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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 …
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