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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.

Background and purpose X‐linked Charcot‐Marie‐Tooth disease type 1 (CMTX1) ranks as the second most prevalent hereditary neuropathy and, currently, has no definitive cure. Emerging preclinical trials offer hope for potential clinical studies in the near future. While it is widely accepted that experimental groups in these trials should be balanced for age and gender, there is a current shortfall in data regarding phenotype–genotype correlations. Our aim was to provide a more detailed understanding of these correlations to facilitate the formation of well‐matched patient groups in upcoming clinical trials. Methods We conducted a retrospective evaluation of CMTX1 patients from 13 designated reference centers in France. Data on genetics, clinical features, and nerve conduction were systematically gathered. Results We analyzed the genotype–phenotype correlations in 275 CMTX1 patients belonging to 162 families and carrying 87 distinct variants. Patients with variants affecting the transmembrane domains demonstrated significantly greater severity, as evidenced by a Charcot‐Marie‐Tooth Examination Score of 10.5, compared to 7.1 for those with intracellular domain variants and 8.7 for extracellular domain variants (p < 0.000). These patients also experienced an earlier age of onset, showed slower ulnar nerve conduction velocities and had more substantial loss of motor amplitude. Conclusions This study confirms the presence of a correlation between the mutated protein domain and the clinical phenotype. Patients with a variant in the transmembrane domains demonstrated a more severe clinical and electrophysiological profile. Consequently, the genotype could play a prognostic role in addition to its diagnostic role, and it will be essential to consider this in future clinical trials.

ObjectiveHereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and considered quite rare. Respiratory insufficiency is an early symptom. A collection of families and patients with muscle disease suggestive of HMERF was clinically and genetically studied.MethodsAltogether 12 new families with 19 affected patients and diverse nationalities were studied. Most of the patients were investigated using targeted next-generation sequencing; Sanger sequencing was applied in some of the patients and available family members. Histological data and muscle MRI findings were evaluated.ResultsThree families had several family members studied while the rest were single patients. Most patients had distal and proximal muscle weakness together with respiratory insufficiency. Five heterozygous TTN A-band mutations were identified of which two were novel. Also with the novel mutations the muscle pathology and imaging findings were compatible with the previous reports of HMERF.ConclusionsOur collection of 12 new families expands mutational spectrum with two new mutations identified. HMERF is not that rare and can be found worldwide, but maybe underdiagnosed. Diagnostic process seems to be complex as this study shows with mostly single patients without clear dominant family history.

Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene. In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model. In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples. These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.

Immune checkpoint inhibitor therapy (ICI)-induced myositis (irMyositis) occurs in about 1% of patients treated with anti-PD1 or anti-CTLA-4 antibodies and can be debilitating or even fatal. We compared gene expression profiles from skeletal muscle biopsies between irMyositis patients, patients with spontaneous dermatomyositis (DM, comprising anti-Mi2-positive and anti-TIF1-γ-positive subtypes), and non-diseased controls (NDC). We used the NanoString nCounter PanCancer Immune Profiling Panel to perform differential gene expression (DGE) and pathway enrichment analyses. We identified 93 differentially expressed genes (DEGs) across conditions. Gene set enrichment analysis (GSEA) suggested activation of interferon gamma (type-II IFN) and interferon alpha/beta (type-I IFN) signaling in irMyositis and DM, respectively. For instance, type-II IFN was upregulated exclusively in irMyositis when compared to DM, which conversely showed upregulation of effector genes downstream type-I IFN. The observed fold-change of a subset of 33 genes drove the GSEA. We further characterized the DEGs using network interaction and expression correlation analyses. This allowed us to describe potential differences between regulatory hubs and cells involved in irMyositis susceptible to ICI effects. For example, the downregulation of FOXP3 we observed together with the upregulation of the chemokine CCL14 in irMyositis may have been a consequence of T cell activation upon ICI therapy. The gene expression correlation and putative molecular interactions set irMyositis apart from DM, particularly with respect to IFN response and DGE of interactors of ICI protein targets (CTLA4, PD-1, PD-L1). Our results suggest new avenues for understanding immunotherapy-related adverse events.

Background Autosomal recessive mutations in the SH3TC2 gene cause Charcot–Marie‐Tooth type 4C (CMT4C) demyelinating peripheral neuropathy. Methods In this nationwide observational retrospective study involving 27 French University Hospitals, we analyzed the clinical, electrophysiological, and genetic features of 103 patients from 89 families with homozygous and compound heterozygous SH3TC2 gene mutations identified between 2003 and 2023. Results Mean age was 42 years (2–80), and 49% of patients were female. Mean age at disease onset was 14 years (0–52), 60% of patients started the disease before age 10 years, and 24% after age 20 years. Patients presented with distal motor weakness (93% of cases), sensory loss (86%), foot deformities (83%), scoliosis (73%), proximal limb weakness (40%), cranial nerve involvement (48%), hearing loss (37%), scoliosis‐related respiratory insufficiency (14%), and genitourinary disorders (6%). Half the patients (48%) walked independently before age 50 years, in contrast with only 13% after age 50 years. After age 50 years, 23% of patients were wheelchair‐bound. Nerve conduction studies showed sensorimotor abnormalities within the demyelinating range in all cases. We identified 56 different pathogenic variants in the SH3TC2 gene, including 22 previously undescribed. Patients with two SH3TC2 gene truncating variants had more severe symptoms than patients with one or zero truncating variants. Interpretation This study shows CMT4C is a severe childhood‐ and adult‐onset demyelinating peripheral neuropathy often associated with scoliosis, hearing loss, and ambulation loss in a significant proportion of patients after age 50 years. Genotype–phenotype correlations suggest two truncating SH3TC2 gene variants cause a more severe phenotype. We analysed the clinical, electrophysiological, and genetic features of 103 patients from 89 families with SH3TC2 gene mutations identified in 27 French University Hospitals causing Charcot–Marie‐Tooth type 4C (CMT4C) demyelinating peripheral neuropathy. This study shows CMT4C is a severe childhood‐ and adult‐onset demyelinating peripheral neuropathy often associated with scoliosis, hearing loss, and ambulation loss in a significant proportion of patients after age 50 years. Genotype–phenotype correlations suggest two truncating SH3TC2 gene variants cause a more severe phenotype.

Background and Aims In 2019, we conducted a cross‐sectional study, collecting information on 50 patients with CMT4B, an ultrarare CMT subtype, to better define the clinical phenotype. We now aimed at investigating disease progression in 26 patients with CMT4B1/CMT4B2, recruited from the previous study and among the Inherited Neuropathy Consortium. Materials and Methods We retrospectively analysed disease progression in patients with CMT4B1/CMT4B2, collecting MRC scores from nine muscle pairs, Charcot‐Marie‐Tooth Examination Score (CMTES), and a minimal dataset of clinical information (walking difficulties, aids dependency, upper limb impairment, cranial nerves involvement) at baseline and follow‐up visits. Thirteen centres from four continents were involved. Results Thirteen CMT4B1 and 13 CMT4B2 patients were followed up for 7.1 ± 4.9 and 7.9 ± 4.5 years, respectively. During follow‐up, walking aid dependency increased: two CMT4B1 patients adopted AFOs (overall 11/12 at follow‐up), and one started using wheelchair (6/12 at follow‐up) at the age of 19; among CMT4B2 patients, two more required unilateral support in walking (4/11 at follow‐up) by the age of 33 and 49 years, respectively. We found that disease progression, as measured by CMTES, was faster in CMT4B1 as compared to CMT4B2 patients (ΔCMTES/year 0.7 vs. 0.3, p = 0.037) but tended to slow down over time as burden of disease increased. At the end of follow‐up, CMT4B1 was associated to higher disability. Conclusions This international collective effort enabled collection of relevant data for characterizing natural history and estimating disease progression of CMT4B1/CMT4B2 ultrarare diseases, aiming at improving their management and paving the way for designing future clinical trials.

Currently only 25–30% of patients with axonal forms of Charcot-Marie-Tooth disease (CMT) receive a genetic diagnosis. We aimed to identify the causative gene of CMT type 2 in 8 non-related French families with a distinct clinical phenotype. We collected clinical, electrophysiological, and laboratory findings and performed genetic analyses in four different French laboratories. Seventy-two patients with autosomal dominant inheritance were identified. The disease usually started in the fourth decade and the clinical picture was dominated by sensory ataxia (80%), neuropathic pain (38%), and length-dependent sensory loss to all modalities. Electrophysiological studies showed a primarily axonal neuropathy, with possible isolated sensory involvement in milder phenotypes. Disease severity varied greatly but the clinical course was generally mild. We identified 2 novel variants in LRSAM1 gene: a deletion of 4 amino acids, p.(Gln698_Gln701del), was found in 7 families and a duplication of a neighboring region of 10 amino acids, p.(Pro702_Gln711dup), in the remaining family. A common haplotype of ~450 kb suggesting a founder effect was noted around LRSAM1 in 4 families carrying the first variant. LRSAM1 gene encodes for an E3 ubiquitin ligase important for neural functioning. Our results confirm the localization of variants in its catalytic C-terminal RING domain and broaden the phenotypic spectrum of LRSAM1-related neuropathies, including painful and predominantly sensory ataxic forms.

BackgroundMyosin heavy chain 7 (MYH7)-related myopathies (MYH7-RMs) are a group of muscle disorders linked to pathogenic variants in the MYH7 gene, encoding the slow/beta-cardiac myosin heavy chain, which is highly expressed in skeletal muscle and heart. The phenotype is heterogeneous including distal, predominantly axial or scapuloperoneal myopathies with variable cardiac involvement.MethodsWe retrospectively analysed the clinical, muscle MRI, genetic and myopathological features of 57 MYH7 patients. Patients received a thorough neurological (n=57, 100%), cardiac (n=51, 89%) and respiratory (n=45, 79%) assessment. Muscle imaging findings and muscle biopsies were reappraised in 19 (33%) and 27 (47%) patients, respectively.ResultsWe identified three phenotypes with varying degrees of overlap: distal myopathy (70%), scapuloperoneal (23%) and axial with peculiar cervical spine rigidity called the ‘sphinx’ phenotype (7%). 14% of patients had either dilated cardiomyopathy, hypertrophic cardiomyopathy or left ventricular non-compaction cardiomyopathy. 31% of patients had prominent respiratory involvement, including all patients with the ‘sphinx’ phenotype. Muscle MRI showed involvement of tibialis anterior, followed by quadriceps, and erector spinae in patients with axial phenotype. Cores represented the most common myopathological lesion. We report 26 pathogenic variants of MYH7 gene, 9 of which are novel.Conclusions MYH7-RMs have a large phenotypic spectrum, including distal, scapuloperoneal or axial weakness, and variable cardiac and respiratory involvement. Tibialis anterior is constantly and precociously affected both clinically and on muscle imaging. Cores represent the most common myopathological lesion. Our detailed description of MYH7-RMs should improve their recognition and management.