Platzer Konrad, Yuan Hongjie, Schütz Hannah, Winschel Alexander, Chen Wenjuan, Hu Chun, Kusumoto Hirofumi, Heyne Henrike O, Helbig Katherine L, Tang Sha, Willing Marcia C, Tinkle Brad T, Adams Darius J, Depienne Christel, Keren Boris, Mignot Cyril, Frengen Eirik, Strømme Petter, Biskup Saskia, Döcker Dennis, Strom Tim M, Mefford Heather C, Myers Candace T, Muir Alison M, LaCroix Amy, Sadleir Lynette, Scheffer Ingrid E, Brilstra Eva, van Haelst Mieke M, van der Smagt Jasper J, Bok Levinus A, Møller Rikke S, Jensen Uffe B, Millichap John J, Berg Anne T, Goldberg Ethan M, De Bie Isabelle, Fox Stephanie, Major Philippe, Jones Julie R, Zackai Elaine H, Abou Jamra Rami, Rolfs Arndt, Leventer Richard J, Lawson John A, Roscioli Tony, Jansen Floor E, Ranza Emmanuelle, Korff Christian M, Lehesjoki Anna-Elina, Courage Carolina, Linnankivi Tarja, Smith Douglas R, Stanley Christine, Mintz Mark, McKnight Dianalee, Decker Amy, Tan Wen-Hann, Tarnopolsky Mark A, Brady Lauren I, Wolff Markus, Dondit Lutz, Pedro Helio F, Parisotto Sarah E, Jones Kelly L, Patel Anup D, Franz David N, Vanzo Rena, Marco Elysa, Ranells Judith D, Di Donato Nataliya, Dobyns William B, Laube Bodo, Traynelis Stephen F, Lemke Johannes R
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia, USA.
J Med Genet. 2017 Jul;54(7):460-470. doi: 10.1136/jmedgenet-2016-104509. Epub 2017 Apr 4.
We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of encephalopathy and explored potential prospects of personalised medicine.
Data of 48 individuals with de novo variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care.
Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated.
In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.
我们旨在全面描绘脑病的遗传、功能和表型特征,并探索个性化医疗的潜在前景。
从多个诊断和研究队列以及文献中的43例患者收集了48例具有新发变异个体的数据。在体外研究了功能后果及对美金刚治疗的反应,并最终转化为患者护理。
总体而言,86例患者中的新发变异被分类为致病性/可能致病性。患者表现为神经发育障碍以及一系列肌张力减退、运动障碍、皮质视力损害、脑容量减少和癫痫。6例患者表现出介于微管病变和多小脑回之间的一致的皮质发育畸形(MCD)。错义变异聚集在跨膜段和配体结合位点。变异的功能后果多种多样,揭示了各种潜在的功能获得和功能丧失机制以及对使用依赖性阻滞剂美金刚的敏感性。然而,在各自患者中可客观证实的有益治疗反应仍有待证明。
除了先前已知的智力残疾、癫痫和自闭症特征外,我们发现有证据表明脑病还经常与运动障碍、皮质视力损害和MCD相关,揭示了通道病的新表型后果。