Amyloid‐like IgM deposition neuropathy: a distinct clinico‐pathologic and proteomic profiled disorder

Abstract

Some patients with immunoglobulin paraproteinemic neuropathy have intra‐nerve deposits that morphologically mimick amyloid, but do no stain with Congo red. Patients with amyloid‐like deposits were identified. The nerve amyloid‐like aggregates were studied by laser microdissection and dual mass spectrometry. Three male patients, all with IgM gammopathy, and neuropathy were identified. Follow‐up, disease duration was 5, 19, and 7 years, respectively. All had progressive asymmetric sensory‐onset distal axonal polyneuropathy with late motor involvement. Autonomic symptoms occurred in only one after 13 years of symptoms. None had clinical cardio‐renal involvement. One had skin papules with dermal amyloid‐like deposits. Endoneurial amyloid‐like deposits had granulo‐fibrillar ultrastructure. Mass spectrometry of laser‐dissected deposits identified IgM pentameric macroglobulin (heavy, light, and joining chains) without amyloid‐associated proteins including absent apolipoprotein E and serum amyloid P‐component. Amyloid‐like neuropathy has distinct clinical, pathologic, and proteomic features which expand the spectrum of IgM neuropathies. Patients have favorable survival, relative absence of autonomic features, and distinct proteomic profiles of the infiltrative protein in nerve.

Pathogenic mechanisms in inflammatory and paraproteinaemic peripheral neuropathies

“…In contrast to disease caused by antibodyantigen recognition and immune activation, a subset of immunoglobulin M-paraprotein patients appears to develop an asymmetric onset, upper limb and sensory predominant, axonal neuropathy associated with amyloid-like immunoglobulin M deposition (Fig. 3d), and has been postulated to result from mechanical compression and/or disruption of the microcirculation [71]. This occurs without the autonomic disturbance characteristic of amyloid infiltration (Fig.…”

Peripheral Nervous System Involvement in Lymphoproliferative Disorders

“…Multiple mononeuritis have been described as the predominant clinical manifestation in rare patients with Waldenström’s macroglobulinaemia in which the underlying mechanism is a massive light and heavy chain deposition within the nerves resulting in massive fascicular hyalinosis ( Figure 3 A–D ). 4 , 8 – 9 In these cases, protein accumulation in the endoneurium and epineurium behaves differently from amyloid as it does not stain with Congo Red. 4 , 8 – 9 The presence of polyneuropathy is currently considered an indication to start treatment in smouldering Waldenström macroglobulinemia.…”

“… 4 , 8 – 9 In these cases, protein accumulation in the endoneurium and epineurium behaves differently from amyloid as it does not stain with Congo Red. 4 , 8 – 9 The presence of polyneuropathy is currently considered an indication to start treatment in smouldering Waldenström macroglobulinemia. 10 …”

Polyneuropathy associated with a monoclonal gammopathy

“…Immunoglobulins Immunoglobulin deposits of any kind: IgG, IgA or IgM or light chains can only be proven by nerve biopsy [55,56]. These monoclonal dysglobulinemias are usually malignant (multiple myeloma, Waldenstrom's disease or non-Hodgkin's lymphoma).…”