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Immunoglobulin M (IgM) anti-myelin-associated glycoprotein (MAG) paraprotein-associated peripheral neuropathy (anti-MAG PN) is the most frequent type of paraprotein-associated neuropathy. It typically presents as a chronic demyelinating disorder with progressive ataxia, tremor and sensory disturbance.1 By definition, IgM paraproteinaemia and high-titre anti-MAG antibodies are present. Up to 50% of patients develop significant disability. Progressive disease-related disability is considered an indication to start treatment. However, there is no consensus on the optimal treatment approach and a high clinical need for effective therapies.1
IgM paraproteinaemia is the hallmark of Waldenstrom’s macroglobulinaemia (WM) and IgM monoclonal gammopathy of unknown significance (MGUS). WM is an indolent B-cell malignancy with lymphoplasmacytic differentiation typically localised in the bone marrow (BM), while IgM MGUS is considered a premalignant condition, defined as asymptomatic IgM paraproteinaemia with <10% BM infiltration by lymphoplasmacytic cells. The term ‘IgM-related disease’ is reserved for IgM MGUS with symptoms that are attributable to the paraprotein, such as cryoglobulinaemia, cold agglutinin disease and indeed IgM-related neuropathy.2
Recently, a recurrent somatic point mutation of the myeloid differentiation factor 88 (MYD88) gene, leading to an amino acid change from leucine to proline (L265P), has been reported in the vast majority (>90%) of patients with WM and approximately 50% of patients with IgM MGUS. The mutation is absent in healthy donors, multiple myeloma and non-IgM MGUS.3 MYD88 is an adaptor protein of the interleukin-1R and toll-like receptor signalling pathways that ultimately lead to activation of nuclear factor …
Contributors JMV, NCN, SD, MPL, WLvdP, MJK, STP and MCM initiated and designed the study. JMV, NCN, SD, WK, MMR, JC, RG and MCM performed the research. JMV, NCN, STP and MCM performed data analysis. JMV, NCN, SD, MJK, STP and MCM wrote the paper. All authors reviewed the manuscript and approved the final version.
Funding This research was supported by grants from Fonds Stimulans and the International Waldenstrom Macroglobulinaemia Foundation (IWMF).
Competing interests MJK has consulted for or received compensation for presentations from Gilead, Celgene, Novartis, Roche, Millennium/Takeda, Kite Pharma and BMS, and has received research support from Celgene, Roche, Millennium and Sanofi. SD has received honoraria from Janssen. MPL has received honoraria from CSL Behring Grifols, UCB Pharma, Baxter and LfB. MCM has consulted for Jansen Cilag, Takeda, Amgen, BMS. The other authors had no disclosures to report.
Ethics approval UMCU and Leeds East Research Ethics Committees.
Provenance and peer review Not commissioned; externally peer reviewed.
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