肌酸转运蛋白缺乏症（）患者的临床特征、发展轨迹和照顾者负担。

Clinical Characteristics, Developmental Trajectory, and Caregiver Burden of Patients With Creatine Transporter Deficiency ().

机构信息

From the Child Neurology Department and Reference Centre of Rare Disease with Intellectual Disability (A.C., L.L.-F., M.G., A.B.-L., F.G., M.B., V.D.P.), Hospices Civils de Lyon, Lyon University Hospital; Lyon Neuroscience Research Centre (A.C., M.G., A.B.-L., F.G., M.B., V.D.P.), CNRS UMR5292, INSERM U1028; Lyon University (A.C., V.D.P.); Reference Centre for Inherited Metabolic Diseases (V.V., A.B., P.D.L.), Imagine Institute, Necker Enfants-Malades Hospital, Paris University Hospital, University of Paris Descartes; Clinical Investigation Center 1407/INSERM-Hospices Civils de Lyon (N.P., N.T., H.H., B.K.), Bron; Inborn Errors of Metabolism Unit (D.C.), Biochemistry and Molecular Biology Department; Department of Biostatistics (C.M.), Lyon University Hospital; and Reference Centre for Inherited Metabolic Diseases (B.D.), Department of Child Neurology, Marseille University Hospital, France.

出版信息

Neurology. 2024 Apr 23;102(8):e209243. doi: 10.1212/WNL.0000000000209243. Epub 2024 Mar 26.

DOI:10.1212/WNL.0000000000209243

PMID:38531017

Abstract

BACKGROUND AND OBJECTIVES

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 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.

DISCUSSION

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.

TRIAL REGISTRATION INFORMATION

ANSM Registration Number 2010-A00327-32.

摘要

背景和目的

肌酸转运蛋白缺乏症（CTD）是一种罕见的 X 连锁遗传性疾病，其特征为智力障碍（ID）。我们评估了 CTD 患者的临床特征和疾病轨迹，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，根据（1）致病变异和（2）ID 和/或自闭症谱系障碍，选择 CTD 患者。通过罕见病因和遗传性代谢疾病的 ID 参考中心，由开具基因分析的医生推荐患者和家庭参加研究。在向患者及其父母/监护人告知研究情况后，他们均签署了书面同意书并被纳入研究。我们还纳入了年龄和性别匹配的脆性 X 综合征患者作为对照组。评估体格检查、神经心理学评估和护理人员的影响。所有数据均使用 R 软件进行分析。

结果

共纳入 31 名患者（27 名男性，4 名女性）（25/31 名年龄在 18 岁或以下）。大多数患者（71%）在<24 个月时出现症状。诊断时的平均年龄为 6.5 岁。癫痫的发病率为 45%（平均发病年龄为 8 岁）。早发性行为障碍发生率为 82%。发育轨迹始终延迟（精细和粗大运动技能、语言和交流/社交能力）。一半的 CTD 患者在生命的第一年存在轴性张力减退。所有患者均能独立行走，但 7/31 名患者有共济失调，仅有 14/31 名患者能走并排行走。他们大多存在精细运动技能异常（31 名中有 27 名），大多数存在语言障碍（31 名中有 30 名），但 23 名男性患者中有 12 名（52.2%）通过了 Peabody 图片词汇测试。约一半（31 名中有 14 名）身材苗条。他们大多需要护理（31 名中有 20 名），通常每天 1-4 小时。适应能力评估（Vineland）证实，CTD 男性患者存在中重度 ID。大多数护理人员（79%）存在倦怠风险，这一点通过 Caregiver Burden Inventory（CBI）>36 表明（明显高于脆性 X 综合征患者），护理人员时间依赖性负担高。