Christianson syndrome (CS) is a recently described rare neurogenetic disorder presenting early in life with a broad range of neurological symptoms, including severe intellectual disability with nonverbal status, hyperactivity, epilepsy, and progressive ataxia due to cerebellar atrophy. CS is due to loss-of-function mutations in SLC9A6, encoding NHE6, a sodium-hydrogen exchanger involved in the regulation of early endosomal pH. Here we review what is currently known about the neuropathogenesis of CS, based on insights from experimental models, which to date have focused on mechanisms that affect the CNS, specifically the brain. In addition, parental reports of sensory disturbances in their children with CS, including an apparent insensitivity to pain, led us to explore sensory function and related neuropathology in Slc9a6 KO mice. We present new data showing sensory deficits in Slc9a6 KO mice, which had reduced behavioral responses to noxious thermal and mechanical stimuli (Hargreaves and Von Frey assays, respectively) compared to wild type (WT) littermates. Immunohistochemical and ultrastructural analysis of the spinal cord and peripheral nervous system revealed intracellular accumulation of the glycosphingolipid GM2 ganglioside in KO but not WT mice. This cellular storage phenotype was most abundant in neurons of lamina I-II of the dorsal horn, a major relay site in the processing of painful stimuli. Spinal cords of KO mice also exhibited changes in astroglial and microglial populations throughout the gray matter suggestive of a neuroinflammatory process. Our findings establish the Slc9a6 KO mouse as a relevant tool for studying the sensory deficits in CS, and highlight selective vulnerabilities in relevant cell populations that may contribute to this phenotype. How NHE6 loss of function leads to such a multifaceted neurological syndrome is still undefined, and it is likely that NHE6 is involved with many cellular processes critical to normal nervous system development and function. In addition, the sensory issues exhibited by Slc9a6 KO mice, in combination with our neuropathological findings, are consistent with NHE6 loss of function impacting the entire nervous system. Sensory dysfunction in intellectually disabled individuals is challenging to assess and may impair patient safety and quality of life. Further mechanistic studies of the neurological impairments underlying CS and other genetic intellectual disability disorders must also take into account mechanisms affecting broader nervous system function in order to understand the full range of associated disabilities.

中文翻译：

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克里斯蒂安森综合症的病理生物学：将内体溶酶体功能紊乱与智力残疾和感觉障碍联系起来。

克里斯琴森综合症（CS）是最近描述的一种罕见的神经遗传疾病，在生命的早期出现，具有广泛的神经系统症状，包括严重的智力障碍，具有非言语状态，活动过度，癫痫和小脑萎缩引起的进行性共济失调。CS是由于SLC9A6的功能丧失突变所致，该突变编码NHE6，后者是参与早期内体pH调节的钠氢交换剂。在这里，我们根据实验模型得出的见解，回顾一下CS的神经病理学的最新知识，迄今为止，这些见解都集中在影响中枢神经系统（特别是大脑）的机制上。此外，父母对他们的CS儿童的感觉障碍的报道，包括对疼痛的明显不敏感性，促使我们探索Slc9a6 KO小鼠的感觉功能和相关的神经病理学。我们提供了新的数据，显示Slc9a6 KO小鼠的感觉缺陷，与野生型（WT）同窝仔相比，Slc9a6 KO小鼠对有害的热和机械刺激（分别为Hargreaves和Von Frey试验）的行为反应减少。脊髓和周围神经系统的免疫组织化学和超微结构分析显示，糖脂鞘脂GM2神经节苷脂在KO小鼠中存在细胞内蓄积，而在WT小鼠中却没有。这种细胞存储表型在背角I-II层的神经元中最为丰富，背角是疼痛刺激过程中的主要中继部位。KO小鼠的脊髓在整个灰质中的星形胶质和小胶质细胞数量也显示出变化，提示神经炎性过程。我们的发现将Slc9a6 KO小鼠确立为研究CS感官缺陷的相关工具，并突出显示可能导致此表型的相关细胞群体中的选择性漏洞。NHE6的功能丧失如何导致这种多方面的神经系统综合症尚不清楚，并且NHE6可能参与了许多对正常神经系统发育和功能至关重要的细胞过程。此外，与我们的神经病理学发现相结合，Slc9a6 KO小鼠表现出的感觉问题与影响整个神经系统的NHE6功能丧失相一致。智障人士的感觉功能障碍难以评估，可能会损害患者的安全性和生活质量。