Fumarate hydratase deficiency is characterized by progressive neurologic abnormalities that first manifest prenatally as polyhydramnios and brain malformations (periventricular cysts, Dandy-Walker malformation, agenesis of the corpus callosum, deficient closure of the sylvian opercula, diffuse bilateral polymicrogyria, and enlarged cerebral ventricles). Neonates demonstrate severe neurologic abnormalities, poor feeding, failure to thrive, and hypotonia. Infants can have seizures, infantile spasms, severe developmental delay, and microcephaly along with limb dystonia, athetosis, and autistic features. Neonatal polycythemia, leukopenia, neutropenia, and mild hepatosplenomegaly can be seen. Neuroimaging may reveal mild hypomyelination, progressive cerebral atrophy, and ventricular dilatation. Many children with fumarate hydratase deficiency do not survive infancy or childhood; those surviving beyond childhood have severe psychomotor retardation.
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 known to be associated with 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.
Fumarate hydratase deficiency is inherited in an autosomal recessive manner. 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 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 mutations have been identified in the family. Prenatal diagnosis for pregnancies at increased risk for fumarate hydratase deficiency is possible either by measurement of fumarate hydratase enzyme activity or by molecular genetic testing if both disease-causing mutations in the family are known.