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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.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.issn 0028-3878
dc.identifier.uri http://hdl.handle.net/10230/42976
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.language.iso eng
dc.publisher Wolters Kluwer (LWW)
dc.relation.ispartof Neurology. 2018; 90(21):e1842-e1848
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.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.identifier.doi http://dx.doi.org/10.1212/WNL.0000000000005566
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.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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