From the Guidelines
Elevated Myelin-Associated Glycoprotein (MAG) antibodies are primarily caused by IgM monoclonal gammopathies, such as monoclonal gammopathy of undetermined significance (MGUS) or Waldenström's macroglobulinemia, which lead to the abnormal production of IgM antibodies targeting MAG. These conditions are characterized by the production of IgM antibodies that mistakenly target MAG, a protein essential for maintaining myelin sheath integrity in the peripheral nervous system, resulting in demyelination and subsequent nerve damage, manifesting as peripheral neuropathy with symptoms like numbness, tingling, and weakness, typically beginning in the feet and progressing upward 1.
Causes of Elevated MAG Antibodies
- IgM monoclonal gammopathies, such as MGUS or Waldenström's macroglobulinemia, are the primary causes of elevated MAG antibodies, with approximately 50% of patients with IgM MGUS and peripheral neuropathy having anti-MAG antibodies 1.
- Other potential causes include certain lymphoproliferative disorders and chronic inflammatory conditions.
- The pathophysiology involves these antibodies binding to MAG in the myelin sheath, triggering complement activation and inflammatory processes that damage the protective covering of peripheral nerves.
Diagnosis and Treatment
- Diagnosis typically involves blood tests measuring MAG antibody levels, serum protein electrophoresis, and nerve conduction studies.
- Treatment focuses on addressing the underlying condition, often using immunosuppressive therapies like rituximab, plasma exchange, or intravenous immunoglobulin to reduce antibody levels, with rituximab monotherapy recommended in cases of IgM-related disease, such as anti-MAG polyneuropathy 1.
- The most effective treatment of M-protein-related disorders is directed to the underlying clone, and clone-directed therapy should only be considered in cases of aggressive and disabling disease.
From the Research
Causes of Elevated MAG Antibodies
Elevated Myelin-Associated Glycoprotein (MAG) antibodies are associated with several conditions, including:
- Anti-MAG neuropathy, a distal demyelinating polyneuropathy characterized by IgM monoclonal gammopathy and elevated titers of anti-MAG antibodies 2
- Chronic inflammatory demyelinating polyneuropathy (CIDP), where mildly elevated antibody levels can occur 3
- IgM monoclonal gammopathy, which is often associated with anti-MAG neuropathy, but can also occur without detectable monoclonal gammopathy 4
Clinical Correlations
The presence of anti-MAG antibodies is associated with a high predictive value for certain neuropathies, including:
- A positive predictive value of 100% for neuropathy and IgM monoclonal gammopathy (PN+IgM) in patients with anti-MAG IgM 5
- A positive predictive value of 91.4% for neuropathy in patients with IgM monoclonal gammopathy, including those without neuropathy 5
- A significant association with multifocal motor neuropathy (MMN) in patients with anti-GM1 IgM 5
Diagnostic Considerations
The diagnosis of anti-MAG neuropathy should be considered in patients with demyelinating neuropathy, even in the absence of a monoclonal gammopathy or typical phenotype 3
- Testing for cross-reactivity with HNK1 can add to the specificity of the antibody assays 3
- Assays for anti-MAG antibodies by Enzyme-Linked Immunosorbent Assay can be improved by testing for antibody binding at multiple serum dilutions and including antigen-negative microwells as internal controls for each sample 3