Department of Clinical Genetics, VU University Medical Center, P.O. Box 7057, Amsterdam 1007MB, The Netherlands.
J Med Genet. 2013 Jul;50(7):463-72. doi: 10.1136/jmedgenet-2013-101658. Epub 2013 May 3.
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.
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).
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.
肌酸转运蛋白缺乏症是一种 X 连锁智力障碍的单基因病因。自 2001 年首次描述以来，已经发表了几例病例报告，但缺乏对表型、基因型和表型-基因型相关性的概述。
我们对 85 个具有肌酸转运蛋白基因（SLC6A8）致病突变的家庭中的 101 名男性 X 连锁肌酸转运蛋白缺乏症患者的临床、生化和分子遗传学数据进行了回顾性研究。
大多数患者出现中度至重度智力障碍；轻度智力障碍在成年患者中罕见。言语发育特别延迟，但近三分之一的患者能够说句子。除了行为问题和癫痫外，轻度至中度运动功能障碍，包括锥体外系运动异常和胃肠道问题，是常见的临床特征。除了磁共振波谱、分子遗传学检测和肌酸摄取研究外，尿肌酸与肌酐比值也是一种可靠的筛选方法，允许定义诊断指南。三分之一的患者在 SLC6A8 基因中存在新生突变。由于可能存在低水平的体细胞或生殖细胞嵌合体，具有新生突变的受影响儿子的母亲应在进一步妊娠中告知复发风险。具有残留活性的错义突变可能与较轻的表型相关，而延伸至 SLC6A8 基因 3'端的大片段缺失与更严重的表型相关。生化表型的评估显示出人意料的高脑脊液肌酸水平，这表明大脑能够合成肌酸，而大脑肌酸缺乏是由于神经元内肌酸再摄取缺陷所致。
