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Introduction: A typically distal and symmetrical, slowly progressive sensorimotor demyelinating neuropathy is caused by monoclonal IgM against myelin-associated glycoprotein (MAG) and SGPG, SGLPG glycolipids in the context of a benign IgM paraproteinemia. We studied a patient with a neuropathy that fulfilled the diagnostic criteria for CIDP in whom IgM kappa anti-MAG/SGPG/SGLPG were detected., Observation: The patient was a 57-year-old man who had developed a slowly progressive distal sensorimotor neuropathy, involving the lower then upper limbs, with cranial nerves palsies (oro-pharyngo-laryngo territory). ENMG showed a demyelinating neuropathy with a disproportionate slowing of conduction in distal segments of motor and axonal features in the lower limbs. The first routine laboratory analysis revealed negative or normal findings. Several serum protein electrophoreses were normal. The third cerebrospinal fluid examination demonstrated a moderate and late rise in CSF protein level with no cells. Monoclonal IgM-kappa against MAG/SGPG/SGLPG, was detected; anti-MAG antibody titre in the serum was 20 059 BTU (N<1000). A small IgM-kappa paraprotein was identified by immunofixation. Electron microscopy failed to show nerve fibers with widening of outer lamellae of the myelin. There is no clinical improvement after different treatments, immunoglobulins IV, cortisteroids, plasma exchange, rituximab., Conclusion: It is not known whether this neuropathy is an atypical form of PNMAG or an CIDP associated with anti-MAG. When ENMG show a disproportionate slowing of conduction in distal segments of motor nerves, one should screen the serum with immunofixation to identify small monoclonal components. If IgM-MGUS is present, search should be undertaken for anti-MAG/SGPG/SGLPG antibodies. Diagnosis enables optimal treatment using, in severe cases, expensive current strategies with immunoglobulins IV, plasma exchange, and corticosteroids, or, in the event of no response, rituximab before resorting to more toxic drugs like cyclophosphamide.

The clinical and laboratory phenotype of a paraproteinaemic neuropathy syndrome termed chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies is described in a series of 18 cases. Previous single case reports have outlined some features of this syndrome. All 18 cases were defined by the presence of serum IgM antibodies which react principally with NeuAc (alpha2-8)NeuAc(alpha2-3)Gal-configured disialosyl epitopes common to many gangliosides including GDlb, GD3, GTlb and GQlb. In 17 out of 18 cases, the serum contained benign IgM paraproteins, and in four of these cases at least two IgM paraproteins were present. The IgM antibodies were also cold agglutinins in 50% of cases. The clinical picture comprised a chronic neuropathy with marked sensory ataxia and areflexia, and with relatively preserved motor function in the limbs. In addition, 16 out of 18 cases had motor weakness affecting oculomotor and bulbar muscles as fixed or as relapsing-remitting features. When present in their entirety, these clinical features have been described previously under the acronym CANOMAD: chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies. This distribution of clinical features is reminiscent of Miller Fisher syndrome, in which acute-phase anti-disialylated ganglioside IgG antibodies are found. Clinical electrophysiology and nerve biopsy show both demyelinating and axonal features. A partial response to intravenous immunoglobulin and other treatments is reported in some cases.

Serum monoclonal IgM lambda from a patient with axonal neuropathy reacted with axonal, nuclear, cytoplasmic and cell surface components by immunofluorescence. Experiments performed with Fab fragments of the monoclonal IgM proved that this reactivity was clearly due to actual antibody activity. Further study by Western blotting and ELISA showed that the IgM lambda reacted with the 200 kDa neurofilament protein, H1 and H2b histones and L14, L24 and L7 ribosomal proteins. This reactivity was abolished after adsorption either on purified 200 kDa neurofilament protein or on ribosomal proteins, demonstrating that these reactive proteins share a common epitope which possibly reflects sequence similarities. Sequence homology pointed to the involvement of the peptide AKSPEKAK in the epitope, and this was confirmed by dot blot analysis and adsorption experiments with this peptide. In addition, monoclonal IgM showed low level polyreactivity.

A possibly pathogenic serum monoclonal IgM lambda from a patient with chronic relapsing polyneuropathy was shown to react with the disialosyl-lactosyl residue (NeuAc alpha 2-8NeuAc alpha 2-3) -Gal beta 1-4Glc expressed by GD1b, GT1b, GQ1b, GD2 and GD3. A part of this epitope in terminal position in GM3, GD1a and LM1 was also recognized by the IgM lambda.

Schwann cells in cultures derived from human fetal peripheral nervous system were characterized by their morphology and indirect immunofluorescence with anti-galactocerebroside and anti-laminin antibodies. They stained strongly with human monoclonal IgM anti-sulfated glucuronyl glycolipid antibodies in double labeling experiments.

Small amounts of oligoclonal immunoglobulins were detected by Western blotting in the serum from a patient with motor neuron syndrome. The prominent one, a monoclonal IgM lambda, reacted strongly with the gangliosides GM1 and GD1b and more weakly with asialo GM1, as shown by immunoenzymatic staining of thin-layer chromatograms of gangliosides, ELISA on purified glycolipid coats and immunoadsorption with purified GM1. Affinity-chromatography with purified GM1 resulted in the purification of monoclonal IgM lambda. This purified IgM and its Fab fragments showed the same pattern of reactivity with gangliosides as that observed with whole serum. Such monoclonal IgM could be responsible for motor neuron diseases in some patients with overt or barely detectable monoclonal gammopathies.

An immunological mechanism may be responsible for the peripheral neuropathies related to IgM monoclonal gammopathies. Myelin-associated glycoprotein (MAG) has been found to be one the main target antigens for these paraproteinemias. Glycosphingolipids of peripheral nerve have been also found to be targets for these antibodies, especially a sulfated glycosphingolipid containing glucuronic acid (GLSG) specific for peripheral nerve. Crossed reactivity has been found between MAG and GLSG. Anti-glycolipid antibodies were determined in 14 patients with IgM gammopathy and polyneuropathy. Glycosphingolipids from human peripheral nerve were purified and chromatographed by thin-layer chromatography for immunodetection of the antibodies. The 12 patients who had GLSG antibody activity had a clinical status identical to the reported cases of dysglobulinemic neuropathies with anti-MAG antibodies.

A chronic sensory neuropathy was the initial symptom in a case of Waldenström's macroglobulinemia in a 53-year-old woman. Ultrastructural analysis of a biopsied peripheral nerve revealed a modification of the lamellar structure of the myelin sheath. Immunofluorescent microscopy showed IgM-positive deposits on the myelin sheath. The monoclonal globulin (M component) present in the myelin appears to be a causative factor in the neuropathy.

A 59-year-old man developed a sensorimotor neuropathy of the upper and lower limbs, associated with a biclonal gammopathy, within the space of a few months. Each of two paraproteins was coupled with a distinct IgM kappa IgG lambda light chain. Examination of a nerve biopsy specimen by electron microscopy revealed a demyelinative process with a widening of the interlaminar space in the myelin sheath, as well as deposits of amyloid substance between nerve fibers. Direct immunofluorescence revealed the presence of IgM and of the kappa light chain in certain Schwann cells, while the lambda IgG was fixed to the amyloid deposits. Immunoperoxidase histochemistry showed a positive reaction in normal human nerve tissue to the immune serum IgM and kappa light chain. The findings suggest that the widening of the interlaminar space of the diseased myelin corresponds to an active fixation of immunoglobulin on the sheath of the Schwann cell. The presence of two light chains in this patient's gammopathy caused a dual pathology: the kappa chain, a demyelinative neuropathy, and the lambda chain, a primary amyloidosis, with deposits in the peripheral nerve and in the kidney.

Background and purpose: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous autoimmune disorder critically lacking diagnostic biomarkers. Autoantibodies to nodal and paranodal components have recently been described in a small subset of patients. Here, the diagnostic value of immune reactivity toward the myelin compartment was investigated. Methods: Ninety‐four French CIDP patients were retrospectively studied. The reactivity toward the peripheral nerve was investigated. Sural nerve biopsies were examined by electron microscopy and immunofluorescence. Results: Twenty‐one patients (22%) and three patients (3%) presented with a strong immunoglobulin G or immunoglobulin M reactivity respectively against the myelin compartment. The clinical, electrophysiological and morphological features were examined in nine of these patients for whom sural nerve biopsies were available. Seven patients were electrodiagnosed with definite CIDP, one with possible CIDP and one was unclassifiable but sural nerve biopsy argued for CIDP diagnosis. Electron microscopy of sural nerve biopsies demonstrated the presence of macrophage‐mediated demyelination restricted to the internode in all nine patients. Immunolabelling for voltage‐gated sodium channels, myelin and axonal markers confirmed the presence of segmental demyelination and of remyelination. The nodal and paranodal regions, however, were unaffected in these patients. Nerve conduction studies corroborated the multifocal and segmental profile, and seven patients showed increased duration of proximal (1.5–5.1 times) and/or distal (1.2–3.4 times) compound muscle action potential in at least two nerves. Conclusion: Antibody‐ and macrophage‐mediated demyelination appears responsible for conduction alterations in CIDP patients and nerve immunostaining assays may serve as a supportive diagnostic biomarker. [ABSTRACT FROM AUTHOR]