A cross-sectional natural history study of aspartylglucosaminuria.
A cross-sectional natural history study of aspartylglucosaminuria.
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DOI：
10.1002/jmd2.12294
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发表时间：
2022-09
影响因子：
3.8
通讯作者：
Wang, Jerry
中科院分区：
文献类型：
--
作者：
Goodspeed, Kimberly;Edgar, Veronica Bordes;Horton, Daniel;Lowden, Andrea;Sguina, Peter;Booth, Tim;Wang, Jerry
天冬氨酸氨基葡萄糖尿症（AGU）是一种罕见的溶酶体储存疾病，可导致青春期发育停滞和成年早期神经退行性变。包括基因转移疗法在内的精确疗法正在开发中，其目标是利用缓慢的临床过程。了解疾病自然史和识别疾病相关生物标志物是临床试验准备的重要步骤。我们描述了不同AGU患者人群的临床特征，包括潜在的影像学和电生理学生物标志物。这是一项关于AGU临床、神经心理学、电生理学和影像学特征的单中心、横断面研究。对8名参与者（5名非芬兰人）的综合评估显示，平均非语言智商（NVIQ）为70.25 ± 10.33，随年龄增长而下降（rs =-0.85，p = 0.008）。所有参与者均表现出沟通和粗大/精细运动功能障碍的缺陷。听觉和视觉诱发电位表现出异常的一个或两个模式中的7 8名受试者，提示感觉通路功能障碍。脑成像显示枕核T2 FLAIR低信号和脑萎缩，如先前在芬兰AGU人群中所示。磁共振波谱（MRS）显示对应于毒性底物（GlcNAc-Asn）的5.1 ppm峰，其在AGU中蓄积。我们的研究结果表明，芬兰和非芬兰患者之间没有显著差异，标准化认知和运动测试的表现与之前的研究相似。功能评估的年龄相关变化和替代生物标志物（如MRS）的疾病相关异常可用作临床试验的结局指标。
Aspartylglucosaminuria (AGU) is a rare lysosomal storage disorder that causes stagnation of development in adolescence and neurodegeneration in early adulthood. Precision therapies, including gene transfer therapy, are in development with a goal of taking advantage of the slow clinical course. Understanding of disease natural history and identification of disease‐relevant biomarkers are important steps in clinical trial readiness. We describe the clinical features of a diverse population of patients with AGU, including potential imaging and electrophysiological biomarkers. This is a single‐center, cross‐sectional study of the clinical, neuropsychological, electrophysiological, and imaging characteristics of AGU. A comprehensive assessment of eight participants (5 Non‐Finnish) revealed a mean non‐verbal IQ (NVIQ) of 70.25 ± 10.33 which decreased with age (rs = −0.85, p = 0.008). All participants demonstrated deficits in communication and gross/fine motor dysfunction. Auditory and visual evoked potentials demonstrated abnormalities in one or both modalities in 7 of 8 subjects, suggesting sensory pathway dysfunction. Brain imaging demonstrated T2 FLAIR hypointensity in the pulvinar nuclei and cerebral atrophy, as previously shown in the Finnish AGU population. Magnetic resonance spectroscopy (MRS) showed a 5.1 ppm peak corresponding to the toxic substrate (GlcNAc‐Asn), which accumulates in AGU. Our results showed there was no significant difference between Finnish and Non‐Finnish patients, and performance on standardized cognitive and motor testing was similar to prior studies. Age‐related changes on functional assessments and disease‐relevant abnormalities on surrogate biomarkers, such as MRS, could be used as outcome measures in a clinical trial.