Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation

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• dc.contributor.author Bansagi, Boglarka
• dc.contributor.author Phan, Vietxuan
• dc.contributor.author Baker, Mark R.
• dc.contributor.author O'Sullivan, Julia
• dc.contributor.author Jennings, Matthew J.
• dc.contributor.author Whittaker, Roger G.
• dc.contributor.author Müller, Juliane
• dc.contributor.author Duff, Jennifer
• dc.contributor.author Griffin, Helen
• dc.contributor.author Miller, James A.L.
• dc.contributor.author Gorman, Grainne S.
• dc.contributor.author Lochmüller, Hanns
• dc.contributor.author Chinnery, Patrick F.
• dc.contributor.author Roos, Andreas
• dc.contributor.author Swan, Laura E.
• dc.contributor.author Horvath, Rita
• dc.date.accessioned 2019-11-26T07:53:55Z
• dc.date.available 2019-11-26T07:53:55Z
• dc.date.issued 2018
• dc.description.abstract Objective: To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog (PTEN), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases. Methods: We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patient's fibroblasts. Results: The predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) PTEN variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN-deficient mice. Conclusion: We describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway.
• dc.description.sponsorship R.H. is a Wellcome Trust Investigator (109915/Z/15/Z) who receives support from the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), Medical Research Council (UK) (MR/N025431/1), and the European Research Council (309548). H.L. receives funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 305444 (RD-Connect) and 305121 (Neuromics), from the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z), and from the Newton Fund (UK/Turkey, MR/N027302/1). P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2), the Medical Research Council (UK) Centre for Translational Muscle Disease (G0601943), EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. A.R. received financial support from the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Senatsverwaltung für Wirtschaft, Technologie und Forschung des Landes Berlin and the Bundesministerium für Bildung und Forschung. L.E.S. was supported by Wellcome Trust (105616/Z/14/Z) and the Medical Research Council (MRC/N010035/1).
• dc.format.mimetype application/pdf
• dc.identifier.citation Bansagi B, Phan V, Baker MR, O'Sullivan J, Jennings MJ, Whittaker RG, Müller JS, Duff J, Griffin H, Miller JAL, Gorman GS, Lochmüller H, Chinnery PF, Roos A, Swan LE, Horvath R. Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation. Neurology. 2018; 90(21):e1842-e1848. DOI 10.1212/WNL.0000000000005566
• dc.identifier.doi http://dx.doi.org/10.1212/WNL.0000000000005566
• dc.identifier.issn 0028-3878
• dc.identifier.uri http://hdl.handle.net/10230/42976
• dc.language.iso eng
• dc.publisher Wolters Kluwer (LWW)
• dc.relation.ispartof Neurology. 2018; 90(21):e1842-e1848
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309548
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305444
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305121
• dc.rights © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.title Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion