Rare Immunology News

Disease Profile

Homocystinuria due to MTHFR deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Infancy

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ICD-10

E72.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Homocysteinemia due to methylenetetrahydro-folate reductase deficiency; Methylenetetrahydro-folate reductase deficiency; Homocysteinuria due to methylenetetrahydro-folate reductase deficiency;

Categories

Congenital and Genetic Diseases; Metabolic disorders; Nervous System Diseases

Summary

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.[1]

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. 

Homocystinuria usually does not show symptoms in a newborn baby. If untreated, children show signs and symptoms of severe homocystinuria in infancy. Newborn screening in most states includes a screening test for homocystinuria so that newborn infants can be treated early in their lives.

However, homocystinuria due to MTHFR variants can be milder, presenting in later childhood or in adulthood. Symptoms may include abnormal clotting, developmental delay, seizures, intellectual disability, and microcephaly.[1] Severe homocystinuria can also be caused by gene variants in other genes besides MTHFR. For more information about other causes of homocystinuria, see the GARD page:
https://rarediseases.info.nih.gov/diseases/10770/homocystinuria 

For more information on having two common MTHFR gene variants (specifically, C677T and A1298C) visit our page: MTHFR gene variant

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.[2]

For information on signs and symptoms reported in association with having two common MTHFR gene mutations, such as C677T and A1298C, please visit our MTHFR Gene Mutation resource page.

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormal enzyme/coenzyme activity
0012379
Cystathioninemia
High blood cystathionine levels
0003286
Gait disturbance
Abnormal gait
Abnormal walk
Impaired gait

[ more ]

0001288
Homocystinuria
High urine homocystine levels
0002156
Hyperhomocystinemia
Elevated blood homocystine
0002160
Lower limb muscle weakness
Lower extremity weakness
Lower limb weakness
Muscle weakness in lower limbs

[ more ]

0007340
30%-79% of people have these symptoms
Abnormality of the periventricular white matter
0002518
Ataxia
0001251
Brain imaging abnormality
0410263
Hypomethioninemia
Decreased plasma methionine
Decreased serum methionine

[ more ]

0003658
Mental deterioration
Cognitive decline
Cognitive decline, progressive
Intellectual deterioration
Progressive cognitive decline

[ more ]

0001268
Peripheral neuropathy
0009830
Psychotic episodes
0000725
Spastic paraparesis
0002313
5%-29% of people have these symptoms
Apnea
0002104
Atrophy of the spinal cord
Degeneration of the spinal cord
0006827
Bilateral tonic-clonic seizure
Grand mal seizures
0002069
Brain atrophy
Brain degeneration
Brain wasting

[ more ]

0012444
Deep venous thrombosis
Blood clot in a deep vein
0002625
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Feeding difficulties in infancy
0008872
Focal-onset seizure
Seizure affecting one half of brain
0007359
Generalized neonatal hypotonia
Generalized low muscle tone in neonate
0008935
Global developmental delay
0001263
Headache
Headaches
0002315
Hemiparesis
Weakness of one side of body
0001269
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Lethargy
0001254
Psychotic mentation
0001345
Specific learning disability
0001328
Thromboembolic stroke
0001727
1%-4% of people have these symptoms
Encephalopathy
0001298
Generalized myoclonic seizure
0002123
Generalized non-motor (absence) seizure
Brief seizures with staring spells
0002121
Hydrocephalus
Too much cerebrospinal fluid in the brain
0000238
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference

[ more ]

0000252
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Optic atrophy
0000648
Stroke
0001297
Ventriculomegaly
0002119
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance
0000007
Behavioral abnormality
Behavioral changes
Behavioral disorders
Behavioral disturbances
Behavioral problems
Behavioral/psychiatric abnormalities
Behavioural/Psychiatric abnormality
Psychiatric disorders
Psychiatric disturbances

[ more ]

0000708
Incoordination
Difficulties in coordination
Incoordination of limb movements
Limb incoordination

[ more ]

0002311
Muscle weakness
Muscular weakness
0001324
Paresthesia
Pins and needles feeling
Tingling

[ more ]

0003401
Seizure
0001250

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.[3]

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    Treatment of MTHFR deficiency involves taking betaine, folinic acid, Vitamins B6 and B12, methionine, and methyltetrahydrofolate supplements.[2][4] If MTHFR deficiency is diagnosed early and betaine treatment is started right away, affected infants have a much better developmental outcome.[2] Treatments started later do not reverse symptoms but can cause favorable improvements in symptoms.[2]

    FDA-Approved Treatments

    The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Organizations Providing General Support

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

        • LabTests Online provides information on testing homocysteine levels in general. Click on LabTests Online to view the information page.
        • Genetics Home Reference (GHR) contains information on Homocystinuria due to MTHFR deficiency. This website is maintained by the National Library of Medicine.

          In-Depth Information

          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss Homocystinuria due to MTHFR deficiency. Click on the link to view a sample search on this topic.

            References

            1. Homocystinuria. Genetics Home Reference (GHR). March, 2016; https://ghr.nlm.nih.gov/condition=homocystinuria.
            2. Munoz T, Patel J, Badilla-Porras R, Kronick J, Mercimek-Mahmutoglu S. Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency. Brain Dev. 2015 Jan; 37(1):168-70. Accessed 9/10/2015.
            3. MTHFR. Genetics Home Reference (GHR). November, 2014; https://ghr.nlm.nih.gov/gene/MTHFR.
            4. Physician's Guide to The Homocystinurias. The National Organization of Rare Disorders. https://nordphysicianguides.org/wp-content/uploads/2012/02/Homocystinuria_11_29b.pdf. Accessed 9/10/2015.
            5. Homocystinuria due to deficiency of N(5,10)-Metylenetetrahydrofolate Reductase Activity. Online Medelian Inheritance of Man (OMIM). 2014; https://www.omim.org/entry/236250.
            6. Varga EA, Sturm AC, Misita CP & Moll S. Homocysteine and MTHFR Mutations: Relation to Thrombosis and Coronary Artery Disease. Circulation. 2005; 111:e289-e293. https://circ.ahajournals.org/content/111/19/e289.full.
            7. Rosenson RS & Kang DS. Overview of homocysteine. UpToDate. July 21 2017; https://www.uptodate.com/contents/overview-of-homocysteine.
            8. Homocysteine. American Academy of Family Physicians. 2006; https://familydoctor.org/online/famdocen/home/articles/249.html. Accessed 5/13/2009.
            9. Homocystinuria due to deficiency of N(5,10)-Methylenetetrahydrofoloate reductase activity. Online Mendelian Inheritance in Man. 2007; https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=236250.
            10. Liew SC & Gupta ED. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet. January 2015; 58(1):1-10. https://www.ncbi.nlm.nih.gov/pubmed/25449138.

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