Genetic characterization identifies bottom-of-sulcus dysplasia as an mTORopathy.

Adolescent Child Child, Preschool Drug Resistant Epilepsy / complications Epilepsies, Partial / complications Female Humans Infant Male Malformations of Cortical Development / complications Mutation TOR Serine-Threonine Kinases / genetics

Journal

Neurology
ISSN: 1526-632X
Titre abrégé: Neurology
Pays: United States
ID NLM: 0401060

Informations de publication

Date de publication:
03 11 2020
Historique:
received: 06 02 2020
accepted: 03 06 2020
pubmed: 28 8 2020
medline: 15 12 2020
entrez: 28 8 2020
Statut: ppublish

Résumé

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. 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. Brain-specific pathogenic somatic variants were found in 6 patients and heterozygous pathogenic germline variants were found in 2. Somatic variants were identified in 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.

Identifiants

DOI: 10.1212/WNL.0000000000010670 PMID: 32847954
pubmed: 32847954
pii: WNL.0000000000010670
doi: 10.1212/WNL.0000000000010670
doi:

Substances chimiques

MTOR protein, human EC 2.7.1.1
TOR Serine-Threonine Kinases EC 2.7.11.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2542-e2551

Informations de copyright

© 2020 American Academy of Neurology.

Auteurs

Wei Shern Lee (WS)

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.

Sarah E M Stephenson (SEM)

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.

Kate Pope (K)

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.

Greta Gillies (G)

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.

Wirginia Maixner (W)

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.

Emma Macdonald-Laurs (E)

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.

Duncan MacGregor (D)

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.

Colleen D'Arcy (C)

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.

Graeme Jackson (G)

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.

A Simon Harvey (AS)

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.

Richard J Leventer (RJ)

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 J Lockhart (PJ)

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.
ORCID: 0000-0003-2531-8413

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › Genetic characterization identifies...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Genetic characterization identifies...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Enfant d'âge préscolaire › Genetic characterization identifies...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Encéphalopathies › Épilepsie › Épilepsie pharmacorésistante › Genetic characterization identifies...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Encéphalopathies › Épilepsie › Épilepsies partielles › Genetic characterization identifies...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genetic characterization identifies...
questionsmedicales.fr › Personnes › Tranches d'âge › Nourrisson › Genetic characterization identifies...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations du système nerveux › Malformations corticales › Genetic characterization identifies...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Genetic characterization identifies...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Genetic characterization identifies...