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

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Bansagi, Boglarka 
Phan, Vietxuan 
Baker, Mark R 
O'Sullivan, Julia 
Jennings, Matthew J 


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.



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

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Ovid Technologies (Wolters Kluwer Health)
Wellcome Trust (101876/Z/13/Z)
Wellcome Trust (109915_A_15_Z)
Medical Research Council (MR/N025431/2)