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High prevalence of the MYD88 L265P mutation in IgM anti-MAG paraprotein-associated peripheral neuropathy
  1. Josephine Mathilde Vos1,
  2. Nicolette C Notermans2,
  3. Shirley D’Sa3,
  4. Michael P Lunn3,
  5. W Ludo van der Pol2,
  6. Willem Kraan4,5,
  7. Mary M Reilly6,
  8. Jane Chalker7,
  9. Rajeev Gupta3,
  10. Marie-José Kersten5,8,
  11. Steven T Pals4,5,
  12. Monique C Minnema9
  1. 1Department of Hematology, St. Antonius Ziekenhuis, Nieuwegein, The Netherlands
  2. 2Brain Center Rudolf Magnus, UMC Utrecht, Utrecht, The Netherlands
  3. 3University College London Hospitals NHS Foundation Trust, London, UK
  4. 4Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
  5. 5Lymphoma and Myeloma Center (LYMMCARE), Amsterdam, The Netherlands
  6. 6MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK
  7. 7Great Ormond Street Hospital, London, UK
  8. 8Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands
  9. 9Department of Hematology, UMC Utrecht Cancer Center, Amsterdam, The Netherlands
  1. Correspondence to Josephine Mathilde Vos, Department of Hematology, St. Antonius Ziekenhuis, Nieuwegein, The Netherlands; jm.vos{at}

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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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