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

Lookup NU author(s): Dr Boglárka Bánsági, Professor Mark BakerORCiD, Matt Jennings, Professor Roger Whittaker, Dr Jennifer Duff, Dr Helen GriffinORCiD, Dr James Miller, Professor Grainne Gorman, Professor Hanns Lochmuller, Professor Patrick Chinnery, Dr Andreas Roos, Professor Rita HorvathORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Neurology

Year: 2018

Volume: 90

Issue: 21

Pages: e1842-e1848

Print publication date: 22/05/2018

Online publication date: 02/05/2018

Acceptance date: 01/03/2018

Date deposited: 28/06/2018

ISSN (print): 0028-3878

ISSN (electronic): 1526-632X

Publisher: Wolters Kluwer


DOI: 10.1212/WNL.0000000000005566

PubMed id: 29720545


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Funder referenceFunder name
201064/Z/16/ZWellcome Trust
101876/Z/13/ZWellcome Trust
203105/Z/16/ZWellcome Trust
109915/Z/15/ZWellcome Trust
MR/N025431/1Medical Research Council (MRC)
MR/N027302/1Medical Research Council (MRC)