DiagnosisClinical DiagnosisFumarate 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 individualsDysmorphic facial features including frontal bossing, depressed nasal bridge, and widely spaced eyesAbnormalities on brain magnetic resonance imaging, including enlarged ventricles and polymicrogyriaMildly 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 mutations.TestingUrine 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 TestingGene. FH, encoding the enzyme fumarate hydratase, is the only gene in which mutations are known to cause fumarate hydratase deficiency.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Fumarate Hydratase DeficiencyView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityFHSequence analysisSequence variants 2, including the most frequent mutant allele c.1431_1433dupAAA 3 >90%Clinical Deletion / duplication testing 4Exonic and whole-gene deletions Unknown 51. The ability of the test method used to detect a mutation that is present in the indicated gene 2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. To date all affected individuals with this allele (identified in ~30% of individuals) are compound heterozygotes with a different mutation on the other allele.4. Testing that identifies 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.5. Tomlinson et al [2002], Mroch et al [2012]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband 1.Urine organic acid analysis to confirm isolated increased fumaric acid excretion2.Measurement of fumarate hydratase enzyme activity to confirm the diagnosis of fumarate hydratase deficiency3.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 appropriateCarrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersHomozygous loss-of-function mutations of the fumarate hydratase gene result in fumarate hydratase deficiency syndrome (fumarase deficiency, fumaric aciduria), as described in this GeneReview.However, fumarate hydratase also functions as a tumor suppressor, which is unanticipated and rare for an enzyme involved in intermediary metabolism [Bayley et al 2008]. Haploinsufficiency of fumarate hydratase caused by a heterozygous loss-of-function mutation predisposes to multiple cutaneous and uterine leiomyomas (MCUL) and hereditary leiomyomatosis with renal cell cancer (HLRCC) [Tomlinson et al 2002, Alam et al 2003, Toro et al 2003, Alam et al 2005, Badeloe et al 2006, Wei et al 2006, Ylisaukko-oja et al 2006]. MCUL is characterized by:Multiple cutaneous leiomyomas;Early-onset uterine leiomyomas (fibroids).HLRCC has the additional feature of renal tumors:Renal tumors can be 'type 2' papillary renal cancer, collecting duct renal cell carcinoma, and clear cell renal carcinoma.}

Natural HistoryFumarate 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 2012]. 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 academia, 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 Natural History, 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 non-verbal and non-ambulatory) 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).

Differential DiagnosisIncreased 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.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 statusMedical genetics consultationTreatment of ManifestationsSeizures 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 Kreb’s 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 ManifestationsThere 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]. SurveillanceSpecific 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 AvoidThe ketogenic diet is usually considered to be contraindicated for treating epilepsy associated with fumarate hydratase deficiency or other enzymatic defects within the Kreb’s tricarboxylic acid cycle. Evaluation of Relatives at RiskIf the fumarate hydratase-causing mutations are known in the family, 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 purposesTherapies Under InvestigationIncreasingly 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 for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherNo significant clinical or biochemical improvement was noted by treatment with a protein-restricted diet [Shih et al 1991; Campeau et al, personal communication (2008)].

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFH1q43Fumarate hydratase, mitochondrialTCA Cycle Gene Mutation Database (FH)FHData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Fumarate Hydratase Deficiency (View All in OMIM) View in own window 136850FUMARATE HYDRATASE; FH 606812FUMARASE DEFICIENCYNormal allelic variants. 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). Pathologic allelic variants. See Table 2. Mutations have been identified in the entire coding region of FH. Pathologic variants include missense mutations, insertions, and deletions [Tomlinson et al 2002, Toro et al 2003]; most are missense mutations. 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 mutations have been reported in families with fumarate hydratase deficiency. Affected individuals have two mutant 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 mutations 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 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencesc.1127A>Cp.Gln376ProNM_000143​.2
NP_000134​.2c.1431_1433dupAAA ^{1p.Lys477dup 1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).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 mutation disrupts the structure of the active site of fumarate hydratase, providing a possible explanation for the loss of activity in the mutant fumarate hydratase enzyme [Remes et al 2004].}