Chiara Pisciotta1, Yunhong Bai2, Kathryn M Brennan2, Xingyao Wu2, Tiffany Grider2, Shawna Feely2, Suola Wang2, Steven Moore2, Carly Siskind2, Michael Gonzalez2, Stephan Zuchner2, Michael E Shy2. 1. From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL. chiara.pisciotta@gmail.com. 2. From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL.
Abstract
OBJECTIVE: To investigate the effects of NEFL Glu396Lys mutation on the expression and assembly of neurofilaments (NFs) in cutaneous nerve fibers of patients with Charcot-Marie-Tooth disease type 2E (CMT2E). METHODS: A large family with CMT2E underwent clinical, electrophysiologic, and skin biopsy studies. Biopsies were processed by indirect immunofluorescence (IF), electron microscopy (EM), and Western blot analysis. RESULTS: The clinical features demonstrated intrafamilial phenotypic variability, and the electrophysiologic findings revealed nerve conductions that were either slow or in the intermediate range. All patients had reduced or absent compound muscular action potential amplitudes. Skin biopsies showed axons labeled with the axonal markers protein gene product 9.5 and α-tubulin, but not with NFs. The results of Western blot analysis were consistent with those of IF, showing reduced or absent NFs and normal expression of α-tubulin. EM revealed clusters of regenerated fibers, in absence of myelin sheath abnormalities. Both IF and EM failed to show NF aggregates in dermal axons. The morphometric analysis showed a smaller axonal caliber in patients than in controls. The study of the nodal/paranodal architecture demonstrated that sodium channels and Caspr were correctly localized in patients with CMT2E. CONCLUSIONS: Decrease in NF abundance may be a pathologic marker of CMT2E. The lack of NF aggregates, consistent with prior studies, suggests that they occur proximally leading to subsequent alterations in the axonal cytoskeleton. The small axonal caliber, along with the normal molecular architecture of nodes and paranodes, explain the reduced velocities detected in patients with CMT2E. Our results also demonstrate that skin biopsy can provide evidence of pathologic and pathogenic abnormalities in patients with CMT2E.
OBJECTIVE: To investigate the effects of NEFL Glu396Lys mutation on the expression and assembly of neurofilaments (NFs) in cutaneous nerve fibers of patients with Charcot-Marie-Tooth disease type 2E (CMT2E). METHODS: A large family with CMT2E underwent clinical, electrophysiologic, and skin biopsy studies. Biopsies were processed by indirect immunofluorescence (IF), electron microscopy (EM), and Western blot analysis. RESULTS: The clinical features demonstrated intrafamilial phenotypic variability, and the electrophysiologic findings revealed nerve conductions that were either slow or in the intermediate range. All patients had reduced or absent compound muscular action potential amplitudes. Skin biopsies showed axons labeled with the axonal markers protein gene product 9.5 and α-tubulin, but not with NFs. The results of Western blot analysis were consistent with those of IF, showing reduced or absent NFs and normal expression of α-tubulin. EM revealed clusters of regenerated fibers, in absence of myelin sheath abnormalities. Both IF and EM failed to show NF aggregates in dermal axons. The morphometric analysis showed a smaller axonal caliber in patients than in controls. The study of the nodal/paranodal architecture demonstrated that sodium channels and Caspr were correctly localized in patients with CMT2E. CONCLUSIONS: Decrease in NF abundance may be a pathologic marker of CMT2E. The lack of NF aggregates, consistent with prior studies, suggests that they occur proximally leading to subsequent alterations in the axonal cytoskeleton. The small axonal caliber, along with the normal molecular architecture of nodes and paranodes, explain the reduced velocities detected in patients with CMT2E. Our results also demonstrate that skin biopsy can provide evidence of pathologic and pathogenic abnormalities in patients with CMT2E.
Authors: Hailian Shen; Devin M Barry; Jeffrey M Dale; Virginia B Garcia; Nigel A Calcutt; Michael L Garcia Journal: Hum Mol Genet Date: 2011-04-14 Impact factor: 6.150
Authors: Constantin d'Ydewalle; Jyothsna Krishnan; Driss M Chiheb; Philip Van Damme; Joy Irobi; Alan P Kozikowski; Pieter Vanden Berghe; Vincent Timmerman; Wim Robberecht; Ludo Van Den Bosch Journal: Nat Med Date: 2011-07-24 Impact factor: 53.440
Authors: Miranda L Tradewell; Heather D Durham; Walter E Mushynski; Benoit J Gentil Journal: J Neuropathol Exp Neurol Date: 2009-06 Impact factor: 3.685
Authors: Gabriel Miltenberger-Miltenyi; Andreas R Janecke; Julia V Wanschitz; Vincent Timmerman; Christian Windpassinger; Michaela Auer-Grumbach; Wolfgang N Löscher Journal: Arch Neurol Date: 2007-07
Authors: Sinéad M Murphy; David N Herrmann; Michael P McDermott; Steven S Scherer; Michael E Shy; Mary M Reilly; Davide Pareyson Journal: J Peripher Nerv Syst Date: 2011-09 Impact factor: 3.494
Authors: John Svaren; John J Moran; Xingyao Wu; Riccardo Zuccarino; Chelsea Bacon; Yunhong Bai; Raghu Ramesh; Laurie Gutmann; Daniel M Anderson; Derek Pavelec; Michael E Shy Journal: Ann Neurol Date: 2019-04-22 Impact factor: 10.422
Authors: E Villalón; M R Jones; C Sibigtroth; S J Zino; J M Dale; D S Landayan; H Shen; D D W Cornelison; M L Garcia Journal: Genes Brain Behav Date: 2016-10-11 Impact factor: 3.449
Authors: Menelaos Pipis; Andrea Cortese; James M Polke; Roy Poh; Jana Vandrovcova; Matilde Laura; Mariola Skorupinska; Arnaud Jacquier; Raul Juntas-Morales; Philippe Latour; Philippe Petiot; Guilhem Sole; Yves Fromes; Sachit Shah; Julian Blake; Byung-Ok Choi; Ki Wha Chung; Tanya Stojkovic; Alexander M Rossor; Mary M Reilly Journal: J Neurol Neurosurg Psychiatry Date: 2021-09-13 Impact factor: 13.654
Authors: José Berciano; Kristien Peeters; Antonio García; Tomás López-Alburquerque; Elena Gallardo; Arantxa Hernández-Fabián; Ana L Pelayo-Negro; Els De Vriendt; Jon Infante; Albena Jordanova Journal: J Neurol Date: 2015-12-08 Impact factor: 4.849
Authors: Alejandro Horga; Matilde Laurà; Zane Jaunmuktane; Nivedita U Jerath; Michael A Gonzalez; James M Polke; Roy Poh; Julian C Blake; Yo-Tsen Liu; Sarah Wiethoff; Conceição Bettencourt; Michael Pt Lunn; Hadi Manji; Michael G Hanna; Henry Houlden; Sebastian Brandner; Stephan Züchner; Michael Shy; Mary M Reilly Journal: J Neurol Neurosurg Psychiatry Date: 2017-05-13 Impact factor: 10.154
Authors: Markus T Sainio; Emil Ylikallio; Laura Mäenpää; Jenni Lahtela; Pirkko Mattila; Mari Auranen; Johanna Palmio; Henna Tyynismaa Journal: Neurol Genet Date: 2018-06-05