Background and Objectives This study describes the human leukocyte antigen (HLA) Class II allele frequencies in patients with anti-CNTN1+ and anti-Caspr1+ autoimmune nodopathy (AN).Methods Forty-four AN patients and 50 seronegative CIDP patients from 19 different European hospitals were included in the study. Thirty AN patients had anti-contactin 1 (CNTN1) antibodies, 11 anti-contactin-associated protein 1 (Caspr1) antibodies, and 3 had antibodies against both proteins. HLA-DRB1 was genotyped at the 4-digit allele levels, and the percentage of individuals carrying each allele was compared with that of the general population, obtained from the Allele frequencies database.Results HLA-DRB1*11 alleles appeared in higher proportions in anti-CNTN1+ patients than in seronegative CIDP patients and in the general population (46.7% vs 18% vs 28.4%), with an odds ratio of 3.99 (CI = 1.44 to 11.03, p = 0.01) and 2.2 (CI = 1.07 to 4.53, p = 0.04), respectively. HLA-DRB1*03:01 alleles appeared in significantly higher proportions in anti-Caspr1+ patients than in CIDP patients and in the general population (64.3% vs 22% vs 24.2%), with an odds ratio of 6.38 (CI = 1.77 to 22.99, p = 0.007) and 5.64 (CI = 1.876 to 16.96, p = 0.002), respectively. In the anti-Caspr1+ group, we included 3 patients presenting with antibodies against both CNTN1 and Caspr1 proteins in the acute phase, in which the anti-CNTN1 antibodies disappeared in the chronic phase.Discussion HLA-DRB1*11 alleles are associated with the detection of anti-CNTN1 antibodies in AN patients, and HLA-DRB1*03:01 alleles associate with anti-Caspr1 antibodies. In addition, our study suggests that antiparanodal antibodies targeting both Caspr1 and CNTN1 are present in a small number of patients with AN. These data reinforce the idea that these patients represent specific subsets with clinical features and risk factors that differ from seronegative CIDP patients and from other AN patients. However, further studies should address the functional relevance of these associations and their pathophysiologic implications.

Résumé La neuropathie à anticorps anti-Myelin Associated Glycoprotein (MAG) est une neuropathie périphérique dysimmunitaire rare associée à une gammapathie monoclonale. Le diagnostic de cette neuropathie repose sur des arguments clinico-électriques et sur la détection d’anticorps anti-MAG (quantifiés en ELISA). Le seuil de positivité du fournisseur est de 1 000 Bühlmann titer unit (BTU). L’objectif de notre étude était de proposer un seuil de positivité adapté à la pratique médicale courante. Sur la période de janvier 2022 à décembre 2024, une cohorte de 303 sujets adultes des CHU de Montpellier, Strasbourg et AP-HP-Kremlin-Bicêtre a été constituée dont 103 patients atteints de neuropathie à anticorps anti-MAG. Le projet a été validé par le comité scientifique et éthique de Montpellier (CSE n° A029/2024-08-124/002). Les analyses ont été réalisées avec le kit ELISA Bühlmann®. Le seuil fournisseur de 1 000 BTU montre une sensibilité de 99 % (95 % IC : 95 % à 100 %) et une spécificité de 64 % (95 % IC : 57 % à 70 %) avec un indice de Youden à 0,6253. Un seuil de 3 000 BTU a une sensibilité à 95 % (95 % IC : 89 % à 98 %) et une spécificité à 84 % (95 % IC : 78 % à 88 %) avec un indice de Youden à 0,7915. Le seuil de 1 000 BTU montrait un défaut de spécificité corrigé en élevant le seuil à 3 000 BTU tout en conservant une excellente sensibilité. Notre étude a permis de proposer un seuil optimal de positivité des anticorps anti-MAG adapté à la pratique clinique.

ObjectivesDihydrolipoamide S-acetyltransferase (DLAT), the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC-E2), has recently been suggested to be a biomarker of chronic inflammatory demyelinating polyneuropathy (CIDP). It was particularly associated with sensory variants of CIDP. Antimitochondrial antibodies are important for the diagnosis of primary biliary cholangitis, but insofar, only 2 studies have reported an association with CIDP. Here, we aimed to validate these observations in a cohort of French patients with immune-mediated neuropathy.MethodsThe positivity against PDC-E2/DLAT was examined using ELISA and confirmed using commercially available immuno-DOT and by indirect immunofluorescence on stomach, kidney, and liver sections.ResultsNone of the 20 healthy controls, 31 patients with Guillain-Barr & eacute; syndrome, 102 patients with CIDP (including 24 patients with sensory CIDP), 26 patients with monoclonal gammopathy, 23 patients with Charcot-Marie-Tooth disease, or 20 patients with autoimmune nodopathy showed IgG against PDC-E2/DLAT.DiscussionPDC-E2/DLAT is accurately a target antigen in immune-mediated neuropathies.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder marked by social deficits, repetitive behaviors and atypical sensory perception. The link between ASD and skin abnormalities, inducing itchiness, has never been investigated in depth. This study explores mechanical itch sensitivity in the Shank3ΔC/ΔC mouse model. Key observations include heightened scratching in response to skin deformation and hypersensitivity to mechanical itch (i.e. alloknesis) in Shank3ΔC/ΔC mice. In Shank3ΔC/ΔC mice, ex vivo electrophysiological experiments revealed that C-fiber low-threshold mechanoreceptors (C-LTMRs) were hyporesponsive and transcriptomic analysis showed a downregulation of TAFA4, a protein secreted by C-LMTRs. Interestingly, pharmacologically inhibiting Aβ-LTMR, important in mechanical itch initiation, abolished the itch hypersensitivity. Also, TAFA4 injections reduced the spontaneous scratching response to skin deformation but failed to restore itch sensitivity. Our data suggest that somatosensory deficits in Shank3ΔC/ΔC mice lead to a hypersensitivity to itchiness and indicate that two pathways might be regulating mechanical itchiness, dependent or not on TAFA4.

OBJECTIVE:To describe four cases of Charcot-Marie-Tooth disease type 1A (CMT1A) who developed Guillain-Barré syndrome (GBS), respectively the most frequent genetic and inflammatory neuropathies. METHODS:We described the patients' clinical and electrodiagnostic characteristics. RESULTS:Our CMT1A patients developed typical GBS at various ages (3 to 76 years). GBS-related clinical manifestations were different within patients, with various severity degrees of seve (weakness, respiratory failure). Nerve conduction studies revealed more severe demyelinating features than expected in patients with no CMT1A. High cerebrospinal fluid protein level was found in 3 patients. GBS outcome was mainly good, although some patients only slowly improved. CONCLUSIONS:Our cases are close to the previously described cases of acute worsening in CMT1A, and presented with many electrophysiological features of GBS. Overall, GBS prognosis does not seem worse in CMT1A patients than in other patients. If GBS and CMT1A were independent, the expected frequency of co-occurrence of GBS and CMT1A in our two French regions should be 1 case every 137 years. As we observed 4 cases in only 5 years, we suspect that CMT1A is a risk factor of GBS. SIGNIFICANCE:These cases bring further evidence for a non-random link between inflammatory and genetic neuropathies.

Aim: Autoimmune nodopathies have specific clinicopathologic features, antibodies directed against nodal proteins (neurofascin 186) or paranodal proteins (neurofascin 155, contactin 1, contactin-associated protein 1 (Caspr1)), and usually have a poor response to first-line therapies for chronic inflammatory demyelinating polyradiculoneuropathy. Anti-Caspr1 nodopathy treated with autologous hematopoietic stem cell transplantation (AHSCT) has not been previously reported.Methods: We report the first case of an anti-Caspr1 antibody-positive nodopathy refractory to high-intensity immunosuppressive treatment, including rituximab, that responded dramatically to AHSCT.Results: A 53-year-old woman presented with a rapidly progressive generalized ataxic, painful motor, and inflammatory neuropathy supported by neurophysiologic and MRI studies. Initial tests for antibodies to nodal/paranodal proteins were negative. She was treated with multiple courses of intravenous immunoglobulin and methylprednisolone, plasma exchange, rituximab, and cyclophosphamide without significant clinical benefit. Repeated testing for antibodies to nodal/paranodal proteins yielded a positive result for anti-Caspr1/IgG4 isotype antibodies. Given the poor response to multiple high intensity treatments and the relatively young age of the patient, we decided to perform AHSCT at 30 months post-onset. Immediately after AHSCT, she stopped all immunomodulatory or immunosuppressive therapy. The Overall Neuropathy Limitation Score improved from 8/12 to 4/12 at 6 months post-AHSCT. At 3 months post-AHSCT, IgG4 against Caspr1 was negative and no reactivity against paranodes could be detected.Conclusion: We report a particularly severe anti-Caspr1 antibody autoimmune nodopathy that responded dramatically to AHSCT. Although the rarity of the disease limits the possibility of larger studies, AHSCT may be a valuable therapy in treatment-refractory cases.

OBJECTIVES:Autoimmune nodopathy (AN) is a life-threatening peripheral neuropathy mediated by four autoantibodies targeting axoglial cell adhesion molecules at the nodes of Ranvier: Neurofascin-155 (Nfasc155), PanNeurofascin (PanNfasc), Contactin-1 (CNTN1), and Contactin-associated protein 1 (CASPR1). Antibody detection is a strong biomarker for AN diagnosis and treatment monitoring. The aim of this study was to develop an immuno-dot assay (immuno-DOT) compatible with routine implementation in medical laboratories. METHODS:This new approach was compared to standard techniques: indirect immunofluorescence assay, cell-based assay, and ELISA. Sensitivities (Se) and specificities (Sp) were calculated on a cohort composed of 58 patients diagnosed with AN, 50 seronegative patients with chronic inflammatory demyelinating polyradiculoneuropathy, 20 healthy controls, 30 patients with Guillain-Barré syndrome, 20 with monoclonal gammopathy and 20 with Charcot-Marie-Tooth disease. The patients were diagnosed with AN based on compatible electro-clinical arguments and at least two positive standard techniques. RESULTS:Immuno-DOT sensitivities and specificities were Se=91 %, Sp=97 % for anti-Nfasc155; Se=80 %, Sp=94 % for anti-PanNfasc; Se=93 %, Sp=98 % for anti-CNTN1; and Se=87 %, Sp=94 % for anti-CASPR1. Immuno-DOT allowed the diagnosis within 3 h and the accurate follow-up of the immune reactivity and isotype, and dot intensity correlated with antibody titers following treatments. A longitudinal study indicated that immuno-DOT yielded reliable results even after six months of storage at -20 °C. CONCLUSIONS:The diagnostic performance of immuno-DOT was satisfactory and compatible with routine implementation in medical laboratories.

BACKGROUND AND OBJECTIVES:Immune-mediated small fiber neuropathy (SFN) is increasingly recognized. Acute-onset SFN (AOSFN) remains poorly described. Herein, we report a series of AOSFN cases in which immune origins are debatable.METHODS:We included consecutive patients with probable or definite AOSFN. Diagnosis of SFN was based on the NEURODIAB criteria. Acute onset was considered when the maximum intensity and extension of both symptoms and signs were reached within 28 days. We performed the following investigations: clinical examination, neurophysiologic assessment encompassing a nerve conduction study to rule out large fiber neuropathy, laser-evoked potentials (LEPs), warm detection thresholds (WDTs), electrochemical skin conductance (ESC), epidermal nerve fiber density (ENF), and patient serum reactivity against mouse sciatic nerve teased fibers, mouse dorsal root ganglion (DRG) sections, and cultured DRG. The serum reactivity of healthy subjects (n = 10) and diseased controls (n = 12) was also analyzed. Data on baseline characteristics, biological investigations, and disease course were collected.RESULTS:Twenty patients presenting AOSFN were identified (60% women; median age: 44.2 years [interquartile range: 35.7-56.2]). SFN was definite in 18 patients (90%) and probable in 2 patients. A precipitating event was present in 16 patients (80%). The median duration of the progression phase was 14 days [5-28]. Pain was present in 17 patients (85%). Twelve patients (60%) reported autonomic involvement. The clinical pattern was predominantly non-length-dependent (85%). Diagnosis was confirmed by abnormal LEPs (60%), ENF (55%), WDT (39%), or ESC (31%). CSF analysis was normal in 5 of 5 patients. Antifibroblast growth factor 3 antibodies were positive in 4 of 18 patients (22%) and anticontactin-associated protein-2 antibodies in one patient. In vitro studies showed IgG immunoreactivity against nerve tissue in 14 patients (70%), but not in healthy subjects or diseased controls. Patient serum antibodies bound to unmyelinated fibers, Schwann cells, juxtaparanodes, paranodes, or DRG. Patients' condition improved after a short course of oral corticosteroids (3/3). Thirteen patients (65%) showed partial or complete recovery. Others displayed relapses or a chronic course.DISCUSSION:AOSFN primarily presents as an acute, non-length-dependent, symmetric painful neuropathy with a variable disease course. An immune-mediated origin has been suggested based on in vitro immunohistochemical studies.

IntroductionAutoimmune nodopathies (AN) have been diagnosed in a subset of patients fulfilling criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who display no or poor response to intravenous immunoglobulins. Biomarkers of AN are autoantibodies, mainly IgG4, directed against the ternary paranodal complex composed by neurofascin-155, contactin-1 (CNTN1), and Contactin-associated-protein-1 (CASPR1) or against the nodal isoforms of neurofascin. IgG4 can undergo a Fab-arm exchange (FAE) which results in functionally monovalent antibody. This phenomenon differentially affects the pathogenicity of IgG4 depending on the target of autoantibodies. Here, we have evaluated this issue by examining the impact of valency on anti-CNTN1 IgG4 which induces paranodal destruction through a function blocking activity. MethodsSera were obtained from 20 patients with AN associated with anti-CNTN1 antibodies. The proportion of monospecific/bispecific anti-CNTN1 antibodies was estimated in each patient by ELISA by examining the ability of serum antibodies to cross-link untagged CNTN1 with biotinylated CNTN1. To determine the impact of monovalency, anti-CNTN1 IgG4 were enzymatically digested into monovalent Fab and tested in vitro on cell aggregation assay. Also, intraneural injections were performed to determine whether monovalent Fab and native IgG4 may penetrate paranode, and antibody infiltration was monitored 1- and 3-days post injection. Results and discussionWe found that the percentage of monospecific antibodies were lower than 5% in 14 out of 20 patients (70%), suggesting that IgG4 have undergone extensive FAE in situ. The levels of monospecific antibodies correlated with the titers of anti-CNTN1 antibodies. However, no correlation was found with clinical severity, and patients with low or high percentage of monospecific antibodies similarly showed a severe phenotype. Native anti-CNTN1 IgG4 were shown to inhibit the interaction between cells expressing CNTN1/CASPR1 and cells expressing neurofascin-155 using an in vitro aggregation assay. Similarly, monovalent Fab significantly inhibited the interaction between CNTN1/CASPR1 and neurofascin-155. Intraneural injections of Fab and native anti-CNTN1 IgG4 indicated that both mono- and bivalent anti-CNTN1 IgG4 potently penetrated the paranodal regions and completely invaded this region by day 3. Altogether, these data indicate anti-CNTN1 IgG4 are mostly bispecific in patients, and that functionally monovalent anti-CNTN1 antibodies have the pathogenic potency to alter paranode.

Les nodopathies auto-immunes (NA) sont des pathologies démyélinisantes du système nerveux périphérique qui ont la particularité d’avoir une physiopathologie médiée par des anticorps majoritairement d’isotype IgG4. La présence de ces anticorps, l’installation aiguë ou subaiguë de la neuropathie, la mauvaise réponse aux immunoglobulines intraveineuses et la bonne sensibilité au rituximab (anticorps monoclonal thérapeutique anti-CD20) ont récemment conduit à exclure les NA du groupe des polyradiculoneuropathies inflammatoires démyélinisantes chroniques. À ce jour, quatre auto-anticorps ciblant des protéines axo-gliales au niveau des nœuds de Ranvier et des paranœuds ont été identifiés : les anti-pan-neurofascine (anti-pan-Nfasc) qui reconnaissent toutes les isoformes de neurofascine, les anti-neurofascine 155 (anti-Nfasc155), les anti-contactine 1 (anti-CNTN1) et les anti-contactin associated protein 1 (anti-CASPR1). Actuellement en France, l’identification biologique de ces anticorps s’effectue en cytométrie en flux sur cellules transfectées HEK dans le laboratoire d’immunologie de l’AP-HM, à l’Hôpital La Conception à Marseille. Les NA engagent le pronostic fonctionnel et parfois même le pronostic vital. Leur diagnostic doit donc être le plus rapide possible pour de ne pas retarder la prise en charge thérapeutique. Autoimmune nodopathy (AN) are demyelinating pathologies of the peripheral nervous system which have the particularity of having a pathophysiology mediated by antibodies mainly of IgG4 isotype. Specific autoantibodies, the acute or subacute onset of neuropathy, the poor response to intravenous immunoglobulins and the improvement after rituximab led to exclude AN from the group of chronic inflammatory demyelinating polyradiculoneuropathies. Currently, 4 auto-antibodies targeting axo-glial proteins at the nodes of Ranvier and paranodes have been identified: anti-pan-neurofascin (anti-pan-Nfasc) antibodies which recognize all neurofascin isoforms, anti-neurofascin 155 (anti-Nfasc155), anti-contactin 1 (anti-CNTNI) and anti-contactin associated protein 1 (anti-CASPRI). Currently, in France, the identification of these antibodies is processed by flow cytometry on transfected HEK cells in the Immunology laboratory at the hospital La Conception in Marseille. As AN can cause severe disability and sometimes be life-threatening, their diagnosis should be done as soon as possible in order to start promptly the treatment.

While lactate shuttle theory states that glial cells metabolize glucose into lactate to shuttle it to neurons, how glial cells support axonal metabolism and function remains unclear. Lactate production is a common occurrence following anaerobic glycolysis in muscles. However, several other cell types, including some stem cells, activated macrophages and tumor cells, can produce lactate in presence of oxygen and cellular respiration, using Pyruvate Kinase 2 (PKM2) to divert pyruvate to lactate dehydrogenase. We show here that PKM2 is also upregulated in myelinating Schwann cells (mSC) of mature mouse sciatic nerve versus postnatal immature nerve. Deletion of this isoform in PLP-expressing cells in mice leads to a deficit of lactate in mSC and in peripheral nerves. While the structure of myelin sheath was preserved, mutant mice developed a peripheral neuropathy. Peripheral nerve axons of mutant mice failed to maintain lactate homeostasis upon activity, resulting in an impaired production of mitochondrial ATP. Action potential propagation was not altered but axonal mitochondria transport was slowed down, muscle axon terminals retracted and motor neurons displayed cellular stress. Additional reduction of lactate availability through dichloroacetate treatment, which diverts pyruvate to mitochondrial oxidative phosphorylation, further aggravated motor dysfunction in mutant mice. Thus, lactate production through PKM2 enzyme and aerobic glycolysis is essential in mSC for the long-term maintenance of peripheral nerve axon physiology and function.

We report on our cohort of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who fulfilled the 2010 diagnostic criteria of CIDP. Patients were consecutively recruited and their demographics, clinical features and serological analysis of autoantibodies against neurofascin (NF)-155, NF-186, contactin-1 (CNTN1) and contactin-associated protein 1 were obtained. A total of 26 patients for which there was serologic testing were included: 22 typical CIDP, 3 distal CIDP and 1 multifocal CIDP. Of these, 2 patients had previously reported paranodal antibodies; one with autoantibodies IgG4 against NF155 and one with IgG4 against CNTN1. The patient with IgG4 anti-NF155 had young-onset, predominantly distal phenotype with associated tremor and sensory ataxia and poor response to intravenous immunoglobulin (IVIG). The patient with IgG4 anti-CNTN1 antibodies had a subacute onset, sensory ataxia, membranous nephropathy but responded poorly to IVIG. Autoimmune nodopathies represented 8% of our CIDP cohort. The clinical features and treatment response of patients with IgG4 anti-NF155 and anti-CNTN1 were similar to previous reports. Detecting the presence of autoimmune nodopathies was crucial in refining the diagnosis and determining the prognosis.