{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:37:33Z","timestamp":1790613453659,"version":"4.1.0"},"reference-count":21,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Euro J of Neurology"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and purpose<\/jats:title><jats:p>Mutations in <jats:italic>DNAJB2<\/jats:italic> are associated with autosomal recessive hereditary motor neuropathies\/ Charcot\u2010Marie\u2010Tooth disease type 2 (CMT2). We describe an Italian family with CMT2 due to a homozygous <jats:italic>DNAJB2<\/jats:italic> mutation and provide insight into the pathomechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients with <jats:italic>DNAJB2<\/jats:italic> mutations were characterized clinically, electrophysiologically and by means of skin biopsy. mRNA and protein levels were studied in lymphoblastoid cells (LCLs) from patients and controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Three affected siblings were found to carry a homozygous <jats:italic>DNAJB2<\/jats:italic> null mutation segregating with the disease. The disease manifested in the second to third decade of life. Clinical examination showed severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles. Sensation was reduced in the lower limbs. All patients had severe hearing loss and the proband also had Parkinson\u2019s disease (PD). Nerve conduction studies showed an axonal motor and sensory length\u2010dependent polyneuropathy. DNAJB2 expression studies revealed reduced mRNA levels and the absence of the protein in the homozygous subject in both LCLs and skin biopsy. Interestingly, we detected phospho\u2010alpha\u2010synuclein deposits in the proband, as already seen in PD patients, and demonstrated TDP\u201043 accumulation in patients\u2019 skin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results broaden the clinical spectrum of <jats:italic>DNAJB2<\/jats:italic>\u2010related neuropathies and provide evidence that <jats:italic>DNAJB2<\/jats:italic>\u00a0mutations should be taken into account as another causative gene of CMT2 with hearing loss and parkinsonism. The mutation likely acts through a loss\u2010of\u2010function mechanism, leading to toxic protein aggregation such as TDP\u201043. The associated parkinsonism resembles the classic PD form with the addition of abnormal accumulation of\u00a0phospho\u2010alpha\u2010synuclein.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.15326","type":"journal-article","created":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T19:12:39Z","timestamp":1647285159000},"page":"2056-2065","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["<i>DNAJB2<\/i>\u2010related Charcot\u2010Marie\u2010Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening"],"prefix":"10.1111","volume":"29","author":[{"given":"Paola","family":"Saveri","sequence":"first","affiliation":[{"name":"Department of Clinical Neurosciences Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Magri","sequence":"additional","affiliation":[{"name":"Department of Diagnostics and Applied 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