Antibody testing in neuropathy associated with anti-Myelin-Associated Glycoprotein antibodies: where we are after 40 years

Abstract

Purpose of reviewThe diagnosis of Myelin-Associated Glycoprotein (MAG) neuropathy is based on the presence of elevated titers of IgM anti-MAG antibodies, which are typically associated with IgM monoclonal gammopathy, and a slowly progressive, distal demyelinating phenotype. The condition, however, can be under or over diagnosed in patients with mildly elevated antibody titers, absent monoclonal gammopathy, or an atypical presentation. The purpose of this paper is to examine recent advances in our understanding of the currently available anti-MAG antibody assays, their reliability, and their use in deciding treatment or monitoring the response to therapy.Recent findingsHigher titers of anti-MAG antibodies are more likely to be associated with the typical MAG phenotype or response to therapy. Mildly elevated antibody levels can occur in patients with chronic inflammatory demyelinating polyneuropathy. Testing for cross-reactivity with HNK1 can add to the specificity of the antibody assays. Patients with MAG neuropathy can present with an atypical phenotype and in the absence of a detectable monoclonal gammopathy.SummaryAssays for anti-MAG antibodies by Enzyme-Linked Immunosorbent Assay can be improved by testing for antibody binding at multiple serum dilutions, the inclusion of antigen-negative microwells as internal controls for each sample, testing for cross-reactivity with HNK1, and formal validation. The diagnosis needs to be considered in patients with demyelinating neuropathy, even in the absence of a monoclonal gammopathy or typical phenotype. The change in antibody levels needs to be considered in evaluating the response to therapy with B-cell depleting agents.

Serum neurofilament light chain, contactin-1 and complement activation in anti-MAG IgM paraprotein-related peripheral neuropathy

“…It is a demyelinating neuropathy and typically presents as a chronic disorder with progressive imbalance, gait ataxia, sensory disturbances and tremor, leading to invalidating symptoms in up to 50% of patients [ 2 ]. Presence of IgM paraproteinemia and high titer anti-MAG antibodies are required for the diagnosis [ 3 ]. The underlying B-cell clone represents in most patients a premalignant state, i.e., IgM monoclonal gammopathy of undetermined significance (MGUS).…”

Efficacy of rituximab in anti‐myelin‐associated glycoprotein demyelinating polyneuropathy: Clinical, hematological and neurophysiological correlations during 2 years of follow‐up

“…We underline that, in such patients, the treatment decision should be based on the anti‐MAG antibody titer. Highly elevated levels of anti‐MAG antibodies are more likely to be diagnostic (and pathogenic) than mildly elevated titers [ 39 ]. We believe that this is important because of implications for treatment indication and subsequent possible benefit.…”

Mutational Profile in 75 Patients With Anti–Myelin-Associated Glycoprotein Neuropathy

“…Inclusion criteria were clinical and neurophysiologic diagnosis of anti-MAG antibody neuropathy associated with histologically confirmed IgM monoclonal gammopathy (IgM MGUS or lymphoproliferative diseases); anti-MAG antibody titer >7,000 Bühlmann titre units (BTU). 14 , 15 All the patients had neurophysiologic evidence of distal acquired demyelinating symmetric neuropathy with low conduction velocities and markedly prolonged distal latencies and no conduction blocks. Patients with atypical forms of anti-MAG antibody neuropathy 16 were not included.…”