NORD gratefully acknowledges Nicola Longo, MD, PhD, Chief, Division of Medical Genetics, University of Utah Health Care; Scientific and Medical Advisory Board, Association for Creatine Deficiencies, for the preparation of this report.
The severity of GAMT varies from patient to patient. Global developmental delays affect all individuals with this disorder and may be the first sign, appearing before other symptoms.The majority of individuals with GAMT deficiency have intellectual disabilities, seizure disorders, muscle weakness, behavior disorders, and movement disorders. People with GAMT may have weak muscle tone and delayed development of motor skills such as sitting or walking. Severely affected patients may lose previously acquired skills such as the ability to support their head or to sit unsupported.
GAMT is a caused by a mutation in the GAMT gene that makes the enzyme that creates creatine, resulting in a shortage of creatine. It is the most severe of the three CCDS due to the elevation of guanidinoacetate (which is neurotoxic) in addition to creatine deficiency. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy and high GAA in urine.
The inheritance pattern for GAMT is autosomal recessive. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
The prevalence of GAMT deficiency has been estimated to be from 1 out of 2,640,000 to 1 out of 550,000 patients being diagnosed to a conflicting report of 1 out of 115,000 patients being diagnosed. As of 2015, there have only been 110 individuals with GAMT deficiency diagnosed worldwide.
Testing in both urine and plasma is recommended by measuring the concentration of creatine (Cr), guanidinoacetate (GAA), and creatinine (Crn). A positive screen for GAMT is based on plasma GAA that is elevated with creatine being low and urine GAA that is elevated and creatine being low to normal.
Follow up genomic testing for mutations in the GAMT gene may be ordered along with brain MRI with spectroscopy to confirm GAMT diagnosis. MRI with spectroscopy is useful for measuring creatine levels in the brain.
Generally not required for diagnosis, but a cultured skin fibroblast may be helpful when gene sequencing test results are unclear.
Individuals diagnosed with GAMT may require the coordinated efforts of a team of specialists. A pediatrician or an adult primary care physician, neurologist, geneticist, dietician and a doctor who is familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech, and physical therapists may be necessary to treat developmental disabilities and behavior therapy to address behavior problems.
Treatments vary with each GAMT patient. Oral supplementation is available and effective if initiated early in life.
Oral creatine monohydrate is given to replenish creatine levels in the brain and other tissues in individuals with GAMT. A low arginine/protein diet, L-ornithine supplementation, and sodium benzoate are used to reduce toxic levels of guanidinoacetate in individuals with GAMT deficiency. For GAMT patients being treated with creatine monohydrate, a routine measurement of renal function should be considered to detect possible creatine-associated kidney disease (nephropathy).
Prevention of Primary Symptoms
Early treatment at the first sign of symptoms in patients with GAMT is effective in improving patient’s quality of life. The treatment in newborn siblings of individuals with GAMT has been shown to prevent disease manifestation.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
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Dunbar M. Jaggumantri S, Sargent M, Stockler-Ipsiroglu S(2), van Karnebeek CD. Treatment of X-linked creatine transporter (SLC6A8 deficiency: a systematic review of the literature and three new cases. Mol Genet Metab. 2014;112:259-74.
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Van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, Abulhoul L, et al. Phenotype and genotype in 1010 males withX-linked creatine transporter deficiency. J Med Genet. 2013; 50:463-72.
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Rosenberg EH, Almeida LS, Kleefstra T, deGrauw RS, et all. High prevalence of SLC6A8 deficiency in X-linked mental retardation. AM J Hum Genet. 2004;75:97-105.
Mercimek-Mahmutoglu S, Salomons GS. Creatine Deficiency Syndromes. 2009 Jan 15 [Updated 2015 Dec 10]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.Available from: https://www.ncbi.nlm.nih.gov/books/NBK3794/ Accessed Feb. 5, 2019.
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