Vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS)

Abstract

Background: Monoclonal gammopathy (MG) has been reported in association with numerous neurological disorders but the spectrum of MG-associated myopathies remains poorly described.

Objective: To report a newly acquired myopathy associated with MG.

Methods: Three adult patients with the same phenotype from two French referral centers were prospectively analyzed. Clinical, electrophysiological, muscle biopsy data, and patients' outcomes under treatment are reported.

Results: The patients, aged 37, 46, and 56 years, presented progressive weakness with subacute worsening and stiffness, in the context of severe weight loss. The weakness mainly involved the proximal limbs and axial muscles. Creatine kinase levels were 1400-2900 IU/L and electromyography revealed a myopathic pattern with spontaneous complex repetitive discharges. Muscle biopsies showed vacuoles containing glycogen and autophagic material along with the presence of sarcolemmal complement membrane attack complex deposits. There was no evidence of a genetic glycogen metabolic disorder. IgGκ monoclonal gammopathy was identified in all cases, without signs of lymphoplasmocytic proliferation. All patients improved with a treatment combining corticosteroids, intravenous immunoglobulins, and immunosuppressants, and two patients recovered walking ability.

Conclusion and relevance: We report a new muscle disease defined by a vacuolar myopathy characterized by axial and proximal muscle weakness with prominent stiffness and high frequency discharges on electromyography associated with monoclonal gammopathy, defined under the acronym VAMMGAS.

Keywords: elevated CK; monoclonal gammopathy; stiffness; vacuolar myopathy.

FIGURE 1

Muscle morphological studies. Deltoid muscle biopsy was performed at ages 53, 37, and 59 in patient 1, 2, and 3, respectively. Cross‐serial sections. Patient 1 (a–d): H&E (a) and mGT (b) showing an abnormal fiber (the same fiber is indicated by a star) harboring multiple subsarcolemmal vacuoles containing some granular/dotted material appearing fuchsinophilic with mGT staining. Marked fiber size/diameter variation is also evident. (c) MAC/C5b9 immunostaining shows the presence of granular complement deposition at the sarcolemma in several fibers. (d) Electron micrograph shows the presence of an abundant subsarcolemmal membrane vacuolization formed by different compartments separated by redundant membrane layers. Autophagic material and cellular debris filled the vacuoles. Scale bars: 20 μm (a–c), 2 μm (d). Patient 2 (e–h): H&E (e) and mGT (f) show a few fibers (one of the fibers is indicated by a star) with multiple subsarcolemmal vacuoles. (g) MAC/C5b9 immunostaining shows the presence of granular complement deposition at the sarcolemma in a few fibers. (h) Electron micrographs showing a completely disrupted muscle cell containing autophagic material with myelinic profiles, cellular debris, and prominent proliferation of reticular structures. Scale bars: 20 μm (e–g), 2 μm (h). Patient 3 (i–l): H&E and mGT (P and S) show a few fibers with multiple subsarcolemmal as well as central vacuoles containing slightly granular material, variations in fiber size and diameter, and rare internalized nuclei. (k) MAC/C5b9 immunostaining shows the presence of granular complement deposition at the sarcolemma in three fibers. (l) The ultrastructural analysis shows multiple sarcoplasmic vacuolization. Scale bars: 20 μm (i–k), 2 μm (l).

FIGURE 2

Muscle MRI and ¹⁸FDG‐PET scan studies in patient 3 at age 68. Muscle MRI of pelvic girdle (a) and thigh (b): fatty degeneration of gluteus, biceps femoris, semimembranosus, semitendinosus, biceps femoris, and adductors sparing gracilis. At the leg level (c), note fatty infiltration of the posterior compartment (soleus, gastrocnemius medialis, gastrocnemius lateralis) sparing tibialis posterior. ¹⁸FDG‐PET scan (d) shows increased symmetric FDG uptake in both proximal and distal muscles of all four limbs (arrows).