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Fumaric aciduria

Synonym(s) Fumarase deficiency
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
  • E88.8
  • C0342770
  • C2936826
  • C538191
MedDRA -


Disease definition

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.


FA is very rare, fewer than 100 cases have been reported to date.

Clinical description

Newborns are frequently microcephalic and may present with facial dysmorphisms. Severe encephalopathy manifests with poor feeding, failure to thrive, hypotonia, lethargy and epileptic seizures. In the most severe cases APGAR scores are low immediately following birth, and bradycardia and respiratory failure may follow. Most children do not achieve visual fixation and are unable to speak or walk. Less severely affected individuals survive beyond childhood, most nonetheless displaying moderate cognitive impairment. Some patients have been reported to present with only moderate cognitive deficits. An increased risk of certain tumors has also been reported, in particular familial leiomyomatosis (see this term).


FA is caused by mutations in the FH gene (1q42.1) encoding fumarate hydratase, an enzyme that catalyzes the transformation of fumarate into malate in the Krebs cycle. Complete deletions of FH have been reported to be fatal, whereas more mildly affected individuals retain some residual enzymatic activity.

Diagnostic methods

Chromatography of organic acids provides evidence of excreted fumaric acid, often associated with succinic acid and alphacetoglutaric acid. Hyperlactacidemia and moderate hyperammonemia are other common findings. Diagnosis can be confirmed by measuring fumarate hydratase activity in leukocytes or cultured fibroblasts. Brain MRI reveals a variety of anomalies including cerebral atrophy, enlarged ventricles and enlarged extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum and an abnormally small brain stem. Developmental malformations including bilateral polymicrogyria and absence of the corpus callosum may also be observed.

Differential diagnosis

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).

Antenatal diagnosis

Polyhydramnios, intrauterine growth delay and premature birth occur in over one third of cases. Fetal ultrasound reveals enlarged cerebral ventricles and other brain abnormalities.

Genetic counseling

FA is transmitted as an autosomal recessive trait.

Management and treatment

Only symptomatic treatment is available to FA patients. Gastrostomy may be necessary to facilitate feeding in newborns. Therapies to control seizures should not include a ketogenic diet, which is contraindicated for this family of enzymatic defects. Physical therapy to reduce scoliosis and improve mobility may be helpful in some cases. Special education and occupational therapy are required to attempt to improve motor skills and language development in less severely affected cases. For patients that survive long-term, regular tumor testing is required.


Prognosis is poor, except for those patients with only moderate cognitive impairment. Complete losses of enzymatic activity are fatal during childhood with severe psychomotor handicap: verbal communication and independent mobility remain limited. Some milder cases have been reported to survive longer, a diagnosis that is most likely underestimated.

Expert reviewer(s)

  • Pr Pascale DE LONLAY

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