Milone, Margherita

ABSTRACT Background Agrin‐congenital myasthenic syndrome ( AGRN ‐CMS) is a rare, heterogeneous genetic disorder of the neuromuscular transmission that can present from infancy to adulthood. The clinical phenotype includes distal weakness mimicking distal myopathies. Additionally, electromyography and muscle biopsy may demonstrate myopathic features, increasing the diagnostic challenge. Mitochondrial dysfunction has not been reported in the muscle of AGRN ‐CMS patients. Methods We report the clinical, electrophysiological, radiological, myopathological, and genetic findings of a patient with AGRN‐ CMS. Results A 47‐year‐old male presented at age 18 with sudden onset of eyelid ptosis, weakness, and fatigue, followed by dysphagia, dyspnea on exertion, exercise intolerance, and myalgias. Three sisters had similar symptoms. Neurological examination showed lower limb weakness, predominantly affecting the calf muscles with associated atrophy. Tendon reflexes were normal but absent at the ankles. Creatine kinase levels were normal. Electromyography demonstrated myopathic changes in distal muscles with fibrillation potentials in the gastrocnemius. 2 Hz‐Repetitive nerve stimulation of the fibular nerve revealed a 32% decrement in the extensor digitorum brevis without facilitation. Tibialis anterior biopsy showed non‐specific myopathic changes, neurogenic features, and histological evidence of mitochondrial dysfunction, as suggested by the scattered cytochrome c oxidase‐negative fibers. Whole exome sequencing detected a homozygous pathogenic AGRN variant (c.5012G>A, p.Arg1671Gln). No pathogenic or suspected pathogenic variants were detected in muscle mitochondrial DNA or in nuclear genes affecting mitochondrial function. Conclusions This patient expands the pathological spectrum of AGRN ‐CMS to include mitochondrial dysfunction and highlights the importance of low‐frequency repetitive nerve stimulation in the assessment of patients with distal weakness for differentiating myopathies from CMS.

Abstract GNE myopathy (GNEM) is a neuromuscular disorder caused by biallelic mutations in the gene GNE , which encodes a bifunctional enzyme essential for the biosynthesis of sialic acid. Despite extensive characterization, no effective therapies or validated biomarkers exist, and the molecular mechanisms driving disease pathology remain poorly understood. This study identifies the proteoglycan serglycin as a preliminary candidate biomarker in GNEM and investigates the mechanisms underlying its dysregulation. Proteomic analysis of serum samples from GNEM patients revealed reduced circulating serglycin levels. In contrast, increased intracellular serglycin was observed in GNE knockout and GNEM patient iPSC-derived myoblasts, suggesting impaired secretion and/or degradation. To investigate the basis of this accumulation, intracellular trafficking and autophagic pathways were examined. Proteomic profiling from HEK GNE knockout cells revealed alterations in pathways involved in membrane trafficking, Golgi function, and glycoprotein processing, consistent with broader disruptions in the secretory system that may impair serglycin export and contribute to its intracellular retention. In GNEM iPSC-derived myoblasts, serglycin overlapped with LAMP1-positive lysosomal compartments and the ER-phagy receptor FAM134B, suggesting association with lysosomal and ER-phagy related pathways. Functional assays further indicated impaired autophagic flux in mutant cells. Together, these findings support a model in which combined defects in secretion and autophagic clearance contribute to intracellular serglycin accumulation and reduced circulating levels. This study identifies serglycin as a potential circulating biomarker for GNEM and highlights dysregulation of secretory and degradative pathways as converging features of disease pathology.

ABSTRACT Autoantibody internalization has been implicated in autoimmune disease pathogenesis, yet its mechanisms, and generality across different diseases, cell types, and affected tissues remain poorly defined. Using bulk RNA sequencing, we identified reproducible, autoantibody-specific transcriptomic signatures consistent with autoantigen dysfunction in muscle biopsies from patients with anti-Mi2 dermatomyositis and anti-PM/Scl scleromyositis across independent cohorts. Electroporation of purified patient IgG into primary cultures of healthy cells was sufficient to induce the corresponding transcriptomic programs in vitro . Direct immunofluorescence demonstrated immunoglobulin internalization into subcellular compartments matching the localization of the autoantigen in different affected tissues. Spatial transcriptomic analyses revealed that antibody-secreting cells translocated cytoplasmic material (i.e., immunoglobulin RNA) into adjacent affected cells expressing autoantibody-specific transcripts. The disease-specific transcripts were present not only in muscle fibers, but also in other cells, including macrophages, endothelial cells, and fibroblasts. Autoantibody-induced transcriptomic programs were associated with cell damage and autoantibody-specific reactive inflammatory programs, including activation of type I interferon and TGF-ß1 signaling in anti-Mi2 dermatomyositis and activation of type II interferon in anti-PM/Scl scleromyositis. Antibody internalization was also observed in different tissues from patients with other autoimmune diseases, including anti-U1RNP mixed connective tissue disease, anti-Ku overlap syndrome, and anti-Scl70 systemic sclerosis. Together, these findings establish autoantibody internalization as a shared pathogenic mechanism across diverse autoimmune diseases, providing a unifying framework for conditions driven by autoantibodies against intracellular antigens.

Ramdas et al. propose renaming ‘congenital myasthenic syndrome’ as ‘genetic myasthenic syndrome’. They argue that ‘congenital’ misleadingly implies neonatal onset, which may contribute to delayed diagnosis and management, and that revised nomenclature could improve patient outcomes.

ABSTRACT Objectives T‐cell large granular lymphocytic leukemia (T‐LGLL), reported in up to 58% of inclusion body myositis (IBM) patients, is a rare leukemia of cytotoxic or less commonly helper T cells. The range of myopathies in T‐LGLL and the impact of coexisting T‐LGLL in IBM are not well understood. Our objectives are to investigate the spectrum of myopathies in patients with T‐LGLL and compare the clinical, serological, pathological, and transcriptomic features of IBM patients with and without T‐LGLL. Methods We reviewed two Mayo Clinic cohorts: (1) T‐LGLL patients evaluated for myopathies (2003–2018), and (2) IBM patients tested for T‐LGLL via T‐cell receptor gene rearrangement or flow cytometry (2016–2022). We also compared transcriptomic profiles of IBM muscle biopsies with and without T‐LGLL. Results Of 447 T‐LGLL patients, 13 (2.9%) had myopathies, IBM being the most common ( n = 7). Of 43 IBM patients, 9 (20.9%) had T‐LGLL, with 5 diagnosed prior to the onset of weakness. Clinical and pathological features were largely similar between IBM patients with and without T‐LGLL, except for milder finger flexor weakness and more frequent neutropenia (55.6% vs. 0%, p < 0.001) in the T‐LGLL group. However, transcriptomic analysis of muscle tissues revealed a more immunologically active profile, with upregulation of T‐cell and macrophage markers, elevated levels of IFN‐γ gene and IFN‐γ–inducible genes, heightened cytokine activity, and enhanced immunoglobulin production in IBM patients with T‐LGLL. Interpretation IBM is the most common myopathy in T‐LGLL patients. While clinico‐sero‐pathological features were largely similar, transcriptomic differences suggest IBM with T‐LGLL may represent a distinct, more immune‐driven subtype.