Rare Hematology News

Disease Profile

Fumarase deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Infancy

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ICD-10

E88.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Fumaric aciduria; Fumarate hydratase deficiency

Categories

Congenital and Genetic Diseases; Metabolic disorders; Nervous System Diseases

Summary

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]

Symptoms

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]

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.

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

Cause

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]

Diagnosis

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.

    Treatment

    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.

    Organizations

    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

      Organizations Providing General Support

        Learn more

        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.

            References

            1. Fumarase deficiency. Genetics Home Reference. September, 2017; https://ghr.nlm.nih.gov/condition/fumarase-deficiency.
            2. de Lonlay P, Ottolenghi C. Fumaric aciduria. Orphanet. June, 2013; https://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; https://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.

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