Sprugnoli Giulia, Vatti Giampaolo, Rossi Simone, Cerase Alfonso, Renieri Alessandra, Mencarelli Maria A, Zara Federico, Rossi Alessandro, Santarnecchi Emiliano
Department of Medicine, Surgery and Neuroscience, Brain Investigation & Neuromodulation Laboratory, University of Siena, Siena, Italy.
Department of Medicine, Surgery and Neuroscience, Neurology and Clinical Neurophysiology Section, University of Siena, Siena, Italy.
Front Integr Neurosci. 2018 Jun 12;12:22. doi: 10.3389/fnint.2018.00022. eCollection 2018.
Laminar heterotopia is a rare condition consisting in an extra layer of gray matter under properly migrated cortex; it configures an atypical presentation of periventricular nodular heterotopia (PNH) or a double cortex (DC) syndrome. We conducted an original functional MRI (fMRI) analysis in a drug-resistant epilepsy patient with "double-cortex"-like malformation to reveal her functional connectivity (FC) as well as a wide genetic analysis to identify possible genetic substrates. Heterotopias were segmented into region of interests (ROIs), whose voxel-wise FC was compared to that of (i) its normally migrated counterpart, (ii) its contralateral homologous, and (iii) those of 30 age-matched healthy controls. Extensive genetic analysis was conducted to screen cortical malformations-associated genes. Compared to healthy controls, both laminar heterotopias and the overlying cortex showed significant reduction of FC with the contralateral hemisphere. Two heterozygous variants of uncertain clinical significance were found, involving autosomal recessive disease-causing genes, FAT4 and COL18A1. This first FC analysis of a unique case of "double-cortex"-like malformation revealed a hemispheric connectivity segregation both in the laminar cortex as in the correctly migrated one, with a new pattern of genes' mutations. Our study suggests the altered FC could have an electrophysiological and functional impact on large-scale brain networks, and the involvement of not yet identified genes in "double-cortex"-like malformation with a possible role of rare variants in recessive genes as pathogenic cofactors.
层状异位是一种罕见的病症，表现为在正常迁移的皮质下方存在额外的灰质层；它构成了室管膜下结节性异位（PNH）或双皮质（DC）综合征的非典型表现。我们对一名患有“双皮质”样畸形的耐药性癫痫患者进行了原始的功能磁共振成像（fMRI）分析，以揭示其功能连接性（FC），并进行了广泛的基因分析以确定可能的遗传底物。将异位灶分割为感兴趣区域（ROI），将其体素水平的FC与以下三者进行比较：（i）其正常迁移的对应区域，（ii）其对侧同源区域，以及（iii）30名年龄匹配的健康对照者的对应区域。进行了广泛的基因分析以筛选与皮质畸形相关的基因。与健康对照相比，层状异位灶及其上方的皮质与对侧半球的FC均显著降低。发现了两个临床意义不确定的杂合变异，涉及常染色体隐性致病基因FAT4和COL18A1。对这一独特的“双皮质”样畸形病例进行的首次FC分析揭示，在层状皮质和正确迁移的皮质中均存在半球连接性分离，并伴有新的基因突变模式。我们的研究表明，改变的FC可能对大规模脑网络产生电生理和功能影响，并且尚未确定的基因参与了“双皮质”样畸形，罕见变异在隐性基因中可能作为致病辅助因子发挥作用。
