5,10-methenyltetrahydrofolate synthetase deficiency

A rare metabolic disorder affecting folate metabolism

5,10-Methenyltetrahydrofolate synthetase deficiency is a rare metabolic disorder that affects the body's ability to process folate, a type of B vitamin that is crucial for numerous bodily functions, including DNA synthesis and repair. This condition is caused by mutations in the MTHFS gene, which encodes the enzyme 5,10-methenyltetrahydrofolate synthetase. This enzyme plays a critical role in the folate cycle, which is essential for the production of nucleotides and the methylation of homocysteine to methionine.

Pathophysiology

The deficiency of 5,10-methenyltetrahydrofolate synthetase leads to disruptions in the folate cycle. This enzyme is responsible for converting 5-formyltetrahydrofolate (5-formyl-THF) to 5,10-methenyltetrahydrofolate (5,10-methenyl-THF), a critical step in the folate cycle. Without this conversion, there is an accumulation of 5-formyl-THF and a deficiency of 5,10-methenyl-THF, which impairs the synthesis of purines and thymidylate, essential components of DNA.

Clinical Presentation

Patients with 5,10-methenyltetrahydrofolate synthetase deficiency typically present with a range of neurological symptoms. These may include developmental delay, seizures, and microcephaly. The severity of symptoms can vary widely among affected individuals. Some patients may also exhibit hypotonia, ataxia, and intellectual disability.

Diagnosis

The diagnosis of 5,10-methenyltetrahydrofolate synthetase deficiency is based on clinical evaluation, biochemical testing, and genetic analysis. Biochemical tests may reveal elevated levels of 5-formyl-THF in the blood and cerebrospinal fluid. Genetic testing can confirm mutations in the MTHFS gene.

Treatment

Currently, there is no cure for 5,10-methenyltetrahydrofolate synthetase deficiency. Treatment is primarily supportive and symptomatic. Some patients may benefit from supplementation with folinic acid, which can bypass the metabolic block caused by the enzyme deficiency. Management of seizures and other neurological symptoms is also important.

Prognosis

The prognosis for individuals with 5,10-methenyltetrahydrofolate synthetase deficiency varies depending on the severity of the condition and the effectiveness of symptom management. Early diagnosis and intervention can improve outcomes for some patients.

Genetics

Axial T1-weighted MRI of the brain at 10 months old with MTHFS deficiency

The MTHFS gene is located on chromosome 15 and encodes the enzyme 5,10-methenyltetrahydrofolate synthetase. Mutations in this gene disrupt the normal function of the enzyme, leading to the accumulation of 5-formyl-THF and a deficiency of 5,10-methenyl-THF. This autosomal recessive disorder requires that an individual inherit two copies of the mutated gene, one from each parent, to manifest the disease.

Related pages

• Folate metabolism
• Metabolic disorder
• Genetic disorder
• Neurological disorder