For hereditary polyneuropathies, termed Charcot-Marie-Tooth diseases, recent advances in the identification of the responsible genes allow a genetic diagnosis in a growing number of cases. Acquired neuropathies are more frequent than hereditary neuropathies and their diagnosis is based on a combination of clinical, electrophysiological, biological and, when necessary, histopathological evidence. Despite thorough investigations, no cause is found in 10–15% of patients with chronic polyneuropathies. Here, we studied two types of chronic acquired polyneuropathies whose diagnosis can be challenging, chronic inflammatory demyelinating polyneuropathy and chronic idiopathic axonal polyneuropathy. The distinction is important since specific treatment options are available for CIDP, whereas there is none of proven efficacy for CIAP. CIDP is an immune-mediated disorder of peripheral nerves, with a progressive or relapsing course. Its diagnosis is based mainly on clinical and electrophysiological features. In its most common clinical presentation, CIDP combines motor deficits involving proximal and/or distal segments of the limbs, and superficial and/or deep sensory loss, progressing for at least two months. Cerebrospinal fluid examination often shows increased protein levels without cells. However, CIDP clinical presentation may be atypical, and electrodiagnostic criteria for demyelination may be missing because segmental demyelination affects only a few myelinated fibers or proximal segments not easily studied by electroneuromyography. CIAPs are slowly progressive distal polyneuropathies, involving sensory or motor and sensory modalities, for which no cause is found after a thorough biological investigation. In some cases, CIDP may be impossible to differentiate from CIAP on the basis of clinical and electrophysiological examinations, a situation that requires a nerve biopsy. This procedure must be performed by trained physicians and examined in a laboratory with expertise in nerve pathology, as it requires sophisticated approaches, such as electron microscopy of transverse sections of peripheral nerve. The paranodal Y-27632 septatelike junctions separate the nodal and juxtaparanodal regions, attach the glial loops to the axonal membrane, and restrict the lateral diffusion of axonal membrane proteins between the node and the internodal space. Several proteins involved in axoglial contacts have been identified, including paranodin, also known as Caspr. Nodal and paranodal proteins are altered in mouse models of CMT, and have been investigated in skin biopsies from CMT patients. However, the possible alterations of nodal and paranodal regions in CIDP and CIAP are not known.