Early brain vulnerability in Wolfram syndrome.
Early brain vulnerability in Wolfram syndrome.
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DOI：
10.1371/journal.pone.0040604
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Washington University Wolfram Study Group
中科院分区：
文献类型：
--
作者：
Hershey T;Lugar HM;Shimony JS;Rutlin J;Koller JM;Perantie DC;Paciorkowski AR;Eisenstein SA;Permutt MA;Washington University Wolfram Study Group
Wolfram 综合征 (WFS) 是一种罕见的常染色体隐性遗传疾病，其特征是胰岛素依赖型糖尿病、视神经萎缩、尿崩症、耳聋和神经功能障碍，导致中年死亡。 WFS 是由 WFS1 基因突变引起的，该突变会导致内质网 (ER) 应激介导的细胞死亡。案例研究发现 WFS 晚期存在广泛的脑萎缩。然而，尚不清楚在疾病过程中这些大脑异常何时出现，以及大脑区域和组织类别之间是否存在不同的脆弱性。为了解决这一局限性，我们对处于 WFS 相对早期阶段的年轻患者队列中多种成像方式的区域大脑异常进行了量化。通过神经、认知和结构磁共振成像措施对患有 WFS 的儿童和年轻人进行评估。与正常数据相比，WFS 组认知完整，但存在明显的焦虑和抑郁以及步态异常。与健康组和1型糖尿病对照组相比，WFS组的颅内容积更小，并且优先影响脑干、小脑和视放射的灰质体积和白质微结构完整性。即使是症状最轻微的最年轻患者也发现了异常，而且一些指标并不遵循典型的年龄依赖性发育轨迹。这些结果表明，WFS 与颅内体积较小以及脑干和小脑的特定异常有关，即使在临床症状的最早阶段也是如此。这种异常模式表明，除了后期的神经退行性影响外，WFS 对早期大脑发育也有显着影响，代表了对 WFS 疾病过程的重要新见解。纵向研究对于确认和扩大我们对内质网应激失调对大脑发育影响的理解至关重要。
Wolfram Syndrome (WFS) is a rare autosomal recessive disease characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, deafness, and neurological dysfunction leading to death in mid-adulthood. WFS is caused by mutations in the WFS1 gene, which lead to endoplasmic reticulum (ER) stress-mediated cell death. Case studies have found widespread brain atrophy in late stage WFS. However, it is not known when in the disease course these brain abnormalities arise, and whether there is differential vulnerability across brain regions and tissue classes. To address this limitation, we quantified regional brain abnormalities across multiple imaging modalities in a cohort of young patients in relatively early stages of WFS. Children and young adults with WFS were evaluated with neurological, cognitive and structural magnetic resonance imaging measures. Compared to normative data, the WFS group had intact cognition, significant anxiety and depression, and gait abnormalities. Compared to healthy and type 1 diabetic control groups, the WFS group had smaller intracranial volume and preferentially affected gray matter volume and white matter microstructural integrity in the brainstem, cerebellum and optic radiations. Abnormalities were detected in even the youngest patients with mildest symptoms, and some measures did not follow the typical age-dependent developmental trajectory. These results establish that WFS is associated with smaller intracranial volume with specific abnormalities in the brainstem and cerebellum, even at the earliest stage of clinical symptoms. This pattern of abnormalities suggests that WFS has a pronounced impact on early brain development in addition to later neurodegenerative effects, representing a significant new insight into the WFS disease process. Longitudinal studies will be critical for confirming and expanding our understanding of the impact of ER stress dysregulation on brain development.
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