Última actualización:
2/8/2023
Años publicados: 2018, 2019, 2023
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 transport of creatine. Creatine is necessary to render available the energy of adenosine triphosphate (ATP) 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 or variant)) in the creatine transporter gene, SLC6A8. This variant 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, but 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.
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 deficiency is a caused by a variant in the GAMT gene that codes for the enzyme that transforms guanidinoacetate into creatine, resulting in a shortage of creatine and the accumulation of guanidinoacetate (GAA). 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 have cerebral creatine deficiency on MR spectroscopy and high GAA in plasma. 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 deficiency impairs the first step of creatine production, resulting in decreased formation of guanidinoacetate, the immediate precursor of creatine. Variants 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 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 regard to GAMT deficiency, there have been estimations from 1 out of 250,000 to 1 out of 550,000. 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 too few 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. GAMT deficiency is also part of the recommended uniform newborn screening panel and children can be identified at birth in states that have adopted it.
Treatments
Individuals diagnosed with a CCDS 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, glycine, and betaine. 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.
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: prpl@cc.nih.gov
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
Stockler-Ipsiroglu S, Apatean D, Battini R, DeBrosse S, et al. Arginine: glycine amidinotransferase (AGAT) deficiency: Clinical features and long-term outcomes in 16 patients diagnosed worldwide. Mol Genet Metab. 2015; Dec;116(4):252-9.
Dunbar M. Jaggumantri S, Sargent M, Stockler-Ipsiroglu S(2), van Karnebeek CD. Treatment of X-linked creatine transporter (SLC6A8 deficiency: a systematic review of the literature and three new cases. Mol Genet Metab. 2014;112:259-74.
Stockler-Ipsiroglu S, van Karnebeek C, Longo N, Korenke GC, et all. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment, and monitoring. Mol Genet Metab. 2014;111:16-25.
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.
Trotier-Faurion A, Dezard S, Taran F, Valayannopoulos V, de Lonlay P, Mabondzo A. Synthesis and biological evaluation of new creatine fatty esters revealed dodecyl creatine ester as a promising drug candidate for the treatment of the creatine transporter deficiency. J Med Chem. 2013; Jun 27;56(12):5173-81.
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, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK3794/ Accessed Dec 7, 2022.
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