Fumarate Hydratase Deficiency

[Fumaric Aciduria, Fumarase Deficiency]

Clinical Diagnosis

Fumarate hydratase deficiency is suspected in infants with multiple severe neurologic abnormalities in the absence of an acute metabolic crisis. Individuals surviving beyond infancy have severe psychomotor delay.

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. Fumarate hydratase deficiency is evident in both isoenzymes, the mitochondrial form and the cytosolic form.

• Fumarate hydratase activity observed in obligate heterozygotes is 22%-60% of the control mean.

For laboratories offering biochemical testing, see .

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene. FH, encoding the enzyme fumarate hydratase, is the only gene known to be associated with fumarate hydratase deficiency.

Clinical testing

• Targeted mutation analysis. The 3-bp AAA duplication (c.1431_1433dupAAA) coding for a lysine has been detected in approximately one-third of families studied and is the most frequent abnormal allele. All affected individuals with this allele are compound heterozygotes with a different mutation on the other allele.

• Sequence analysis. 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; Phillips et al 2006; Maradin et al 2006; Zeng et al 2006; C Gellera et al, personal communication]. Sequence analysis identifies both mutations in more than 90% of individuals.

• Deletion/duplication testing. The mutation detection frequency for deletion/duplication testing is unknown. To date no exonic or whole-gene deletions in FH have been reported to be associated with fumarate hydratase deficiency.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Fumarate Hydratase Deficiency

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
FH	Targeted mutation analysis	c.1431_1433dupAAA	30% 1	Clinical
	Sequence analysis	Sequence variations	>90%
	Deletion/duplication testing 2	Exonic and whole-gene deletions	Unknown

1. To date all affected individuals with this allele are compound heterozygotes with a different mutation on the other allele.

2. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and array GH may be used.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To 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

  Molecular genetic testing to confirm the diagnosis of fumarate hydratase deficiency if fumarate hydratase enzyme activity is not diagnostic

Carrier 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) Disorders

Multiple cutaneous and uterine leiomyomas (MCUL) and hereditary leiomyomatosis with renal cell cancer (HLRCC) are caused by heterozygous mutations in FH [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 History

Some pregnancies of fetuses with fumarate hydratase deficiency are complicated by polyhydramnios [Coughlin et al 1998]. Intrauterine growth retardation has been described [Maradin et al 2006]. Enlarged cerebral ventricles and brain abnormalities identified by fetal ultrasound examination have been reported [Coughlin et al 1998].

Most neonates with fumarate hydratase deficiency show severe neurologic abnormalities, including poor feeding, failure to thrive, and hypotonia. Early-onset infantile encephalopathy, seizures, and severe developmental delay with microcephaly are also common. Other findings can include infantile spasms, truncal hypotonia with hypertonic and dystonic posturing of the limbs, athetoid movements, and autistic features [Coughlin et al 1998, Kimonis et al 2000, Remes et al 2004, Loeffen et al 2005]. EEG abnormalities including hypsarrhythmia have been reported [Remes et al 2004, Loeffen et al 2005].

Distinctive facial features have been reported in some but not all affected individuals [Coughlin et al 1998, Kimonis et al 2000, Maradin et al 2006]. One individual had frontal bossing, low-set ears, and a small jaw [Zeman et al 2000]. All eight affected persons in one family had macrocephaly and dysmorphic facial features with frontal bossing, ocular hypertelorism, and a depressed nasal bridge; some had notched or anteverted nares and high-arched palate [Kerrigan et al 2000].

Other findings can include neonatal polycythemia, leukopenia and neutropenia, mild hepatosplenomegaly, and pancreatitis [Kerrigan et al 2000, Zeman et al 2000, Phillips et al 2006].

Visual disturbances and optic nerve abnormalities were described in one family [Kerrigan et al 2000]. Abnormalities in succinylpurines were observed in the CSF of one person [Zeman et al 2000]; increased CSF lactate and pyruvate concentrations were reported in two sibs.

Of note, acute metabolic crises with findings such as ketosis, hyperammonemia, or acidosis are rarely observed in fumarate hydratase deficiency. One neonate presented shortly after birth with acidosis, hyperammonemia, and lactic academia, which resolved following treatment [Campeau et al 2008, personal communication]. Many children with fumarate hydratase deficiency do not survive infancy or childhood. Those surviving beyond childhood have severe psychomotor retardation.

Neuroimaging may reveal nonspecific mild hypomyelination, progressive cerebral atrophy, ventricular dilatation, periventricular cysts [Coughlin et al 1998, Kerrigan et al 2000, Loeffen et al 2005]; Dandy-Walker malformation and agenesis of the corpus callosum [Coughlin et al 1998]; deficient closure of the sylvian opercula, large lateral ventricles, and diffuse, bilateral polymicrogyria [Kerrigan et al 2000]. Some individuals have normal MRI imaging of the brain.

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.

Evaluations Following Initial Diagnosis

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

• Neurologic evaluation

• Feeding assessment and evaluation of nutritional status

Treatment of Manifestations

Nutritional intervention (e.g., feeding gastrostomy) may be appropriate in hypotonic children with feeding difficulties.

Physical therapy and wheelchairs can be useful for some individuals.

Testing of Relatives at Risk

If 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 purposes

Therapies Under Investigation

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.

Other

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

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 mutant allele. Two exceptions have been reported:

• A father whose paternity was confirmed by haplotyping had normal fumarate hydratase enzyme activity and no evidence of either of his child's FH mutations [Coughlin et al 1998]. The proband most likely had fumarate hydratase deficiency as the result of a new mutation in the paternal allele, although germline mosaicism was not ruled out.

• In another family, fumarate hydratase deficiency resulted from partial uniparental isodisomy of chromosome 1 [Zeng et al 2006].Thus, only one of the parents carried an FH mutation.

• The heterozygous parents of a proband may have or be at risk of developing multiple cutaneous and uterine leiomyomas (MCUL). They have 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 mutation), each sib of an affected individual has at conception a 25% chance of having fumarate hydratase deficiency and a 25% chance of having no mutation in the FH gene. 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 mutation in one allele, uniparental isodisomy), the risk to the sibs of a proband are 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 mutation in the FH gene. Such carriers have a relatively high risk of developing MCUL but a low risk (2%-6%) of developing HLRCC.

Carrier 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 mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and clarification of carrier status 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 at risk of being carriers.

DNA banking. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles must be identified before prenatal testing can be performed.

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

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]. No laboratories offering measurement of amniotic fluid fumarate for prenatal diagnosis of fumarate hydratase deficiency are listed in the GeneTests Laboratory Directory. However, such prenatal testing may be available in a clinical laboratory.

• 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.

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].

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Revision History

• 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 to live Web site

• 2 February 2005 (ves) Original submission