Previous studies have described the clinical, serological and pathological features of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and antibodies directed against the paranodal proteins neurofascin-155, contactin-1 (CNTN1), contactin-associated protein-1 (Caspr1), or nodal forms of neurofascin. Such antibodies are useful for diagnosis and potentially treatment selection. However, antibodies targeting Caspr1 only or the Caspr1/CNTN1 complex have been reported in few patients with CIDP. Moreover, it is unclear if these patients belong to the same pathophysiological subgroup. Using cell-based assays in routine clinical testing, we identified sera from patients with CIDP showing strong membrane reactivity when both CNTN1 and Caspr1 were co-transfected (but not when CNTN1 was transfected alone). Fifteen patients (10 male; aged between 40 and 75) with antibodies targeting Caspr1/CNTN1 co-transfected cells were enrolled for characterization. The prevalence of anti-Caspr1/CNTN1 antibodies was 1.9% (1/52) in the Sant Pau CIDP cohort, and 4.3% (1/23) in a German cohort of acute-onset CIDP. All patients fulfilled European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite diagnostic criteria for CIDP. Seven (47%) were initially diagnosed with Guillain-Barré syndrome due to an acute-subacute onset. Six (40%) patients had cranial nerve involvement, eight (53%) reported neuropathic pain and 12 (80%) ataxia. Axonal involvement and acute denervation were frequent in electrophysiological studies. Complete response to intravenous immunoglobulin was not observed, while most (90%) responded well to rituximab. Enzyme-linked immunosorbent assay (ELISA) and teased nerve fibre immunohistochemistry confirmed reactivity against the paranodal Caspr1/CNTN1 complex. Weaker reactivity against Caspr1 transfected alone was also detected in 10/15 (67%). Sera from 13 of these patients were available for testing by ELISA. All 13 samples reacted against Caspr1 by ELISA and this reactivity was enhanced when CNTN1 was added to the Caspr1 ELISA. IgG subclasses were also investigated by ELISA. IgG4 was the predominant subclass in 10 patients, while IgG3 was predominant in other three patients. In conclusion, patients with antibodies to the Caspr1/CNTN1 complex display similar serological and clinical features and constitute a single subgroup within the CIDP syndrome. These antibodies likely target Caspr1 primarily and are detected with Caspr1-only ELISA, but reactivity is optimal when CNTN1 is added to Caspr1 in cell-based assays and ELISA.

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Mutations in GDAP1, an outer mitochondrial membrane protein responsible for recessive Charcot-Marie-Tooth disease (CMT4A), have also been associated with CMT2K, a dominant form of the disease. The three CMT2K patients we studied carried a novel dominant GDAP1 mutation, C240Y (c.719G > A). Mitochondrial respiratory chain complex I activity in fibroblasts from CMT2K patients was 40% lower than in controls, whereas the tubular mitochondria were 33% larger in diameter and the mitochondrial mass was 20% greater. Thus, besides the regulatory role GDAP1 plays in mitochondrial network dynamics, it may also be involved in energy production and in the control of mitochondrial volume.

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Background and purpose: Fifteen percent of patients with myasthenia gravis (MG) are refractory to conventional treatment. Case reports and a few studies show probable benefit of rituximab in these cases. Our objective was to assess the efficacy and the safety of rituximab in patients with MG, in a multicentric real-life study. Method: Inclusion criteria were: age > 18 years; MG with anti-acetylcholine receptor (AChR) antibodies, anti-muscle-specific kinase (MuSk) antibodies or significant decrement after repetitive nerve stimulation; Myasthenia Gravis Foundation of America (MGFA) class >II; refractory or steroid-dependent MG; and treatment with rituximab. Efficacy was assessed at 6 months using the MGFA-post-intervention status (PIS) score, the myasthenic muscle score (MMS) and the number of patients receiving steroids <10 mg/day. Data on adverse events were collected. Results: Twenty-nine patients were included: 20 with anti-AChR MG, five with anti-MuSK MG and four with seronegative MG. MGFA-PIS score was improved or better (improved, minimal manifestations or remission) in 86.2% of patients after 6 months of treatment (P < 0.0001). The mean MMS increased from 68.8 to 83.1 (P < 0.0001). A decrease in steroid dosage (<10 mg/day) was effective in 57.9% of treated patients. In all, 42.8% of patients experienced adverse events: infections (21.4% of patients); infusion reaction (7%); bradycardia (3.7%); and cytopenia (7%). Conclusion: The present study demonstrates the efficacy and safety of rituximab in patients with MG. Additional studies remain necessary to determine the role of rituximab in the pharmacopeia of MG treatment and to establish precise recommendations for the infusion protocol.

Autosomal-dominant optic atrophy (ADOA) is the most common inherited optic neuropathy, due to mutations in the optic atrophy 1 gene (OPA1) in about 60%-80% of cases. At present, the clinical heterogeneity of patients carrying OPA1 variants renders genotype-phenotype correlations difficulty. Since 2005, when we published the first locus-specific database (LSDB) dedicated to OPA1, a large amount of new clinical and genetic knowledge has emerged, prompting us to update this database. We have used the Leiden Open-Source Variation Database to develop a clinico-biological database, aiming to add clinical phenotypes related to OPA1 variants. As a first step, we validated this new database by registering several patients previously reported in the literature, as well as new patients from our own institution. Contributors may now make online submissions of clinical and molecular descriptions of phenotypes due to OPA1 variants, including detailed ophthalmological and neurological data, with due respect to patient anonymity. The updated OPA1 LSDB (http://opa1.mitodyn.org/) should prove useful for molecular diagnoses, large-scale variant statistics, and genotype-phenotype correlations in ADOA studies.

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