Fumaric aciduria

Fumaric aciduria (AF) is an autosomal recessive disorder of metabolism that is usually characterized by an early onset but without specific clinical signs: hypotonia , severe psychomotor impairment, seizures, respiratory difficulties, in feeding and frequent brain malformations, together with peculiar facies. Some patients have only a moderate intellectual deficit.


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  • 1 Epidemiology
  • 2 Clinical description
  • 3 Etiology
  • 4 Diagnostic methods
    • 1 Differential diagnosis
    • 2 Prenatal diagnosis
  • 5 Management and treatment
  • 6 Forecast
  • 7 Sources


Fumaric aciduria is very rare, and less than 100 cases have been described to date.

Clinical description

Newborns are frequently microcephalic and may have facial dysmorphism. The encephalopathy serious manifests difficulty in feeding, growth retardation, hypotonia , lethargy and seizures epileptic. In more severe cases APGAR scores at birth are low right after birth, and may continue with bradycardia and respiratory failure. Most children cannot fix their eyes and are unable to speak or walk. Affected individuals with less severity survive childhood, although most show a significant cognitive deficit. Some patients have been reported to have only moderate cognitive deficits. An increased risk has also been described for certain tumors, in particular familial leiomyomatosis (see this term).


AF is caused by mutations in the FH gene (1q42.1) that codes for fumarate hydratase, an enzyme that catalyzes the transformation of fumarate to malate in the Krebs cycle. Complete FH deletions are fatal, whereas less severely affected individuals retain some residual enzyme activity.

Diagnostic methods

Organic acid chromatography shows an excretion of excreted fumaric acid , often associated with succinic acid and alpha-facetoglutaric acid. Other common findings are hyperlactacidemia and moderate hyperammonemia . The diagnosis can be confirmed by measuring the activity of fumarate hydratase in leukocytesor fibroblast culture. Brain MRI reveals a variety of abnormalities including cerebral atrophy, enlarged ventricles, and enlarged extra-axial cerebrospinal fluid (CSF) spaces, delayed myelination for age, corpus callosum thinning, and an abnormally small brain stem. Developmental malformations including bilateral polymicrogyria and absence of the corpus callosum may also be observed.

Differential diagnosis

A high level of fumaric acid in urine can be caused by metabolic stress; therefore, tests for fumaric aciduria should be repeated after the patient has stabilized. Differential diagnosis includes polymicrogyria and Leigh syndrome .

Prenatal diagnosis

Polyhydramnios, intrauterine growth retardation, and premature birth occur in one third of cases. Fetal ultrasound reveals an increase in the cerebral ventricles and other abnormalities of the brain.

Management and treatment

For FA patients, only symptomatic treatment is available. A gastrostomy may be necessary to facilitate feeding in newborns. Therapies to control seizures should not include a ketogenic diet, contraindicated for this family of enzyme defects. Physical therapy to reduce scoliosis and improve mobility may be beneficial in some cases. Special education and occupational therapy is required to try to improve motor skills and language development in less severely affected cases. For patients who survive long term, regular tumor tests are required.


The prognosis is poor, except for those patients with moderate cognitive impairment. Complete loss of enzyme activity is fatal during childhood with severe psychomotor disabilities: verbal communication and independent mobility are limited.

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