目的:肌酸转运体缺乏症(CTD)是一种罕见的X连锁遗传性疾病,以智力障碍(ID)为特征。我们评估了CTD患者的临床特征和轨迹以及疾病对护理人员的影响,以确定未来治疗试验的相关终点。
方法:作为法国国家研究计划的一部分,CTD患者是基于(1)致病性SLC6A8变异体和(2)ID和/或自闭症谱系障碍纳入的.家庭和患者由医生转介,他们通过ID参考中心从罕见原因和遗传代谢疾病中进行遗传分析。在我们向患者及其父母/监护人通报了这项研究之后,他们都给出了书面同意和包括.还包括年龄匹配和性别匹配的脆性X综合征患者的对照组。体格检查,神经心理学评估,和护理人员的影响进行了评估。使用R软件分析所有数据。
结果:31例患者(27例男性,包括4名女性)(25/31岁18岁或以下)。大多数患者(71%)在<24个月大时出现症状。诊断时的平均年龄为6.5岁。癫痫发生率为45%(平均发病年龄:8岁)。82%的人发生早发性行为障碍。发育轨迹一直被延迟(精细和粗大的运动技能,语言,和沟通/社交能力)。一半的CTD患者在出生后的第一年有轴向低张力。所有患者都能在没有帮助的情况下行走,但是7/31有共济失调,只有14/31可以行走串联步态。他们中的大多数都有异常的精细运动技能(27/31),他们中的大多数都有语言障碍(30/31),但是12/23的男性患者(52.2%)完成了Peabody图片词汇测试。大约一半(14/31)的建筑细长。他们中的大多数需要护理(20/31),一般为1-4小时/天。适应性评估(Vineland)证实,男性CTD患者患有中度至重度ID。大多数护理人员(79%)有倦怠的风险,如照顾者负担量表(CBI)>36(显着高于脆性X综合征患者)所示,具有较高的时间依赖性负担。
结论:除了临床终点,比如癫痫的评估和患者的发展轨迹,Vineland尺度,PPVT5和CBI作为未来试验的结局指标尤其令人感兴趣。
■ANSM注册号2010-A00327-32。
OBJECTIVE: Creatine transporter deficiency (CTD) is a rare X-linked genetic disorder characterized by intellectual disability (ID). We evaluated the clinical characteristics and trajectory of patients with CTD and the impact of the disease on caregivers to identify relevant endpoints for future therapeutic trials.
METHODS: As part of a French National Research Program, patients with CTD were included based on (1) a pathogenic SLC6A8 variant and (2) ID and/or autism spectrum disorder. Families and patients were referred by the physician who ordered the genetic analysis through Reference Centers of ID from rare causes and inherited metabolic diseases. After we informed the patients and their parents/guardians about the study, all of them gave written consent and were included. A control group of age-matched and sex-matched patients with Fragile X syndrome was also included. Physical examination, neuropsychological assessments, and caregiver impact were assessed. All data were analyzed using R software.
RESULTS: Thirty-one patients (27 male, 4 female) were included (25/31 aged 18 years or younger). Most of the patients (71%) had symptoms at <24 months of age. The mean age at diagnosis was 6.5 years. Epilepsy occurred in 45% (mean age at onset: 8 years). Early-onset behavioral disorder occurred in 82%. Developmental trajectory was consistently delayed (fine and gross motor skills, language, and communication/sociability). Half of the patients with CTD had axial hypotonia during the first year of life. All patients were able to walk without help, but 7/31 had ataxia and only 14/31 could walk tandem gait. Most of them had abnormal fine motor skills (27/31), and most of them had language impairment (30/31), but 12/23 male patients (52.2%) completed the Peabody Picture Vocabulary Test. Approximately half (14/31) had slender build. Most of them needed nursing care (20/31), generally 1-4 h/d. Adaptive assessment (Vineland) confirmed that male patients with CTD had moderate-to-severe ID. Most caregivers (79%) were at risk of burnout, as shown by Caregiver Burden Inventory (CBI) > 36 (significantly higher than for patients with Fragile X syndrome) with a high burden of time dependence.
CONCLUSIONS: In addition to clinical endpoints, such as the assessment of epilepsy and the developmental trajectory of the patient, the Vineland scale, PPVT5, and CBI are of particular interest as outcome measures for future trials.
UNASSIGNED: ANSM Registration Number 2010-A00327-32.