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Disease Profile

Guanidinoacetate 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.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Infancy

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ICD-10

E72.8

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)

GAMT deficiency; Cerebral creatine deficiency syndrome 2

Categories

Congenital and Genetic Diseases; Metabolic disorders; Nervous System Diseases

Summary

Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited disease that affects the brain and muscles. People with this disease may begin showing symptoms from early infancy to age three. Signs and symptoms can vary but may include mild to severe intellectual disability, recurrent seizures (epilepsy), problems with speech, and involuntary movements. People with this disease may also have behavioral problems, including hyperactivity, autistic behaviors, and self-mutilation.[1]

GAMT deficiency is caused by changes (mutations) in the GAMT gene. The disease is inherited in an autosomal recessive manner. Diagnosis of the disease may be based on finding increased levels of guanidinoacetate in the urine, and the diagnosis can be confirmed with genetic testing. Treatment for the disease aims to increase the levels of creatine in the brain through supplementation with high doses of oral creatine monohydrate.[2]

Symptoms

Signs and symptoms of guanidinoacetate methyltransferase (GAMT) deficiency typically become noticeable between the age of 3 months to 3 years. These symptoms typically include meeting milestones such as sitting up and walking later than expected (developmental delay), weak muscle tone (hypotonia), recurrent seizures (epilepsy), and problems coordinating movements (ataxia). As an affected individual gets older, other signs such as intellectual disability and behavior problems may become apparent. Behavior problems can include hyperactivity, autistic behaviors, and a tendency to harm oneself (self-mutilation).[2]

Symptoms of GAMT deficiency may worsen with age if a person is undiagnosed and does not receive the necessary treatment.[2] 

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
30%-79% of people have these symptoms
Intellectual disability, severe
Early and severe mental retardation
Mental retardation, severe
Severe mental retardation

[ more ]

0010864
Poor speech
0002465
Progressive extrapyramidal movement disorder
0007153
Severe global developmental delay
0011344
5%-29% of people have these symptoms
Abnormal head movements
0002457
Aggressive behavior
Aggression
Aggressive behaviour
Aggressiveness

[ more ]

0000718
Ataxia
0001251
Athetosis
Involuntary writhing movements in fingers, hands, toes, and feet
0002305
Atonic seizure
0010819
Autism
0000717
Bilateral tonic-clonic seizure
Grand mal seizures
0002069
Chorea
0002072
Dystonia
0001332
Focal impaired awareness seizure
0002384
Generalized myoclonic seizure
0002123
Hyperactivity
More active than typical
0000752
Self-injurious behavior
Self-injurious behaviour
0100716
1%-4% of people have these symptoms
Muscular hypotonia
Low or weak muscle tone
0001252
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance
0000007
Delayed speech and language development
Deficiency of speech development
Delayed language development
Delayed speech
Delayed speech acquisition
Delayed speech development
Impaired speech and language development
Impaired speech development
Language delay
Language delayed
Language development deficit
Late-onset speech development
Poor language development
Speech and language delay
Speech and language difficulties
Speech delay

[ more ]

0000750
Global developmental delay
0001263
Hyperreflexia
Increased reflexes
0001347
Hypertonia
0001276
Infantile muscular hypotonia
Decreased muscle tone in infant
0008947
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Myoclonus
0001336
Reduced brain creatine level by MRS
0025051
Seizure
0001250

Cause

Guanidinoacetate methyltransferase (GAMT) deficiency is caused by changes (mutations) in the GAMT gene. This gene provides instructions to the body to create a substance called creatine. Creatine helps the body store and use energy properly. When there is a mutation in GAMT, the body does not receive enough creatine to function. This causes body parts that use a lot of energy, such as the brain and the muscles, to not work properly.[1] In addition, when the body does not have enough GAMT, there is a buildup of a substance called guanidinoacetate. This buildup causes problems in the brain and muscles as well.[1]

Diagnosis

Guanidinoacetate methyltransferase (GAMT) deficiency can be diagnosed when guanidinoacetate is present in high levels in the urine. Doctors may also be suspicious that this disease is causing symptoms if there is shown to be a deficiency of creatine in the brain based on brain imaging. Genetic testing can then be used to confirm the diagnosis. If genetic testing is inconclusive, doctors may wish to take a sample of skin to see if the enzyme guanidinoacetate methyltransferase is working properly.[2] 

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

    Guanidinoacetate methyltransferase (GAMT) deficiency is treated by supplementation with oral creatine monohydrate. By taking creatine orally, people with GAMT deficiency are able to supplement the amount of creatine in their systems so that the brain and muscles have more energy.[2]

    People with GAMT deficiency may also be on a diet that restricts their arginine or protein intake. This is necessary so that the body creates less guanidinoacetate, which can result in the symptoms related to the buildup being less severe.[3] In order to allow the body to get enough nutrients with this diet restriction, people with GAMT deficiency may need to take a formula that has all amino acids except arginine in it.[2]

    Doctors will recommend that people affected by GAMT deficiency be monitored closely to see how treatment is working for them. Treatment for GAMT deficiency can keep the symptoms of the disease from progressing, but treatment has not been shown to improve intellectual disability or developmental delay. [4][5] Treatment has been shown to help improve the coordination of movements and behavioral problems associated with GAMT deficiency.[6]

    Other forms of therapy that may help people with GAMT deficiency include speech, occupational, and physical therapy. Behavioral therapy may reduce the behavioral symptoms of the disease as well.[2] 

    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

        • Genetics Home Reference (GHR) contains information on Guanidinoacetate methyltransferase deficiency. This website is maintained by the National Library of Medicine.

          In-Depth Information

          • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
          • 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 Guanidinoacetate methyltransferase deficiency. Click on the link to view a sample search on this topic.

            References

            1. Guanidinoacetate methyltransferase deficiency. Genetics Home Reference. June 2015; https://ghr.nlm.nih.gov/condition/guanidinoacetate-methyltransferase-deficiency.
            2. Mercimek-Mahmutoglu S, Salomons GS. Creatine Deficiency Syndromes. GeneReviews. Updated Dec. 10, 2015; https://www.ncbi.nlm.nih.gov/books/NBK3794.
            3. Stockler-Ipsiroglu S, van Karnebeek C, Longo N, Korenke GC, Mercimek-Mahmutoglu S, Marquart I, Barshop B, Grolik C, Schlune A, Angle B, Araujo HC, Coskun T, Diogo L, Geraghty M, Haliloglu G, Konstantopoulou V, Leuzzi V, Levtova A, Mackenzie J, Maranda B, Mhanni AA, Mitchell G, Morris A, Newlove T, Renaud D, Scaglia F, Valayannopoulos V, van Spronsen FJ, Verbruggen KT, Yuskiv N, Nyhan W, and Schulze A. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment, and monitoring. Molecular Genetics and Metabolism.. January 2014; 111(1):16-25. https://www.ncbi.nlm.nih.gov/pubmed/24268530.
            4. Cerebral Creatine Deficiency Syndrome2; CCDS2. Online Mendelian Inheritance in Man. June 18, 2014; https://www.omim.org/entry/612736.
            5. Iqbal F. Review: Human guanidinoacetate n-methyl transferase (GAMT) deficiency: A treatable inborn error of metabolism. Pakistan Journal of Pharmaceutical Sciences. November 2015; 28(6):2207-2211. https://www.ncbi.nlm.nih.gov/pubmed/26639513.
            6. Stockler S. Guanidinoacetate methyltransferase deficiency. Orphanet. December 2014; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=382.
            7. Mercimek-Mahmutoglu S, Pop A, Kanhai W, Fernandez Ojeda M, Holwerda U, Smith D, Loeber JG, Schielen PC, and Salomons GC. A pilot study to estimate incidence of guanidinoacetate methyltransferase deficiency in newborns by direct sequencing of the GAMT gene. Gene. January 2016; 575(1):127-131. https://www.ncbi.nlm.nih.gov/pubmed/26319512.
            8. Ombrone D, Giocaliere E, Forni G, Malvagia S, and Ia Marca G. Expanded newborn screening by mass spectrometry: New tests, future perspectives. Mass Spectrometry Reviews. January-February 2016; 35(1):71-84. https://www.ncbi.nlm.nih.gov/pubmed/25952022.
            9. Pitt JJ, Tzanakos N, and Nguyen T. Newborn screening for guanidinoacetate methyl transferase deficiency. Molecular Genetics and Metabolism. March 2014; 111(3):303-304. https://www.ncbi.nlm.nih.gov/pubmed/24477282.
            10. Pasquali M, Schwarz E, Jensen M, Yuzyuk T, DeBiase I, Randall H, and Longo N. Feasibility of newborn screening for guanidinoacetate methyltransferase (GAMT) deficiency. Journal of Inherited Metabolic Disease. March 2014; 37(2):231-236. https://www.ncbi.nlm.nih.gov/pubmed/24276113.

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