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fumaric aciduria - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

fumaric aciduria

MONDO:0011730

Also known as:fumarase deficiencyFMRDfumarate hydratase deficiency

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Overview

Fumaric aciduria (FA), an autosomal recessive metabolic disorder, is most often characterized by early onset but non-specific clinical signs: hypotonia, severe psychomotor impairment, convulsions, respiratory distress, feeding difficulties and frequent cerebral malformations, along with a distinctive facies. Some patients present with only moderate intellectual impairment.

GeneticsAutosomal recessive · FH (chr 1)

Clinical Trials2 registered · 1 recruiting

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

Features include always present findings: Hepatic failure, Mitochondrial swelling, Agenesis of corpus callosum, and Intrahepatic cholestasis and others; and very common findings: Decreased fumarate hydratase activity. 72 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	14	Hypoplasia of the brainstem, Abnormal speech pattern, Profound intellectual disability

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

FH encodes fumarate hydratase (510 aa). Catalyzes the reversible stereospecific interconversion of fumarate to L-malate. Highest expression in Cells EBV-transformed lymphocytes (139.4 TPM) and Cells Cultured fibroblasts (128.8 TPM).

Fumaric aciduria is associated with mutations in the FH gene on chromosome 1.

The FH protein participates in STRN(1-265)-PDGFRA(580-1089) fusion, WDR48(1-323)-PDGFRB(559-1106) fusion, and p-11Y-STRN(1-265)-PDGFRA(580-1089) fusion pathways.

FH is classified as a druggable target (Clinically Actionable, Dna Repair, and Enzyme categories) with score 10.4.

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

Suggestive Findings

Fumarate hydratase (FH) deficiency should be suspected in individuals with the following clinical, laboratory, and imaging findings.

Clinical findings

Neonatal and early-infantile severe encephalopathy, which may include poor feeding, hypotonia, and decreased levels of consciousness (lethargy, stupor, and coma)
Seizures, present in many but not all affected individuals

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for fumaric aciduria. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with fumarate hydratase (FH) deficiency, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with Fumarate Hydratase Deficiency

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

Table 5. Recommended Surveillance for Individuals with Fumarate Hydratase Deficiency

System/Concern

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

2 clinical trials registered, 1 recruiting. Interventions under study include other interventions. Pipeline includes 1 PHASE2, 1 NA. Research is primarily sponsored by academic and government institutions.

72 publications have been identified in PubMed for fumaric aciduria. Research spans Case Report / Case Series (39%), Basic Science / Preclinical (21%), and Diagnostic / Biomarker (11%).

Research Type	Count	% of Total
Patient case studies	28

Data assembled from 8 of 12 sources · Last updated Sep 18, 2026, 7:38 PM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:606812

Orphanet

European rare disease database

Orphanet:24

GARD

Genetic and Rare Diseases Info Center

GARD:6476

Questions for Your Care Team

→Should my partner and I meet with a genetic counselor to discuss carrier status and family planning?
→Are any of the 2 active clinical trials a good fit for my situation?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

← Back to All Diseases

GeneReviews

Clinical Guidance

To date, approximately 50 individuals have been identified with fumarate hydratase (FH) deficiency [, , , , , , , , , , ]. The following description of the phenotypic features associated with this condition is based on these reports. Table 2. Select Features of Fumarate Hydratase Deficiency

Feature	% of Personsw/Feature	Comment
Antenatal manifestations	12/51 (23%)	Oligohydramnios, polyhydramnios, IUGR, maternal intrahepatic cholestasis, preeclampsia
Prematurity	15/51 (30%)	—
DD	44/51 (86%)1	Severe
Mild-moderate ID	4/51 (8%)	—
Hypotonia	35/51 (68%)	—
Seizures	22/51 (43%)	—
Cortical visual impairment	13/51 (25%)	—
Dysmorphic facial features	20/51 (39%)	Frontal bossing, depressed nasal bridge, anteverted nares
Microcephaly	17/51 (33%)	—
Macrocephaly	10/51 (20%)	—
Abnormal brain imaging	47/51 (92%)	Incl MRI, CT, antenatal ultrasound findings; most notably: cerebral atrophy, white matter volume loss, polymicrogyria
Acute metabolic perturbations	4/51 (8%)	Metabolic acidosis, lactic acidosis, hypoglycemia, hyperammonemia
Hematologic abnormalities	11/51 (22%)	Neonatal polycythemia (9 persons); neutropenia (2 persons)
Dystonic posturing	4/51 (8%)	—
Excessive irritability	3/51 (6%)	—
Hepatic involvement	5/51 (10%)	Cirrhosis, acute hepatic neonatal hepatic failure, biliary atresia DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth retardation 1. Note: Some infants died in the neonatal period. Few clinical reports comment on complications of affected pregnancies.

Source: GeneReviews — "Fumarate Hydratase Deficiency"

System/Concern	Evaluation	Comment
Neurologic	Eval by pediatric neurologist	Eval will likely incl brain MRI exam.
Nutrition	Feeding assessment eval of nutritional status	—
Other	Consultation w/clinical geneticist /or genetic counselor	Treatment of Manifestations Table 4.
Treatment of Manifestations in Individuals with Fumarate Hydratase Deficiency Manifestation/Concern	Treatment	Considerations/Other
Seizures	Eval mgmt by pediatric neurologist	Ketogenic diet is considered contraindicated.; Seizures are often difficult to control. Developmental
delay	Gastrostomy tube feeding	May be appropriate in hypotonic /or lethargic children w/feeding difficulties /or aspiration Special needs services
Contractures	Physical therapy	To minimize contractures Wheelchair /or other mobility device
Scoliosis	Mgmt per orthopedist	One individual with FH deficiency has been treated with a high-fat/low-carbohydrate diet with 60% of the dietary energy goals coming from fat, 30% from carbohydrate, and 10% from protein .
Recommended Surveillance for Individuals with Fumarate Hydratase Deficiency System/Concern	Evaluation	Frequency
Seizures	Eval by pediatric neurologist	At least annually to monitor for /or treat epilepsy
Musculoskeletal complications	Physical medicine eval	At least annually to monitor for equipment needs to monitor for /or treat manifestations of spasticity Orthopedics eval
Ophthalmology	Ophthalmology eval for visual acuity nystagmus	As recommended by ophthalmologist 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.

Kisho

fumaric aciduria

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Medical References

External Resources

OMIM

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Explore clinical features

Clinical Guidance

Differential Diagnosis

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Recent Publications

fumaric aciduria

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Explore clinical features

Clinical Guidance

Differential Diagnosis

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Recent Publications