Homocystinuria due to MTHFR deficiency

Other Names: Homocysteinemia due to methylenetetrahydro-folate reductase deficiency; Methylenetetrahydro-folate reductase deficiency; Homocysteinuria due to methylenetetrahydro-folate reductase deficiency; 5,10-alpha-methylenetetrahydro-folate reductase deficiency; 5,10 alpha methylenetetrahydro-folate reductase deficiency

Homocystinuria due to MTHFR deficiency is a genetic condition that results from poor metabolism of folate (also called vitamin B9), due to a lack of working enzyme called MTHFR. The gene that tells our body how to make the enzyme is also called MTHFR. At least 40 rare MTHFR gene variants have been found in people with decreased or no working enzyme.

Cause

Homocystinuria due to MTHFR deficiency is caused by mutations in the MTHFR gene. This gene tells the body how to make an enzyme, also called MTHFR. MTHFR is important for a chemical reaction in the body involving forms of the vitamin folate. Mutations in the MTHFR gene result in an enzyme that doesn't work like it should, causing a buildup of homocysteine in the body. Very common gene variants (C677T and A1298C) can cause some decrease in enzyme function. People with homocystinuria due to MTHFR deficiency tend to have two rare variants or sometimes a rare variant and a common variant. Very rarely people inherit a combination of three or four common variants from their parents (for example two C677T variants and two A1298C variants) and may also develop very high levels of homocystine in their body.

Inheritance

Autosomal recessive inheritance, a 25% chance

Homocystinuria due to MTHFR deficiency is inherited in an autosomal recessive fashion, which means that both copies of the gene in each cell have mutations in the MTHFR gene.

Symptoms

Signs and symptoms of severe MTHFR deficiency may include:

Global developmental delays (46% of cases) Low muscle tone (35%) Seizures (33%) Failure to thrive (17%) Blood vessel disease (16%) (blood clots) Small head size (15%) Ataxia (9%) Peripheral neuropathy (7%) Other possible symptoms include bone disease (scoliosis), mental health problems, and behavior problems (e.g., attention deficit disorder and hyperactivity). Life expectancy will vary depending on the severity of the deficiency.

Diagnosis

Methylenetetrahydrofolate Reductase (MTHFR) Deficiency is the most common genetic cause of elevated levels of homocysteine in the plasma (hyperhomocysteinemia). A blood test that measures total homocysteine levels can diagnose hyperhomocysteinemia.

Genetic testing of the MTHFR gene may be used to confirm the diagnosis of an inherited hyperhomocysteinemia caused by MTHFR deficiency. However, a 2013 Practice Guideline from the American College of Medical Genetics and Genomics (ACMG) states that there is growing evidence that “MTHFR polymorphism testing has minimal clinical utility and, therefore should not be ordered as a part of a routine evaluation for thrombophilia” (4).

In an infant or child in whom autosomal recessive severe MTHFR deficiency is suspected, tests for plasma homocysteine and serum amino acids levels would be expected to show a pattern of extremely elevated homocysteine and low methionine. MTHFR full gene sequencing (as opposed to targeted polymorphism testing) can confirm the suspected clinical diagnosis.

Treatment

Treatment of MTHFR deficiency involves taking betaine, folinic acid, Vitamins B6 and B12, methionine, and methyltetrahydrofolate supplements. If MTHFR deficiency is diagnosed early and betaine treatment is started right away, affected infants have a much better developmental outcome Treatments started later do not reverse symptoms but can cause favorable improvements in symptoms. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Betaine (Brand name: Cystadane)Treatment of homocystinuria to decrease elevated homocysteine blood levels.

NIH genetic and rare disease info

• NIH info on Homocystinuria due to MTHFR deficiency

Homocystinuria due to MTHFR deficiency is a rare disease.

Homocystinuria due to MTHFR deficiency Resources
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