Wei Shern Lee1, Sarah E M Stephenson1, Kate Pope1, Greta Gillies1, Wirginia Maixner1, Emma Macdonald-Laurs1, Duncan MacGregor1, Colleen D'Arcy1, Graeme Jackson1, A Simon Harvey1, Richard J Leventer1, Paul J Lockhart2. 1. From the Bruce Lefroy Centre (W.S.L., S.E.M.S., K.P., G.G., P.J.L.), Murdoch Children's Research Institute (W.M., A.S.H., R.J.L.); Department of Paediatrics (W.S.L., S.E.M.S., W.M., E.M.-L., A.S.H., R.J.L., P.J.L.), The University of Melbourne; Departments of Neurosurgery (W.M.), Neurology (E.M.-L., A.S.H., R.J.L.), and Anatomical Pathology (D.M., C.D.), The Royal Children's Hospital, Parkville; and Melbourne Brain Centre (G.J.), The Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia. 2. From the Bruce Lefroy Centre (W.S.L., S.E.M.S., K.P., G.G., P.J.L.), Murdoch Children's Research Institute (W.M., A.S.H., R.J.L.); Department of Paediatrics (W.S.L., S.E.M.S., W.M., E.M.-L., A.S.H., R.J.L., P.J.L.), The University of Melbourne; Departments of Neurosurgery (W.M.), Neurology (E.M.-L., A.S.H., R.J.L.), and Anatomical Pathology (D.M., C.D.), The Royal Children's Hospital, Parkville; and Melbourne Brain Centre (G.J.), The Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia. paul.lockhart@mcri.edu.au.
Abstract
OBJECTIVE: To determine the genetic basis of bottom-of-sulcus dysplasia (BOSD), which is a highly focal and epileptogenic cortical malformation in which the imaging, electrophysiologic, and pathologic abnormalities are maximal at the bottom of sulcus, tapering to a normal gyral crown. METHODS: Targeted panel deep sequencing (>500×) was performed on paired blood and brain-derived genomic DNA from 20 operated patients with drug-resistant focal epilepsy and BOSD. Histopathology was assessed using immunohistochemistry. RESULTS: Brain-specific pathogenic somatic variants were found in 6 patients and heterozygous pathogenic germline variants were found in 2. Somatic variants were identified in MTOR and germline variants were identified in DEPDC5 and NPRL3. Two patients with somatic MTOR variants showed a mutation gradient, with higher mutation load at the bottom of sulcus compared to the gyral crown. Immunohistochemistry revealed an abundance of dysmorphic neurons and balloon cells in the bottom of sulcus but not in the gyral crown or adjacent gyri. CONCLUSIONS: BOSD is associated with mTOR pathway dysregulation and shares common genetic etiologies and pathogenic mechanisms with other forms of focal and hemispheric cortical dysplasia, suggesting these disorders are on a genetic continuum.
OBJECTIVE: To determine the genetic basis of bottom-of-sulcus dysplasia (BOSD), which is a highly focal and epileptogenic cortical malformation in which the imaging, electrophysiologic, and pathologic abnormalities are maximal at the bottom of sulcus, tapering to a normal gyral crown. METHODS: Targeted panel deep sequencing (>500×) was performed on paired blood and brain-derived genomic DNA from 20 operated patients with drug-resistant focal epilepsy and BOSD. Histopathology was assessed using immunohistochemistry. RESULTS: Brain-specific pathogenic somatic variants were found in 6 patients and heterozygous pathogenic germline variants were found in 2. Somatic variants were identified in MTOR and germline variants were identified in DEPDC5 and NPRL3. Two patients with somatic MTOR variants showed a mutation gradient, with higher mutation load at the bottom of sulcus compared to the gyral crown. Immunohistochemistry revealed an abundance of dysmorphic neurons and balloon cells in the bottom of sulcus but not in the gyral crown or adjacent gyri. CONCLUSIONS: BOSD is associated with mTOR pathway dysregulation and shares common genetic etiologies and pathogenic mechanisms with other forms of focal and hemispheric cortical dysplasia, suggesting these disorders are on a genetic continuum.
Authors: Sonia Mayo; Irene Gómez-Manjón; Francisco Javier Fernández-Martínez; Ana Camacho; Francisco Martínez; Julián Benito-León Journal: Int J Mol Sci Date: 2022-04-28 Impact factor: 6.208
Authors: Chloe A Stutterd; Stefanie Brock; Katrien Stouffs; Miriam Fanjul-Fernandez; Paul J Lockhart; George McGillivray; Simone Mandelstam; Kate Pope; Martin B Delatycki; Anna Jansen; Richard J Leventer Journal: Brain Commun Date: 2020-12-26
Authors: Imad Najm; Dennis Lal; Mario Alonso Vanegas; Fernando Cendes; Iscia Lopes-Cendes; Andre Palmini; Eliseu Paglioli; Harvey B Sarnat; Christopher A Walsh; Samuel Wiebe; Eleonora Aronica; Stéphanie Baulac; Roland Coras; Katja Kobow; J Helen Cross; Rita Garbelli; Hans Holthausen; Karl Rössler; Maria Thom; Assam El-Osta; Jeong Ho Lee; Hajime Miyata; Renzo Guerrini; Yue-Shan Piao; Dong Zhou; Ingmar Blümcke Journal: Epilepsia Date: 2022-06-15 Impact factor: 6.740