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Phenotype and genotype in 101 males with X-linked creatine transporter deficiency
  1. J M van de Kamp1,
  2. O T Betsalel2,
  3. S Mercimek-Mahmutoglu3,
  4. L Abulhoul4,
  5. S Grünewald4,
  6. I Anselm5,
  7. H Azzouz6,
  8. D Bratkovic7,
  9. A de Brouwer8,
  10. B Hamel8,
  11. T Kleefstra8,
  12. H Yntema8,
  13. J Campistol9,
  14. M A Vilaseca9,
  15. D Cheillan10,
  16. M D’Hooghe11,
  17. L Diogo12,
  18. P Garcia12,
  19. C Valongo13,
  20. M Fonseca14,
  21. S Frints15,
  22. B Wilcken16,
  23. S von der Haar17,
  24. H E Meijers-Heijboer1,
  25. F Hofstede18,
  26. D Johnson19,
  27. S G Kant20,
  28. L Lion-Francois21,
  29. G Pitelet21,
  30. N Longo22,
  31. J A Maat-Kievit23,
  32. J P Monteiro24,
  33. A Munnich25,
  34. A C Muntau26,
  35. M C Nassogne27,
  36. H Osaka28,
  37. K Ounap29,
  38. J M Pinard30,
  39. S Quijano-Roy30,
  40. I Poggenburg31,
  41. N Poplawski32,
  42. O Abdul-Rahman33,
  43. A Ribes34,
  44. A Arias34,
  45. J Yaplito-Lee35,
  46. A Schulze3,
  47. C E Schwartz36,
  48. S Schwenger37,
  49. G Soares38,
  50. Y Sznajer39,
  51. V Valayannopoulos40,
  52. H Van Esch41,
  53. S Waltz42,
  54. M M C Wamelink2,
  55. P J W Pouwels43,
  56. A Errami44,
  57. M S van der Knaap45,
  58. C Jakobs2,
  59. G M Mancini23,
  60. G S Salomons2
  1. 1Department of Clinical Genetics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
  2. 2Department of Clinical Chemistry, Metabolic Unit, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
  3. 3Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada
  4. 4Paediatric Metabolic Medicine Unit, Great Ormond Street Hospital, UCL Institute of Child Health, London, UK
  5. 5Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  6. 6Service de Pédiatrie et des maladies métaboliques, l'Hôpital la RABTA, Tunis, Tunisia
  7. 7Metabolic Clinic, SA Pathology, North-Adelaide, Australia
  8. 8Department of Human Genetics, Institute of Genetic and Metabolic Disease, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
  9. 9Neuropediatric Department, Hospital Sant Joan de Déu, Barcelona, Spain
  10. 10Service Maladies Héréditaires du Métabolisme, Groupement Hospitalier Est, INSERM U.1060/Université Lyon-1/Hospices Civils de Lyon, Lyon, France
  11. 11Department of Neurology, Algemeen Ziekenhuis Sint-Jan, Bruges, Belgium
  12. 12Unidade de Doenças Metabólicas, Centro de Desenvolvimento da Criança, Hospital Pediátrico—CHUC, Coimbra, Portugal
  13. 13Unidade de Rastreio Neonatal, Metabolismo e Genética, Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge I.P., Porto, Portugal
  14. 14Unidade de Neuropediatria e Desesenvolvimento, Hospital Garcia de Orta, Almada, Portugal
  15. 15Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
  16. 16Department of Paediatrics & Child Health, Children's Hospital Westmead, Westmead, Australia
  17. 17Pränatalmedizin und Genetik Nürnberg, Medizinisches Versorgungszentrum, Nuremberg, Germany
  18. 18Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands
  19. 19Department of Paediatric Genetics, Sheffield Children's Hospital, Sheffield, UK
  20. 20Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  21. 21Service de neurologie pédiatrique, Hôpital Femme Mère Enfant, Lyon, France
  22. 22Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, Utah, USA
  23. 23Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
  24. 24Department of Pediatrics, Child Development Center Torrado da Silva, Garcia de Orta Hospital, Almada, Portugal
  25. 25Département de Génétique et Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Hôpital des Enfants Malades, Paris, France
  26. 26Abteilung für Molekulare Paediatrie, Dr. von Haunersches Kinderspital, München, Germany
  27. 27Departement de Neurologie pédiatrique, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
  28. 28Division of Neurology Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan
  29. 29Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia
  30. 30Unité de Neurologie Pédiatrique, Département de Pédiatrie, Hôpital Raymond Poincare, Paris-IdF-Ouest University, Paris, France
  31. 31Department of Neuropädiatrie, Klinikum Oldenburg, Oldenburg, Germany
  32. 32South Australia Clinical Genetics Service, Genetics and Molecular Pathology, SA Pathology at the Women's and Children's Hospital, North-Adelaide, Australia
  33. 33Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi, USA
  34. 34Sección de Errores Congénitos del Metabolismo-IBC, Servicio de Bioquímica y Genética Molecular, Hospital Clínic, Ciberer, Barcelona, Spain
  35. 35Department of Metabolic Genetics, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia
  36. 36Center of Molecular Studies, Greenwood Genetic Center, Greenwood, South Carolina, USA
  37. 37Department of Pädiatrie, Kinderzentrum München, München, Germany
  38. 38Unidade Genética Médica, Centro de Genética Médica Jacinto Magalhães, Porto, Portugal
  39. 39Centre de génétique humaine, Cliniques Universitaires Saint-Luc, Brussels, Belgium
  40. 40Reference Center for Inherited Metabolic Disorders, Necker-Enfants Malades Hospital and Paris Descartes University, Paris, France
  41. 41Department of Genetics, Centre for Human Genetics, University Hospitals Leuven, Leuven, Belgium
  42. 42Department of Neuropediatrics, City Hospital Cologne, Cologne, Germany
  43. 43Department of Physics and Medical Technology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
  44. 44MRC Holland BV, Amsterdam, The Netherlands
  45. 45Department of Child Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
  1. Correspondence to Jiddeke Matuja van de Kamp, Department of Clinical Genetics, VU University Medical Center, P.O. Box 7057, Amsterdam 1007MB, The Netherlands; jm.vandekamp{at}


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.

  • Intellectual disability
  • Diagnosis
  • Prognosis
  • genetic counselling
  • SLC6A8

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