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.
Cerebral creatine deficiency syndromes (CCDS) 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.
There are three types of CCDS: creatine transporter deficiency (CTD), guanidinoacetate methyltransferase deficiency (GAMT) and arginine: glycine amidinotransferase deficiency (AGAT).
The severity of CCDS varies from patient to patient. Global developmental delays affect all children with these disorders and may be the first sign, appearing before other symptoms. Speech delay may be particularly severe and is present in all affected children. Intellectual disability of variable severity is typically present in all older children and adults.
Additional symptoms may include seizure disorders, muscle weakness, behavior disorders, autism-like behaviors, movement disorders, gastrointestinal problems, and failure to thrive.
creatine transporter defect (CTD)
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. CTD is the most common CCDS. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy, normal GAA in urine, and high creatine: creatinine ratio in urine. Individuals typically present with intellectual disabilities and severe expressive speech delays, seizures, and autistic behaviors. The age of diagnosis ranges from 2 to 66 years of age, indicating that life expectancy can be normal. 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.
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.
guanidinoacetate methyltransferase deficiency (GAMT)
GAMT is a caused by a mutation in the GAMT gene that makes the enzyme that creates creatine, resulting in a shortage of creatine. It is the most severe of the three CCDS due to the elevation of guanidinoacetate (which is neurotoxic) in addition to creatine deficiency. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy and high GAA in urine. People with GAMT deficiency typically present with severe intellectual disabilities, seizure disorders, and autistic behaviors. The onset of symptoms is between ages 3 months and 3 years of age.
The inheritance pattern for GAMT 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.
arginine: glycine amidinotransferase deficiency (AGAT)
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.
CTD is estimated to account for 1-2% of all unexplained X-linked intellectual disabilities. In regards to GAMT deficiency, there have been estimations from 1 out of 2,640,000 to 1 out of 550,000 patients being diagnosed to a conflicting report of 1 out of 115,000 patients being diagnosed. As of 2015, there have only been 110 individuals with GAMT deficiency diagnosed worldwide. The prevalence of AGAT is not known because there have been no studies on record.
CCDS screening is non-invasive. Testing in both urine and plasma is recommended for all three types of CCDS by measuring the concentration of creatine (Cr), guanidinoacetate (GAA), and creatinine (Crn). Follow up genomic testing for specific genes and brain MRI with spectroscopy may be ordered to confirm a CCDS diagnosis.
Individuals diagnosed with a CCDS 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 CCDS patient. Oral supplementation is available and effective if initiated early for GAMT and AGAT. To date, this type of therapy has not shown to improve outcomes in individuals with CTD. Additional treatments for CTD are under investigation.
Oral creatine monohydrate is given to replenish creatine levels in the brain and other tissues in individuals with GAMT and AGAT. A low arginine/protein diet, L-ornithine supplementation, and sodium benzoate are used to reduce toxic levels of guanidinoacetate in individuals with GAMT. There may be some clinical benefits to a subset of individuals with CTD when treated with creatine monohydrate, L-arginine, and glycine. For CCDS 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 GAMT and AGAT is effective in improving patient’s quality of life. The treatment in newborn siblings of individuals with GAMT or AGAT has been shown to prevent disease manifestation.
There are standard treatments for GAMT and AGAT. No known investigational therapies have been reported.
As for CTD, treatments are being investigated. 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.
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