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Disease Profile

Methionine adenosyltransferase 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.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

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)

MAT deficiency

Categories

Congenital and Genetic Diseases; Metabolic disorders; Nervous System Diseases;

Summary

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]

Symptoms

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]

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
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

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.

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.

Treatment

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]

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.

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

  • 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.

References

  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.

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