Division of Pediatric Neurology, Department of Pediatrics, BC Children's Hospital, Vancouver, Canada.
Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, Child & Family Research Institute, University of British Columbia, Vancouver, Canada; Treatable Intellectual Disability Endeavor in British Columbia (TIDE-BC), Vancouver, Canada.
Mol Genet Metab. 2014 Aug;112(4):259-74. doi: 10.1016/j.ymgme.2014.05.011. Epub 2014 May 29.
Creatine transporter deficiency (CTD) is an X-linked inborn error of creatine metabolism characterized by reduced intra-cerebral creatine, developmental delay/intellectual disability, (ID), behavioral disturbance, seizures, and hypotonia in individuals harboring mutations in the SLC6A8 gene. Treatment for CTD includes supplementation with creatine, either alone or in combination with creatine precursors (arginine or glycine). Unlike other disorders of creatine metabolism, the efficacy of its treatment remains controversial.
We present our systematic literature review (2001-2013) comprising 7 publications (case series/reports), collectively describing 25 patients who met the inclusion criteria, and 3 additional cases treated at our institution. Definitions were established and extracted data analyzed for cognitive ability, psychiatric and behavioral disturbances, epilepsy, and cerebral proton magnetic resonance spectroscopy measurements at pre- and post-treatment.
Treatment regimens varied among the 28 cases: 2 patients received creatine-monohydrate supplementation; 7 patients received L-arginine; 2 patients received creatine-monohydrate and L-arginine; and 17 patients received a combination of creatine-monohydrate, L-arginine and glycine. Median treatment duration was 34.6 months (range 3 months-5 years). Level of evidence was IV. A total of 10 patients (36%) demonstrated response to treatment, manifested by either an increase in cerebral creatine, or improved clinical parameters. Seven of the 28 patients had quantified pre- and post-treatment creatine, and it was significantly increased post-treatment. All of the patients with increased cerebral creatine also experienced clinical improvement. In addition, the majority of patients with clinical improvement had detectable cerebral creatine prior to treatment. 90% of the patients who improved were initiated on treatment before nine years of age.
Acknowledging the limitations of this systematic review, we conclude that a proportion of CTD patients show amenability to treatment-particularly milder cases with residual brain creatine, and therefore probable residual protein function. We propose systematic screening for CTD in patients with ID, to allow early initiation of treatment, which currently comprises oral creatine, arginine and/or glycine supplementation. Standardized monitoring for safety and evaluation of treatment effects are required in all patients. This study provides effectiveness on currently available treatment, which can be used to discern effectiveness of future interventions (e.g. cyclocreatine).
肌酸转运蛋白缺乏症（CTD）是一种 X 连锁的先天性肌酸代谢异常，其特征是脑内肌酸减少、发育迟缓/智力障碍（ID）、行为障碍、癫痫发作和低张力，这些症状存在于 SLC6A8 基因突变的个体中。CTD 的治疗包括肌酸补充治疗，单独使用或与肌酸前体（精氨酸或甘氨酸）联合使用。与其他肌酸代谢紊乱不同，其治疗效果仍存在争议。
我们进行了系统的文献综述（2001-2013 年），包括 7 篇出版物（病例系列/报告），共描述了 25 名符合纳入标准的患者，以及我们机构治疗的 3 例额外病例。我们确定了定义并提取了治疗前后认知能力、精神和行为障碍、癫痫和脑质子磁共振波谱测量的数据进行分析。
28 例患者的治疗方案不同：2 例患者接受肌酸一水合物补充治疗；7 例患者接受 L-精氨酸；2 例患者接受肌酸一水合物和 L-精氨酸治疗；17 例患者接受肌酸一水合物、L-精氨酸和甘氨酸的联合治疗。中位治疗时间为 34.6 个月（3 个月至 5 年）。证据水平为 IV 级。共有 10 例（36%）患者对治疗有反应，表现为脑肌酸增加或临床参数改善。28 例患者中有 7 例进行了治疗前后的肌酸定量检测，结果显示治疗后肌酸明显增加。所有脑肌酸增加的患者均有临床改善。此外，大多数临床改善的患者在治疗前均有可检测到的脑肌酸。90%改善的患者在 9 岁之前开始接受治疗。
鉴于本系统综述的局限性，我们得出结论，一部分 CTD 患者对治疗有反应，尤其是那些有残留脑肌酸的轻症患者，因此可能有残留的蛋白功能。我们建议对 ID 患者进行 CTD 的系统筛查，以便早期开始治疗，目前包括口服肌酸、精氨酸和/或甘氨酸补充治疗。所有患者均需要进行安全性系统监测和治疗效果评估。本研究提供了目前可用治疗的有效性，可用于判断未来干预措施（如环肌酸）的有效性。
