RARE DISEASE
Polyneuropathy associated with IgM monoclonal gammopathy with anti-MAG
Polyneuropathy associated with IgM monoclonal gammopathy with anti-MAG
Polyneuropathy associated with IgM monoclonal gammopathy with anti-MAG
Synonyms: Anti-MAG neuropathy, Neuropathy associated with monoclonal IgM antibodies to myelin-associated glycoprotein
Synonyms: Anti-MAG neuropathy, Neuropathy associated with monoclonal IgM antibodies to myelin-associated glycoprotein
Synonyms: Anti-MAG neuropathy, Neuropathy associated with monoclonal IgM antibodies to myelin-associated glycoprotein
Drug discovery
2
drugs
With orphan designations
Overview
Polyneuropathy associated with IgM monoclonal gammopathy and anti-myelin-associated glycoprotein (MAG) antibodies is a rare, immune-mediated demyelinating neuropathy characterized by slowly progressive distal sensory deficits, sensory ataxia, postural tremor, and variable motor involvement. It arises from IgM autoantibodies targeting MAG, a peripheral nerve glycoprotein, leading to complement-mediated nerve damage. Diagnosis requires anti-MAG antibody detection (via ELISA/Western blot) and evidence of IgM monoclonal gammopathy [1][7][12].
Burden
Disability: 10% develop severe disability (modified Rankin Scale ≥3); sensory ataxia increases fall risk [3][8][12].
Chronicity: Progressive decline in 50–70% despite therapy; long-term neuropathy correlates weakly with serological markers [1][7][12].
Economic: High healthcare utilization due to diagnostic delays (median 2–5 years) and limited therapies [3][7][17].
Therapies
B-cell targeting: Rituximab (anti-CD20) is first-line, improving symptoms in 30–50% via IgM reduction; BTK inhibitors (e.g., ibrutinib) show promise in early studies [5][7][17].
Limited efficacy: IV immunoglobulin and plasma exchange provide transient benefits; cyclophosphamide/cladribine are used but have toxicity risks [5][7][12].
Trials: Two ongoing BTK inhibitor trials aim to address unmet needs [7][19].
Categories: rare neurological diseases
Research Papers
212 drug discovery papers about Polyneuropathy associated with IgM monoclonal gammopathy with anti-MAG, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
212 drug discovery papers about Polyneuropathy associated with IgM monoclonal gammopathy with anti-MAG, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-07-21 | Management and long-term haematological and neurological outcomes of Immunoglobulin M and Waldenström's macroglobulinaemia-related neuropathy: A single-centre experience.
Immunoglobulin M-related peripheral neuropathy (IgM-PN) is typically demyelinating and associated with anti-myelin-associated glycoprotein antibodies; however, limited data on clinical outcomes are available. We retrospectively analysed consecutive patients with IgM-PN assessed prospectively with the Rasch-built Overall Disability Scale (RODS) and the Inflammatory Neuropathy Cause and Treatment (INCAT) questionnaires. Twenty-eight patients were retrospectively enrolled. The median follow-up was 5.54 years. Treatment was initiated in all solely due to neuropathy symptoms: 19 (67.9%) dexamethasone-rituximab-cyclophosphamide, 6 (21.4%) rituximab and 3 (10.7%) ibrutinib. The baseline median INCAT score was 2.0 and improved to 1.0 at further time points; within-patient improvements compared to baseline were significant (p < 0.005). A clinically relevant improvement was evident in 13 (46.4%), 18 (64.3%) and 17 (60.7%) patients at 6, 12 and 24 months respectively. IgM reduction was associated with improvement in INCAT scores at 6 (p = 0.041) and 12 months (p = 0.030). At baseline, the median RODS score was 38.0, improved to 41.5 at 6 months, then to 43.0 and 43.5 at 1 and 2 years (all p < 0.001). A clinically relevant improvement was evident in 5 (17.9%), 7 (25%) and 9 (32.1%) patients at 6, 12 and 24 months respectively. Patients with IgM-PN, treated mainly with rituximab-based regimens, showed significant improvement in functional and neurological ability over a 2-year follow-up.
2026-07-12 | Anti-MAG-associated neuropathy: a case report and literature review.
Anti-myelin-associated glycoprotein (MAG) neuropathy is an uncommon IgM-mediated autoimmune demyelinating peripheral neuropathy, which is prone to misdiagnosis due to overlapping clinical manifestations with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Serum anti-MAG IgM ≥ 1:1000 is widely accepted as the standard diagnostic cut-off value clinically, while cases with low-titer positive results remain poorly summarized. We report one low-titer MAG-antibody-positive case receiving individualized low-dose rituximab to supplement clinical evidence for this disease. A 65-year-old male patient presented with progressive numbness and limb unsteadiness lasting for 5 months. Neurological examination identified predominantly distal lower limb weakness and prominent deep sensory ataxia. Pre-treatment INCAT disability score was 4 and decreased to 2 one month after intervention. Serum anti-MAG IgM was positive at 1:320; all nodal/paranodal antibodies including NF155, CNTN1, Caspr1 and pan-neurofascin tested negative. Immunofixation electrophoresis demonstrated an IgM-λ monoclonal gammopathy, with serum free κ/λ light chain within normal reference ranges. Cerebrospinal fluid (CSF) protein was markedly elevated. Nerve conduction study (NCS) performed prior to medication revealed diffuse distal-predominant demyelination combined with axonal injury. The patient failed high-dose methylprednisolone pulse therapy, then received split low-dose rituximab (100 mg on Day 1, 500 mg on Day 2). One-month follow-up showed antibody titer dropped to 1:100 and obvious clinical improvement; incident hyperthyroidism was detected during hospitalization. Bone marrow biopsy excluded B-cell proliferative disorders. Low-titer anti-MAG IgM combined with typical clinical, electrophysiological and serological findings can confirm MAG neuropathy. Individualized low-dose rituximab achieves satisfactory efficacy for elderly patients complicated with underlying cerebrovascular disorders in early disease stage. Concurrent new-onset autoimmune hyperthyroidism is a rare clinical coincidence in this disease, requiring long-term follow-up observation.
2026-07-03 | Anti-MAG Polyneuropathy: Characterization of the Monoclonal Gammopathy and Clonal B-Cell Population.
Polyneuropathy due to antibodies to myelin-associated glycoprotein (MAG) is a rare disease with an estimated prevalence of 1 per 100,000. Symptoms start in the sixth or seventh decade of life, presenting sensory polyneuropathy with sensory ataxia, paresthesia, mild motor deficit, and tremor of upper extremities. The neurophysiological features are compatible with length-dependent demyelination. It is caused by monoclonal gammopathy of the IgM type produced by clonal B cells. In recent years the monoclonal anti-CD20 antibody has become the preferred first-line treatment, but with limited efficacy. We identified a cohort of 42 patients diagnosed with anti-MAG polyneuropathy. Clinical data were collected retrospectively, and flow cytometry files and immune histochemistry slides were reassessed. We report that in most cases of anti-MAG polyneuropathy, the monoclonal IgM is kappa-restricted, the B-cell population shows lymphoplasmacytic differentiation, MYD88L265P mutation is a frequent finding, and the clonal B-cell population includes plasma cells. These findings most likely explain the low efficacy of rituximab monotherapy. We found the burden of symptoms to be high among patients with anti-MAG polyneuropathy as most of our patients had received intravenous immunoglobulin infusions and/or B-cell-directed treatment. We suggest that future treatment protocols for anti-MAG polyneuropathy should incorporate plasma cell-directed drugs. Furthermore, we found complement receptor 1 (CD35) to be down regulated on clonal B lymphocytes but not on normal B lymphocytes in these patients. We suggest that this may be a common feature of clonal B lymphocytes in chronic lymphoproliferative diseases.
2026-02-09 | Prevalence and Patterns of Cranial Nerve Involvement in CIDP, Autoimmune Nodopathy, MMN, and Anti-MAG Neuropathy: A Multicenter Korea/UK Study of 582 Patients.
Cranial nerve involvement is a well-recognized feature in Guillain-Barré syndrome (GBS) but remains less well understood in chronic forms of autoimmune neuropathies. Earlier studies of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were conducted before updated diagnostic criteria and the recognition of autoimmune nodopathy (AN), which may limit the interpretation of their findings. We retrospectively analyzed 582 patients with chronic autoimmune neuropathies-CIDP (n = 431), multifocal motor neuropathy (MMN) (n = 64), anti-myelin-associated glycoprotein (MAG) neuropathy (n = 54), and AN (n = 33)-from 4 Korean and 1 UK centers. Patients with cranial nerve involvement were identified and described. CIDP patients with cranial nerve involvement (cranial+ CIDP) were compared with those without (cranial- CIDP). Cranial nerve involvement was observed in 8.8% (38/431) of CIDP and 24.2% (8/33) of AN patients but was absent in MMN (0/64) and anti-MAG neuropathy (0/54). Facial palsy was overall the most common manifestation (CIDP: 45%, AN: 50%). Patients with AN more frequently exhibited bilateral optic neuropathy (50%) and facial diplegia (38%), while CIDP patients more often showed trigeminal neuropathy and oculomotor nerve palsy (both 32%). Compared with cranial- CIDP, cranial+ CIDP patients were more often younger, of variant subtypes (especially multifocal), presented (sub)acutely with preceding infection/vaccination, followed by relapsing-remitting rather than progressive courses, and achieved greater improvement despite greater pre-treatment disability. Cranial nerve involvement serves as a diagnostic clue in chronic autoimmune neuropathies, particularly in identifying AN and CIDP. Cranial+ CIDP appears to represent a distinct subset with partial overlap to GBS, suggesting unique underlying mechanisms.
2025-11-26 | 7 Common symptoms, uncommon neuropathy: a case of anti-MAG neuropathy
a:2:{s:4:"lang";s:2:"en";s:7:"content";s:1475:" We present a case of anti-myelin-associated glycoprotein (anti-MAG) neuropathy in a 62-year-old male with sensory symptoms predominantly affecting the lower limbs. The patient reported a 10-month history of bilateral pins and needles sensation, initially in the toes and progressively extending to the ankles. Intermittent sensory disturbance was also noted in the hands, without weakness, imbalance, or autonomic dysfunction. His medical history included hypertension and hyperlipidemia, managed with statin therapy. Neurological examination found absent reflexes bilaterally, reduced vibration sense at the right ankle and left knee, and hypersensitivity to pinprick up to the ankles. No cerebellar signs were identified. Romberg’s test was negative. Laboratory findings showed positive anti-MAG antibodies and an IgM kappa paraprotein band on serum electrophoresis, with negative urine Bence Jones proteins. Electrophysiology demonstrated asymmetric, non-length-dependent neuropathy, despite the symmetrical clinical presentation. Following a multidisciplinary discussion, immunotherapy such as rituximab was deferred, and a haematology referral was made due to investigate the paraprotein. This case underscores the importance of considering anti-MAG neuropathy in patients presenting with sensory symptoms and no tremor, especially if the neurophysiological findings are in keeping with an inflammatory neuropathy. jidhin.raj{at}nhs.net ";}
proteins
2025-07-25 | Reversible rituximab demyelination in anti-MAG polyneuropathy: A role for IVIG?
Anti-myelin-associated glycoprotein (MAG) demyelinating neuropathy is a clinically heterogeneous slowly progressive large fiber sensorimotor polyneuropathy. Management of anti-MAG neuropathy is challenging, and a small subset of anti-MAG neuropathy patients have been previously reported to deteriorate after rituximab therapy, perhaps triggered by an upsurge in autoantibody release secondary to B lymphocyte lysis. We report a patient with this complication that responded to IVIg therapy. Case description and serial electrophysiological studies. Serial electrophysiological studies confirmed subacute demyelination in our patient with anti-MAG neuropathy treated with rituximab followed by improvement following IVIg. The use of IVIG therapy can be considered in cases where rituximab leads to clinical and electrophysiological worsening of anti-MAG neuropathy.
2015-08-04 | Methylcobalamin promotes the differentiation of Schwann cells and remyelination in lysophosphatidylcholine-induced demyelination of the rat sciatic nerve
Schwann cells (SCs) are constituents of the peripheral nervous system. The differentiation of SCs in injured peripheral nerves is critical for regeneration after injury. Methylcobalamin (MeCbl) is a vitamin B12 analog that is necessary for the maintenance of the peripheral nervous system. In this study, we estimated the effect of MeCbl on SCs. We showed that MeCbl downregulated the activity of Erk1/2 and promoted the expression of the myelin basic protein in SCs. In a dorsal root ganglion neuron-SC coculture system, myelination was promoted by MeCbl. In a focal demyelination rat model, MeCbl promoted remyelination and motor and sensory functional regeneration. MeCbl promoted the in vitro differentiation of SCs and in vivo myelination in a rat demyelination model and may be a novel therapy for several types of nervous disorders.
2000-08-01 | A randomised double blind trial versus placebo does not confirm the benefit of alpha -interferon in polyneuropathy associated with monoclonal IgM
The peripheral neuropathy associated with a monoclonal anti-MAG IgM is considered as a specific entity.1-3 The clinical features are different from those seen with monoclonal IgG or IgA, with sensory loss and ataxia more often found. A causal link between the monoclonal IgM and the development of neuropathy is suggested by the antibody activity of the IgM to nerve polypeptides or glycolipids,3-7 the detection of IgM deposits on the myelin sheaths of patients' nerve biopsies,2 8 9 and the induction of the neuropathological process through the transfer of the anti-MAG IgM in animal models.10 11 The low rate (30%) of clinical improvement with chlorambucil (CLB) or plasma exchange in such patients justifies the search for new therapeutic strategies.12 13 In a previous phase II open clinical trial randomly comparing intravenous immunoglobulins (IVIg) and α-interferon (α-IFN), we concluded that IVIg was inefficient but that α-IFN produced a significant clinical improvement in eight out of 10 patients at 6 months and in seven of them at 12 months.14 The mechanism of action of α-IFN was unclear as the concentration of the monoclonal IgM as well as the titre of anti-MAG antibody were unchanged. As the improvement with α-IFN was mainly related to an improvement of sensory symptoms, most of them being subjective, we designed a multicentre, prospective, randomised double blind study of α-IFN versus placebo. Patients included in this study had to fulfill all the following criteria: (1) have had stable or progressive neuropathy for at least 3 months; (2) show the presence of a serum monoclonal IgM with anti-MAG …
1999-01-01 | Clinical features, evaluation, and treatment of patients with polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS)
A number of common disorders of the peripheral nervous system are closely linked to a monoclonal gammopathy. In a minority of patients, the neuropathy represents the sentinel feature of a malignant plasma cell dyscrasia, such as multiple myeloma or its osteosclerotic variant, Waldenstrom's disease, amyloidosis, cryoglobulinemia or lymphoma; the vast majority have so-called "monoclonal gammopathy of undetermined significance" (MGUS). Sensory symptoms predominate with paresthesias, numbness, imbalance, and gait ataxia. Electrodiagnostic studies show mixed demyelinating and axonal features and often may be indistinguishable from findings in chronic inflammatory demyelinating polyneuropathy. Some have a pure axonal polyneuropathy, and in these patients the relationship to the paraprotein is less certain. With limited success, correlations have been made between the immunoglobulin type (IgM, IgG, or IgA) and the clinical and electromyographic characteristics of the neuropathy. The treatment of MGUS neuropathies poses a considerable challenge. Patients with IgG/IgA-MGUS have improved with corticosteroids or intravenous immune globulin. Only the benefit of plasma exchange has been substantiated in a controlled trial. The IgM neuropathies tend to be more refractory but often improve with similar regimens, particularly if cytotoxic agents are added in doses sufficient to reduce the amount of the M-protein. In addition to plasma exchange, chlorambucil, and cyclophosphamide, interferon-alpha is a novel therapy that holds promise for patients with IgM neuropathies associated with anti-myelin associated antibodies. J. Clin. Apheresis 14:149–153, 1999. © 1999 Wiley-Liss, Inc.
1997-07-01 | A randomised clinical trial comparing interferon-alpha and intravenous immunoglobulin in polyneuropathy associated with monoclonal IgM
The polyneuropathy associated with a monoclonal IgM directed to the myelin associated glycoprotein (MAG) is a specific entity with a putative causal link between the IgM and the neuropathy. The small benefit offered by alkylating agents or plasma exchanges in these patients justifies the search for alternative treatments. A 12 month multicentre, prospective, randomised, open clinical trial was carried out comparing intravenous immunoglobulin (IVIg; 2g/kg and then 1 g/kg every three weeks) and recombinant interferon-α (IFN-α; 3 MU/m2 subcutaneously three times weekly). The main end point was a clinical neuropathy disability score (CNDS) after six months of treatment. Twenty patients were enrolled; 10 were assigned to IVIg and 10 to IFN-α. At six months, one out of 10 patients treated with IVIg had a CNDS improvement of more than 20% whereas eight out of 10 patients treated with IFN-α had such an improvement (P=0.005). The mean CNDS worsened by 2.3 (SD 7.6) (8%) in the IVIg group whereas it improved by 7.5 (SD 11.1) (31%) in the IFN-α group (P=0.02). This improvement persisted after 12 months and was mainly related to an improvement of the sensory component (P=0.02) whereas the motor component was unchanged (P=0.39). Electrophysiological data did not show improvement of motor nerve conduction velocities whereas sensory nerve conduction velocities improved in the upper limbs. A decrease in the level of the monoclonal IgM was seen in two patients treated with IFN-α. At the end of the treatment, antibody activity to MAG was still detected in the serum of all patients. IVIg, as used in this study, did not improve patients with polyneuropathy and monoclonal IgM. By contrast, although its mechanism of action remains to be fully elucided, IFN-α was effective in eight out of 10 patients at six months.
small molecules
2026-08-08 | Peripheral neuropathies associated with immunoglobulin M monoclonal gammopathies and low-grade B-cell lymphomas: diagnostic and therapeutic approach.
Peripheral neuropathies associated with monoclonal gammopathies and low-grade B-cell lymphomas represent a clinically heterogeneous group of disorders encountered by both neurologists and hematologists. This review provides a practical and updated approach to their diagnosis and management, with a particular focus on IgM-associated neuropathies and anti-MAG neuropathy. IgM-related neuropathies encompass immune-mediated disorders - most commonly driven by antibodies against myelin-associated glycoprotein (MAG) - as well as infiltrative mechanisms (neurolymphomatosis, Bing-Neel syndrome) and protein deposition diseases (AL amyloidosis). Anti-MAG neuropathy remains the most common and best-characterized entity. Over the past decade, therapeutic strategies have evolved substantially with the emergence of clone-directed approaches, including anti-CD20-based regimens and covalent Bruton tyrosine kinase inhibitors (cBTKi). However, high-quality evidence remains limited. Establishing a causal relationship between neuropathy and IgM gammopathy is essential and requires a multidisciplinary approach. Treatment should be individualized and primarily reserved for progressive, functionally impairing disease. Despite therapeutic advances, many patients experience persistent disability, underscoring the need for novel strategies and prospective clinical trials using validated neurological endpoints.
2026-07-27 | Anesthetic Management of a Patient with Advanced Anti-Myelin-Associated Glycoprotein Antibody Neuropathy in the Absence of Measurable Quantitative Neuromuscular Responses: A Case Report
Background and Clinical Significance: Anti–myelin-associated glycoprotein (MAG) antibody polyneuropathy is a rare, chronic IgM-mediated demyelinating peripheral neuropathy predominantly affecting sensory nerves in older adults, commonly in association with monoclonal gammopathy of undetermined significance. Reports describing anesthetic management in patients with this condition remain extremely limited, and no specific guidelines currently exist regarding neuromuscular blocking agent (NMBA) use or neuromuscular monitoring in this population. Case Presentation: A 79-year-old man with anti-MAG antibody polyneuropathy (diagnosed in 2007) and IgM monoclonal gammopathy of undetermined significance developed disproportionate progressive lower-extremity weakness and became wheelchair-dependent following COVID-19 infection in 2020. Preoperative evaluation revealed mildly reduced left ventricular function (ejection fraction 49%), mild chronic kidney disease, and marked intrinsic hand muscle atrophy with absent deep tendon reflexes. He was scheduled for robot-assisted radical cystectomy with ileal conduit diversion under combined general and thoracic epidural anesthesia. Before NMBA administration, neuromuscular monitoring was systematically attempted at the ulnar nerve (electromyography and acceleromyography, up to 60 mA/300 μs) and the corrugator supercilii; despite visible muscle contractions following peripheral nerve stimulation, neither modality produced reliable responses at either site. Given the inability to establish reliable monitoring, the administration of NMBAs was considered to carry an unacceptable risk of a prolonged, undetectable blockade. Anesthesia was maintained with deep sevoflurane (2.0–2.5% end-tidal) and remifentanil infusion without NMBAs, titrated to a bispectral index of 40–60. Tracheal intubation was accomplished via video laryngoscopy without NMBA. The 7 h and 30 min surgery was completed without patient movement or surgical compromise. Postoperatively, the patient developed transient upper airway obstruction attributed to glossoptosis, managed successfully with head elevation and nasopharyngeal airway insertion; supplemental oxygen was required until postoperative day 3, and the patient was discharged from the high-dependency unit on postoperative day 5. Conclusions: No measurable quantitative neuromuscular response could be obtained in this patient with advanced anti-MAG antibody neuropathy, despite appropriate application of electromyography- and acceleromyography-based monitoring and the presence of visible muscle contractions following peripheral nerve stimulation. In such circumstances, avoiding NMBA administration in favor of deep volatile or intravenous anesthesia with opioid supplementation may represent a reasonable, hypothesis-generating approach in carefully selected patients; this observation does not establish the general superiority of an NMBA-free strategy, and caution is warranted before generalizing it to procedures such as robotic surgery, in which profound neuromuscular blockade is often considered desirable.
2026-07-17 | Anti-MAG Neuropathy: Disease Overview, Gait Characteristics, and Rehabilitation Needs.
Anti-myelin-associated glycoprotein (MAG) neuropathy is a rare autoimmune neuropathy that preferentially affects the myelin of distal fibers. This distal demyelination and secondary axon loss lead to its characteristic clinical features of distal sensory loss and weakness, upper limb tremor, and ataxia, leading to significant disability for the patient. Diagnosis is predicated on its distinct electrodiagnostic and serological profile of distally accentuated demyelination and high IgM anti-MAG antibody titers. Accurate diagnosis of anti-MAG neuropathy is critical, as standard CIDP therapies do not work, but some novel treatments like Bruton tyrosine kinase inhibitors may prove effective. Currently, rituximab is the most frequently used treatment, despite current evidence showing benefit in only a subset of patients. This review highlights the value of gait analysis in the clinical and research assessment of anti-MAG neuropathy, using existing quality of life-based data. The unique pathophysiology and clinical features of anti-MAG neuropathy create specific rehabilitation challenges, making awareness of this disorder critical for electromyographers and those treating neuropathies in all settings.
2026-03-31 | Anti-MAG Antibody Neuropathy Treated Successfully with Pomalidomide and Dexamethasone: A Case Report
Anti-myelin-associated glycoprotein (MAG) neuropathy is a rare, immune-mediated demyelinating condition.It is characterised by an association with an IgM monoclonal gammopathy and the presence of pathogenic anti-MAG antibodies.Research into this field began in the 1980s.Initial therapeutic approaches aimed to reduce the M protein concentration using treatments such as plasma exchange, steroids, chlorambucil, azathioprine and cyclophosphamide.Some patients experienced partial benefit, indicating that mechanisms beyond damage solely caused by elevated M protein are involved.Consequently, immune-directed therapies, such as IVIg and rituximab, have demonstrated some efficacy in this patient group.Some case reports suggested the use of Lenalidomide as a potential therapeutic option.This is the first case report showing the successful use of pomalidomide in anti-MAG neuropathy.
2026-01-13 | Immunotherapies in chronic immune-mediated neuropathies.
Steroids and immunoglobulins, either intravenous or subcutaneous, have represented the cornerstone treatment of chronic immune-mediated neuropathies for many years. In the last decade, new therapeutic targets are being studied, with the potential to selectively dampen aberrant immune responses, including drugs that act both on the complement pathways and the recycling mechanism of IgG immunoglobulins by the neonatal receptor (FcRn). Among the latter, efgartigimod has recently been approved for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Also rituximab, an anti-CD20 monoclonal antibody mostly used in antimyelin-associated glycoprotein (MAG) antibody neuropathy and in autoimmune nodo-paranodopathies, has been tested both in open and double-blind studies in CIDP, whereas ARGX-117, an antibody targeting the C2 fraction of the complement, is under investigation in multifocal motor neuropathy. In anti-MAG antibody neuropathy, Bruton's tyrosine kinase inhibitors, zanubrutinib and acalabrutinib, are currently tested either as a single agent or in combination with rituximab.
antibodies
2026-07-21 | Management and long-term haematological and neurological outcomes of Immunoglobulin M and Waldenström's macroglobulinaemia-related neuropathy: A single-centre experience.
Immunoglobulin M-related peripheral neuropathy (IgM-PN) is typically demyelinating and associated with anti-myelin-associated glycoprotein antibodies; however, limited data on clinical outcomes are available. We retrospectively analysed consecutive patients with IgM-PN assessed prospectively with the Rasch-built Overall Disability Scale (RODS) and the Inflammatory Neuropathy Cause and Treatment (INCAT) questionnaires. Twenty-eight patients were retrospectively enrolled. The median follow-up was 5.54 years. Treatment was initiated in all solely due to neuropathy symptoms: 19 (67.9%) dexamethasone-rituximab-cyclophosphamide, 6 (21.4%) rituximab and 3 (10.7%) ibrutinib. The baseline median INCAT score was 2.0 and improved to 1.0 at further time points; within-patient improvements compared to baseline were significant (p < 0.005). A clinically relevant improvement was evident in 13 (46.4%), 18 (64.3%) and 17 (60.7%) patients at 6, 12 and 24 months respectively. IgM reduction was associated with improvement in INCAT scores at 6 (p = 0.041) and 12 months (p = 0.030). At baseline, the median RODS score was 38.0, improved to 41.5 at 6 months, then to 43.0 and 43.5 at 1 and 2 years (all p < 0.001). A clinically relevant improvement was evident in 5 (17.9%), 7 (25%) and 9 (32.1%) patients at 6, 12 and 24 months respectively. Patients with IgM-PN, treated mainly with rituximab-based regimens, showed significant improvement in functional and neurological ability over a 2-year follow-up.
2026-07-12 | Anti-MAG-associated neuropathy: a case report and literature review.
Anti-myelin-associated glycoprotein (MAG) neuropathy is an uncommon IgM-mediated autoimmune demyelinating peripheral neuropathy, which is prone to misdiagnosis due to overlapping clinical manifestations with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Serum anti-MAG IgM ≥ 1:1000 is widely accepted as the standard diagnostic cut-off value clinically, while cases with low-titer positive results remain poorly summarized. We report one low-titer MAG-antibody-positive case receiving individualized low-dose rituximab to supplement clinical evidence for this disease. A 65-year-old male patient presented with progressive numbness and limb unsteadiness lasting for 5 months. Neurological examination identified predominantly distal lower limb weakness and prominent deep sensory ataxia. Pre-treatment INCAT disability score was 4 and decreased to 2 one month after intervention. Serum anti-MAG IgM was positive at 1:320; all nodal/paranodal antibodies including NF155, CNTN1, Caspr1 and pan-neurofascin tested negative. Immunofixation electrophoresis demonstrated an IgM-λ monoclonal gammopathy, with serum free κ/λ light chain within normal reference ranges. Cerebrospinal fluid (CSF) protein was markedly elevated. Nerve conduction study (NCS) performed prior to medication revealed diffuse distal-predominant demyelination combined with axonal injury. The patient failed high-dose methylprednisolone pulse therapy, then received split low-dose rituximab (100 mg on Day 1, 500 mg on Day 2). One-month follow-up showed antibody titer dropped to 1:100 and obvious clinical improvement; incident hyperthyroidism was detected during hospitalization. Bone marrow biopsy excluded B-cell proliferative disorders. Low-titer anti-MAG IgM combined with typical clinical, electrophysiological and serological findings can confirm MAG neuropathy. Individualized low-dose rituximab achieves satisfactory efficacy for elderly patients complicated with underlying cerebrovascular disorders in early disease stage. Concurrent new-onset autoimmune hyperthyroidism is a rare clinical coincidence in this disease, requiring long-term follow-up observation.
2026-07-03 | Anti-MAG Polyneuropathy: Characterization of the Monoclonal Gammopathy and Clonal B-Cell Population.
Polyneuropathy due to antibodies to myelin-associated glycoprotein (MAG) is a rare disease with an estimated prevalence of 1 per 100,000. Symptoms start in the sixth or seventh decade of life, presenting sensory polyneuropathy with sensory ataxia, paresthesia, mild motor deficit, and tremor of upper extremities. The neurophysiological features are compatible with length-dependent demyelination. It is caused by monoclonal gammopathy of the IgM type produced by clonal B cells. In recent years the monoclonal anti-CD20 antibody has become the preferred first-line treatment, but with limited efficacy. We identified a cohort of 42 patients diagnosed with anti-MAG polyneuropathy. Clinical data were collected retrospectively, and flow cytometry files and immune histochemistry slides were reassessed. We report that in most cases of anti-MAG polyneuropathy, the monoclonal IgM is kappa-restricted, the B-cell population shows lymphoplasmacytic differentiation, MYD88L265P mutation is a frequent finding, and the clonal B-cell population includes plasma cells. These findings most likely explain the low efficacy of rituximab monotherapy. We found the burden of symptoms to be high among patients with anti-MAG polyneuropathy as most of our patients had received intravenous immunoglobulin infusions and/or B-cell-directed treatment. We suggest that future treatment protocols for anti-MAG polyneuropathy should incorporate plasma cell-directed drugs. Furthermore, we found complement receptor 1 (CD35) to be down regulated on clonal B lymphocytes but not on normal B lymphocytes in these patients. We suggest that this may be a common feature of clonal B lymphocytes in chronic lymphoproliferative diseases.
2026-02-09 | Prevalence and Patterns of Cranial Nerve Involvement in CIDP, Autoimmune Nodopathy, MMN, and Anti-MAG Neuropathy: A Multicenter Korea/UK Study of 582 Patients.
Cranial nerve involvement is a well-recognized feature in Guillain-Barré syndrome (GBS) but remains less well understood in chronic forms of autoimmune neuropathies. Earlier studies of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were conducted before updated diagnostic criteria and the recognition of autoimmune nodopathy (AN), which may limit the interpretation of their findings. We retrospectively analyzed 582 patients with chronic autoimmune neuropathies-CIDP (n = 431), multifocal motor neuropathy (MMN) (n = 64), anti-myelin-associated glycoprotein (MAG) neuropathy (n = 54), and AN (n = 33)-from 4 Korean and 1 UK centers. Patients with cranial nerve involvement were identified and described. CIDP patients with cranial nerve involvement (cranial+ CIDP) were compared with those without (cranial- CIDP). Cranial nerve involvement was observed in 8.8% (38/431) of CIDP and 24.2% (8/33) of AN patients but was absent in MMN (0/64) and anti-MAG neuropathy (0/54). Facial palsy was overall the most common manifestation (CIDP: 45%, AN: 50%). Patients with AN more frequently exhibited bilateral optic neuropathy (50%) and facial diplegia (38%), while CIDP patients more often showed trigeminal neuropathy and oculomotor nerve palsy (both 32%). Compared with cranial- CIDP, cranial+ CIDP patients were more often younger, of variant subtypes (especially multifocal), presented (sub)acutely with preceding infection/vaccination, followed by relapsing-remitting rather than progressive courses, and achieved greater improvement despite greater pre-treatment disability. Cranial nerve involvement serves as a diagnostic clue in chronic autoimmune neuropathies, particularly in identifying AN and CIDP. Cranial+ CIDP appears to represent a distinct subset with partial overlap to GBS, suggesting unique underlying mechanisms.
2025-11-26 | 7 Common symptoms, uncommon neuropathy: a case of anti-MAG neuropathy
a:2:{s:4:"lang";s:2:"en";s:7:"content";s:1475:" We present a case of anti-myelin-associated glycoprotein (anti-MAG) neuropathy in a 62-year-old male with sensory symptoms predominantly affecting the lower limbs. The patient reported a 10-month history of bilateral pins and needles sensation, initially in the toes and progressively extending to the ankles. Intermittent sensory disturbance was also noted in the hands, without weakness, imbalance, or autonomic dysfunction. His medical history included hypertension and hyperlipidemia, managed with statin therapy. Neurological examination found absent reflexes bilaterally, reduced vibration sense at the right ankle and left knee, and hypersensitivity to pinprick up to the ankles. No cerebellar signs were identified. Romberg’s test was negative. Laboratory findings showed positive anti-MAG antibodies and an IgM kappa paraprotein band on serum electrophoresis, with negative urine Bence Jones proteins. Electrophysiology demonstrated asymmetric, non-length-dependent neuropathy, despite the symmetrical clinical presentation. Following a multidisciplinary discussion, immunotherapy such as rituximab was deferred, and a haematology referral was made due to investigate the paraprotein. This case underscores the importance of considering anti-MAG neuropathy in patients presenting with sensory symptoms and no tremor, especially if the neurophysiological findings are in keeping with an inflammatory neuropathy. jidhin.raj{at}nhs.net ";}
proteins
2025-07-25 | Reversible rituximab demyelination in anti-MAG polyneuropathy: A role for IVIG?
Anti-myelin-associated glycoprotein (MAG) demyelinating neuropathy is a clinically heterogeneous slowly progressive large fiber sensorimotor polyneuropathy. Management of anti-MAG neuropathy is challenging, and a small subset of anti-MAG neuropathy patients have been previously reported to deteriorate after rituximab therapy, perhaps triggered by an upsurge in autoantibody release secondary to B lymphocyte lysis. We report a patient with this complication that responded to IVIg therapy. Case description and serial electrophysiological studies. Serial electrophysiological studies confirmed subacute demyelination in our patient with anti-MAG neuropathy treated with rituximab followed by improvement following IVIg. The use of IVIG therapy can be considered in cases where rituximab leads to clinical and electrophysiological worsening of anti-MAG neuropathy.
2015-08-04 | Methylcobalamin promotes the differentiation of Schwann cells and remyelination in lysophosphatidylcholine-induced demyelination of the rat sciatic nerve
Schwann cells (SCs) are constituents of the peripheral nervous system. The differentiation of SCs in injured peripheral nerves is critical for regeneration after injury. Methylcobalamin (MeCbl) is a vitamin B12 analog that is necessary for the maintenance of the peripheral nervous system. In this study, we estimated the effect of MeCbl on SCs. We showed that MeCbl downregulated the activity of Erk1/2 and promoted the expression of the myelin basic protein in SCs. In a dorsal root ganglion neuron-SC coculture system, myelination was promoted by MeCbl. In a focal demyelination rat model, MeCbl promoted remyelination and motor and sensory functional regeneration. MeCbl promoted the in vitro differentiation of SCs and in vivo myelination in a rat demyelination model and may be a novel therapy for several types of nervous disorders.
2000-08-01 | A randomised double blind trial versus placebo does not confirm the benefit of alpha -interferon in polyneuropathy associated with monoclonal IgM
The peripheral neuropathy associated with a monoclonal anti-MAG IgM is considered as a specific entity.1-3 The clinical features are different from those seen with monoclonal IgG or IgA, with sensory loss and ataxia more often found. A causal link between the monoclonal IgM and the development of neuropathy is suggested by the antibody activity of the IgM to nerve polypeptides or glycolipids,3-7 the detection of IgM deposits on the myelin sheaths of patients' nerve biopsies,2 8 9 and the induction of the neuropathological process through the transfer of the anti-MAG IgM in animal models.10 11 The low rate (30%) of clinical improvement with chlorambucil (CLB) or plasma exchange in such patients justifies the search for new therapeutic strategies.12 13 In a previous phase II open clinical trial randomly comparing intravenous immunoglobulins (IVIg) and α-interferon (α-IFN), we concluded that IVIg was inefficient but that α-IFN produced a significant clinical improvement in eight out of 10 patients at 6 months and in seven of them at 12 months.14 The mechanism of action of α-IFN was unclear as the concentration of the monoclonal IgM as well as the titre of anti-MAG antibody were unchanged. As the improvement with α-IFN was mainly related to an improvement of sensory symptoms, most of them being subjective, we designed a multicentre, prospective, randomised double blind study of α-IFN versus placebo. Patients included in this study had to fulfill all the following criteria: (1) have had stable or progressive neuropathy for at least 3 months; (2) show the presence of a serum monoclonal IgM with anti-MAG …
1999-01-01 | Clinical features, evaluation, and treatment of patients with polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS)
A number of common disorders of the peripheral nervous system are closely linked to a monoclonal gammopathy. In a minority of patients, the neuropathy represents the sentinel feature of a malignant plasma cell dyscrasia, such as multiple myeloma or its osteosclerotic variant, Waldenstrom's disease, amyloidosis, cryoglobulinemia or lymphoma; the vast majority have so-called "monoclonal gammopathy of undetermined significance" (MGUS). Sensory symptoms predominate with paresthesias, numbness, imbalance, and gait ataxia. Electrodiagnostic studies show mixed demyelinating and axonal features and often may be indistinguishable from findings in chronic inflammatory demyelinating polyneuropathy. Some have a pure axonal polyneuropathy, and in these patients the relationship to the paraprotein is less certain. With limited success, correlations have been made between the immunoglobulin type (IgM, IgG, or IgA) and the clinical and electromyographic characteristics of the neuropathy. The treatment of MGUS neuropathies poses a considerable challenge. Patients with IgG/IgA-MGUS have improved with corticosteroids or intravenous immune globulin. Only the benefit of plasma exchange has been substantiated in a controlled trial. The IgM neuropathies tend to be more refractory but often improve with similar regimens, particularly if cytotoxic agents are added in doses sufficient to reduce the amount of the M-protein. In addition to plasma exchange, chlorambucil, and cyclophosphamide, interferon-alpha is a novel therapy that holds promise for patients with IgM neuropathies associated with anti-myelin associated antibodies. J. Clin. Apheresis 14:149–153, 1999. © 1999 Wiley-Liss, Inc.
1997-07-01 | A randomised clinical trial comparing interferon-alpha and intravenous immunoglobulin in polyneuropathy associated with monoclonal IgM
The polyneuropathy associated with a monoclonal IgM directed to the myelin associated glycoprotein (MAG) is a specific entity with a putative causal link between the IgM and the neuropathy. The small benefit offered by alkylating agents or plasma exchanges in these patients justifies the search for alternative treatments. A 12 month multicentre, prospective, randomised, open clinical trial was carried out comparing intravenous immunoglobulin (IVIg; 2g/kg and then 1 g/kg every three weeks) and recombinant interferon-α (IFN-α; 3 MU/m2 subcutaneously three times weekly). The main end point was a clinical neuropathy disability score (CNDS) after six months of treatment. Twenty patients were enrolled; 10 were assigned to IVIg and 10 to IFN-α. At six months, one out of 10 patients treated with IVIg had a CNDS improvement of more than 20% whereas eight out of 10 patients treated with IFN-α had such an improvement (P=0.005). The mean CNDS worsened by 2.3 (SD 7.6) (8%) in the IVIg group whereas it improved by 7.5 (SD 11.1) (31%) in the IFN-α group (P=0.02). This improvement persisted after 12 months and was mainly related to an improvement of the sensory component (P=0.02) whereas the motor component was unchanged (P=0.39). Electrophysiological data did not show improvement of motor nerve conduction velocities whereas sensory nerve conduction velocities improved in the upper limbs. A decrease in the level of the monoclonal IgM was seen in two patients treated with IFN-α. At the end of the treatment, antibody activity to MAG was still detected in the serum of all patients. IVIg, as used in this study, did not improve patients with polyneuropathy and monoclonal IgM. By contrast, although its mechanism of action remains to be fully elucided, IFN-α was effective in eight out of 10 patients at six months.
small molecules
2026-08-08 | Peripheral neuropathies associated with immunoglobulin M monoclonal gammopathies and low-grade B-cell lymphomas: diagnostic and therapeutic approach.
Peripheral neuropathies associated with monoclonal gammopathies and low-grade B-cell lymphomas represent a clinically heterogeneous group of disorders encountered by both neurologists and hematologists. This review provides a practical and updated approach to their diagnosis and management, with a particular focus on IgM-associated neuropathies and anti-MAG neuropathy. IgM-related neuropathies encompass immune-mediated disorders - most commonly driven by antibodies against myelin-associated glycoprotein (MAG) - as well as infiltrative mechanisms (neurolymphomatosis, Bing-Neel syndrome) and protein deposition diseases (AL amyloidosis). Anti-MAG neuropathy remains the most common and best-characterized entity. Over the past decade, therapeutic strategies have evolved substantially with the emergence of clone-directed approaches, including anti-CD20-based regimens and covalent Bruton tyrosine kinase inhibitors (cBTKi). However, high-quality evidence remains limited. Establishing a causal relationship between neuropathy and IgM gammopathy is essential and requires a multidisciplinary approach. Treatment should be individualized and primarily reserved for progressive, functionally impairing disease. Despite therapeutic advances, many patients experience persistent disability, underscoring the need for novel strategies and prospective clinical trials using validated neurological endpoints.
2026-07-27 | Anesthetic Management of a Patient with Advanced Anti-Myelin-Associated Glycoprotein Antibody Neuropathy in the Absence of Measurable Quantitative Neuromuscular Responses: A Case Report
Background and Clinical Significance: Anti–myelin-associated glycoprotein (MAG) antibody polyneuropathy is a rare, chronic IgM-mediated demyelinating peripheral neuropathy predominantly affecting sensory nerves in older adults, commonly in association with monoclonal gammopathy of undetermined significance. Reports describing anesthetic management in patients with this condition remain extremely limited, and no specific guidelines currently exist regarding neuromuscular blocking agent (NMBA) use or neuromuscular monitoring in this population. Case Presentation: A 79-year-old man with anti-MAG antibody polyneuropathy (diagnosed in 2007) and IgM monoclonal gammopathy of undetermined significance developed disproportionate progressive lower-extremity weakness and became wheelchair-dependent following COVID-19 infection in 2020. Preoperative evaluation revealed mildly reduced left ventricular function (ejection fraction 49%), mild chronic kidney disease, and marked intrinsic hand muscle atrophy with absent deep tendon reflexes. He was scheduled for robot-assisted radical cystectomy with ileal conduit diversion under combined general and thoracic epidural anesthesia. Before NMBA administration, neuromuscular monitoring was systematically attempted at the ulnar nerve (electromyography and acceleromyography, up to 60 mA/300 μs) and the corrugator supercilii; despite visible muscle contractions following peripheral nerve stimulation, neither modality produced reliable responses at either site. Given the inability to establish reliable monitoring, the administration of NMBAs was considered to carry an unacceptable risk of a prolonged, undetectable blockade. Anesthesia was maintained with deep sevoflurane (2.0–2.5% end-tidal) and remifentanil infusion without NMBAs, titrated to a bispectral index of 40–60. Tracheal intubation was accomplished via video laryngoscopy without NMBA. The 7 h and 30 min surgery was completed without patient movement or surgical compromise. Postoperatively, the patient developed transient upper airway obstruction attributed to glossoptosis, managed successfully with head elevation and nasopharyngeal airway insertion; supplemental oxygen was required until postoperative day 3, and the patient was discharged from the high-dependency unit on postoperative day 5. Conclusions: No measurable quantitative neuromuscular response could be obtained in this patient with advanced anti-MAG antibody neuropathy, despite appropriate application of electromyography- and acceleromyography-based monitoring and the presence of visible muscle contractions following peripheral nerve stimulation. In such circumstances, avoiding NMBA administration in favor of deep volatile or intravenous anesthesia with opioid supplementation may represent a reasonable, hypothesis-generating approach in carefully selected patients; this observation does not establish the general superiority of an NMBA-free strategy, and caution is warranted before generalizing it to procedures such as robotic surgery, in which profound neuromuscular blockade is often considered desirable.
2026-07-17 | Anti-MAG Neuropathy: Disease Overview, Gait Characteristics, and Rehabilitation Needs.
Anti-myelin-associated glycoprotein (MAG) neuropathy is a rare autoimmune neuropathy that preferentially affects the myelin of distal fibers. This distal demyelination and secondary axon loss lead to its characteristic clinical features of distal sensory loss and weakness, upper limb tremor, and ataxia, leading to significant disability for the patient. Diagnosis is predicated on its distinct electrodiagnostic and serological profile of distally accentuated demyelination and high IgM anti-MAG antibody titers. Accurate diagnosis of anti-MAG neuropathy is critical, as standard CIDP therapies do not work, but some novel treatments like Bruton tyrosine kinase inhibitors may prove effective. Currently, rituximab is the most frequently used treatment, despite current evidence showing benefit in only a subset of patients. This review highlights the value of gait analysis in the clinical and research assessment of anti-MAG neuropathy, using existing quality of life-based data. The unique pathophysiology and clinical features of anti-MAG neuropathy create specific rehabilitation challenges, making awareness of this disorder critical for electromyographers and those treating neuropathies in all settings.
2026-03-31 | Anti-MAG Antibody Neuropathy Treated Successfully with Pomalidomide and Dexamethasone: A Case Report
Anti-myelin-associated glycoprotein (MAG) neuropathy is a rare, immune-mediated demyelinating condition.It is characterised by an association with an IgM monoclonal gammopathy and the presence of pathogenic anti-MAG antibodies.Research into this field began in the 1980s.Initial therapeutic approaches aimed to reduce the M protein concentration using treatments such as plasma exchange, steroids, chlorambucil, azathioprine and cyclophosphamide.Some patients experienced partial benefit, indicating that mechanisms beyond damage solely caused by elevated M protein are involved.Consequently, immune-directed therapies, such as IVIg and rituximab, have demonstrated some efficacy in this patient group.Some case reports suggested the use of Lenalidomide as a potential therapeutic option.This is the first case report showing the successful use of pomalidomide in anti-MAG neuropathy.
2026-01-13 | Immunotherapies in chronic immune-mediated neuropathies.
Steroids and immunoglobulins, either intravenous or subcutaneous, have represented the cornerstone treatment of chronic immune-mediated neuropathies for many years. In the last decade, new therapeutic targets are being studied, with the potential to selectively dampen aberrant immune responses, including drugs that act both on the complement pathways and the recycling mechanism of IgG immunoglobulins by the neonatal receptor (FcRn). Among the latter, efgartigimod has recently been approved for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Also rituximab, an anti-CD20 monoclonal antibody mostly used in antimyelin-associated glycoprotein (MAG) antibody neuropathy and in autoimmune nodo-paranodopathies, has been tested both in open and double-blind studies in CIDP, whereas ARGX-117, an antibody targeting the C2 fraction of the complement, is under investigation in multifocal motor neuropathy. In anti-MAG antibody neuropathy, Bruton's tyrosine kinase inhibitors, zanubrutinib and acalabrutinib, are currently tested either as a single agent or in combination with rituximab.
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Drug Discovery Landscape
2 orphan drug designations for Polyneuropathy associated with IgM monoclonal gammopathy with anti-MAG.
2 orphan drug designations for Polyneuropathy associated with IgM monoclonal gammopathy with anti-MAG.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Poly (Phenyl Sulfoglucuronate Galactoside) | small molecules | FDA | 2020-05-14 | — | Polyneuron Pharmaceuticals AG |
Polyphenyl(disodium 3-O-sulfo-beta-D-glucopyranuronate)-(1->3)-beta-D-galactopyranoside | small molecules | EMA | 2017-07-17 | — | Pharma Gateway AB |
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