Miyatake Satoko, Kato Mitsuhiro, Kumamoto Takuma, Hirose Tomonori, Koshimizu Eriko, Matsui Takaaki, Takeuchi Hideyuki, Doi Hiroshi, Hamada Keisuke, Nakashima Mitsuko, Sasaki Kazunori, Yamashita Akio, Takata Atsushi, Hamanaka Kohei, Satoh Mai, Miyama Takabumi, Sonoda Yuri, Sasazuki Momoko, Torisu Hiroyuki, Hara Toshiro, Sakai Yasunari, Noguchi Yushi, Miura Mazumi, Nishimura Yoko, Nakamura Kazuyuki, Asai Hideyuki, Hinokuma Nodoka, Miya Fuyuki, Tsunoda Tatsuhiko, Togawa Masami, Ikeda Yukihiro, Kimura Nobusuke, Amemiya Kaoru, Horino Asako, Fukuoka Masataka, Ikeda Hiroko, Merhav Goni, Ekhilevitch Nina, Miura Masaki, Mizuguchi Takeshi, Miyake Noriko, Suzuki Atsushi, Ohga Shouichi, Saitsu Hirotomo, Takahashi Hidehisa, Tanaka Fumiaki, Ogata Kazuhiro, Ohtaka-Maruyama Chiaki, Matsumoto Naomichi
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Kanagawa 236-0004, Japan.
Sci Adv. 2021 Mar 24;7(13). doi: 10.1126/sciadv.abd2368. Print 2021 Mar.
Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo variants in eight patients. Mutated causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with abnormalities.
多小脑回是一种常见的皮质发育畸形，其病因尚不清楚。我们对124例多小脑回患者进行了全外显子组测序，在8例患者中鉴定出新生变异。突变导致功能性脑部疾病，包括儿童交替性偏瘫（AHC）、快速发作性肌张力障碍帕金森综合征（RDP）以及小脑性共济失调、无反射、弓形足、视神经萎缩和感音神经性耳聋（CAPOS）。然而，我们的患者没有AHC、RDP或CAPOS的临床特征，而是具有完全不同的表型：一种伴有癫痫和发育迟缓的严重多小脑回形式。与AHC、RDP或CAPOS相关变异相比，检测到的变异在位置和功能特性上有所不同。在小鼠发育中的大脑皮质中，过表达最严重患者变异体的神经元的放射状神经元迁移受损，这表明该变异体参与了皮质畸形的发病机制。我们提出了一种先前未被识别的与异常相关的多小脑回类型。
