What are the other Names for this Condition? (Also known as/Synonyms)

• 5,10-Alpha-Methylenetetrahydro-Folate Reductase Deficiency
• Homocysteinemia due to Methylene Tetrahydrofolate Reductase Deficiency
• Homocysteinuria due to Methylene Tetrahydrofolate Reductase Deficiency

What is Homocystinuria due to MTHFR Deficiency? (Definition/Background Information)

• Homocystinuria due to MTHFR Deficiency is a genetic condition where the body does a poor job of metabolizing folate (vitamin B6), due to a lack of working enzyme, called MTHFR
• The condition is caused by mutations in the MTHFR gene. This gene tells the body how to make an enzyme, also called MTHFR. Homocystinuria due to MTHFR Deficiency is inherited in an autosomal recessive fashion
• Signs and symptoms of severe homocystinuria often become apparent in infancy, however the condition can be milder, presenting in later childhood or adulthood
• Symptoms may include abnormal clotting, developmental delay, seizures, intellectual disability, and microcephaly

(Source: Homocystinuria due to MTHFR Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Homocystinuria due to MTHFR Deficiency? (Age and Sex Distribution)

• Homocystinuria due to MTHFR Deficiency is a rare congenital disorder, and presently, its prevalence is not known
• The presentation of symptoms may occur at birth, in the first year of life, or during adolescence, depending on the severity of the disorder
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Homocystinuria due to MTHFR Deficiency? (Predisposing Factors)

• A positive family history may be an important risk factor, since Homocystinuria due to MTHFR Deficiency can be inherited
• Currently, no other risk factors have been clearly identified for this disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Homocystinuria due to MTHFR Deficiency? (Etiology)

Homocystinuria due to MTHFR Deficiency is caused by mutation(s) in the MTHFR gene.

• This gene codes for the enzyme methylene tetrahydrofolate reductase, which is involved in a chemical reaction for normal folic acid metabolism within cells
• A deficiency in this enzyme leads to abnormal folic acid metabolism, leading to the build-up of homocysteine in the body
• Homocystinuria due to MTHFR Deficiency is inherited in an autosomal recessive manner

Autosomal recessive inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Homocystinuria due to MTHFR Deficiency?

The signs and symptoms of Homocystinuria due to MTHFR Deficiency may include:

Very frequently present symptoms in 80-99% of the cases:

• Gait disturbance
• Global developmental delay
• Homocystinuria
• Hyperhomocystinemia
• Incoordination
• Microcephaly
• Muscle weakness
• Paresthesia
• Seizures
• Stroke

Other possible symptoms include 

• Bone disease (scoliosis)
• Mental health problems
• Behavior problems (e.g., attention deficit disorder and hyperactivity)

(Source: Homocystinuria due to MTHFR Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Homocystinuria due to MTHFR Deficiency Diagnosed?

Homocystinuria due to MTHFR Deficiency is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary
• Molecular genetic testing to check for or confirm causative MTHFR gene mutation(s)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Homocystinuria due to MTHFR Deficiency?

The complications of Homocystinuria due to MTHFR Deficiency may include:

• Inability to walk properly
• Severe back pain due to scoliosis
• Crowding of organs in the chest cavity if scoliosis is present, with resultant abnormalities in heart and lung functions
• Risk of falls and injury if seizures occur
• Risk of paralysis due to stroke
• Severe intellectual deficiency and behavioral problems
• Reduced quality of life

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Homocystinuria due to MTHFR Deficiency Treated?

There is no cure for Homocystinuria due to MTHFR Deficiency, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. One or more of the following supplements may be recommended:

• High dose betaine
• Folinic acid 
• Vitamins B6 and B12
• Methionine
• Methyltetrahydrofolate

How can Homocystinuria due to MTHFR Deficiency be Prevented?

Currently, Homocystinuria due to MTHFR Deficiency may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Homocystinuria due to MTHFR Deficiency? (Outcomes/Resolutions)

• The prognosis of Homocystinuria due to MTHFR Deficiency is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Homocystinuria due to MTHFR Deficiency:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/