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

Neurology. 2018 May 22;90(21):e1842-e1848. doi: 10.1212/WNL.0000000000005566. Epub 2018 May 2.


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 types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • PTEN Phosphohydrolase
  • PTEN protein, human