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.
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 recognized and screening is available, it is anticipated that diagnosis will primarily occur within the first 3 years of life.
CTD 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. Creatine is essential to sustain the high energy levels needed for muscle and brain development.
The severity of CTD varies from patient to patient. Global developmental delays affect all children with this disorder and may be the first sign, appearing before other symptoms. 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 experience slow growth (failure to thrive) and delayed development of motor skills such as sitting and walking. Affected individuals tend to tire easily.
CTD is caused by a change (mutation) in the creatine transporter gene, SLC6A8. This mutation results in a blockage in the transportation of creatine to the brain and muscle.
The inheritance pattern for CTD is X-linked. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene 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 is able to reproduce, he will pass the non-working gene to all of 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 offspring.
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 plasma GAA that is normal with creatine being normal and urine GAA that is normal and creatine being elevated (maybe normal in females).
Follow up genomic testing for mutations in the SLC6A8 gene may be ordered along with brain MRI with spectroscopy to confirm a CTD diagnosis. MRI with spectroscopy is useful for measuring creatine levels in the brain.
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, and glycine. 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).
Treatments are being investigated for CTD. One such investigation is the transport of dodecyl creatine ester incorporated into lipid nanocapsules. This strategy has shown to be able to cross the blood-brain barrier and enter brain cells. This investigation is highly preliminary. Another is a creatine analog called cyclocreatine that has shown improvements in cognitive abilities in SLC6A8 deficiency mice. This therapy is being investigated and shows the most promising for a possible treatment for CTD patients.
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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