title: Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes.
abstract: Cerebral creatine deficiency syndromes (CCDS) are a group of inborn errors of creatine metabolism that involve AGAT and GAMT for creatine biosynthesis disorders and SLC6A8 for creatine transporter (CT1) deficiency. Deficiencies in the three enzymes can be distinguished by intermediate metabolite levels, and a definitive diagnosis relies on the presence of deleterious mutations in the causative genes. Mutations and unclassified variants were identified in 41 unrelated patients, and 22 of these mutations were novel. Correlation of sequencing and biochemical data reveals that using plasma guanidinoacetate (GAA) as a biomarker has 100% specificity for both AGAT and GAMT deficiencies, but AGAT deficiency has decreased sensitivity in this assay. Furthermore, the urine creatine:creatinine ratio is an effective screening test with 100% specificity in males suspected of having creatine transporter deficiency. This test has a high false-positive rate due to dietary factors or dilute urine samples and lacks sensitivity in females. We conclude that biochemical screening for plasma GAA and measuring of the urine creatine:creatinine ratio should be performed for suspected CCDS patients prior to sequencing. Also, based on the results of this study, we feel that sequencing should only be considered if a patient has abnormal biochemical results on repeat testing.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Matthew S
authors: MS
authors: Comeaux
authors: Jing
authors: J
authors: Wang
authors: Guoli
authors: G
authors: Wang
authors: Soledad
authors: S
authors: Kleppe
authors: Victor Wei
authors: VW
authors: Zhang
authors: Eric S
authors: ES
authors: Schmitt
authors: William J
authors: WJ
authors: Craigen
authors: Deborah
authors: D
authors: Renaud
authors: Qin
authors: Q
authors: Sun
authors: Lee-Jun
authors: LJ
authors: Wong
mesh_terms: D000579:Amidinotransferases / Q000097:blood / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D020739:Brain Diseases, Metabolic, Inborn / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D003401:Creatine / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D005260:Female; D050937:Guanidinoacetate N-Methyltransferase / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D007805:Language Development Disorders / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D038901:X-Linked Intellectual Disability / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009069:Movement Disorders / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D013064:Speech Disorders / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D013577:Syndrome
chemical_list: D026901:Membrane Transport Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C080679:creatine transporter; D003404:Creatinine; D050937:Guanidinoacetate N-Methyltransferase; D000579:Amidinotransferases; D003401:Creatine