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Disease\u2010associated variants in the <jats:italic>MPZ<\/jats:italic> gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype\u2010specific morphological features. Here, we aimed at enhancing the understanding of these subtype\u2010specific features and pathophysiological aspects of <jats:italic>MPZ<\/jats:italic> neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with <jats:italic>MPZ<\/jats:italic> mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; <jats:italic>n<\/jats:italic>\u2009=\u20092), demyelinating Charcot\u2013Marie\u2010Tooth (CMT type 1; <jats:italic>n<\/jats:italic>\u2009=\u200911), intermediate (CMTi; <jats:italic>n<\/jats:italic>\u2009=\u20093), and axonal CMT (type 2; <jats:italic>n<\/jats:italic>\u2009=\u20095). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four <jats:italic>MPZ<\/jats:italic> gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2\/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2\/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that <jats:italic>MPZ<\/jats:italic> alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non\u2010myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in <jats:italic>MPZ<\/jats:italic> neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle.<\/jats:p>","DOI":"10.1111\/bpa.13200","type":"journal-article","created":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T10:50:43Z","timestamp":1692183043000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Myelin protein zero mutation\u2010related hereditary neuropathies: Neuropathological insight from a new nerve biopsy cohort"],"prefix":"10.1111","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0268-9425","authenticated-orcid":false,"given":"Juliane","family":"Bremer","sequence":"first","affiliation":[{"name":"Institute of Neuropathology RWTH Aachen University Hospital  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Meinhardt","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology RWTH Aachen University Hospital  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istvan","family":"Katona","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology RWTH Aachen University Hospital  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Senderek","sequence":"additional","affiliation":[{"name":"Friedrich Baur Institute at the Department of Neurology University Hospital, LMU Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke K.","family":"K\u00e4mmerer\u2010Gassler","sequence":"additional","affiliation":[{"name":"Institute of Pathology RWTH Aachen University Hospital  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Roos","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology RWTH Aachen University Hospital  Aachen Germany"},{"name":"Department of Neuropaediatrics University of Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Ferbert","sequence":"additional","affiliation":[{"name":"Department of Neurology Klinikum Kassel  Kassel Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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