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Disease Profile

Glycine N-methyltransferase 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

-

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)

GNMT deficiency; Hypermethioninemia due to GNMT deficiency; Hypermethioninemia due to glycine N-methyltransferase deficiency

Categories

Congenital and Genetic Diseases; Metabolic disorders; Newborn Screening

Summary

Glycine N-methyltransferase deficiency (GNMT deficiency) is a very rare condition characterized by persistent and isolated excess levels of methionine in the blood (hypermethioninemia). The only clinical abnormalities are mild increase of the liver size (hepatomegaly) and chronic elevation of the transaminase levels in the blood without liver disease. Methionine may also be increased in urine. However, because elevated levels of methionine in the blood itself is a risk factor for development of neurological signs and symptoms, people with GNMT deficiency can have neurological problems when methionine levels are greater than 800 μmol/L. GNMT deficiency is caused by mutations in the GNMT gene. Inheritance is autosomal recessive. Treatment is not needed in most cases.[1][2][3]

Symptoms

Glycine N-methyltransferase (GNMT) deficiency in humans is an autosomal recessive defect which was discovered 15 years ago. However, to date, only five individuals from four families have been diagnosed, four of whom have been described in detail. The fact that three of the individuals 18, 15 and 17 years after diagnosis are still well suggests that this is a benign disorder in humans. However, because highly elevated levels of methionine in the blood itself is a risk factor for development of neurological signs and symptoms, people with GNMT deficiency can have methionine levels in the range which has been shown to be associated with clinical problems.[1][3][4] 

Based on the findings in the five diagnosed individuals, characteristics of GNMT deficiency are mild to moderate fluctuating elevations of aminotransferases and lack of clinical symptoms—the only clinical sign present in two individuals (siblings) being mild increase in the size of the liver (hepatomegaly). Presenting symptoms in three individuals were upper respiratory tract infection, failure to thrive and febrile convulsions, respectively. It is unclear whether these symptoms were related to GNMT deficiency.[1][4]

One of the patients had a normal liver ultrasound and a normal liver biopsy.[1]

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
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance
0000007
Elevated hepatic transaminase
High liver enzymes
0002910
Hepatomegaly
Enlarged liver
0002240
Hypermethioninemia
Increased methionine in blood
0003235

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.

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

Because there are usually no symptoms, treatment may not be needed. It is important, however, to have a careful follow-up. A low methionine diet (300 mg/day) can correct the biochemical abnormalities. In general, methionine restriction should be done when levels are greater than 800 μmol/L. The aim of the diet should be to maintain methionine levels around 500–600 μmol/L.[5][4] 

Physicians following patients should be aware that besides the liver, GNMT protein is expressed in a number of tissues (prostate, pancreas, kidney, submaxillary glands, intestinal mucosa, and brain). Regular measurements of aminotransferases, liver function (albumin, prothrombin time) and methionine levels may be useful. Yearly assessments of plasma alpha-fetoprotein levels as well as liver ultrasound and neurological examination may also be recommended.[1][3][4]

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

  • MedlinePlus Genetics contains information on Glycine N-methyltransferase 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. Augoustides-Savvopoulou P. Glycine N-methyltransferase deficiency: a new patient with a novel mutation. J. Inherit. Metab Dis. 2003; 26:745-759. https://www.ncbi.nlm.nih.gov/pubmed/14739680.
  4. Baric I & cols. Glycine N-Methyltransferase Deficiency: A Member of Dysmethylating Liver Disorders?. JIMD Rep. May 21, 2016; https://www.ncbi.nlm.nih.gov/pubmed/27207470.
  5. 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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