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Creatine Deficiency Syndromes.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.
2009 Jan 15 [updated 2015 Dec 10].

Excerpt

CLINICAL CHARACTERISTICS:

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) deficiency, and the creatine transporter (CRTR) 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; about 40% have movement disorder. Onset is between ages three months and three years. Only 14 individuals with AGAT deficiency have been reported. The phenotype of CRTR deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, movement disorder and behavior disorder; age at diagnosis ranges from two to 66 years. Clinical phenotype of females heterozygous for CRTR deficiency ranges from asymptomatic to severe phenotype resembling male phenotype.

DIAGNOSIS/TESTING:

Cerebral creatine deficiency in brain MR spectroscopy (1H-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, and 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.

MANAGEMENT:

Treatment of manifestations: GAMT deficiency and AGAT deficiency are treated with oral creatine monohydrate to replenish cerebral creatine levels. Treatment of GAMT deficiency requires supplementation of ornithine and dietary restriction of arginine or protein. In males with CRTR deficiency creatine supplementation alone does not improve clinical outcome and does not result in replenished cerebral creatine levels; likewise, high-dose L-arginine and L-glycine supplementation so far has not consistently improve clinical or biochemical outcome in males although some have been reported to have increased muscle mass and improved motor and personal social IQ skills. One female with intractable epilepsy responded to high-dose L-arginine and L-glycine supplementation with cessation of seizures. Prevention of primary manifestations: Early treatment at the asymptomatic stage of the disease in individuals with GAMT and AGAT deficiencies appears to be beneficial: treatment in newborn sibs of individuals with AGAT or GAMT deficiency prevented disease manifestations. 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 CRTR deficiency by biochemical or molecular genetic testing allows for early diagnosis and treatment of the defects in creatine metabolism.

GENETIC COUNSELING:

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. CRTR deficiency is inherited in an X-linked manner. Mothers who are carriers have a 50% chance of transmitting the pathogenic variant in each pregnancy; sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant will be heterozygous and may have learning and behavior 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 pathogenic variants in the family are known.

Copyright © 1993-2016, University of Washington, Seattle. All rights reserved.

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