National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Methionine adenosyltransferase deficiency

Methionine adenosyltransferase deficiency is a very rare metabolic disorder resulting in an isolated increase of the amino acid methionine in the blood (hypermethioninemia). In most cases there are no symptoms and it is usually a benign condition, but some patients may present with neurologic or developmental problems and/or bad breath. It is caused by mutations in the MAT1A gene. Inheritance is autosomal recessive.[1] When needed, treatment is with a diet restricting methionine.[1][2] S-adenosylmethionine (SAMe) supplementation may also be useful.[2]
Last updated: 12/3/2016
The disease is considered benign in many cases and most patients only have isolated hypermethioninemia. However, about 50% of patients with mutations in the MAT1A gene have developed neurological symptoms later in life, so it cannot be considered to be a benign genetic disorder for all patients. Symptoms that have been described include:[1][3]
  • Problems with psychomotor development or intelligence
  • Tremor
  • Abnormal muscle contractions,
  • Lack of control involving range of movement,
  • Severe headaches,
  • Abnormal eye movements (nystagmus),
  • Impaired ability to make rapid, alternating movements (dysdiadochokinesis),
  • Increased tendon reflexes,
  • Language difficulties and learning disabilities.
Neurological abnormalities are more common when methionine levels in the blood are above 800 μmol/L and rare in people with lower levels. Brain images may show some changes, such as inflammation and demyelination, especially in patients with neurological problems.[3]

Hypermethioninemia can also be associated with an unusual breath odor likely due to formation of a substance known as dimethylsulfide that results from the problem with the enzyme deficiency.[3]

Liver function tests in patients have been normal so far.[3]

Methionine adenosyltransferase deficiency is the most common cause of persistent isolated hypermethioninemia and should be suspected in people with unexplained hypermethioninemia. Also, when a patient has unexplained neurological signs and symptoms, disorders of methylation should be investigated at least by analysis of plasma amino acids.[3]
Last updated: 12/3/2016

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.

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Medical Terms Other Names
Learn More:
HPO ID
5%-29% of people have these symptoms
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation
[ more ] 		0001249
Percent of people who have these symptoms is not available through HPO
Autosomal dominant inheritance 0000006
Autosomal recessive inheritance 0000007
CNS demyelination 0007305
Dystonia 0001332
Halitosis
Bad breath
0100812
Hypermethioninemia
Increased methionine in blood
0003235
Hyperreflexia
Increased reflexes
0001347
Peripheral demyelination 0011096
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Last updated: 7/1/2020

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.

Newborn Screening

  • An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
  • An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.
All patients, even when they do not have any symptoms, should have regular neurological and cognitive testing due to the possibility of neurological symptoms. If indicated, a brain MRI could also be done. Symptomatic patients should be treated with a methionine restricted diet if the methionine level is above 600 μmol/L. Treatment aims to get the methionine levels around 500 to 600 μmol/L.[3][2] Neurological symptoms are more likely to develop when methionine levels in the blood are around 800 μmol/L.

S-adenosylmethionine (SAMe) supplementation (AdoMet supplementation) may be indicated if clinical signs and symptoms develop while on methionine restriction. The most effective oral dose of AdoMet is unknown. Doses between 400 to 1600 mg/day have been used in various conditions and seem to be well tolerated. Some evidence suggests that AdoMet supplementation may lead to normalization of brain changes seen on imaging.[3]
Last updated: 12/3/2016

Management Guidelines

  • Orphanet Emergency Guidelines is an article which is expert-authored and peer-reviewed that is intended to guide health care professionals in emergency situations involving this condition.  

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • ClinicalTrials.gov lists trials that are related to Methionine adenosyltransferase deficiency. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

    Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.

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

  • Genetics Home Reference (GHR) contains information on Methionine adenosyltransferase 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.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.

  1. Hypermethioninemia. Genetics Home Reference:. April, 2007; https://ghr.nlm.nih.gov/condition/hypermethioninemia.
  2. Labrune P & cols. Familial hypermethioninemia partially responsive to dietary restriction. J. Pediat. 1990; 117:220-226. https://www.ncbi.nlm.nih.gov/pubmed/2380820.
  3. Baric I. Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders. J Inherit Metab Dis. September 26, 2016; https://www.ncbi.nlm.nih.gov/pubmed/27671891.