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

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.

• Authors: Boglarka Bansagi, Vietxuan Phan, Mark R Baker, Julia O'Sullivan, Matthew J Jennings, Roger G Whittaker, Juliane S Müller, Jennifer Duff, Helen Griffin, James A L Miller, Grainne S Gorman, Hanns Lochmüller, Patrick F Chinnery, Andreas Roos, Laura E Swan, Rita Horvath
• Journal: Neurology (Neurology) Vol. 90 Issue 21 Pg. e1842-e1848 (05 22 2018) ISSN: 1526-632X [Electronic] United States
• PMID: 29720545 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Chemical References

• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Adult
• Genetic Predisposition to Disease
• Hamartoma (complications, genetics)
• Hereditary Central Nervous System Demyelinating Diseases (complications, genetics)
• Hereditary Sensory and Motor Neuropathy (complications, genetics)
• Humans
• Male
• Mutation
• PTEN Phosphohydrolase (genetics)
• Exome Sequencing