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:
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.
2026-07-21 | 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.
2026-07-17 | 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.
2026-07-12 | 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.
2026-08-08 | 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.
2026-07-21 | 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.
2026-07-17 | 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.
2026-07-12 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
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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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