Scleromyxedema-Associated Myopathy and Vacuolar Myopathy with Monoclonal Gammopathy and Stiffness (VAMMGAS) as manifestations of Monoclonal Gammopathy of Clinical Significance (MGCS): a disease spectrum between autophagy dysfunction and inflammation.

Scleromyxedema-Associated Myopathy (SAM) and Vacuolar Myopathy with Monoclonal Gammopathy and Stiffness (VAMMGAS) are rare clinical entities associated with Monoclonal Gammopathy of Clinical Significance (MGCS). We compared the clinical, neurophysiological, histopathological, and ultrastructural features of three patients (two with SAM and one with VAMMGAS), together with a review of the available literature, to further characterize the similarities and differences between these two conditions. Our analysis suggests that SAM and VAMMGAS may represent part of a clinical spectrum characterized by progressive proximal muscle weakness and prominent pathological spontaneous activity on electromyography. By definition, SAM is associated with scleromyxedema, which may occasionally develop after the onset of myopathy, whereas VAMMGAS is characterized by muscle stiffness. The underlying monoclonal gammopathy is most commonly IgG ? in SAM, while IgG ? appears to be more frequent in VAMMGAS. Histopathologically, both conditions show a myopathy with features suggestive of impaired autophagy and evidence of immune activation (abnormal HLA-I expression and sarcolemmal C5b-9 deposits), although inflammatory infiltrates appear to be more characteristic of SAM, providing insights into potentially shared pathogenic mechanisms. Taken together, these findings support the concept that SAM and VAMMGAS may represent related manifestations within the spectrum of MGCS-associated muscle disease. Recognition of their overlapping clinical, neurophysiological, and histological features may facilitate diagnosis and broaden our understanding of the underlying pathophysiological mechanisms, potentially informing therapeutic strategies. Importantly, both conditions appear to be treatable with immunomodulatory approaches (including intravenous immunoglobulins and plasma exchange) as well as clone-directed therapies.