Fumarase Hydratase Deficiency

Fumarase hydratase deficiency is an inherited disorder that primarily affects the nervous system, especially the brain. It is caused by a lack of the enzyme fumarase, or fumarate hydratase. Newborns with fumarase deficiency show severe neurologic abnormalities, including poor feeding, failure to grow or gain weight at a normal rate, poor muscle tone, lethargy, and seizures. Small head size is often seen in affected individuals, along with brain structure abnormalities. Enlarged liver and spleen, pancreatitis, excess red blood cells and/or deficiency of white blood cells have also been reported. Severely affected individuals are non-verbal and non-ambulatory while less severely affected individuals may have only moderate intellectual disability. Many severely affected children die during early childhood. Some less severely affected individuals have lived into adulthood. No effective treatment is currently available. This condition is caused by pathogenic variants in the fumarate hydratase (FH) gene.

Fumarase deficiency is inherited in an autosomal recessive manner. This type of inheritance requires the presence of two copies of a pathogenic variant in the gene for a person to have the genetic disease. Both parents must be carriers of a pathogenic variant in the gene in order to be at risk to have an affected child. The child must inherit a pathogenic variant from each carrier parent in order to be affected. There is a 1 in 4 chance that a baby will inherit two mutated copies of the gene and be affected when both parents are carriers.

There are generally no signs or symptoms associated with being a carrier for fumarase deficiency, however they do have a higher than average risk for developing cutaneous leiomyomas, and in females, uterine leiomyomas or fibroids. The risk to have a child affected with fumarase deficiency is also increased. Testing of reproductive partners is recommended for carriers of fumarase deficiency.

Fumarase deficiency is a very rare disorder. Approximately 100 affected individuals have been reported worldwide. Several were born in an isolated religious community in the Southwestern area of the United States.

Genetics Home Reference: Fumarase deficiency (http://ghr.nlm.nih.gov/)

OMIM [Fumarase deficiency: 606812] (http://www.ncbi.nlm.nih.gov/omim)
Gene Reviews: Fumarase deficiency (http://www.ncbi.nlm.nih.gov/books/NBK1116/)

• Full gene sequencing