Creatine Transporter Deficiency (CTD) Information
Mutations in the SLC6A8 gene result in CTD. CTD is also referred to as SLC6A8 Deficiency, CRTR, and X-linked Creatine Transporter Deficiency.
While patients with CTD have the necessary AGAT and GAMT enzymes to form creatine, the creatine transporter does not function properly. This results in creatine in the bloodstream, but not in the brain and muscles.
CTD patients do not experience high levels of GAA like GAMT patients and are not typically prescribed a restricted diet. To date, there is no proven treatment for CTD.
Symptoms
CTD severity varies by patient, with global developmental delays often appearing first. Common features include intellectual disability, speech and language delays, autistic behavior, and seizures. Additional symptoms may include muscle weakness, hyperactivity, behavior issues, gastrointestinal problems, slow growth, delayed motor skills, and easy fatigue.
CTD is caused by a defect in a gene located on the X chromosome. It can be inherited from a female parent and is more likely to affect male children.
CTD is an X-linked disorder, which means it is caused by a defect in a gene located on the X chromosome (Mercimek-Andrews et al., 2022). Because females have two X chromosomes, their symptoms are usually less severe, due to the possibility of having one affected copy of the gene and one functional copy of the gene. Males generally have more severe symptoms because they only have one X chromosome, which has the defective gene. Over 60 versions of the SLC6A8 gene have been reported (Goldstein et al., 2024), and work is currently ongoing to understand how different mutations lead to different clinical outcomes.
Additional Information
CCDS Symptoms
The most common CCDS symptoms are listed below.
- Speech delay may be particularly severe and appears to be present in all untreated children. Some individuals develop no speech or speak only in single words.
- Global Developmental Delay affects young children with these disorders. It may be the first sign, appearing before other symptoms.
- Intellectual Disability of variable severity is typically present in all older children and adults.
- Seizure disorders have a variable age of onset and severity and are not always present.
- Hypotonia, muscle weakness, and muscle hypotrophy are common.
- Behavior disorders including autism-like behaviors and hyperactivity often occur.
- Movement disorder including dystonia and dyskinesia (sometimes labeled as cerebral palsy) may be present.
- Gastrointestinal problems such as chronic constipation and vomiting are common, especially in children with CTD.
- Failure to thrive is a term often used to describe CCDS patients.
Initial Diagnoses
It is often many years before the CCDS patient is diagnosed due to the non-specific symptoms of the disorders and the lack of clear dysmorphic features. CCDS patients are often first diagnosed with other disorders, including:
- Developmental Delay/Disability
- Failure to Thrive
- Cerebral Palsy
- Unknown Mitochondrial Disorder
- Movement Disorders
- Gastrointestinal Disorders
- Epilepsy
- Autism
View Clinician Screening recommendations.
CCDS Prevalence
The exact prevalence of Cerebral Creatine Deficiency Syndromes is unknown. Yet, sources estimate that approximately 1% of individuals with intellectual disabilities of unknown origin may have a Cerebral Creatine Deficiency Syndrome. It is also estimated that Creatine Transporter Deficiency (CTD) represents the second largest cause of x-linked mental disability behind Fragile X syndrome. There are more than 100 documented cases of GAMT Deficiency. AGAT is the rarest of the CCDS with only a few dozen known cases.
