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BACKGROUND AND OBJECTIVES: Immune-mediated necrotizing myopathy (IMNM) caused by antibodies against 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an inflammatory myopathy that has been epidemiologically correlated with previous statin exposure. We characterized in detail a series of 11 young statin-naïve patients experiencing a chronic disease course mimicking a limb-girdle muscular dystrophy. With the hypothesis that HMGCR upregulation may increase immunogenicity and trigger the production of autoantibodies, our aim was to expand pathophysiologic knowledge of this distinct phenotype. METHODS: Clinical and epidemiologic data, autoantibody titers, creatine kinase (CK) levels, response to treatment, muscle imaging, and muscle biopsies were assessed. HMGCR expression in patients' muscle was assessed by incubating sections of affected patients with purified anti-HMGCR+ serum. Whole-exome sequencing (WES) with a special focus on cholesterol biosynthesis-related genes and high-resolution human leukocyte antigen (HLA) typing were performed. RESULTS: Patients, aged 3-25 years and mostly female (90.9%), presented with subacute proximal weakness progressing over many years and high CK levels (>1,000 U/L). Diagnostic delay ranged from 3 to 27 years. WES did not reveal any pathogenic variants. HLA-DRB1*11:01 carrier frequency was 60%, a significantly higher proportion than in the control population. No upregulation or mislocalization of the enzyme in statin-exposed or statin-naïve anti-HMGCR+ patients was observed, compared with controls. DISCUSSION: WES of a cohort of patients with dystrophy-like anti-HMGCR IMNM did not reveal any common rare variants of any gene, including cholesterol biosynthesis-related genes. HLA analysis showed a strong association with HLA-DRB1*11:01, previously mostly described in statin-exposed adult patients; consequently, a common immunogenic predisposition should be suspected, irrespective of statin exposure. Moreover, we were unable to conclusively demonstrate muscle upregulation/mislocalization of HMGCR in IMNM, whether or not driven by statins.
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Cadenas HLA-DRB1 , Hidroximetilglutaril-CoA Reductasas , Humanos , Hidroximetilglutaril-CoA Reductasas/genética , Hidroximetilglutaril-CoA Reductasas/inmunología , Femenino , Masculino , Adulto , Cadenas HLA-DRB1/genética , Adulto Joven , Niño , Adolescente , Preescolar , Mutación , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Necrosis , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Miositis/inmunología , Miositis/genéticaRESUMEN
Late-onset Pompe Disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction due to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage - a classic manifestation of the disease - has been extensively studied by analysing the whole muscle tissue; however, little, if any, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single nuclei RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age and gender matched healthy controls. We matched these changes with histology findings using GeoMx Spatial Transcriptomics to compare the transcriptome of control myofibers from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibers of LODP patients. We observed an increase in the proportion of slow and regenerative muscle fibers and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibers, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes, and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. The upregulation of the genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibers. Notably, enzyme replacement therapy - the only available therapy for the disease - showed a tendency to restore metabolism dysregulation, particularly within slow fibers. A combination of single nuclei RNA sequencing and spatial transcriptomics revealed the landscape of normal and the diseased muscle, and highlighted the early abnormalities associated with the disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention.
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BACKGROUND AND OBJECTIVES: Autoantibody discovery in complex autoimmune diseases is challenging. Diverse successful antigen identification strategies are available, but, so far, have often been unsuccessful, especially in the discovery of protein antigens in which conformational and post-translational modification are critical. Our study assesses the utility of a human membrane and secreted protein microarray technology to detect autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: A cell microarray consisting of human embryonic kidney-293 cells expressing >5,000 human proteins was used. First, a validation step was performed with 4 serum samples from patients with autoimmune nodopathy (AN) to assess the ability of this technology to detect circulating known autoantibodies. The ability of the cell microarray technology to discover novel IgG autoantibodies was assessed incubating the array with 8 CIDP serum samples. Identified autoantibodies were subsequently validated using cell-based assays (CBAs), ELISA, and/or tissue immunohistochemistry and analyzed in a cohort of CIDP and AN (n = 96) and control (n = 100) samples. RESULTS: Serum anti-contactin-1 and anti-neurofascin-155 were detected by the human cell microarray technology. Nine potentially relevant antigens were found in patients with CIDP without other detectable antibodies; confirmation was possible in six of them: ephrin type-A receptor 7 (EPHA7); potassium-transporting ATPase alpha chain 1 and subunit beta (ATP4A/4B); leukemia-inhibitory factor (LIF); and interferon lambda 1, 2, and 3 (IFNL1, IFNL2, IFNL3). Anti-ATP4A/4B and anti-EPHA7 antibodies were detected in patients and controls and considered unrelated to CIDP. Both anti-LIF and anti-IFNL antibodies were found in the same 2 patients and were not detected in any control. Both patients showed the same staining pattern against myelinating fibers of peripheral nerve tissue and of myelinating neuron-Schwann cell cocultures. Clinically relevant correlations could not be established for anti-LIF and anti-IFNL3 antibodies. DISCUSSION: Our work demonstrates the utility of human cell microarray technology to detect known and discover unknown autoantibodies in human serum samples. Despite potential CIDP-associated autoantibodies (anti-LIF and anti-IFNL3) being identified, their clinical and pathogenic relevance needs to be elucidated in bigger cohorts.
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Enfermedades Autoinmunes , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Autoanticuerpos , Proteoma , Neuronas/químicaRESUMEN
OBJECTIVE: To describe a new phenotype associated with a novel variant in BAG3: autosomal dominant adult-onset distal hereditary motor neuronopathy. METHODS: This study enrolled eight affected individuals from a single family and included a comprehensive evaluation of the clinical phenotype, neurophysiologic testing, muscle MRI, muscle biopsy and western blot of BAG3 protein in skeletal muscle. Genetic workup included whole exome sequencing and segregation analysis of the detected variant in BAG3. RESULTS: Seven patients developed slowly progressive and symmetric distal weakness and atrophy of lower limb muscles, along with absent Achilles reflexes. The mean age of onset was 46 years. The neurophysiological examination was consistent with the diagnosis of distal motor neuronopathy. One 57-year-old female patient was minimally symptomatic. The pattern of inheritance was autosomal dominant, with one caveat: one female patient who was an obligate carrier of the variant died at the age of 73 years without exhibiting any muscle weakness. The muscle biopsies revealed neurogenic changes. A novel heterozygous truncating variant c.1513_1514insGGAC (p.Val505GlyfsTer6) in the gene BAG3 was identified in all affected family members. CONCLUSIONS: We report an autosomal dominant adult-onset distal hereditary motor neuronopathy with incomplete penetrance in women as a new phenotype related to a truncating variant in the BAG3 gene. Our findings expand the phenotypic spectrum of BAG3-related disorders, which previously included dilated cardiomyopathy, myofibrillar myopathy and adult-onset Charcot-Marie-Tooth type 2 neuropathy. Variants in BAG3 should be considered in the differential diagnosis of distal hereditary motor neuronopathies.
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Enfermedad de Charcot-Marie-Tooth , Atrofia Muscular Espinal , Adulto , Humanos , Femenino , Persona de Mediana Edad , Anciano , Linaje , Enfermedad de Charcot-Marie-Tooth/genética , Fenotipo , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Atrofia Muscular Espinal/patología , Mutación/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genéticaRESUMEN
Pompe disease is a rare genetic disorder with an estimated prevalence of 1:60.000. The two main phenotypes are Infantile Onset Pompe Disease (IOPD) and Late Onset Pompe Disease (LOPD). There is no published data from Spain regarding the existing number of cases, regional distribution, clinical features or, access and response to the treatment. We created a registry to collect all these data from patients with Pompe in Spain. Here, we report the data of the 122 patients registered including nine IOPD and 113 LOPD patients. There was a high variability in how the diagnosis was obtained and how the follow-up was performed among different centres. Seven IOPD patients were still alive being all treated with enzymatic replacement therapy (ERT) at last visit. Ninety four of the 113 LOPD patients had muscle weakness of which 81 were receiving ERT. We observed a progressive decline in the results of muscle function tests during follow-up. Overall, the Spanish Pompe Registry is a valuable resource for understanding the demographics, patient's journey and clinical characteristics of patients in Spain. Our data supports the development of agreed guidelines to ensure that the care provided to the patients is standardized across the country.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/terapia , alfa-Glucosidasas/genética , Fenotipo , Sistema de Registros , Terapia de Reemplazo Enzimático/métodosRESUMEN
Welander distal myopathy typically manifests in late adulthood and is caused by the founder TIA1 c.1150G>A (p.Glu384Lys) variant in families of Swedish and Finnish descent. Recently, a similar phenotype has been attributed to the digenic inheritance of TIA1 c.1070A>G (p.Asn357Ser) and SQSTM1 c.1175C>T (p.Pro392Leu) variants. We describe two unrelated Spanish patients presenting with slowly progressive gait disturbance, distal-predominant weakness, and mildly elevated creatine kinase (CK) levels since their 6th decade. Electromyography revealed abnormal spontaneous activity and a myopathic pattern. Muscle magnetic resonance imaging (MRI) showed marked fatty replacement in distal leg muscles. A muscle biopsy, performed on one patient, revealed myopathic changes with rimmed vacuoles. Both patients carried the TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu variants. Digenic inheritance is supported by evidence from unrelated pedigrees and a plausible biological interaction between both proteins in protein quality control processes. Recent functional studies and additional case descriptions further support this. Clinical suspicion is necessary to seek both variants.
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Miopatías Distales , Enfermedades Musculares , Adulto , Humanos , Miopatías Distales/patología , Electromiografía , Músculo Esquelético/patología , Enfermedades Musculares/genética , Proteína Sequestosoma-1/genética , Antígeno Intracelular 1 de las Células T/genéticaRESUMEN
Distal motor neuropathies (dHMN) are an heterogenous group of diseases characterized by progressive muscle weakness affecting predominantly the distal muscles of the lower and upper limbs. Our aim was to study the imaging features and pattern of muscle involvement in muscle magnetic resonance imaging (MRI) in dHMN patients of suspected genetic origin (dHMN). We conducted a retrospective study collecting clinical, genetic and muscle imaging data. Muscle MRI included T1-weighted and T2 weighted Short Tau Inversion Recovery images (STIR-T2w) sequences. Muscle replacement by fat was quantified using the Mercuri score. Identification of selective patterns of involvement was performed using hierarchical clustering. Eighty-four patients with diagnosis of dHMN were studied. Fat replacement was predominant in the distal lower leg muscles (82/84 cases), although also affected thigh and pelvis muscles. Asymmetric involvement was present in 29% of patients. The superficial posterior compartment of the leg, including the soleus and gastrocnemius muscles, was the most affected area (77/84). We observed a reticular pattern of fatty replacement progressing towards what is commonly known as "muscle islands" in 79.8%. Hyperintensities in STIR-T2w were observed in 78.6% patients mainly in distal leg muscles. Besides features common to all individuals, we identified and describe a pattern of muscle fat replacement characteristic of BICD2, HSPB1 and DYNC1H1 patients. We conclude that muscle MRI of patients with suspected dHMN reveals common features helpful in diagnosis process.
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Extremidad Inferior , Músculo Esquelético , Humanos , Estudios Retrospectivos , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Pierna , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: The diagnosis of patients with mutations in the VCP gene can be complicated due to their broad phenotypic spectrum including myopathy, motor neuron disease and peripheral neuropathy. Muscle MRI guides the diagnosis in neuromuscular diseases (NMDs); however, comprehensive muscle MRI features for VCP patients have not been reported so far. METHODS: We collected muscle MRIs of 80 of the 255 patients who participated in the "VCP International Study" and reviewed the T1-weighted (T1w) and short tau inversion recovery (STIR) sequences. We identified a series of potential diagnostic MRI based characteristics useful for the diagnosis of VCP disease and validated them in 1089 MRIs from patients with other genetically confirmed NMDs. RESULTS: Fat replacement of at least one muscle was identified in all symptomatic patients. The most common finding was the existence of patchy areas of fat replacement. Although there was a wide variability of muscles affected, we observed a common pattern characterized by the involvement of periscapular, paraspinal, gluteal and quadriceps muscles. STIR signal was enhanced in 67% of the patients, either in the muscle itself or in the surrounding fascia. We identified 10 diagnostic characteristics based on the pattern identified that allowed us to distinguish VCP disease from other neuromuscular diseases with high accuracy. CONCLUSIONS: Patients with mutations in the VCP gene had common features on muscle MRI that are helpful for diagnosis purposes, including the presence of patchy fat replacement and a prominent involvement of the periscapular, paraspinal, abdominal and thigh muscles.
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Músculo Esquelético , Enfermedades Musculares , Humanos , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Enfermedades Musculares/diagnóstico por imagen , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Mutación/genética , Imagen por Resonancia Magnética/métodos , Proteína que Contiene Valosina/genéticaRESUMEN
Anoctamin-5 related muscle disease is caused by biallelic pathogenic variants in the anoctamin-5 gene (ANO5) and shows variable clinical phenotypes: limb-girdle muscular dystrophy type 12 (LGMD-R12), distal muscular dystrophy type 3 (MMD3), pseudometabolic myopathy or asymptomatic hyperCKaemia. In this retrospective, observational, multicentre study we gathered a large European cohort of patients with ANO5-related muscle disease to study the clinical and genetic spectrum and genotype-phenotype correlations. We included 234 patients from 212 different families, contributed by 15 centres from 11 European countries. The largest subgroup was LGMD-R12 (52.6%), followed by pseudometabolic myopathy (20.5%), asymptomatic hyperCKaemia (13.7%) and MMD3 (13.2%). In all subgroups, there was a male predominance, except for pseudometabolic myopathy. Median age at symptom onset of all patients was 33 years (range 23-45 years). The most frequent symptoms at onset were myalgia (35.3%) and exercise intolerance (34.1%), while at last clinical evaluation most frequent symptoms and signs were proximal lower limb weakness (56.9%) and atrophy (38.1%), myalgia (45.1%) and atrophy of the medial gastrocnemius muscle (38.4%). Most patients remained ambulatory (79.4%). At last evaluation, 45.9% of patients with LGMD-R12 additionally had distal weakness in the lower limbs and 48.4% of patients with MMD3 also showed proximal lower limb weakness. Age at symptom onset did not differ significantly between males and females. However, males had a higher risk of using walking aids earlier (P = 0.035). No significant association was identified between sportive versus non-sportive lifestyle before symptom onset and age at symptom onset nor any of the motor outcomes. Cardiac and respiratory involvement that would require treatment occurred very rarely. Ninety-nine different pathogenic variants were identified in ANO5 of which 25 were novel. The most frequent variants were c.191dupA (p.Asn64Lysfs*15) (57.7%) and c.2272C>T (p.Arg758Cys) (11.1%). Patients with two loss-of function variants used walking aids at a significantly earlier age (P = 0.037). Patients homozygous for the c.2272C>T variant showed a later use of walking aids compared to patients with other variants (P = 0.043). We conclude that there was no correlation of the clinical phenotype with the specific genetic variants, and that LGMD-R12 and MMD3 predominantly affect males who have a significantly worse motor outcome. Our study provides useful information for clinical follow up of the patients and for the design of clinical trials with novel therapeutic agents.
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Enfermedades Musculares , Distrofia Muscular de Cinturas , Femenino , Masculino , Humanos , Mialgia/genética , Estudios Retrospectivos , Anoctaminas/genética , Mutación/genética , Enfermedades Musculares/epidemiología , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Músculo Esquelético/patología , Distrofia Muscular de Cinturas/epidemiología , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/diagnóstico , Atrofia/patologíaRESUMEN
Nemaline myopathy (NEM) type 10, caused by biallelic mutations in LMOD3, is a severe congenital myopathy clinically characterized by generalized hypotonia and muscle weakness, respiratory insufficiency, joint contractures, and bulbar weakness. Here, we describe a family with two adult patients presenting mild nemaline myopathy due to a novel homozygous missense variant in LMOD3. Both patients presented mild delayed motor milestones, frequent falls during infancy, prominent facial weakness and mild muscle weakness in the four limbs. Muscle biopsy showed mild myopathic changes and small nemaline bodies in a few fibers. A neuromuscular gene panel revealed a homozygous missense variant in LMOD3 that co-segregated with the disease in the family (NM_198271.4: c.1030C>T; p.Arg344Trp). The patients described here provide evidence of the phenotype-genotype correlation, suggesting that non-truncating variants in LMOD3 lead to milder phenotypes of NEM type 10.
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Miopatías Nemalínicas , Humanos , Miopatías Nemalínicas/genética , Miopatías Nemalínicas/patología , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Mutación Missense , Debilidad Muscular/genética , Debilidad Muscular/patología , Fenotipo , MutaciónRESUMEN
DNAJ/HSP40 co-chaperones are integral to the chaperone network, bind client proteins and recruit them to HSP70 for folding. We performed exome sequencing on patients with a presumed hereditary muscle disease and no genetic diagnosis. This identified four individuals from three unrelated families carrying an unreported homozygous stop gain (c.856A > T; p.Lys286Ter), or homozygous missense variants (c.74G > A; p.Arg25Gln and c.785 T > C; p.Leu262Ser) in DNAJB4. Affected patients presented with axial rigidity and early respiratory failure requiring ventilator support between the 1st and 4th decade of life. Selective involvement of the semitendinosus and biceps femoris muscles was seen on MRI scans of the thigh. On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles. DNAJB4 normally localizes to the Z-disc and was absent from muscle and fibroblasts of affected patients supporting a loss of function. Functional studies confirmed that the p.Lys286Ter and p.Leu262Ser mutant proteins are rapidly degraded in cells. In contrast, the p.Arg25Gln mutant protein is stable but failed to complement for DNAJB function in yeast, disaggregate client proteins or protect from heat shock-induced cell death consistent with its loss of function. DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis. DNAJB4 knockout muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones. These data demonstrate a novel chaperonopathy associated with DNAJB4 causing a myopathy with early respiratory failure. DNAJB4 loss of function variants may lead to the accumulation of DNAJB4 client proteins resulting in muscle dysfunction and degeneration.
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Enfermedades Musculares , Insuficiencia Respiratoria , Animales , Ratones , Mutación/genética , Enfermedades Musculares/diagnóstico por imagen , Enfermedades Musculares/genética , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Mutación Missense , Insuficiencia Respiratoria/genética , Insuficiencia Respiratoria/complicaciones , Insuficiencia Respiratoria/patología , Músculo Esquelético/patologíaRESUMEN
BACKGROUND: Telemedicine (TM) contributes to bridge the gap between healthcare facilities and patients' homes with neuromuscular disease (NMD) because of mobility issues. However, its deployment is limited due to difficulties evaluating subtle neurological signs such as mild weakness or sensory deficits. The COVID-19 pandemic has disrupted healthcare delivery worldwide, necessitating rapid measures implementation by health care providers (HCPs) to protect patients from acquiring SARS-CoV-2 while maintaining the best care and treatment. OBJECTIVES: Given the challenges faced by remote healthcare assistance of NMD patients, we aim to evaluate the use of TM in NMD during the COVID-19 pandemic. METHODS: Based on the Model for Assessment-of-Telemedicine-Applications (MAST), we conducted a survey amongst clinicians of the ERN EURO NMD (European-Reference-Network-for-Rare-Neuromuscular-Diseases). RESULTS: Based on 42 responses over 76 expected ones, our results show that the COVID-19 pandemic significantly increased the number of HCPs using TM (from 60% to 100%). The TM types most used during the COVID-19 period are teleconsultation and consultation by phone, particularly in the context of symptoms worsening in NMD patients with COVID-19 infection. Most European HCPs were satisfied when using TM but as a complementary option to physical consultations. Many responses addressed the issue of technical aspects needing improvement, particularly for elderly patients who need caregivers' assistance for accessing the TM platform. CONCLUSIONS: TM has been essential during COVID-19, but its use still presents some limitations for NMD patients with cognitive deficits or for first-time diagnosis. Thus, TM should be used as complement to, rather than substitute, for face-to-face consultations.
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COVID-19 , Enfermedades Neuromusculares , Telemedicina , Humanos , Anciano , SARS-CoV-2 , Pandemias , Telemedicina/métodosRESUMEN
Sarcoglycanopathies are a group of recessive limb-girdle muscular dystrophies, characterized by progressive muscle weakness. Sarcoglycan deficiency produces instability of the sarcolemma during muscle contraction, leading to continuous muscle fiber injury eventually producing fiber loss and replacement by fibro-adipose tissue. Therapeutic strategies aiming to reduce fibro-adipose expansion could be effective in muscular dystrophies. We report the positive effect of nintedanib in a murine model of alpha-sarcoglycanopathy. We treated 14 Sgca-/- mice, six weeks old, with nintedanib 50 mg/kg every 12 h for 10 weeks and compared muscle function and histology with 14 Sgca-/- mice treated with vehicle and six wild-type littermate mice. Muscle function was assessed using a treadmill and grip strength. A cardiac evaluation was performed by echocardiography and histological study. Structural analysis of the muscles, including a detailed study of the fibrotic and inflammatory processes, was performed using conventional staining and immunofluorescence. In addition, proteomics and transcriptomics studies were carried out. Nintedanib was well tolerated by the animals treated, although we observed weight loss. Sgca-/- mice treated with nintedanib covered a longer distance on the treadmill, compared with non-treated Sgca-/- mice, and showed higher strength in the grip test. Moreover, nintedanib improved the muscle architecture of treated mice, reducing the degenerative area and the fibrotic reaction that was associated with a reversion of the cytokine expression profile. Nintedanib improved muscle function and muscle architecture by reducing muscle fibrosis and degeneration and reverting the chronic inflammatory environment suggesting that it could be a useful therapy for patients with alpha-sarcoglycanopathy.
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ACTN2 encodes alpha-actinin-2, a protein expressed in human cardiac and skeletal muscle. The protein, located in the sarcomere Z-disk, functions as a link between the anti-parallel actin filaments. This important structural protein also binds N-terminal titins, and thus contributes to sarcomere stability. Previously, ACTN2 mutations have been solely associated with cardiomyopathy, without skeletal muscle disease. Recently, however, ACTN2 mutations have been associated with novel congenital and distal myopathy. Previously reported variants are in varying locations across the gene, but the potential clustering effect of pathogenic locations is not clearly understood. Further, the genotype-phenotype correlations of these variants remain unclear. Here we review the previously reported ACTN2-related molecular and clinical findings and present an additional variant, c.1840-2A>T, that further expands the mutation and phenotypic spectrum. Our results show a growing body of clinical, genetic, and functional evidence, which underlines the central role of ACTN2 in the muscle tissue and myopathy. However, limited segregation and functional data are available to support the pathogenicity of most previously reported missense variants and clear-cut genotype-phenotype correlations are currently only demonstrated for some ACTN2-related myopathies.
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Actinina , Corazón , Humanos , Actinina/genética , Actinina/química , Mutación , Músculo Esquelético/metabolismo , Mutación MissenseRESUMEN
Desmin (DES) is the main intermediate muscle filament that connects myofibrils individually and with the nucleus, sarcolemma, and organelles. Pathogenic variants of DES cause desminopathy, a disorder affecting the heart and skeletal muscles. We aimed to analyze the clinical features, morphology, and distribution of desmin aggregates in skeletal muscle biopsies of patients with desminopathy and to correlate these findings with the type and location of disease-causing DES variants. This retrospective study included 30 patients from 20 families with molecularly confirmed desminopathy from 2 neuromuscular referral centers. We identified 2 distinct patterns of desmin aggregates: well-demarcated subsarcolemmal aggregates and diffuse aggregates with poorly delimited borders. Pathogenic variants located in the 1B segment and the tail domain of the desmin molecule are more likely to present with early-onset cardiomyopathy compared to patients with variants in other segments. All patients with mutations in the 1B segment had well-demarcated subsarcolemmal aggregates, but none of the patients with variants in other desmin segments showed such histological features. We suggest that variants located in the 1B segment lead to well-shaped subsarcolemmal desmin aggregation and cause disease with more frequent cardiac manifestations. These findings will facilitate early identification of patients with potentially severe cardiac syndromes.
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Cardiomiopatías , Cardiomiopatías/genética , Cardiomiopatías/patología , Desmina/genética , Humanos , Músculo Esquelético/patología , Mutación/genética , Fenotipo , Estudios RetrospectivosRESUMEN
BACKGROUND: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. METHODS: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. RESULTS: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death. CONCLUSION: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.
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The aim of this study is to evaluate the long-term efficacy, safety, and impact on immunoglobulin G (IgG) levels of rituximab in patients with myasthenia gravis (MG). A retrospective, observational study of drug-refractory MG patients treated with rituximab was done. The MG Foundation of America postintervention status (MGFA-PIS) was used to evaluate clinical response. Serum IgG levels were determined at baseline and post-treatment. Hypogammaglobulinemia was defined as IgG<7g/L. Thirty patients were included, 12 with anti-MuSK and 18 with anti-AChR antibodies. Mean (SD) follow-up was 85.5 (48) months. All 12 MuSK+ patients but only six (33%) AChR+ patients achieved minimal manifestations or remission (p<0.01). Nine severe infections were observed in five patients (17%). One patient was diagnosed with progressive multifocal leukoencephalopathy. At baseline, two patients (2/24; 8%) had hypogammaglobulinemia. During follow-up, hypogammaglobulinemia was observed in 60% (3/5) of patients who developed an infection and in 33% (7/21) who did not. Two of these patients died of infection-related complications. This study supports the effectiveness of rituximab in patients with MG, especially those with anti-MuSK antibodies. Severe infections may appear after rituximab treatment and hypogammaglobulinemia might play a role on it. A standard protocol would be needed to closely monitor IgG levels in MG patients treated with rituximab.
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Agammaglobulinemia , Miastenia Gravis , Agammaglobulinemia/inducido químicamente , Agammaglobulinemia/tratamiento farmacológico , Humanos , Inmunoglobulina G/uso terapéutico , Factores Inmunológicos/efectos adversos , Receptores Colinérgicos , Estudios Retrospectivos , Rituximab/efectos adversosAsunto(s)
Miopatías Nemalínicas , Adulto , Homocigoto , Humanos , Músculo Esquelético , Miopatías Nemalínicas/genética , Troponina TRESUMEN
BACKGROUND AND OBJECTIVES: Evidence regarding the safety and efficacy of messenger RNA (mRNA) vaccines in patients with myasthenia gravis (MG) after immunosuppressive therapies is scarce. Our aim is to determine whether the mRNA-1273 vaccine is safe and able to induce humoral and cellular responses in patients with MG. METHODS: We performed an observational, longitudinal, prospective study including 100 patients with MG of a referral center for MG in our country, conducted from April 2021 to November 2021 during the vaccination campaign. The mRNA-1273 vaccine was scheduled for all participants. Blood samples were collected before vaccination and 3 months after a second dose. Clinical changes in MG were measured using the MG activities of daily life score at baseline and 1 week after the first and second doses. A surveillance of all symptoms of coronavirus disease 2019 (COVID-19) was conducted throughout the study. Humoral and cellular immune responses after vaccination were assessed using a spike-antibody ELISA and interferon gamma release assay in plasma. The primary outcomes were clinically significant changes in MG symptoms after vaccination, adverse events (AEs), and seroconversion and T-cell immune response rates. RESULTS: Ninety-nine patients completed the full vaccination schedule, and 98 had 2 blood samples taken. A statistically significant worsening of symptoms was identified after the first and second doses of the mRNA-1273 vaccine, but this was not clinically relevant. Mild AEs occurred in 14 patients after the first dose and in 21 patients after the second dose. Eighty-seven patients developed a humoral response and 72 patients showed a T-cell response after vaccination. A combined therapy with prednisone and other immunosuppressive drugs correlated with a lower seroconversion ratio (OR = 5.97, 95% CI 1.46-24.09, p = 0.015) and a lower T-cell response ratio (OR = 2.83, 95% CI 1.13-7.13, p = 0.024). DISCUSSION: Our findings indicate that the mRNA vaccination against COVID-19 is safe in patients with MG and show no negative impact on the disease course. Patients achieved high humoral and cellular immune response levels. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that patients with MG receiving the mRNA-1273 vaccine did not show clinical worsening after vaccination and that most of the patients achieved high cellular or immune response levels.