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Guanidinoacetate Methyltransferase (GAMT) Deficiency

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Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Cerebral creatine deficiency syndrome 2 (CCDS2)
Creatine deficiency syndrome due to GAMT deficiency

ICD-10 Coding

E72.8, Other specified disorders of amino-acid metabolism

Disorder Category

Amino acidemia

Screening

Abnormal Finding

Elevated guanidinoacetate

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=100%; specificity=100% [Comeaux: 2013]

Description

Guanidinoacetate methyltransferase (GAMT) deficiency is an inborn error of creatine synthesis resulting in creatine deficiency and an accumulation of guanidinoacetate in tissues and body fluids, including the brain. The clinical phenotype includes developmental delays, speech delay, hypotonia, seizures, extrapyramidal movement, and autism-like behavior.

Clinical Characteristics

With early diagnosis and ongoing treatment of GAMT deficiency, most affected children will have normal development.
Without treatment, symptoms may begin between birth and 5 years of age and include global developmental delays, hypotonia, intellectual disability, impairment of expressive speech, autistic features, and varying neurological manifestations, including epilepsy and movement disorders.

Incidence

The prevalence of GAMT deficiency is unknown but estimated to be 1:114,000 in Utah. [Mercimek-Andrews: 2015]

Inheritance

Autosomal recessive

Follow-up Testing after Positive Screen

Follow-up involves quantitative plasma and urine guanidinoacetate and creatine analysis.

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and evaluate the infant for hypotonia, seizures, and developmental delays.

Confirming the Diagnosis

If the Diagnosis is Confirmed

  • For evaluation and ongoing collaborative management, consult Medical Genetics (see NW providers [1]).
  • Educate the family regarding signs, symptoms, and the need for specialized care.
  • Treatment of GAMT deficiency should be continued for life and includes creatine (300-800 mg/kg/day), ornithine (300-800 mg/kg/day), and benzoate (100 mg/kg/day).
  • A low-protein diet may be indicated.
  • For those identified after irreversible consequences, the therapy above is still helpful and should be started.
  • Developmental and educational interventions are indicated. See Early Intervention for Children with Disabilities/Delays (see NW providers [3]).

Resources

Information & Support

After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

Creatine Deficiency Disorders (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Cerebral Creatine Deficiency Syndrome-2 (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Guanidinoacetate Methyltransferase Deficiency (Orphanet)
An overview of genetics, diagnosis, and management of GAMT; Orphanet is a French-coordinated consortium involving over 40 countries to provide a portal for information about rare diseases and orphan drugs.

Communicating Newborn Screening Results to Families (ACHDNC) (PDF Document 289 KB)
One-page guide to help clinicians effectively communicate positive newborn screening results to parents; Advisory Committee on Heritable Disorders in Newborns and Children.

For Parents and Patients

Guanidinoacetate Methyltransferase Deficiency (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Association for Creatine Deficiencies
Established in 2012, by parents of children diagnosed with a Cerebral Creatine Deficiency Syndrome to provide patient, family, and public education, to advocate for early intervention through newborn screening, and to promote and fund medical research for treatments and cures.

Baby's First Test (Genetic Alliance)
Clearinghouse for local, state, and national newborn screening education, programs, policies, and resources. Also, provides many ways for people to connect and share their viewpoints and questions about newborn screening, supported by the U.S. Department of Health and Human Services.

Disease InfoSearch for GAMT (Genetic Alliance)
Compilation of links to information, articles, research, and case studies for GAMT.

Center for Parent Information and Resources (DOE)
Parent Centers in every state provide training to parents of children with disabilities and provide information about special education, transition to adulthood, health care, support groups, local conferences, and other federal, state, and local services. See the "Find Your Parent Center Link" to find the parent center in your state; Department of Education, Office of Special Education.

Tools

ACT Sheet for GAMT (ACMG) (PDF Document 134 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; from the American College of Genetics and Genomics

Services for Patients & Families Nationwide (NW)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Helpful Articles

PubMed search for GAMT deficiency and newborn screening.

Stockler-Ipsiroglu S, van Karnebeek C, Longo N, Korenke GC, Mercimek-Mahmutoglu S, Marquart I, Barshop B, Grolik C, Schlune A, Angle B, Araújo 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, Schulze A.
Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring.
Mol Genet Metab. 2014;111(1):16-25. PubMed abstract

Viau KS, Ernst SL, Pasquali M, Botto LD, Hedlund G, Longo N.
Evidence-Based Treatment of Guanidinoacetate Methyltransferase (GAMT) Deficiency.
Mol Genet Metab. 2013;110(3):255-62. PubMed abstract

Authors & Reviewers

Initial publication: August 2016
Current Authors and Reviewers:
Author: Kimberly Hart, MS, LCGC
Reviewer: Nicola Longo, MD, Ph.D.

Page Bibliography

Comeaux MS, Wang J, Wang G, Kleppe S, Zhang VW, Schmitt ES, Craigen WJ, Renaud D, Sun Q, Wong LJ.
Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes.
Mol Genet Metab. 2013;109(3):260-8. PubMed abstract

Mercimek-Andrews S, Salomons GS.
Creatine Deficiency Syndromes.
GeneReviews; (2015) http://www.ncbi.nlm.nih.gov/books/NBK3794/. Available from: http://www.ncbi.nlm.nih.gov/books/NBK3794/. Accessed on 1/24/2022.