Genetic Department, Centre Hospitalier Régional d'Orléans, Orléans, France.
UMR7355, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS), Orléans, France.
J Med Case Rep. 2022 May 5;16(1):180. doi: 10.1186/s13256-022-03387-7.
Mutations in the genes encoding the large-conductance calcium-activated potassium channel, especially KCNMA1 encoding its α-subunit, have been linked to several neurological features, including intellectual disability or autism. Associated with neurodevelopmental phenotypes, sensory function disturbances are considered to be important clinical features contributing to a variety of behavioral impairments. Large-conductance calcium-activated potassium channels are important in regulating neurotransmission in sensory circuits, including visual pathways. Deficits in visual function can contribute substantially to poor quality of life, while therapeutic approaches aimed at addressing such visual deficits represent opportunities to improve neurocognitive and neurobehavioral outcomes.
We describe the case of a 25-year-old Caucasian male with autism spectrum disorder and severe intellectual disability presenting large-conductance calcium-activated potassium channel haploinsufficiency due to a de novo balanced translocation (46, XY, t [9; 10] [q23;q22]) disrupting the KCNMA1 gene. The visual processing pathway of the subject was evaluated using both electroretinography and visual contrast sensitivity, indicating that both retinal bipolar cell function and contrast discrimination performance were reduced by approximately 60% compared with normative control values. These findings imply a direct link between KCNMA1 gene disruption and visual dysfunction in humans. In addition, the subject reported photophobia but did not exhibit strabismus, nystagmus, or other visual findings on physical examination.
This case study of a subject with large-conductance calcium-activated potassium channel haploinsufficiency and photophobia revealed a visual pathway deficit at least at the retinal level, with diminished retinal light capture likely due to bipolar cell dysfunction and an associated loss of contrast sensitivity. The data suggest that large-conductance calcium-activated potassium channels play an important role in the normal functioning of the visual pathway in humans, and that their disruption may play a role in visual and other sensory system symptomatology in large-conductance calcium-activated potassium channelopathies or conditions where disruption of large-conductance calcium-activated potassium channel function is a relevant feature of the pathophysiology, such as fragile X syndrome. This work suggests that the combined use of physiological (electroretinography) and functional (contrast sensitivity) approaches may have utility as a biomarker strategy for identifying and characterizing visual processing deficits in individuals with large-conductance calcium-activated potassium channelopathy. Trial registration ID-RCB number 2019-A01015-52, registered 17/05/2019.
编码大电导钙激活钾通道的基因（特别是编码其 α 亚基的 KCNMA1 基因）的突变与多种神经特征有关，包括智力障碍或自闭症。与神经发育表型相关，感觉功能障碍被认为是导致各种行为障碍的重要临床特征。大电导钙激活钾通道在调节包括视觉通路在内的感觉回路中的神经传递中起重要作用。视觉功能缺陷会大大降低生活质量，而针对这些视觉缺陷的治疗方法则为改善神经认知和神经行为结果提供了机会。
我们描述了一名 25 岁的白种男性病例，患有自闭症谱系障碍和严重智力障碍，由于新发的平衡易位（46,XY，t [9;10] [q23;q22]）导致大电导钙激活钾通道单倍体不足，从而破坏 KCNMA1 基因。使用视网膜电图和视觉对比敏感度评估受试者的视觉处理通路，结果表明，与正常对照值相比，视网膜双极细胞功能和对比辨别性能均降低约 60%。这些发现表明，KCNMA1 基因突变与人类视觉功能障碍之间存在直接联系。此外，受试者自述畏光，但在体格检查中并未出现斜视、眼球震颤或其他视觉异常。
这项对患有大电导钙激活钾通道单倍体不足和畏光症的患者的病例研究揭示了视觉通路缺陷，至少在视网膜水平上，由于双极细胞功能障碍导致光捕获减少，以及随之而来的对比敏感度降低。数据表明，大电导钙激活钾通道在人类正常视觉通路功能中起重要作用，其功能障碍可能在大电导钙激活钾通道病或大电导钙激活钾通道功能障碍是病理生理学相关特征的情况下（如脆性 X 综合征）导致视觉和其他感觉系统症状中起作用。这项工作表明，生理（视网膜电图）和功能（对比敏感度）方法的联合使用可能作为一种生物标志物策略，用于识别和描述大电导钙激活钾通道病患者的视觉处理缺陷。试验注册号 RCB 编号 2019-A01015-52，注册于 2019 年 5 月 17 日。
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