Fumarase Deficiency

Fumarase deficiency is a rare inherited metabolic disorder that primarily affects the nervous system, leading to severe neurological impairment, developmental delays, and cellular energy disruption.

Overview

Fumarase deficiency is a genetic condition that primarily affects the nervous system, especially the brain. It interferes with the body's ability to produce energy at the cellular level, leading to severe developmental and physical challenges in infancy. Most affected individuals survive only a few months, although a small number have survived into early adulthood.

Symptoms

Signs and symptoms typically appear in infancy and can vary, primarily involving the nervous system and metabolic function. Features of fumarase deficiency include:

• Abnormally small head size (microcephaly)
• Abnormal brain structure
• Severe developmental delay
• Weak muscle tone (hypotonia)
• Failure to gain weight and grow at the expected rate (failure to thrive)
• Seizures
• Distinctive facial features, such as a prominent forehead, low-set ears, a small jaw, and widely spaced eyes
• Enlarged liver and spleen (hepatosplenomegaly)
• Excess of red blood cells (polycythemia) in infancy
• Deficiency of white blood cells (leukopenia) in infancy

Causes & Genetics

Fumarase deficiency is caused by mutations in the FH gene. This gene provides instructions for producing an enzyme known as fumarase (or fumarate hydratase). This enzyme plays an essential role in the citric acid cycle (also known as the Krebs cycle), a series of chemical reactions that allows cells to use oxygen and generate energy. Specifically, fumarase converts a molecule called fumarate into malate.

Mutations in the FH gene disrupt the enzyme's ability to carry out this conversion, hindering the entire citric acid cycle. The resulting impairment in cellular energy generation is especially harmful to cells in the developing brain, causing the severe symptoms associated with the condition.

Inheritance

This condition is inherited in an autosomal recessive pattern, meaning both copies of the FH gene in each cell must have mutations for the disease to occur. The parents of an affected individual typically carry one copy of the mutated gene and do not show signs and symptoms of fumarase deficiency.

However, individuals who carry one mutated copy of the FH gene in each cell—including parents of affected children—tend to develop benign smooth muscle tumors (leiomyomas) in the skin and, in females, in the uterus. They also face an increased risk of kidney cancer. This related condition is referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC).

Frequency

Fumarase deficiency is an exceptionally rare disorder. Approximately 100 affected individuals have been reported worldwide. Several affected individuals were born in an isolated religious community located in the southwestern United States.

Other Names for This Condition

• Fumarate hydratase deficiency
• Fumaric aciduria