Molecularly confirmed Kabuki (Niikawa-Kuroki) syndrome patients demonstrate a specific cognitive profile with extensive visuospatial abnormalities
Molecularly confirmed Kabuki (Niikawa-Kuroki) syndrome patients demonstrate a specific cognitive profile with extensive visuospatial abnormalities
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DOI：
10.1111/jir.12596
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发表时间：
2019-06-01
影响因子：
3.6
通讯作者：
Bjornsson, H. T.
中科院分区：
文献类型：
--
作者：
Harris, J.;Mahone, E. M.;Bjornsson, H. T.
歌舞伎综合征（Kabuki（Niikawa-Kuroki）syndrome，KS）是由组蛋白甲基化机制的两个组成部分（KMT 2D和KDM 6A）中的任一个的致病变异引起的。几乎所有患有KS的人都有认知困难，大多数人有智力障碍。最近对KS小鼠模型的研究表明，海马齿状回颗粒细胞层的正常成年神经发生中断。与同窝出生的小鼠相比，这些突变小鼠也表现出海马记忆缺陷，但这种表型在出生后用靶向表观遗传机制的药物进行了挽救。如果这些发现与KS患者相关，我们预计这些人的视觉空间功能会受到显著和不成比例的破坏。方法为了验证这一假设，我们编制了一个电池，以稳健地探索视觉空间功能。我们前瞻性地招募了22名分子学证实的KS患者和22名智商匹配的智力残疾患者。结果KS组在视觉运动、视知觉和视觉运动记忆等多项指标上均明显低于IQ匹配组。相比之下，在句子理解任务中，KS组的语言功能似乎略好于智商匹配组。总之，我们的数据表明，具体的视觉空间功能的中断，可能与齿状回，在个人与KS和KS人群的临床试验提供了一个新的和具体的结果措施的基础。
Background Kabuki (Niikawa-Kuroki) syndrome (KS) is caused by disease-causing variants in either of two components (KMT2D and KDM6A) of the histone methylation machinery. Nearly all individuals with KS have cognitive difficulties, and most have intellectual disability. Recent studies on a mouse model of KS suggest disruption of normal adult neurogenesis in the granule cell layer of the dentate gyrus of the hippocampus. These mutant mice also demonstrate hippocampal memory defects compared with littermates, but this phenotype is rescued postnatally with agents that target the epigenetic machinery. If these findings are relevant to humans with KS, we would expect significant and disproportionate disruption of visuospatial functioning in these individuals. Methods To test this hypothesis, we have compiled a battery to robustly explore visuospatial function. We prospectively recruited 22 patients with molecularly confirmed KS and 22 IQ-matched patients with intellectual disability. Results We observed significant deficiencies in visual motor, visual perception and visual motor memory in the KS group compared with the IQ-matched group on several measures. In contrast, language function appeared to be marginally better in the KS group compared with the IQ-matched group in a sentence comprehension task. Conclusions Together, our data suggest specific disruption of visuospatial function, likely linked to the dentate gyrus, in individuals with KS and provide the groundwork for a novel and specific outcome measure for a clinical trial in a KS population.