Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation.
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Authors
Bansagi, Boglarka
Phan, Vietxuan
Baker, Mark R
O'Sullivan, Julia
Jennings, Matthew J
Whittaker, Roger G
Müller, Juliane S
Duff, Jennifer
Griffin, Helen
Miller, James AL
Gorman, Grainne S
Lochmüller, Hanns
Chinnery, Patrick F
Roos, Andreas
Swan, Laura E
Publication Date
2018-05-22Journal Title
Neurology
ISSN
0028-3878
Publisher
Ovid Technologies (Wolters Kluwer Health)
Volume
90
Issue
21
Pages
e1842-e1848
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Bansagi, B., Phan, V., Baker, M. R., O'Sullivan, J., Jennings, M. J., Whittaker, R. G., Müller, J. S., et al. (2018). Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation.. Neurology, 90 (21), e1842-e1848. https://doi.org/10.1212/WNL.0000000000005566
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.
Keywords
Adult, Genetic Predisposition to Disease, Hamartoma, Hereditary Central Nervous System Demyelinating Diseases, Hereditary Sensory and Motor Neuropathy, Humans, Male, Mutation, PTEN Phosphohydrolase, Exome Sequencing
Sponsorship
Wellcome Trust (101876/Z/13/Z)
Wellcome Trust (109915_A_15_Z)
Medical Research Council (MR/N025431/2)
Identifiers
External DOI: https://doi.org/10.1212/WNL.0000000000005566
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284680
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