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Abstract：
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.
摘要：
天冬氨酰氨基葡萄糖尿症（AGU）是一种罕见的溶酶体贮积症，可导致青春期发育停滞和成年早期神经变性。精准疗法,包括基因转移治疗,正在开发中，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的生物标志物是临床试验准备的重要步骤。我们描述了不同人群的AGU患者的临床特征，包括潜在的成像和电生理生物标志物。这是一个单一的中心，临床横断面研究，神经心理学，电生理学,和AGU的成像特征。对八名参与者（5名非芬兰语）的综合评估显示，平均非语言智商（NVIQ）为70.25±10.33，随年龄增长而降低（rs=-0.85，p=0.008）。所有参与者都表现出沟通障碍和粗大/精细运动功能障碍。听觉和视觉诱发电位在8名受试者中有7名表现出一种或两种形式的异常，提示感觉通路功能障碍。脑成像显示髓核中的T2FLAIR低张力和脑萎缩，如先前在芬兰AGU人口中所示。磁共振波谱（MRS）显示5.1ppm的峰对应于有毒底物（GlcNAc-Asn），在AGU中积累。我们的结果显示，芬兰和非芬兰患者之间没有显着差异。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的疾病相关异常，比如MRS，可用作临床试验的结果指标。
