IgM MGUS anti myelin‐associated glycoprotein neuropathy can rarely express as a predominantly distal motor neuropathy

Neuropathy associated with immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) with antibodies against myelin-associated glycoprotein (MAG) is a distinctive clinical syndrome. It is characterized by male predominance, late onset age, slow progression, predominantly sensory symptoms, ataxia due to loss of proprioception, and rare muscle weakness. Kawagashira et al. reported a 62-year-old man with distal lower limb muscle weakness, paresthesias, absent tendon reflexes, severe bilateral distal leg muscle atrophy, and slow progression over 5 years. Strength in the legs was 1/5 [Medical Research Council (MRS) scale] distally; deep and superficial sensations were mildly impaired in a glove-stocking distribution. An IgM kappa M-protein was identified in the serum, with positive anti-MAG IgM and elevated sulfoglucuronyl paragloboside (SGPG) IgM antibodies. Nerve conduction studies suggested demyelination and axon loss in motor and sensory fibers. Sural nerve biopsy showed large fiber loss, tomacula on teased fibers, widely spaced myelin lamellae, and positive indirect immunofluorescence for human IgM antibody. Intravenous immunoglobulin (IVIg) provided benefit. Among a cohort of 46 patients with IgM MGUS and anti-MAG antibody followed at our institution since 1994,we identified 3 men affected by relentlessly progressive, nearly symmetrical disease in the lower limbs with severe distal atrophy; steppage gait; minor sensory loss for touch, vibration, and proprioception; minimal hand tremor; and absent reflexes. On manual muscle testing at the time of diagnosis, distal leg strength ranged between 1/5 and 2/5 on the MRC scale, whereas in the arms it was recorded as level 4/5–5/5. Mean onset age was 67 (range 59–73) years. IgM antibody titer to MAG assayed by enzyme-linked immunosorbent assay (B€ uhlmann Laboratories AG) ranged from 2,000 to 72,242 [mean 31,430, normal< 1,000 B€ uhlmann titer units (BTU); the results were confirmed on Western blot analysis. IgM and IgG antibodies to sulfatide and other gangliosides (GM1, GD1a, and GD1b) were negative. Spinal fluid protein content was high in 1 patient (104 mg/dl, normal< 45 mg/dl). Genetic tests for peripheral myelin protein zero mutations were negative. Nerve conduction findings included prolonged distal latencies up to 16 ms in tibial and fibular nerves, suggesting distal demyelination. There was no evidence of conduction block or abnormal temporal dispersion. Sural sensory nerve action potentials were unelicitable; motor conduction velocities in upper extremities ranged between 34 and 46 m/s. Strength in the lower extremities worsened very slowly over 6–9 years, especially in ankle dorsiflexors and plantarflexors, but it did not change significantly in the upper limbs between baseline and last follow-up. Two patients received periodic IVIg, followed in 1 patient by 2 courses of rituximab, which were associated with worsening of sensory symptoms and foot drop. The third subject, who refused treatment, died from other causes after 12 years. Kawagashira et al. described a patient with positive anti-MAG IgM antibody and elevated anti-SGPG titers, whereas in our patients there was no cross-reactivity between anti-MAG antibody and other glycoconjugates or sulfatide. We agree that wide immunoreactivity between anti-MAG antibodies and glycoconjugates, such as SGPG, may explain the clinical manifestations in the Kawagashira et al. patient, which differs from most commonly described phenotypes. Ellie et al. reported severe weakness in IgM MGUS polyneuropathy, but their patients had marked sensory ataxia. Campagnolo et al. commented recently that heterogeneous immunoreactivity and shared epitopes between MAG and other glycoconjugates in paraproteinemic IgM neuropathies may cause heterogeneous clinical, neurophysiological, pathological features, and response to therapy due to binding to different structures, such as myelin sheaths, axons, or dorsal root ganglia. Carpo et al. hypothesized that in anti-sulfatide IgM polyneuropathy high antibody titers capable of reaching nerve myelin may cause demyelination, whereas lower antibody levels could lead to predominant axonal involvement. In conclusion, practical lessons for clinicians can be drawn from these cases. Although rare, this motorpredominant distal phenotype of anti-MAG neuropathy confirms the heterogeneous clinical features of this disease, but we do not know the reason for motor VC 2016 Wiley Periodicals, Inc.