Last updated:
1/17/2025
Years published: 2019, 2022, 2025
NORD gratefully acknowledges Nicola Longo, MD, PhD, Chief, Division of Clinical Genetics, Department of Human Genetics, University of California Los Angeles; Scientific and Medical Advisory Board, Association for Creatine Deficiencies, for the preparation of this report.
Summary
Creatine transporter deficiency (CTD) is an inborn error of creatine metabolism. The onset of symptoms occurs during infancy, but the average age of diagnosis ranges from 2 to 66 years of age. Since the disease is now becoming better recognized and testing is available, it is anticipated that diagnosis will primarily occur within the first 3 years of life.
Introduction
CTD is one of the three cerebral creatine deficiency syndromes (CCDS). These conditions are inborn errors of creatine metabolism which interrupt the formation or transport of creatine. Creatine is necessary to favor the utilization of adenosine triphosphate (ATP), which provides energy to all cells in the body. Creatine is essential to sustain the high energy levels needed for muscle and brain development.
The severity of CTD varies from person to person. Difficulty growing and gaining weight (failure to thrive) might be the first symptom. Global developmental delays affect all children with this disorder and intellectual disability of variable severity is typically present with prominent speech and language delay, autistic behavior and seizures.
Additional symptoms may include muscle weakness, behavior disorders, hyperactivity and gastrointestinal problems. Children with CTD may have slow growth and delayed development of motor skills such as sitting and walking. Affected individuals tend to get tired easily. Males with CTD might be prone to irregular heartbeat and cardiac arrest due to abnormal electrical properties of their hearts.
CTD is caused by a change (variant) in the creatine transporter gene, SLC6A8. This variant results in a block in the transport of creatine to the brain and muscle.
The inheritance pattern for CTD is X-linked. X-linked genetic disorders are conditions caused by a disease-causing gene variant on the X chromosome and mostly affect males. Females who have a disease-causing gene variant on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the gene variant. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease-causing gene variant, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the gene variant to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
CTD is estimated to account for 1-2% of all unexplained X-linked intellectual disabilities. It is the most common of the three cerebral creatine deficiency syndromes.
Testing in both urine and plasma is recommended by measuring the concentration of creatine (Cr), guanidinoacetate (GAA) and creatinine (Crn). A positive screen for CTD is based on normal plasma GAA and creatine, with abnormally elevated urine creatine being elevated in males (it may be normal in females).
Genomic testing for variants in the SLC6A8 gene or as part of complete genome sequencing can confirm the diagnosis along with brain MRI with spectroscopy. MRI with spectroscopy measures creatine levels in the brain.
Treatment
Individuals diagnosed with CTD 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 with oral supplementation are available for individuals with a cerebral creatine deficiency syndrome, but this type of treatment has not shown to improve the outcomes in most people with CTD.
However, there may be some clinical benefits to a subset of individuals with a CTD when treated with creatine monohydrate, L-arginine, glycine and betaine. Therapy is more likely to be effective in females and individuals in whom the change in the SLC6A8 gene does not completely block creatine transport. Additional treatments for CTD are under investigation.
For CTD patients being treated with creatine monohydrate, a routine measurement of renal function should be considered to detect possible creatine-associated kidney disease (nephropathy).
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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Gechijian LN, Muncipinto G, Rettenmaier TJ, et al. Novel corrector for variants of SLC6A8: a therapeutic opportunity for creatine transporter deficiency. ACS Chem Biol. 2024;19(11):2372-2382. doi:10.1021/acschembio.4c00571
Longo N, Voss LA, Frigeni M, Balakrishnan B, Pasquali M. Response to therapy of creatine transporter deficiency caused by a hypomorphic variant in SLC6A8. Mol Genet Metab. 2024 Nov;143(3):108595. doi: 10.1016/j.ymgme.2024.108595. Epub 2024 Oct 12. PMID: 39418753.
Mabondzo A, van de Kamp J, Mercimek-Andrews S. Dodecyl creatine ester therapy: from promise to reality. Cell Mol Life Sci. 2024;81(1):186. Published 2024 Apr 17. doi:10.1007/s00018-024-05218-y
Tauer K, Theile C, Owens JW, Cecil KM, Shillington A. Arginine, glycine, and creatine supplementation improves symptoms in a female with creatine transporter deficiency. Psychiatr Genet. 2024;34(4):86-90. doi:10.1097/YPG.0000000000000372
Levin MD, Bianconi S, Smith A, et al. X-linked creatine transporter deficiency results in prolonged QTc and increased sudden death risk in humans and disease model. Genet Med. 2021;23(10):1864-1872. doi:10.1038/s41436-021-01224-8
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.
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.
INTERNET
Mercimek-Andrews S, Salomons GS. Creatine Deficiency Disorders. 2009 Jan 15 [Updated 2022 Feb 10]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK3794/ Accessed Jan 16, 2025.
X-Linked creatine deficiency. Genetics Home Reference. Updated February 6, 2023. https://medlineplus.gov/genetics/condition/x-linked-creatine-deficiency/ Accessed Jan 16, 2025.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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