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J Neuropathol Exp Neurol. 2014 Mar;73(3):223-33. doi: 10.1097/NEN.0000000000000047.

Neuropathologic characterization of INF2-related Charcot-Marie-Tooth disease: evidence for a Schwann cell actinopathy.

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From the Service de Neurologie, CHU de Poitiers, Université de Poitiers, Poitiers, France (SM); EA 6309 "Maintenance myélinique et Neuropathies Périphériques", Faculté de Médecine, Université de Limoges, Limoges, France (SM, BF, LM, LR, J-MV); Service et Laboratoire de Neurologie, Centre de Référence "Neuropathies Périphériques Rares", CHU de Limoges, Limoges, France (BF, LM, LR, J-MV); Départements de Génétique, Biochimie et Génétique Moléculaire, CHU de Limoges, Limoges, France (BF); Inserm U983, Institut IMAGINE, Centre de Référence MARHEA, and Service de Néphrologie pédiatrique, Hôpital Necker-Enfants Malades, Assistance publique-Hôpitaux de Paris, Paris, France (OB); Université Paris Descartes, Sorbonne Paris Cité, Paris, France (OB, CA); Services de Neurologie et d'Anatomie Pathologique, CHU de Bicêtre, Paris XI University, 94270 Le Kremlin-Bicêtre, France (CL); Laboratoire de Pathologie, CHU Brest, Brest, France (PM); and Département de Génétique, Hôpital Necker-Enfants Malades, APHP, Paris, France (CA).


The association of Charcot-Marie-Tooth (CMT) disease with renal dysfunction is uncommon but has long been recognized in several families. Recently, mutations in the INF2 gene, which encodes inverted formin-2, were identified in patients with focal segmental glomerulosclerosis and a dominant intermediate form of CMT (CMTDIE, OMIM #614455). We describe the pathologic lesions of nerve biopsies from 6 patients with INF2-related CMTDIE. There were 4 females and 2 males; ages were from 12 to 47 years; durations between neuropathy onset and biopsy were from 2 to 37 years. Clinical phenotypes were similar to those seen in other forms of CMT disease, but there was always an associated proteinuria (and later renal failure). Motor median nerve conduction velocities were in the range of intermediate CMT disease. Pathologic lesions suggested chronic demyelination and remyelination associated with progressive axonal loss. By electron microscopy, we observed unusual whorl-like proliferations of flattened Schwann cell cytoplasm and anomalies of unmyelinating Schwann cell cytoplasm with supernumerary elongated extensions similar to those described in CMT4C. We also observed abnormal accumulation of β-actin in the cytoplasm of Schwann cells. Our results suggest that these lesions reflect a global disorder of the actin cytoskeleton in Schwann cells and that CMTDIE is the first peripheral nerve disorder associated with a Schwann cell actinopathy.

[Indexed for MEDLINE]

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