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  • Updated 10.21.2020
  • Released 03.30.1995
  • Expires For CME 10.21.2023

Fumarase deficiency

Introduction

Overview

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.

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 4.2.1.2) is an enzyme of the Krebs citric acid cycle that catalyzes the reversible conversion of fumarate to malate (43; 14; 02).

Krebs citric acid cycle
(Courtesy of Wikimedia Commons. Creative Commons Attribution ShareAlike 3.0 license.)

Fumarase plays important roles in energy production, DNA repair, and tumor suppression (02).

Fumaric aciduria is a rare metabolic disease that is caused by a profound decrease of both mitochondrial and cytosolic fumarase activity (05). The first reported cases were described in 2 adult siblings with mental retardation (61); 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 (67). Additional patients and sibships have since been reported (36; 60; 19; 16; 42; 09; 32; 12; 23; 65).

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