期刊
NEUROLOGY
卷 90, 期 21, 页码 E1842-E1848出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0000000000005566
关键词
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资金
- Wellcome Centre for Mitochondrial Research [109915/Z/15/Z, 203105/Z/16/Z]
- Medical Research Council (UK) [MR/N025431/1]
- European Research Council [309548]
- European Union Seventh Framework Programme (FP7/2007-2013) [305444, 305121]
- Wellcome Trust Pathfinder Scheme [201064/Z/16/Z]
- Newton Fund (UK/Turkey) [MR/N027302/1]
- Wellcome Trust [101876/Z/13/Z, 105616/Z/14/Z]
- Medical Research Council Mitochondrial Biology Unit [MC_UP_1501/2]
- Medical Research Council (UK) Centre for Translational Muscle Disease [G0601943]
- EU FP7 TIRCON
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust
- University of Cambridge
- Ministerium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen
- Senatsverwaltung fur Wirtschaft, Technologie und Forschung des Landes Berlin
- Bundesministerium fur Bildung und Forschung
- Medical Research Council [MRC/N010035/1]
- MRC [MR/N025431/1, MR/N025431/2, G1000848, 1796467, MR/N010035/1] Funding Source: UKRI
- Wellcome Trust [105616/Z/14/Z] Funding Source: Wellcome Trust
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.
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