Creatine Transporter Deficiency and Prevalence Survey for Healthcare Professionals

  • Creatine transporter deficiency (CTD) is a rare X-linked inborn error of creatine metabolism that causes global developmental delay (GDD) and intellectual disability (ID). It occurs due to a loss of function mutation in the creatine transporter gene, SLC6A8. This protein transports creatine across the blood–brain barrier and cell membranes into neurons, where creatine functions as an essential part of the energy storage and production process. Without the creatine transporter, the brain is deficient in creatine and cannot produce the energy required to function properly. No approved treatment for CTD is currently available.
  • Because CTD is an X-linked disease, it affects males more severely than females. In addition to GDD and ID, symptoms include speech and language delay; seizures; movement disorders, including delays in crawling and walking; and behavior disorders, including autism and attention deficit and/or hyperactivity. Other symptoms of CTD may include hypotonia; vomiting and other gastrointestinal problems; failure to thrive; dysmorphic facial features; and a slender body build.1,4 Diagnosis may occur as early as age 1 or when male infants begin to miss developmental milestones.
  • Females who inherit the defective gene become carriers. They may have a mild intellectual disability or be asymptomatic.1
  • The exact prevalence of CTD is unknown, but it is estimated to be the second largest cause of autism and X-linked intellectual disability after fragile-X syndrome. CTD is estimated to account for 2% to 5% of X-linked intellectual disability, or 1% of all intellectual disability of unknown etiology.2

Scroll down further for more information about diagnostic testing, differential diagnosis, guidelines on CCDS management, etc

CTD Prevalence Survey

Please take a moment to participate in our CTD Prevalence Survey. Your participation will enable us to gain a more accurate assessment of the worldwide prevalence of CTD.

Other Cerebral Creatine Deficiency Syndromes

CTD is one of three cerebral creatine deficiency syndromes (CCDS). The other two—guanadinoacetate methyltransferase (GAMT) deficiency and arginine:glycine amidinotransferase (AGAT) deficiency—are autosomal recessive inborn errors of creatine metabolism. They can affect both males and females, causing GDD and ID. A defect in either the GAMT gene or the GATM gene renders the body incapable of producing an enzyme needed in the manufacture of creatine, so creatine synthesis cannot occur. Like CTD, the creatine biosynthesis disorders result in a lack of creatine in the brain, impairing intellectual development and functioning. They are treatable with supplementary creatine monohydrate.1

GAMT deficiency is rare. About 110 affected individuals have been identified in case reports. In addition to GDD and ID, Individuals with GAMT deficiency  may experience intractable epilepsy; language delay; movement disorders such as chorea, athetosis, dystonia, or ataxia; and behavior disorders, including hyperactivity, autism, or self-injury.1

AGAT deficiency is rarer still, with fewer than 20 cases reported. In addition to GDD and ID, individuals with AGAT deficiency experience language delay and myopathy with low muscle mass and proximal muscle weakness. Less common are behavior disorders such as autistic behavior with poor social contact, short attention span, and repetitive movements of the hand. Seizures are infrequent and rare.3

Differential Diagnosis1

All individuals with creatine biosynthesis disorders and all males with CTD are almost completely lacking in cerebral creatine. (Female carriers may have normal or partially depleted levels of cerebral creatine.) Cerebral creatine deficiency should be suspected when

  • A young child presents with GDD, hypotonia, seizures, and movement disorder, or
  • An older child presents with ID, epilepsy, movement disorder, and behavior problems.1

Proton magnetic resonance spectroscopy (H-MRS) can establish whether patients are deficient in cerebral creatine or not. But H-MRS often requires general anesthesia in infants and children and it may not be available for routine screening. Moreover, H-MRS cannot identify the cause of the cerebral creatine deficiency; this can only be accomplished through biochemical testing and/or molecular genetic testing. So H-MRS of the brain is not usually recommended as the first step in the differential diagnosis of CTD and the creatine biosynthesis disorders (although it may later be appropriate).5

Testing for CCDS

The diagnostic testing algorithm for patients with clinical symptoms of CTD or a creatine biosynthesis disorder (GAMT, AGAT) is established by measuring creatine, guanidinoacetate, and creatinine via LC-MS/MS or GC-MS in plasma, urine and cerebrospinal fluid (CSF).

Urine test
. Screen for creatine (Cr), creatinine (Crn), and guanadinoacetate (GAA).

  • A high creatine-to-creatinine ratio and a normal or slightly elevated GAA concentration in the urine is suggestive of CTD. Proceed with molecular genetic testing of SLC6A8. (Heterozygous female carriers, in addition to having normal cerebral creatine, may have a normal creatine-to-creatinine ratio in the urine. Molecular genetic testing of SLC6A8 is the only way to arrive at a definitive diagnosis.)
  • A high concentration of GAA in the urine points toward GAMT deficiency. Proceed with molecular genetic testing of GAMT.

Plasma test
. Diagnosis of AGAT deficiency requires screening urine and blood plasma. Low concentrations of GAA in both point toward AGAT deficiency. Proceed with molecular genetic testing of GATM.


guanidinoacetate (GA)creatine (Cr)guanidinoacetate/creatininecreatine/creatinine
guanidinoacetate (GA)creatine (Cr)
Note: *inconsistent data (variable urinary creatine/creatinine in females with CTD)

Molecular genetic testing. There are three approaches to molecular genetic testing:

  1. Single gene testing is useful when urine and plasma tests warrant testing for a defect in SLC6A8, GAMT, or GATM.
  2. A multi-gene panel including SLC6A8, GAMT, and GATM may be considered when clinical symptoms suggest CCDS but urine and plasma tests have not been done. Examples include and vary from lab to lab: seizure/epilepsy panels, ID panels and Autism Spectrum Disorder panels.
  3. More comprehensive genomic testing—if available—may be considered in cases where single-gene testing and/or use of a multi-gene panel has not confirmed a diagnosis in an individual with symptoms of CCDS.

Educational Video on Diagnosing Creatine Deficiencies 

Here is the link to a video presentation given at the SERGG (South Eastern Regional Genetics Groups) discussing CCDS diagnosing. The slides are also available for downloads.
Sarah Young PhD
2015 SERC-SERGG Annual Conference
Renaissance Asheville Hotel
Asheville, NC
July 18th, 2015


About the Presentation
Dr. Sarah Young presents, Diagnosing Creatine Deficiency Syndromes.
Presenter Biography
Sarah Young is an Assistant Professor in the Department of Pediatrics, in the Duke School of Medicine, and Co-Director of the Duke Biochemical Genetics Laboratory. She graduated from the Manchester University, UK with a degree in Biochemistry in 1993 and completed a Ph.D. in Biochemistry in 1998 at the Institute of Child Health, University College London. She has worked at the Duke School of Medicine since 1999, completing a fellowship in Clinical Biochemical Genetics in 2005. Her main research interest is the development and application of biomarker assays for rare, inherited metabolic disorders that will improve diagnosis of these conditions, and are useful for monitoring treatments. This includes neurometabolic disorders such as the creatine deficiency syndromes. These disorders can be diagnosed using liquid chromatography-tandem mass spectrometric assays that measure biomarkers in urine and plasma. Additionally, more rapid methods have been developed using tandem mass spectrometry that can be used for newborn screening.

Guidelines on Management of CCDS1

No approved treatment for CTD is currently available, but various therapies can help manage symptoms. Appropriate therapies may include occupational therapy, physiotherapy, speech-language therapy, and behavior therapy. Antiepileptic drugs may be used for seizure management. Supplementary creatine monohydrate, arginine, and glycine are often utilized in the management of CTD patients.

GAMT deficiency is treatable with creatine monohydrate, ornithine supplements (to decrease neurotoxic GAA in the brain), and a protein-restricted diet. The effectiveness of this regimen may depend on how early treatment is begun.

AGAT deficiency is treatable with creatine monohydrate. Treatment begun at an early age may lead to better outcomes.


1.  Mercimek-Mahmutoglu S, Salomons GS. Creatine Deficiency Syndromes. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2015 Published January 15, 2009. Updated December 10, 2015. Accessed December 19, 2016

2. Clark AJ et al. X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology. Hum Genet 2006 Jul;119(6)604-10

3. Stockler-Ipsiroglu S, Apatean D, Battini R et al. Arginine;glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide. Molecular Genetics and Metabolism. 2015;116:252-259.

4. Miller JS et al. Red Flags for Creatine Transporter Deficiency, and Potential Outcome Variables for the Severely Impaired. Poster first presented at Society for Developmental Behavioral Pediatrics (SDBP) 2016 Annual Meeting Savannah,GA September 2016.

5. Stockler-Ipsiroglu S, Mercimek-Mahmutoglu S, Salomons GS. Creatine deficiency syndromes. In: Saudubray JM, Baumgartner MR, Walter JH, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 5th ed. Springer; 2012:239-247.