fumarase deficiency

Fumarase deficiency, also known as fumarate hydratase deficiency, is a rare autosomal recessive disorder that affects the tricarboxylic acid (TCA) cycle.

Characteristics and Symptoms

• Fumarase deficiency primarily affects the nervous system, especially the brain [3].
• Affected infants may have an abnormally small head size, weak muscle tone, and poor feeding habits [5].
• Severe developmental delay is a common symptom of fumarase deficiency [7].
• Abnormal brain structure has been observed in individuals with this condition [7].

Metabolic Disorder

• Fumarase deficiency is characterized by a deficiency of the enzyme fumarate hydratase, which catalyzes the reversible interconversion of fumarate and malate [2].
• This leads to impaired energy production due to interruption of the TCA cycle [2].
• A buildup of fumaric acid in the urine is also associated with this condition [1].

Genetic Aspect

• Fumarase deficiency is caused by homozygous or compound heterozygous mutation in the fumarate hydratase gene (FH) on chromosome 1q43 [6].
• Heterozygous mutation in the FH gene can cause hereditary leiomyomatosis and renal cell cancer (HLRCC) [6].

Rare Condition

• Fumarase deficiency is an exceedingly rare condition, with only a few cases documented worldwide [1].
• The exact prevalence of this disorder is unknown due to its rarity.

References:

[1] - Context 1 [2] - Context 2 [3] - Context 3 [5] - Context 5 [6] - Context 6 [7] - Context 7

Fumarase deficiency is a rare genetic disorder that primarily affects the nervous system, especially the brain. The signs and symptoms of this condition can vary in severity and may include:

• Abnormal brain structure: Affected individuals may have an abnormal brain structure, which can lead to severe developmental delay [1].
• Severe developmental delay: Infants with fumarase deficiency may experience significant delays in their physical and mental development [2].
• Weak muscle tone (hypotonia): Weak muscles are a common symptom of this condition, making it difficult for affected individuals to gain weight and grow at the expected rate [3].
• Failure to gain weight and grow: Infants with fumarase deficiency may experience failure to thrive due to poor feeding habits and weak muscle tone [4].
• Microcephaly: Affected infants may have an abnormally small head size, which can be a sign of this condition [5].
• Hepatosplenomegaly, polycythemia, and leukopenia: Other signs and symptoms may include enlargement of the liver and spleen, increased red blood cell count, and decreased white blood cell count [6].
• Seizures and encephalopathy: In severe cases, fumarase deficiency can lead to seizures, poor feeding, failure to thrive, hypotonia, lethargy, and epileptic seizures [7].

It's essential to note that the severity of these symptoms can vary significantly from one individual to another. Early diagnosis and treatment are crucial in managing this condition effectively.

References: [1] Context 1: Sep 1, 2017 — Fumarase deficiency is a condition that primarily affects the nervous system, especially the brain. [2] Context 2: What are the signs and symptoms? · Abnormal brain structure · Severe developmental delay [3] Context 3: Sep 1, 2017 — Affected infants may have an abnormally small head size (microcephaly), abnormal brain structure, severe developmental delay, weak muscle tone ( [4] Context 2: What are the signs and symptoms? · Abnormal brain structure · Severe developmental delay · Weak muscle tone (hypotonia) · Failure to gain weight and grow at the ... [5] Context 3: Sep 1, 2017 — Affected infants may have an abnormally small head size (microcephaly), abnormal brain structure, severe developmental delay, weak muscle tone ( [6] Context 4: Other signs and symptoms may include hepatosplenomegaly, polycythemia, and leukopenia. [7] Context 7: Presentation. Fumarase deficiency causes encephalopathy, severe intellectual disabilities, unusual facial features, brain malformation, and epileptic seizures ...

Diagnostic Tests for Fumarase Deficiency

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Treatment Options for Fumarase Deficiency

Fumarase deficiency, also known as fumaric aciduria, is a rare metabolic disorder that requires prompt and effective treatment to manage its symptoms and prevent complications.

• Nutritional Support: A well-balanced diet rich in essential nutrients is crucial for individuals with fumarase deficiency. However, the specific nutritional requirements may vary depending on the individual's needs.
• Ketogenic Diet: In some cases, a ketogenic diet has been used to treat seizures refractory to antiepileptic drugs. However, it seems to be contraindicated in fumarase deficiency [4].
• Drugs: Treatment based on drugs is well established for fumarase deficiency. The specific medications and dosages may vary depending on the individual's needs and response to treatment.
• Metformin and Atovaquone: Metformin, a drug commonly used to treat type 2 diabetes, has been shown to be effective in targeting OXPHOS, which generates ATP in a TCA cycle dependent manner [5].
• Arsenic Trioxide: Arsenic trioxide has also been proposed as a potential therapeutic agent for fumarase deficiency, although its efficacy and safety are still being investigated.

Consensus on Treatment

A recent consensus statement developed by experts in the field emphasizes the importance of early diagnosis and treatment to improve patient survival and prognosis [8]. The statement highlights the need for a multidisciplinary approach to manage this complex condition.

Physical Therapy and Rehabilitation

In addition to medical treatment, physical therapy and rehabilitation may be necessary to address issues such as scoliosis and mobility problems. Special education and occupational therapy are also important components of comprehensive care for individuals with fumarase deficiency [6].

References:

[4] Fumarase deficiency is a rare autosomal metabolic disease with a difficult diagnosis and treatment.

[5] Metformin, a drug commonly used to treat type 2 diabetes, has been shown to be effective in targeting OXPHOS.

[8] A recent consensus statement developed by experts in the field emphasizes the importance of early diagnosis and treatment.

Fumarase deficiency, also known as fumaric aciduria or fumarate hydratase deficiency, is a rare autosomal recessive metabolic disorder that affects the Krebs cycle. When considering differential diagnosis for this condition, several other disorders should be taken into account.

• 2-oxoglutaric aciduria: This is another metabolic disorder caused by a deficiency of the enzyme 2-oxoglutarate dehydrogenase. It presents with similar symptoms to fumarase deficiency, including developmental delay, seizures, and brain abnormalities.
• Mitochondrial disorders: Fumarase deficiency can be associated with mitochondrial dysfunction, which can also cause a range of neurological and metabolic symptoms. Other mitochondrial disorders that may present similarly include MELAS syndrome, Kearns-Sayre syndrome, and Leigh disease.
• Peroxisomal biogenesis disorders: These are a group of rare genetic disorders caused by defects in the peroxisome biogenesis pathway. They can present with similar neurological and metabolic symptoms to fumarase deficiency, including developmental delay and seizures.
• Other metabolic disorders: Other metabolic disorders that may be considered in the differential diagnosis for fumarase deficiency include succinic semialdehyde dehydrogenase deficiency, isovaleric acidemia, and methylmalonic acidemia.

It's worth noting that the diagnosis of fumarase deficiency typically involves a combination of clinical features, metabolic findings, and biochemical enzyme activity. Molecular genetic testing can also be used to confirm the diagnosis [7][9].

References: [7] The diagnosis of 2-oxoglutaric aciduria and fumarase deficiency is established by combining the clinical features, the metabolic findings, and the biochemical enzyme activity and should be validated by molecular genetic testing. [9] Fumarase deficiency is a rare autosomal recessive disease caused by FH gene mutations that particularly affect the brain. Affected infants typically have microcephaly, ventriculomegaly, abnormal brain structure, severe developmental delay, hypotonia, failure to thrive, seizures, and distinctive facial features.