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Fumarate Hydratase Deficiency.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
2006 Jul 5 [updated 2013 Apr 4].

Excerpt

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 Kreb’s 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 mutation 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.

Copyright © 1993-2015, University of Washington, Seattle. All rights reserved.

PMID:
20301679
[PubMed]
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