Fumarase deficiency

A rare metabolic disorder

Fumarase deficiency
Synonyms	Fumarate hydratase deficiency
Pronounce
Field	Metabolic disorder, neurology
Symptoms	Encephalopathy, intellectual disabilities, seizures, dysmorphic features, developmental delay
Complications	Seizures, intellectual disabilities, developmental delay, dystonia
Onset	Neonatal to infantile onset
Duration	Lifelong
Types
Causes	Mutation in the Fumarate hydratase gene
Risks	Autosomal recessive inheritance, inbreeding, consanguinity
Diagnosis	Clinical features, enzyme activity testing, genetic testing
Differential diagnosis	Mitochondrial disorders, metabolic disorders, epileptic encephalopathies
Prevention	None
Treatment	Malic acid supplementation, anticonvulsant medications, nutritional support
Medication	Anticonvulsants, malic acid
Prognosis	Poor; typically severe developmental delays and neurological deficits
Frequency	Extremely rare, with a few known cases globally
Deaths	Often early in life due to complications

Fumarase deficiency is a rare metabolic disorder characterized by a deficiency of the enzyme fumarase, which is crucial in the citric acid cycle (also known as the Krebs cycle). This enzyme deficiency leads to a buildup of fumaric acid and a deficiency of malate, disrupting the energy production process in cells.

Pathophysiology

Fumarase, also known as fumarate hydratase, is an enzyme that catalyzes the reversible hydration of fumarate to malate in the citric acid cycle. This cycle is a key component of cellular respiration, which is the process by which cells produce energy in the form of adenosine triphosphate (ATP). In individuals with fumarase deficiency, the lack of functional enzyme impairs the cycle, leading to reduced ATP production and an accumulation of fumarate.

Genetics

Fumarase deficiency is inherited in an autosomal recessive pattern, meaning that an individual must inherit two copies of the defective gene, one from each parent, to manifest the disorder. The gene responsible for encoding fumarase is located on chromosome 1, and mutations in this gene lead to the enzyme deficiency.

Clinical Features

The clinical presentation of fumarase deficiency can vary, but common features include severe neurological impairment, developmental delay, hypotonia (reduced muscle tone), and seizures. Affected individuals may also exhibit microcephaly (a smaller than normal head size), encephalopathy, and dystonia.

Diagnosis

Diagnosis of fumarase deficiency is typically based on clinical features, biochemical testing, and genetic analysis. Elevated levels of fumaric acid in the urine and blood are indicative of the disorder. Genetic testing can confirm mutations in the fumarase gene.

Management

There is currently no cure for fumarase deficiency, and treatment is primarily supportive. Management may include anticonvulsant medications to control seizures, physical therapy to address motor difficulties, and nutritional support. Early intervention and supportive care can improve quality of life for affected individuals.

Prognosis

The prognosis for individuals with fumarase deficiency is generally poor, with many experiencing significant developmental challenges and reduced life expectancy. However, the severity of the condition can vary, and some individuals may achieve limited developmental milestones.

Epidemiology

Fumarase deficiency is extremely rare, with only a few dozen cases reported in the medical literature. It has been observed more frequently in certain populations with higher rates of consanguinity, such as the Mormon community in the United States.

Related pages

• Metabolic disorder
• Citric acid cycle
• Genetic disorder
• Neurological disorder

External links

Classification	ICD-10: E88.8 OMIM: 606812 DiseasesDB: 29835
External resources	Orphanet: 24

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