自己貪食空胞性ミオパチー

Paraproteinemic myopathies are rare but potentially treatable disorders caused by pathogenic monoclonal proteins, yet diagnosis is often delayed because of nonspecific clinical manifestations and the lack of standardized diagnostic approaches. The 294th ENMC International Workshop convened 21 experts from 12 countries and two patient representatives to establish international consensus on their diagnosis and management. The workshop reviewed current evidence on sporadic late-onset nemaline myopathy (SLONM), light-chain (AL) amyloid myopathy, vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS), and scleromyxedema-associated myopathy. Clinical red flags include age at symptom onset ≥40 years, subacute proximal and/or axial weakness, normal or mildly elevated creatine kinase levels (except in VAMMGAS), dysphagia, weight loss, systemic manifestations, and poor response to conventional immunotherapy. Consensus diagnostic criteria for SLONM and a diagnostic algorithm for paraproteinemic myopathies were established. Routine Congo red staining of muscle biopsies, particularly in patients with monoclonal protein, was recommended. The workshop endorsed replacing SLONM-MGUS with SLONM-MP to reflect the pathogenic role of the monoclonal protein and recommended plasma cell-directed therapy as the cornerstone of treatment for SLONM-MP and AL amyloid myopathy. These recommendations provide the first international consensus framework for the diagnosis and management of paraproteinemic myopathies and establish priorities for future collaborative research.

Heat shock protein family B member 8 (HSPB8) is a chaperone involved in the chaperone-assisted selective autophagy (CASA) complex. HSPB8 in conjunction with cochaperone BAG3, promotes autophagy-mediated removal of misfolded proteins associated with various neurodegenerative diseases. Mutations in HSPB8 , previously associated with Charcot Marie Tooth disease type 2L, have recently been linked to an autosomal dominant rimmed vacuolar myopathy (MFM13), and is considered a multisystem proteinopathy. Patients have distal and proximal limb girdle myopathy with muscle biopsy showing fatty replacement, endomysial fibrosis, and rimmed vacuoles leading to muscle atrophy and early demise. We have demonstrated reduced expression of HSPB8, altered autophagy and TDP-43 accumulation in patient fibroblasts. Using CRISPR technology, we generated a knock-in Hspb 8 mouse model of the c.515dupC hot spot frameshift variant to study disease pathology. Overexpressed murine Hspb8 frameshift mutant (c.515dupC, fs) displays insolubility and aggregation propensity in Murine Neuroblastoma X Spinal Cord 34 (NSC-34) cells. Mutant Hspb8 mice developed late-onset muscle weakness beginning at 15 months. Muscle biochemical analyses revealed reduced HSPB8 levels, increased TDP-43, and altered autophagy markers, partially recapitulating the human phenotype. Fiber type analysis, neuromuscular junction integrity, and motor neurons show mild myopathy without neurodegeneration. Given the lack of available treatments, we evaluated trehalose, a natural disaccharide that induces HSPB8 and enhances autophagy. Administration of 2% trehalose in drinking water improves motor performance, restores HSPB8 expression, and ameliorates autophagic and TDP-43 pathology in mutant mice. These findings support the value of our preclinical models for translational studies, and autophagy enhancement as a potential therapeutic strategy for HSPB8-related myopathy.

Autophagic vacuoles in muscle fibers are a characteristic finding in several muscle diseases and usually indicate perturbed lysosomal protein degradation. Some of these are associated with defects in proteins directly involved in autophagy and lysosomal degradation. The gene CLN8 encodes an endoplasmic reticulum transmembrane protein, previously associated with childhood-onset neuronal ceroid lipofuscinosis (NCL), a group of lysosomal storage diseases. We describe the clinical features and results from pathology, genetic, and proteomic investigations in an adult-onset myopathy with autophagic vacuoles associated with biallelic variants in CLN8. A 40-year-old woman presented with seizures followed by transient muscle weakness and myalgia. Creatine kinase and myoglobin levels were moderately elevated. Over time, she developed progressive muscle weakness and cognitive fatigue. Muscle biopsy showed an autophagic vacuolar myopathy with fat tissue replacement and increased interstitial connective tissue. There was a marked immunohistochemical increase of markers of autophagy such as lysosomal-associated membrane protein 2 (LAMP2), microtubule-associated protein 1A/1B-light chain 3 (LC3), and sequestosome1/p62, as well as lysosomal deposition of curvilinear-like, autofluorescent material containing subunit c of mitochondrial adenosine triphosphate (ATP) synthase (mitochondrial ATP synthase membrane subunit c locus 3 [ATP5MC3/SCMAS]), typical for some forms of NCLs, including CLN8. Blood lymphocytes showed typical fingerprint inclusions. Genetic analysis revealed biallelic CLN8 variants, c.511C>T; p.P171S and c.536T>A; p.L179H. Proteomic analysis demonstrated upregulation of proteins involved in autophagy, muscle regeneration, and protein turnover. Proteins associated with oxidative phosphorylation were downregulated, except for ATP5MC3/SCMAS, which showed accumulation. In conclusion, we describe a novel myopathy with autophagic vacuoles and characteristic features of ceroid lipofuscinosis, including autophagosomal/lysosomal deposition of curvilinear-like, autofluorescent material containing ATP5MC3/SCMAS. This disease appears to be an unusual adult-onset form of CLN8.

X-Linked myopathy with excessive autophagy (XMEA) is a rare vacuolar myopathy caused by mutations in Vma21, an assembly chaperone required for vacuolar H⁺-ATPase (V-ATPase) function. However, the mechanisms linking Vma21 deficiency to progressive muscle pathology remain poorly understood, in part due to the lack of suitable animal models. To address this gap, we generated conditional Vma21 knockout mouse models to investigate the consequences of Vma21 loss in striated muscle. Combined deletion of Vma21 in skeletal and cardiac muscle resulted in early lethality driven by severe cardiomyopathy associated with autophagic dysregulation, preceding the development of skeletal muscle pathology. In contrast, inducible skeletal muscle-specific deletion of Vma21 produced progressive muscle weakness and myopathy characterized by centralized nuclei, fiber splitting, and increased fiber size variability. Affected skeletal muscle also recapitulated defining pathological hallmarks of XMEA, including basal lamina reduplication and autophagic vacuoles with sarcolemmal features (AVSFs). Ultrastructural analysis revealed membrane-bound vacuoles containing partially undegraded material that frequently accumulated at the subsarcolemmal region, together with clusters of vesicular structures. Notably, mutant muscle exhibited increased staining for the late endosomal/exosomal marker CD63, which strongly colocalized with the complement membrane attack complex C5b-9. A similar increase in CD63 staining and its colocalization with C5b-9 were observed in skeletal muscle biopsies from patients with XMEA. Together, these models faithfully recapitulate key pathological features of XMEA and identify the accumulation of CD63-positive structures and their colocalization with C5b-9 as previously unrecognized features of Vma21-deficient skeletal muscle, implicating altered vesicle trafficking in XMEA pathogenesis.