1. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency
- Author
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Joy Yaplito-Lee, Charles E. Schwartz, S Waltz, Katrin Õunap, S Mercimek-Mahmutoglu, Marie-Cécile Nassogne, Luísa Diogo, Hitoshi Osaka, Stephanie Grunewald, Carla Valongo, A Schulze, Marc D'Hooghe, A. Errami, I Poggenburg, Nicola K. Poplawski, F Hofstede, Hanne Meijers-Heijboer, C. Jakobs, Yves Sznajer, Angela Arias, Bridget Wilcken, H Azzouz, Suzanna G.M. Frints, A.P.M. de Brouwer, Gajja S. Salomons, M.S. van der Knaap, Diana Johnson, Tjitske Kleefstra, Antonia Ribes, M. A. Vilaseca, S Schwenger, JM Pinard, Grazia M.S. Mancini, Irina Anselm, S von der Haar, Sarina G. Kant, J.M. van de Kamp, J P Monteiro, Nicola Longo, G Soares, Vassili Valayannopoulos, Petra J. W. Pouwels, Drago Bratkovic, H Van Esch, L Abulhoul, David Cheillan, M Fonseca, Helger G. Yntema, Ofir T. Betsalel, J A Maat-Kievit, S Quijano-Roy, L. Lion-François, Jaime Campistol, Gaelle Pitelet, Paula Garcia, M M C Wamelink, Ania C. Muntau, Ben C.J. Hamel, Arnold Munnich, Omar A. Abdul-Rahman, Hematology, Surgery, Clinical Genetics, Functional Genomics, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Human genetics, Laboratory Medicine, Physics and medical technology, Pediatric surgery, NCA - Brain mechanisms in health and disease, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, MUMC+: DA KG Polikliniek (9), Klinische Genetica, and RS: CARIM School for Cardiovascular Diseases
- Subjects
In vivo magnetic resonance spectroscopy ,Adult ,Male ,medicine.medical_specialty ,Genotype ,DCN MP - Plasticity and memory ,Germline mosaicism ,Nerve Tissue Proteins ,DCN PAC - Perception action and control ,SLC6A8 ,Creatine ,Bioinformatics ,Plasma Membrane Neurotransmitter Transport Proteins ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,chemistry.chemical_compound ,SDG 3 - Good Health and Well-being ,Genes, X-Linked ,Molecular genetics ,Intellectual Disability ,Intellectual disability ,Diagnosis ,Genetics ,medicine ,Missense mutation ,Humans ,Genetic Counselling ,Genetic Testing ,Child ,Genetics (clinical) ,Retrospective Studies ,Creatinine ,business.industry ,Brain Diseases, Metabolic, Inborn ,Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3] ,medicine.disease ,Prognosis ,Doenças Genéticas ,Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory [NCMLS 6] ,Phenotype ,chemistry ,Transportador da Creatina ,Mental Retardation, X-Linked ,business - Abstract
Item does not contain fulltext 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.
- Published
- 2013