged ventricles and generous extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum, and an abnormally small brain stem. Brain malformations including bilateral polymicrogyria and absence of the corpus callosum can also be observed. Development is severely affected: most affected individuals are non-verbal and non-ambulatory, and many die during early childhood. Less severely affected individuals with moderate cognitive impairment and long-term survival have been reported.

Diagnosis/testing.

Isolated increased concentration of fumaric acid on urine organic acid analysis is highly suggestive of fumarate hydratase deficiency. The diagnosis is confirmed by identification of deficient fumarate hydratase enzyme activity in fibroblasts, lymphoblasts, or white blood cells and/or by molecular genetic testing of FH, the gene that encodes fumarate hydratase and the only gene in which mutation is known to cause fumarate hydratase deficiency. Fumarate hydratase enzyme activity in severely affected individuals is generally 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, overlapping with that seen in some obligate heterozygotes.

Management.

Treatment of manifestations: There are no therapeutic strategies to reverse or prevent the abnormalities of intermediary metabolism associated with fumarate hydratase deficiency. Supportive treatment measures may include standard therapies to control seizures; gastrostomy placement to optimize nutrition and to prevent aspiration; physical therapy and orthopedic management to minimize contractures and prevent scoliosis; and special needs services to address developmental deficits.

Surveillence: Specific recommendations should be provided to address each person’s individual needs. This may include at least yearly evaluations by pediatric neurology and physical medicine, as well as periodic evaluations by genetics, ophthalmology, and orthopedic surgery.

Agents/circumstances to avoid: The ketogenic diet is usually considered to be contraindicated for treating epilepsy associated with fumarate hydratase deficiency or other enzymatic defects within the Krebs tricarboxylic acid cycle.

Genetic counseling.

Fumarate hydratase deficiency is inherited in an autosomal recessive manner. When both parents are known to be heterozygotes (i.e., carriers of an FH pathogenic variant), each sib of an affected individual has at conception a 25% chance of having fumarate hydratase deficiency and a 25% chance of having no pathogenic variant in FH. Each sib also has a 50% chance of being a heterozygote. Heterozygotes have a higher than average risk of developing cutaneous leiomyomas and in females, uterine leiomyomas or fibroids; however, the absolute risk is unknown. Carrier testing for at-risk family members is possible once the FH pathogenic variants have been identified in the family. Prenatal diagnosis for pregnancies at increased risk for fumarate hydratase deficiency is possible by measurement of fumarate hydratase enzyme activity or, if both pathogenic variants in the family are known, by molecular genetic testing.

Diagnosis

Clinical Diagnosis

Fumarate hydratase deficiency is characterized by the following:

  • Neonatal and early-infantile severe encephalopathy, which may include poor feeding, hypotonia, and decreased levels of consciousness (lethargy, stupor and coma)
  • Seizures, which are present in many but not all affected individuals
  • Dysmorphic facial features including frontal bossing, depressed nasal bridge, and widely spaced eyes
  • Abnormalities on brain magnetic resonance imaging, including enlarged ventricles and polymicrogyria

Mildly affected individuals may present with delayed development leading to a diagnosis of mild-moderate intellectual disability during school age. Mildly affected individuals are less likely to have epilepsy and evidence of structural brain malformations on brain magnetic resonance imaging.

Note: Fumarate hydratase deficiency should be considered early in the diagnostic process in human populations known to be "at risk" as a result of increased prevalence of fumarate hydratase mutation.

Testing

Urine organic acid analysis. Isolated increased concentration of fumaric acid on urine organic acid analysis is highly suggestive of fumarate hydratase deficiency.

Measurement of fumarate hydratase enzyme activity. Fumarate hydratase enzyme activity can be measured in fibroblasts, lymphoblasts, and white blood cells:

  • Fumarate hydratase enzyme activity in severely affected individuals is generally less than 10% of the control mean; however, residual fumarate hydratase enzyme activity in some individuals can be 11%-35% of the control mean. There is evidence to suggest that more severe clinical symptoms correlate with lower levels of enzyme activity [Ottolenghi et al 2011], although this relationship has not been clear and consistent in all studies. Fumarate hydratase deficiency is evident in both isozymes – the mitochondrial form and the cytosolic form.
  • Fumarate hydratase activity observed in obligate heterozygotes is 22%-60% of the control mean.

Molecular Genetic Testing

Gene. FH, encoding the enzyme fumarate hydratase, is the only gene in which mutation is known to cause fumarate hydratase deficiency.

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Fumarate Hydratase Deficiency

Gene 1Test MethodAllelic Variants Detected 2Variant Detection Frequency by Test Method 3
FHSequence analysis 4Sequence variants, including the most frequent mutated allele c.1431_1433dupAAA 5>90%
Deletion/duplication testing 6Exon and whole-gene deletionsUnknown 7
1.
2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a variant that is present in the indicated gene

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

To date all affected individuals with this allele (identified in ~30% of individuals) are compound heterozygotes with a different pathogenic variant on the other allele.

6.

Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7.

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

Urine organic acid analysis to confirm isolated increased fumaric acid excretion

2.

Measurement of fumarate hydratase enzyme activity to confirm the diagnosis of fumarate hydratase deficiency

3.

Sequence analysis of FH to confirm the diagnosis of fumarate hydratase deficiency if fumarate hydratase enzyme activity is not diagnostic; can be followed by duplication/deletion analysis if appropriate

Clinical Characteristics

Clinical Description

Fumarate hydratase deficiency was recently reviewed by Allegri et al [2010], summarizing the prevalence of various clinical and molecular features based on a comprehensive review of prior reports.

Fetal manifestations. Few clinical reports comment on complications of affected pregnancies. However, polyhydramnios, oligohydramnios, intrauterine growth retardation, and premature birth (typically 33-36 weeks) are reported in approximately one-third of affected pregnancies [Coughlin et al 1998, Maradin et al 2006, Allegri et al 2010, Saini & Singhi 2013]. Enlarged cerebral ventricles and other brain abnormalities have been identified by fetal ultrasound [Coughlin et al 1998].

Neonatal and early infantile encephalopathy. Newborns with fumarate hydratase deficiency may be symptomatic immediately following delivery or may appear normal at birth, and be discharged home from the nursery without recognized problems [Phillips et al 2006]. If symptoms are not apparent at birth, affected infants show severe neurologic abnormalities within age one week to one month, including poor feeding, failure to thrive, and hypotonia. These newborns and infants manifest encephalopathy, with poor eye contact and variable degrees of depressed consciousness including lethargy, stupor, and even coma. Head and neck control may be entirely absent. Infants gain weight slowly and may require tube feedings.

Epileptic seizures are common (40%-80%), although age of onset and seizure type are variable [Kerrigan et al 2000, Allegri et al 2010]. Infantile spasms (epileptic spasms) accompanied by hypsarrhythmia on EEG have been reported [Remes et al 2004, Loeffen et al 2005]. Seizures are often treatment resistant.

Dysmorphology. Abnormal facial features with a spectrum of specific findings have been widely reported and should be regarded as a hallmark feature of this condition (although perhaps not universal). Common features (>50% of affected individuals) include depressed nasal bridge, frontal bossing, and widely spaced eyes [Allegri et al 2010]. Less frequent features (<50%) include cleft ala nasi or anteverted nares, ear anomalies, or narrow forehead [Allegri et al 2010].

Head size. Head size has been reported as abnormally small (microcephalic) in 36% of all affected individuals [Allegri et al 2010]. However, in one large kindred (8 affected individuals in 1 consanguineous family), 88% (7 of 8 affected individuals) were reported to have "relative macrocephaly," since head sizes were within the normal range, but in association with brain imaging findings of cerebral atrophy and mild communicating hydrocephalus (enlarged extra-axial CSF spaces) [Kerrigan et al 2000]. That is, it appears that most children with fumarate hydratase deficiency have abnormally limited brain growth.

Acute metabolic derangements. Acute metabolic crises with findings such as hypoglycemia, ketosis, hyperammonemia, or acidosis are rarely observed in fumarate hydratase deficiency. One such patient is reported in detail by Allegri et al [2010], with repeated episodes of hypoglycemia during the first two weeks of life, associated with metabolic acidosis, elevated lactic acidemia, and mild hyperammonemia.

Brain imaging findings. As with abnormal facial features, abnormalities of brain development are to be expected with fumarate hydratase deficiency, but significant person-to-person (or kindred-to-kindred) differences are described. Completely normal brain magnetic resonance imaging (MRI) may occur, but should make one question the diagnosis.

The most common finding is a small brain, representative of cerebral under-development. This may be described by the neuroradiologist as cerebral atrophy (73% of all cases summarized by Allegri et al [2010]), or ventriculomegaly (82% of all cases summarized by Allegri et al [2010]). Brain volume loss (or more likely lack of brain volume development) can be accompanied by a relative decrease in CSF reabsorption, leading to a normal head size with a small brain but modestly expanded CSF compartments. In the series of Kerrigan et al [2000], two such individuals were shunted for possible "hydrocephalus" leading to collapse of the CSF compartments and secondary microcephaly without clinical improvement.

Additional findings on MRI can include nonspecific white matter abnormalities, described as either delayed myelination or hypomyelination [Phillips et al 2006], deficient closure of the Sylvian opercula [Kerrigan et al 2000, Phillips et al 2006], and a small brain stem [Kerrigan et al 2000, Phillips et al 2006]. Abnormalities of the corpus callosum are also reported, including thinning [Maradin et al 2006, Phillips et al 2006] and absence [Coughlin et al 1998]. Diffuse bilateral polymicrogyria of the cerebral cortex has also been reported, a universal feature in the eight affected individuals from one kindred reported by Kerrigan et al [2000] but also noted in three additional unrelated individuals [Zeng et al 2006, Ottolenghi et al 2011].

Other clinical features. Other findings can include neonatal polycythemia [Kerrigan et al 2000], recurrent vomiting with hepatosplenomegaly [Allegri et al 2010], and pancreatitis [Phillips et al 2006].

Visual disturbances and optic nerve hypoplasia were described in one family [Kerrigan et al 2000]. Despite the congenital anomalies of the brain that occur with fumarate hydratase deficiency (see Clinical Description, Brain imaging findings), birth defects involving other organ systems are uncommon.

Clinical course. The clinical outcome for individuals with fumarate hydratase deficiency is not favorable. Many such individuals do not survive infancy, or may die of secondary complications (e.g., respiratory failure) during the first decade of life [Loeffen et al 2005]. Many children are unable to feed successfully, with failure to gain weight and increased risk for aspiration. Accordingly, feedings administered through gastrostomies may be required.

Over time, severely affected children (usually nonverbal and nonambulatory) develop evidence of spasticity, and consequently are at risk for contractures and orthopedic deformities, including scoliosis. Extrapyramidal motor features, including athetosis and dystonic posturing, can also be observed. Epileptic seizures often become more frequent and less responsive to treatment efforts. Seizures may occur daily in some individuals.

However, less severely affected children, who may be ambulatory and capable of engaging in special needs school programs (despite the presence of bilateral polymicrogyria), are also recognized [Ottolenghi et al 2011]. Consequently, counseling families with children with fumarate hydratase deficiency should include recognition of the range of severity.

Heterozygotes. Most heterozygous parents are normal. However, the finding of cutaneous leiomyomata without uterine fibroids in the mother of an affected child [Tomlinson et al 2002], a report of a mother with uterine myomas [Maradin et al 2006], and the death of the mother of an affected child from "renal cell carcinoma" in a third family [Shih, unpublished] raise the possibility of increased risk for MCUL/HLRCC in the heterozygous relatives of children with fumarate hydratase deficiency (see Hereditary Leiomyomatosis with Renal Cell Cancer).

Prevalence

Fumarate hydratase deficiency is rare. Fewer than 100 cases have been reported.

The disorder occurs in individuals of different ethnic backgrounds.

Differential Diagnosis

Increased excretion of fumaric acid in urine. Transient excretion of fumaric acid in urine is common in young infants and has been observed in metabolically stressed infants, such as those with cardiac failure resulting from severe congenital cardiac anomalies. When the infant with cardiac failure is in stable condition, urine organic acid analysis should be repeated to confirm the presence of increased isolated fumaric acid excretion.

Increased excretion of fumaric acid along with other citric acid intermediates is seen in mitochondrial disorders, including subacute necrotizing encephalomyelopathy (Leigh syndrome) and deficiencies of the pyruvate dehydrogenase complex [Nyhan et al 2005]. See Mitochondrial Disorders Overview.

Polymicrogyria. See Polymicrogyria Overview.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with fumarate hydratase deficiency, the following evaluations are recommended:

  • Evaluation by a pediatric neurologist. This evaluation will likely include a brain MRI study.
  • Feeding assessment and evaluation of nutritional status
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Seizures in individuals with fumarate hydratase deficiency are often difficult to control. Individuals with seizures need to be evaluated and treated by a qualified specialist (usually a pediatric neurologist) in order to improve clinical outcome. Recommendation of particular medications or interventions is beyond the scope of this review. However, it should be noted that the ketogenic diet is usually considered to be contraindicated for treating epilepsy associated with fumarate hydratase deficiency or other enzymatic defects within the Krebs tricarboxylic acid cycle.

Nutritional intervention (e.g., feeding gastrostomy) may be appropriate in hypotonic and/or lethargic children with feeding difficulties and/or aspiration.

Physical therapy and orthopedic management is appropriate to minimize contractures and prevent scoliosis. Wheelchairs can be useful for some individuals.

In individuals with significant developmental deficits (including impairment of motor, language, and social development) special needs services are a required component of care.

Prevention of Primary Manifestations

There are no recognized therapies to ameliorate or reverse the metabolic abnormalities resulting from decreased activity of fumarate hydratase. A brief therapeutic trial of a low-protein diet in one mildly affected individual with fumarate hydratase deficiency did not alter urinary excretion of fumaric acid or improve clinical signs [Kimonis et al 2012].

Surveillance

Specific recommendations should be provided after evaluating the individual needs of each affected person. However, the authors would recommend at least annual visits with pediatric neurology (most importantly, to monitor for and/or treat epilepsy) and physical medicine (most importantly, to monitor for equipment needs and to monitor for and/or treat manifestations of spasticity). As part of a special needs program, periodic visits with genetics, ophthalmology, and orthopedic surgery will also be required.

Agents/Circumstances to Avoid

The ketogenic diet is usually considered to be contraindicated for treating epilepsy associated with fumarate hydratase deficiency or other enzymatic defects within the Krebs tricarboxylic acid cycle.

Evaluation of Relatives at Risk

If the fumarate hydratase-causing variants in the family are known, it is appropriate to consider offering molecular genetic testing to relatives who may be at risk of developing multiple cutaneous and uterine leiomyomas (MCUL) or papillary renal cell carcinoma with leiomyomatosis (HLRCC).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes

Therapies Under Investigation

Increasingly sophisticated models of mitochondrial function are being used to study the metabolic derangements associated with identified defects of intermediary metabolism, including fumarate hydratase deficiency [Smith & Robinson 2011]. These models may suggest treatment interventions with supplements or dietary changes that are not presently established.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Other

No significant clinical or biochemical improvement was noted by treatment with a protein-restricted diet [Shih et al 1991; Campeau et al, personal communication, 2008].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Fumarate hydratase deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband. The parents of an affected child are generally unaffected obligate heterozygotes and therefore carry one mutated allele. Two exceptions have been reported:

The heterozygous parents of a proband may have or be at risk of developing multiple cutaneous and uterine leiomyomas (MCUL). They are at a relatively low risk (2%-6%) of developing hereditary leiomyomatosis with renal cell cancer (HLRCC).

Sibs of a proband

  • When both parents are known to be heterozygotes (i.e., carriers of an FH pathogenic variant):
    • Each sib of an affected individual has at conception a 25% chance of having fumarate hydratase deficiency and a 25% chance of having no pathogenic variant in FH. Each sib also has a 50% chance of being a carrier.
    • Carriers have a relatively high risk of developing cutaneous leiomyomas and in females, additional uterine leiomyomas or fibroids. Carriers have a low risk (2%-6%) of developing hereditary leiomyomatosis with renal cell cancer (HLRCC).
  • When fumarate hydratase deficiency occurs as the result of an unusual mechanism (e.g., new pathogenic variant in one allele, uniparental isodisomy), the risk to the sibs of a proband is based on the recurrence risk associated with that mechanism.

Offspring of a proband. Many individuals with fumarate hydratase deficiency do not survive childhood. No affected individuals with offspring have been reported.

Other family members of a proband. Sibs of the proband's parents are at 50% risk of having a pathogenic variant in FH. Such carriers are at a relatively high risk of developing MCUL but a low risk (2%-6%) of developing HLRCC.

Carrier (Heterozygote) Detection

Biochemical testing. Enzyme assay may not be informative for heterozygote detection because the carrier range and the normal range overlap.

Molecular genetic testing. Carrier testing for at-risk family members is possible if the FH pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the FH pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possibble.

Biochemical testing

  • Fumaric acid detection. Prenatal diagnosis for pregnancies at increased risk for fumarate hydratase deficiency is possible by detection of increased fumaric acid in amniotic fluid at approximately 15 to 18 weeks' gestation [Manning et al 2000]. However, such studies are not diagnostic, and should be reviewed with extreme caution.
  • Fumarate hydratase enzyme activity. Prenatal diagnosis for pregnancies at increased risk for fumarate hydratase deficiency is possible by measurement of fumarate hydratase enzyme activity in uncultured and cultured chorionic villi.
    Although analysis of fumarate hydratase enzyme activity can be performed using cultured fetal cells obtained by amniocentesis [Manning et al 2000] or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation [Coughlin et al 1998], some affected fetuses have considerable residual fumarate hydratase enzyme activity, making prenatal diagnosis using enzyme testing problematic.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. Enlarged cerebral ventricles and certain fetal brain abnormalities (agenesis of the corpus callosum and Dandy-Walker cyst) associated with fumarate hydratase deficiency can be identified by ultrasound examination [Coughlin et al 1998].

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Fumarate Hydratase Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
FH1q43Fumarate hydratase, mitochondrialTCA Cycle Gene Mutation Database (FH)FHFH

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Fumarate Hydratase Deficiency (View All in OMIM)

136850FUMARATE HYDRATASE; FH
606812FUMARASE DEFICIENCY; FMRD

Gene structure. FH consists of ten exons encompassing 22.15 kb of DNA. The cDNA for human FH covers the complete coding region of the mature gene (NM_000143.2).

Pathogenic variants. See Table 2. Pathogenic variants have been identified in the entire coding region of FH. They include missense variants, insertions, and deletions [Tomlinson et al 2002, Toro et al 2003]; most are missense variants. Some intragenic deletions and duplications have been reported and c.1431_1433dupAAA has been found in multiple families with fumarate hydratase deficiency. A total of 19 different pathogenic variants have been reported in families with fumarate hydratase deficiency. Affected individuals have two mutated alleles and the majority are compound heterozygotes [Coughlin et al 1998; Kimonis et al 2000; Zeman et al 2000; Alam et al 2003; Remes et al 2004; Loeffen et al 2005; Deschauer et al 2006; Maradin et al 2006; Phillips et al 2006; Zeng et al 2006; C Gellera et al, personal communication]. An online database of pathogenic variants in both fumarate hydratase deficiency and HLRCC has been published [Bayley et al 2008] (see Table A, Locus Specific).

A whole-gene deletion in an individual with FH deficiency was reported by Mroch et al [2012] and large FH deletions were been reported in MCUL/HLRCC [Tomlinson et al 2002] (see Genetically Related Disorders).

Table 2.

FH Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1127A>Cp.Gln376ProNM_000143​.2
NP_000134​.2
c.1431_1433dupAAA 1p.Lys477dup 1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

The numbering system for the FH sequence has changed over the years; hence, the commonly seen AAA duplication in fumarate hydratase deficiency is referred to variously in the literature as 1302insAAA, 435insAAA, 435insK, 1433insAAA, and insK477.

Normal gene product. FH encodes an enzyme, fumarase or fumarate hydratase (EC 4.2.1.2.). The active form of the enzyme is a tetramer. It catalyzes the conversion of fumarate to L-malate in the Krebs tricarboxylic acid cycle. The identity between the rat and human amino acid sequences is 96%. In mammals, the two isozymes of fumarate hydratase, mitochondrial and cytosolic, are encoded by a single gene and translated from one species of mRNA. The cytoplasmic isozyme is produced using an alternative initiation codon that is 43 codons after the initiation codon used for the mitochondrial isoform.

Abnormal gene product. In the majority of the cases reported, the mutated enzyme has some degree of residual activity. Molecular modeling demonstrated that the p.Gln376Pro pathogenic variant disrupts the structure of the active site of fumarate hydratase, providing a possible explanation for the loss of activity in the mutated fumarate hydratase enzyme [Remes et al 2004].

References

Literature Cited

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Chapter Notes

Author History

Kirk Aleck, MD (2013-present)
Clifton Ewbank, MD (2013-present)
John F Kerrigan, MD (2013-present)
Roseann Mandell, BA; Massachusetts General Hospital (2006-2013)
Vivian E Shih, MD; Massachusetts General Hospital (2006-2013)

Revision History

  • 4 April 2013 (me) Comprehensive update posted live
  • 2 June 2009 (me) Comprehensive update posted live
  • 10 August 2006 (cd) Revision: Prenatal diagnosis clinically available by enzyme assay and molecular testing
  • 5 July 2006 (me) Review posted live
  • 2 February 2005 (ves) Original submission
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