RT Journal Article
SR Electronic
T1 Phenotype and genotype in 101 males with X-linked creatine transporter deficiency
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 463
OP 472
DO 10.1136/jmedgenet-2013-101658
VO 50
IS 7
A1 J M van de Kamp
A1 O T Betsalel
A1 S Mercimek-Mahmutoglu
A1 L Abulhoul
A1 S Grünewald
A1 I Anselm
A1 H Azzouz
A1 D Bratkovic
A1 A de Brouwer
A1 B Hamel
A1 T Kleefstra
A1 H Yntema
A1 J Campistol
A1 M A Vilaseca
A1 D Cheillan
A1 M D’Hooghe
A1 L Diogo
A1 P Garcia
A1 C Valongo
A1 M Fonseca
A1 S Frints
A1 B Wilcken
A1 S von der Haar
A1 H E Meijers-Heijboer
A1 F Hofstede
A1 D Johnson
A1 S G Kant
A1 L Lion-Francois
A1 G Pitelet
A1 N Longo
A1 J A Maat-Kievit
A1 J P Monteiro
A1 A Munnich
A1 A C Muntau
A1 M C Nassogne
A1 H Osaka
A1 K Ounap
A1 J M Pinard
A1 S Quijano-Roy
A1 I Poggenburg
A1 N Poplawski
A1 O Abdul-Rahman
A1 A Ribes
A1 A Arias
A1 J Yaplito-Lee
A1 A Schulze
A1 C E Schwartz
A1 S Schwenger
A1 G Soares
A1 Y Sznajer
A1 V Valayannopoulos
A1 H Van Esch
A1 S Waltz
A1 M M C Wamelink
A1 P J W Pouwels
A1 A Errami
A1 M S van der Knaap
A1 C Jakobs
A1 G M Mancini
A1 G S Salomons
YR 2013
UL http://jmg.bmj.com/content/50/7/463.abstract
AB 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.