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Creatine Deficiency Syndromes.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
2009 Jan 15 [updated 2011 Aug 18].



The cerebral creatine deficiency syndromes (CCDS), inborn errors of creatine metabolism, include the two creatine biosynthesis disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT or GATM) deficiency, and the creatine transporter (SLC6A8) deficiency. Intellectual disability and seizures are common to all three CCDS. The majority of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; a significant proportion have pyramidal/extrapyramidal findings. Onset is between ages three months and three years. Only seven individuals with AGAT deficiency have been reported. The phenotype of SLC6A8 deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, and behavior disorder; age at diagnosis ranges from two to 66 years. Females heterozygous for SLC6A8 deficiency may have learning and behavior problems.


Cerebral creatine deficiency in cranial MR spectroscopy (MRS) is the characteristic hallmark of all CCDS. Diagnosis of CCDS relies on: measurement of guanidinoacetate (GAA), creatine, and creatinine in urine and plasma; and molecular genetic testing of the three genes involved, GAMT, GATM, or SLC6A8. If molecular genetic test results are inconclusive, GAMT enzyme activity (in cultured fibroblast or lymphoblasts), GATM enzyme activity (in lymphoblasts), or creatine uptake in cultured fibroblasts can be assessed.


Treatment of manifestations: GAMT deficiency and AGAT deficiency are treated with oral creatine monohydrate to increase cerebral creatine levels. Treatment of GAMT deficiency may also require supplementation of ornithine and dietary restriction of arginine. In males with SLC6A8 deficiency creatine supplementation alone does not improve clinical outcome and does not result in increased cerebral creatine levels; likewise, high-dose L-arginine and L-glycine supplementation did not improve clinical or biochemical outcome. One female with intractable epilepsy responded to high-dose L-arginine and L-glycine supplementation with cessation of seizures. Prevention of primary manifestations: Whether early treatment prevents disease manifestations is unknown; however, newborn sibs of individuals with AGAT or GAMT deficiency seem to benefit from early treatment. Surveillance: In those treated with creatine monohydrate, routine measurement of renal function to detect possible creatine-associated nephropathy is warranted. Evaluation of relatives at risk: Early diagnosis of neonates at risk for GAMT deficiency, AGAT deficiency, and SLC6A8 deficiency by biochemical or molecular genetic testing allows for early diagnosis and treatment of the defects in creatine metabolism.


GAMT deficiency and AGAT deficiency are inherited in an autosomal recessive manner. At conception, each sib of an individual with GAMT deficiency or AGAT deficiency has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. SLC6A8 deficiency is inherited in an X-linked manner. Mothers who are carriers have a 50% chance of transmitting the mutation in each pregnancy: sons who inherit the mutation will be affected; daughters who inherit the mutation will be carriers and may have learning and behavioral problems. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for all three defects in creatine metabolism if the disease-causing mutation(s) in the family are known.

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