Fumarase deficiency

Douglas J Lanska MD FAAN MS MSPH (

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health, the Medical College of Wisconsin, and IM Sechenov First Moscow State Medical University has no relevant financial relationships to disclose.

Originally released March 30, 1995; last updated November 19, 2019; expires November 19, 2022

This article includes discussion of fumarase deficiency, fumaric aciduria, and fumarate hydratase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Key points


• Fumarase deficiency is a rare autosomal recessive disease caused by mutations in the FH gene that particularly affects the brain.


• Affected infants typically have microcephaly, ventriculomegaly, abnormal brain structure, severe developmental delay, hypotonia, failure to thrive, seizures, and distinctive facial features. Other signs and symptoms may include hepatosplenomegaly, polycythemia, and leukopenia.


• There is a high urinary fumaric acid excretion in affected individuals.


• Affected individuals usually survive only a few months, but a few have lived into early adulthood.


• No effective treatment is currently available.

Historical note and terminology

Fumarase (fumarate hydratase, EC is an enzyme of the Krebs citric acid cycle that catalyzes the reversible conversion of fumarate to malate (Robinson 1989; DeVivo 1994; Ajalla Aleixo et al 2019).

Krebs citric acid cycle Image: Krebs citric acid cycle
Fumarase plays important roles in energy production, DNA repair, and tumor suppression (Ajalla Aleixo et al 2019).

Fumaric aciduria is a rare metabolic disease that is caused by a profound decrease of both mitochondrial and cytosolic fumarase activity (Allegri et al 2010). The first reported cases were described in 2 adult siblings with mental retardation (Whelan et al 1983); however, fumarase activity was not measured, and the defect was proposed to be in renal resorption of the acid. In 1986, Zinn and colleagues reported a male infant with severe developmental delay, hypotonia, and progressive microcephaly who died at 8 months of age. Urinary fumarate, succinate, and citrate were elevated and a selective, profound decrease of both mitochondrial and cytosolic fumarase activity was documented (Zinn et al 1986). Additional patients and sibships have since been reported (Petrova-Benedict et al 1987; Walker et al 1989; Gellera et al 1990; Elpeleg et al 1992; Remes et al 1992; Bourgeron et al 1994; Narayanan et al 1996; Coughlin et al 1998; Kerrigan et al 2000; Zeman et al 2000).

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