Clinical characteristics: Fumarate hydratase (FH) 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 nonverbal and nonambulatory, 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 fumaric acid and alpha-ketoglutarate on urine organic acid analysis, combined with increased succinyladenosine on urine purines and pyrimidines is highly suggestive of FH deficiency. The diagnosis of FH deficiency is established in a proband with reduced fumarate hydratase enzyme activity in fibroblasts or leukocytes and/or biallelic pathogenic variants in FH identified by molecular genetic testing.
Management: Treatment of manifestations: Evaluation and management by a pediatric neurologist to treat seizures; gastrostomy tube to optimize nutrition and prevent aspiration in hypotonic or lethargic children; feeding therapy as needed; special needs services to address developmental deficits; physical therapy to minimize contractures; wheelchair and/or other mobility devices; management of scoliosis by orthopedist.
Prevention of primary manifestations: To date, there is limited information regarding use of a high-fat/low-carbohydrate diet with 60% of the dietary energy goals coming from fat, 30% from carbohydrate, and 10% from protein.
Surveillance: At least annual evaluations by pediatric neurology and physical medicine; periodic evaluation by orthopedist to monitor contractures and scoliosis; assessment of visual acuity by ophthalmologist.
Agents/circumstances to avoid: The ketogenic diet is usually considered to be contraindicated for treating epilepsy associated with FH deficiency or other enzymatic defects within the Krebs tricarboxylic acid cycle.
Evaluation of relatives at risk: If the FH pathogenic variants in the family are known, it is appropriate to consider offering molecular genetic testing to relatives who may be at risk for hereditary leiomyomatosis and renal cell cancer.
Genetic counseling: FH deficiency is inherited in an autosomal recessive manner. When both parents are known to be heterozygous for an FH pathogenic variant, each sib of an affected individual has at conception a 25% chance of having FH deficiency, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial FH pathogenic variants. Heterozygotes are at risk of developing hereditary leiomyomatosis and renal cell cancer. Once the FH pathogenic variants have been identified in an affected family member, heterozygote detection for at-risk relatives and molecular genetic prenatal testing and preimplantation genetic testing are possible. Biochemical prenatal testing by measurement of fumarate hydratase enzyme activity is also possible but may be problematic as some affected fetuses have considerable residual fumarate hydratase enzyme activity.
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