National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Fumarase deficiency


Other Names:
Fumaric aciduria; Fumarate hydratase deficiency
Categories:
Fumarase deficiency is an inherited condition that affects the brain and other parts of the nervous system. Signs and symptoms may include a small head (microcephaly), severe developmental delay, poor feeding, weak muscle tone (hypotonia), failure to thrive, seizures, and distinctive facial features.[1][2] Most people with this deficiency are not able to speak or walk.[2][3] A variety of brain abnormalities may be detected on MRI.[3] Fumarase deficiency is caused by mutations in the FH gene and inheritance is autosomal recessive.[1][2][3] Unfortunately, there is no effective treatment at this time.[3] Management aims to improve symptoms and increase quality of life. Many children with fumarase deficiency do not survive past early childhood, but some are less severely affected, have mild cognitive impairment, and survive beyond this time.[2][3]
Last updated: 2/15/2018
Most newborns with fumarase deficiency have severe neurologic abnormalities including poor feeding, failure to thrive, and poor muscle tone (hypotonia). Early-onset infantile encephalopathy (abnormal brain structure or function), seizures, microcephaly, and severe developmental delay are also common. Most children with fumarase deficiency do not learn to walk and talk. Some also have polycythemia (an excess of red blood cells), recurrent vomiting, or pancreatitis. Distinctive facial features that may be present include a prominent forehead (frontal bossing), depressed nasal bridge, and widely-spaced eyes.[3]

A variety of brain abnormalities may be identified on brain MRI. These may include cerebral atrophy (loss of neurons and their connections to each other), enlarged ventricles (cavities where cerebrospinal fluid is produced), thinning or absence (agenesis) of the corpus callosum, and an abnormally small brain stem (the part of the brain that connects to the spinal cord).[3]
Last updated: 2/19/2018

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing of 33 |
Medical Terms Other Names
Learn More:
HPO ID
Percent of people who have these symptoms is not available through HPO
Agenesis of corpus callosum 0001274
Aminoaciduria
High urine amino acid levels
Increased levels of animo acids in urine
[ more ] 		0003355
Anteverted nares
Nasal tip, upturned
Upturned nasal tip
Upturned nose
Upturned nostrils
[ more ] 		0000463
Autosomal recessive inheritance 0000007
Cerebral atrophy
Degeneration of cerebrum
0002059
Cholestasis
Slowed or blocked flow of bile from liver
0001396
Choroid plexus cyst 0002190
Cutaneous leiomyoma 0007620
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root
[ more ] 		0005280
Failure to thrive
Faltering weight
Weight faltering
[ more ] 		0001508
Frontal bossing 0002007
Generalized hypotonia
Decreased muscle tone
Low muscle tone
[ more ] 		0001290
Global developmental delay 0001263
Hepatic failure
Liver failure
0001399
High palate
Elevated palate
Increased palatal height
[ more ] 		0000218
Hyperbilirubinemia
High blood bilirubin levels
0002904
Hypertelorism
Wide-set eyes
Widely spaced eyes
[ more ] 		0000316
Hypoplasia of the brainstem
Small brainstem
Underdeveloped brainstem
[ more ] 		0002365
Intellectual disability, profound
IQ less than 20
0002187
Lactic acidosis
Increased lactate in body
0003128
Metabolic acidosis 0001942
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference
[ more ] 		0000252
Muscular hypotonia
Low or weak muscle tone
0001252
Neurological speech impairment
Speech disorder
Speech impairment
Speech impediment
[ more ] 		0002167
Open operculum 0100954
Optic atrophy 0000648
Pallor 0000980
Polycythemia
Increased red blood cells
0001901
Polymicrogyria
More grooves in brain
0002126
Reduced subcutaneous adipose tissue
Reduced fat tissue below the skin
0003758
Relative macrocephaly
Relatively large head
0004482
Status epilepticus
Repeated seizures without recovery between them
0002133
Visual impairment
Impaired vision
Loss of eyesight
Poor vision
[ more ] 		0000505
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Last updated: 7/1/2020
Fumarase deficiency is caused by mutations in the FH gene.[1][3] This gene gives the body instructions for making an enzyme called fumarase, which helps cells use oxygen and make energy. Mutations in the gene interfere with the enzyme's function. Making energy is particularly important to cells during brain development, so when the enzyme does not work properly, the brain does not develop properly, leading to many of the signs and symptoms of fumarase deficiency.[1]
Last updated: 2/19/2018

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
Currently there is no effective treatment for fumarase deficiency. The goal of management is to improve symptoms, prevent complications, and increase quality of life. Examples of management options include:[3]
  • Standard anticonvulsant medications for seizures.
  • Placement of a feeding tube (if needed) for optimal nutrition and to prevent aspiration.
  • Special needs services for support with motor, language, and social development.
Last updated: 2/19/2018
Fumarase deficiency is a rare disease, with around 100 reported cases worldwide as of 2017.[1][3] The disease occurs in people of different ethnic backgrounds, but several people with fumarase deficiency were from an isolated religious community in the southwestern United States (around the border of northern Arizona and southern Utah).[1] The increased frequency in this area is thought to be due to a founder effect in closed, polygamist communities in which marriage between relatives is more common.[4]
Last updated: 2/19/2018

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
An elevated level of fumaric acid in urine may be caused by metabolic stress; therefore testing for fumaric aciduria must be repeated after the patient has been stabilized. Differential diagnoses include polymicrogyria and Leigh syndrome (see these terms).
Visit the Orphanet disease page for more information.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Fumarase deficiency. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

  • I'm looking to find information on fumaric aciduria. Is there anyone living with this disease anywhere in the world? See answer


  1. Fumarase deficiency. Genetics Home Reference. September, 2017; http://ghr.nlm.nih.gov/condition/fumarase-deficiency.
  2. de Lonlay P, Ottolenghi C. Fumaric aciduria. Orphanet. June, 2013; http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=24.
  3. Ewbank C, Kerrigan JF, Aleck K. Fumarate Hydratase Deficiency. GeneReviews. April 4, 2013; http://www.ncbi.nlm.nih.gov/books/NBK1506/.
  4. Allegri G. et al. Fumaric aciduria: an overview and the first Brazilian case report. J Inherit Metab Dis. August 2010; 33(4):411-419.