Rare Muscle Diseases Tied to Blood Protein Disorders May Be One Spectrum

Two extraordinarily rare muscle disorders, long treated as separate curiosities in the neurological literature, may in fact be two faces of the same underlying disease process. That is the central conclusion of a new study published in the Journal of Neurology, in which a French-led team of neurologists, neuropathologists, dermatologists and hematologists compared patients with scleromyxedema-associated myopathy (SAM) and a recently described condition known as vacuolar myopathy with monoclonal gammopathy and stiffness, or VAMMGAS. Both disorders, the researchers argue, are best understood as manifestations of monoclonal gammopathy of clinical significance, a concept that is rapidly reshaping how physicians think about the strange, sometimes devastating symptoms that a single clone of antibody-producing cells can inflict on the body.

Monoclonal gammopathy of clinical significance, abbreviated MGCS, describes a situation in which a clone of plasma cells in the bone marrow produces an abnormal, monoclonal immunoglobulin. Unlike monoclonal gammopathy of undetermined significance, or MGUS, in which the abnormal protein is a harmless laboratory finding, MGCS means the monoclonal protein is actively damaging tissue. Depending on the properties of the antibody, that damage can take many forms: nerve injury, kidney disease, skin changes, amyloid deposition or, as in the cases examined here, muscle disease. The concept, formalized in a landmark 2018 position paper in the journal Blood, implies something clinically crucial: treating the plasma cell clone itself, rather than only the damaged organ, can halt or reverse the disease.

The first of the two conditions, scleromyxedema-associated myopathy, arises in patients with scleromyxedema, a rare sclerosing skin disease characterized by widespread papular and waxy thickened lesions caused by mucin deposits in the dermis. Scleromyxedema is itself almost always linked to an IgG monoclonal gammopathy, and its systemic complications can include neurological and muscular involvement. Muscle weakness in these patients has been reported sporadically since the 1960s and 1970s, but the pathological picture has remained fragmentary. The second condition, VAMMGAS, was only recently characterized in the European Journal of Neurology by a team including several of the same French investigators. It combines progressive muscle weakness, muscle stiffness, vacuolar changes visible on muscle biopsy and a monoclonal gammopathy, but without the characteristic skin disease of scleromyxedema.

To test whether these entities belong to a single disease family, the researchers performed a detailed side-by-side comparison of three patients: two with SAM and one with VAMMGAS. They examined the clinical course, electrophysiological findings, light-microscopic histopathology and, critically, ultrastructural features seen under the electron microscope. They then placed their observations against the backdrop of the published literature on both disorders and on related monoclonal gammopathy-associated myopathies, including sporadic late-onset nemaline myopathy, amyloid myopathy and newly described glycogen storage myopathies linked to plasma cell clones.

The comparison revealed striking common ground. All three patients showed progressive weakness predominantly affecting the proximal muscles, those closest to the trunk, such as the hip and shoulder girdles. Electromyography, the technique that records the electrical activity of muscle fibers through a needle electrode, showed prominent pathological spontaneous activity in all cases. This finding, which reflects irritable, unstable muscle membranes, indicates that the muscle fibers themselves are being injured, and it helps distinguish these myopathic processes from pure nerve disorders. In both conditions, the muscle biopsy showed a myopathy with features suggesting that autophagy, the cellular housekeeping system that digests and recycles damaged components, was not working properly. Autophagy is essential for muscle health; when it falters, fibers accumulate abnormal vacuoles and material that they cannot clear, a pattern familiar to neuromuscular specialists from genetic disorders such as X-linked myopathy with excessive autophagy and from drug toxicities such as colchicine myopathy.

Alongside the autophagy signature, the biopsies carried clear fingerprints of immune activation. The muscle fibers abnormally expressed HLA class I molecules, the same antigen-presenting machinery that flags cells to the immune system, and deposits of C5b-9, the membrane attack complex of the complement cascade, were found on the sarcolemmal membranes of the fibers. These are the kind of findings typically seen in immune-mediated myopathies, where antibodies and complement attack muscle directly or mark it for destruction. In other words, the muscle in both diseases shows simultaneous evidence of a failed intracellular waste-disposal system and an active immune assault on the fiber surface, a combination that is unusual and diagnostically provocative.

There were differences, too, and they may prove just as informative as the similarities. By definition, SAM occurs in the context of scleromyxedema, and the researchers note that the skin disease may occasionally appear only after the muscle symptoms have begun, a sequencing that can delay diagnosis. VAMMGAS, by contrast, is defined by prominent muscle stiffness. The monoclonal protein also differs in a subtle but potentially meaningful way: in SAM the underlying gammopathy is most commonly IgG of the kappa light-chain type, whereas IgG lambda appears to be more frequent in VAMMGAS. On histology, inflammatory infiltrates, actual clusters of immune cells within the muscle tissue, seem to be more characteristic of SAM, while VAMMGAS leans more heavily toward the vacuolar, autophagy-impaired picture. The authors propose that the two diseases occupy different positions on a spectrum running between autophagy dysfunction at one pole and inflammation at the other, with individual patients landing somewhere in between depending on the biology of their particular monoclonal protein.

Why would a single abnormal antibody cause such a strange mixture of cellular pathology? The study does not deliver a definitive mechanism, but the framework it suggests is biologically plausible. Monoclonal immunoglobulins or their light chains are known to interfere with lysosomal function and autophagic flux in other MGCS-related diseases; in amyloid light-chain cardiotoxicity, for example, lysosomal dysfunction and impaired autophagy are established drivers of tissue damage. At the same time, immune complexes formed by monoclonal antibodies can activate complement, explaining the C5b-9 deposits on muscle membranes. Fibroblast growth factor 2 and transforming growth factor beta signaling have been invoked in the skin fibrosis of scleromyxedema, and TGF-beta is also known to epigenetically regulate autophagy, hinting at possible molecular bridges between the fibrosing, inflammatory and autophagic components of the syndrome.

The therapeutic implications may be the most consequential part of the work. Because both conditions appear to sit within the MGCS framework, they seem to respond to two complementary treatment strategies: immunomodulatory approaches, including intravenous immunoglobulin and plasma exchange, and clone-directed therapies that target the plasma cells producing the offending monoclonal protein. Intravenous immunoglobulin has long been a mainstay for the skin disease of scleromyxedema, and plasma exchange has been used successfully in refractory cases, while plasma cell-directed regimens have shown benefit in monoclonal gammopathy-associated scleromyxedema. Recognizing SAM and VAMMGAS as related MGCS manifestations gives clinicians a rationale for combining these approaches and for monitoring the monoclonal protein as a marker of disease activity, rather than treating the muscle in isolation with nonspecific immunosuppression.

For patients, the practical message is one of awareness. Unexplained progressive proximal weakness, especially when accompanied by muscle stiffness, thickened or waxy skin, or an abnormal protein band on serum electrophoresis, should prompt evaluation by a neuromuscular specialist and a hematologist together. The authors emphasize that recognizing the overlapping clinical, neurophysiological and histological features of SAM and VAMMGAS can shorten the diagnostic odyssey and open the door to treatments that address the root cause. With only a handful of cases described worldwide, much remains to be learned, and the researchers themselves frame their conclusions as hypothesis-generating rather than definitive. But the idea that a lone clone of antibody-producing cells can push muscle fibers simultaneously into autophagic failure and immune-mediated injury, and that this process can be caught and treated, marks a genuine step forward in the understanding of rare immune-muscle disease.

Subject of Research: Scleromyxedema-associated myopathy and VAMMGAS as monoclonal gammopathy-associated muscle diseases

Article Title: 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

Article References: Nicoletti, T., Benveniste, O., Battistella, M., Mahevas, T., Arnulf, B., Stojkovic, T., Staedler, K., Maisonobe, T., Letournel, F., Romero, P., Malfatti, E., Vignon, M., Nadaj-Pakleza, A., Labella, B., Lacene, E., Brochier, G., Evangelista, T., & Leonard-Louis, S. (2026). 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. Journal of Neurology, 273(10), Article 633. https://doi.org/10.1007/s00415-026-14169-2

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14169-2

Keywords: monoclonal gammopathy, MGCS, scleromyxedema, VAMMGAS, vacuolar myopathy, autophagy, muscle weakness, HLA class I, complement C5b-9, intravenous immunoglobulin, plasma exchange, neuromuscular disease