TY - JOUR T1 - Phenotype and genotype in 101 males with X-linked creatine transporter deficiency JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2013-101658 SP - jmedgenet-2013-101658 AU - J M van de Kamp AU - O T Betsalel AU - S Mercimek-Mahmutoglu AU - L Abulhoul AU - S Grünewald AU - I Anselm AU - H Azzouz AU - D Bratkovic AU - A de Brouwer AU - B Hamel AU - T Kleefstra AU - H Yntema AU - J Campistol AU - M A Vilaseca AU - D Cheillan AU - M D’Hooghe AU - L Diogo AU - P Garcia AU - C Valongo AU - M Fonseca AU - S Frints AU - B Wilcken AU - S von der Haar AU - H E Meijers-Heijboer AU - F Hofstede AU - D Johnson AU - S G Kant AU - L Lion-Francois AU - G Pitelet AU - N Longo AU - J A Maat-Kievit AU - J P Monteiro AU - A Munnich AU - A C Muntau AU - M C Nassogne AU - H Osaka AU - K Ounap AU - J M Pinard AU - S Quijano-Roy AU - I Poggenburg AU - N Poplawski AU - O Abdul-Rahman AU - A Ribes AU - A Arias AU - J Yaplito-Lee AU - A Schulze AU - C E Schwartz AU - S Schwenger AU - G Soares AU - Y Sznajer AU - V Valayannopoulos AU - H Van Esch AU - S Waltz AU - M M C Wamelink AU - P J W Pouwels AU - A Errami AU - M S van der Knaap AU - C Jakobs AU - G M Mancini AU - G S Salomons Y1 - 2013/05/02 UR - http://jmg.bmj.com/content/early/2013/05/02/jmedgenet-2013-101658.abstract N2 - Background Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype–genotype correlation has been lacking. Methods We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). Results and conclusions Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3′ end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones. ER -