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.
Argininie: glycine amidinotransferase deficiency (AGAT) is one of the three cerebral creatine deficiency syndromes (CCDS). These conditions are inborn errors of creatine metabolism which interrupt the formation or transportation of creatine. Creatine is necessary to increase adenosine triphosphate (ATP), which provides energy to all cells in the body.
The severity of AGAT varies from patient to patient. People with AGAT typically present with mild to moderate intellectual disabilities, delayed speech, and may have seizure activity. Some individuals may develop autistic like behaviors. Children with AGAT may not gain weight and grow at the expected rate (failure to thrive), and have delayed development of motor skills such as sitting and walking. Affected individuals may also have weak muscle tone and tend to tire easily.
AGAT is the first step of creatine production, resulting in the formation of guanidinoacetate, the immediate precursor of creatine. Mutations found in the GATM gene impair the body’s production of creatine. Out of the three CCDS, AGAT is the least reported. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy and low GAA in urine and plasma. People with AGAT typically present with mild to moderate intellectual disabilities.
The inheritance pattern for AGAT 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.
Testing in both urine and plasma is recommended by measuring the concentration of creatine (Cr), guanidinoacetate (GAA), and creatinine (Crn). A positive screen for AGAT is based on plasma GAA that is low with creatine being low to normal and urine GAA that is low and creatine being low to normal.
Follow up genomic testing for mutations in the GATM gene may be ordered along with brain MRI with spectroscopy to confirm an AGAT 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.
Individual diagnosed with AGAT 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 AGAT patient. Oral supplementation is available and effective if initiated early for AGAT.
Oral creatine monohydrate is given to replenish creatine levels in the brain and other tissues in individuals with AGAT. For AGAT 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 AGAT is effective in improving a patient’s quality of life. The treatment in newborn siblings of individuals with AGAT deficiency can prevent disease manifestation.
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Stockler-Ipsiroglu S, Apatean D, Battini R, DeBrosse S, et al. Arginine: glycine amidinotransferase (AGAT) deficiency: Clinical features and long-term outcomes in 16 patients diagnosed worldwide. Mol Genet Metab. 2015; Dec;116(4):252-9.
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.
Stockler-Ipsiroglu S, van Karnebeek C, Longo N, Korenke GC, et all. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment, and monitoring. Mol Genet Metab. 2014;111:16-25.
Van de Kamp M, Mancini GM, Salomons GS. X-linked creatine transporter deficiency: clinical aspects and pathophysiology. J Inherit Metab Dis. 2014;37:715-33.
Trotier-Faurion A, Dezard S, Taran F, Valayannopoulos V, de Lonlay P, Mabondzo A. Synthesis and biological evaluation of new creatine fatty esters revealed dodecyl creatine ester as a promising drug candidate for the treatment of the creatine transporter deficiency. J Med Chem. 2013; Jun 27;56(12):5173-81.
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.
Longo N, Ardon O, Vanzo R, Schwartz E, Pasquali M. Disorders of creatine transport and metabolism. Am J Med Genet C Semin Med Genet. 2011;157C:72-8.
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.
Arginine:Glycine Amidinotransferase Deficiency. Genetic Home Reference. Rewviewed December 2015. https://ghr.nlm.nih.gov/condition/arginineglycine-amidinotransferase-deficiency Accessed Feb. 5, 2019.
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