[A case of myasthenia gravis with coexistence of anti-acetylcholine receptor antibodies and anti-P/Q-type VGCC antibodies].

A 79-year-old woman who presented ptosis and dysphagia were admitted to our hospital. Anti-acetylcholine receptor antibodies and anti-P/Q-type VGCC antibodies were both positive. Electrophysiological examination showed postsynaptic pattern which supported myasthenia gravis. She did not meet the diagnostic criteria for Lambert-Eaton myasthenic syndrome (LEMS). In cases which these antibodies coexist, careful electrophysiological evaluation is required for the diagnosis. In addition, although anti-P/Q-type VGCC antibodies have been specific to LEMS, patients with these antibodies represent various symptoms other than LEMS. Low and middle titer of the antibodies may be not specific to LEMS.

Starting eculizumab as rescue therapy in refractory myasthenic crisis.

INTRODUCTION: Myasthenia gravis is a long-lasting autoimmune neuromuscular disease caused by antibodies attacking the neuromuscular junction, which can result in muscle weakness, fatigue, and respiratory failure in severe cases. Myasthenic crisis is a life-threatening event that requires hospitalization and treatments with intravenous immunoglobulin or plasma exchange. We reported the case of an AChR-Ab-positive myasthenia gravis patient with refractory myasthenic crisis, in which starting eculizumab as rescue therapy led to a complete resolution of the acute neuromuscular condition. CASE PRESENTATION: A 74-year-old man diagnosed with myasthenia gravis. ACh-receptor antibodies positivity comes to our observation for a recrudescence of symptoms, unresponsive to conventional rescue therapies. Due to the clinical worsening over the following weeks, the patient was admitted to intensive care unit, where he underwent therapy with eculizumab. About 5 days after the treatment, there was a significant and complete recovery of clinical condition with weaning-off from invasive ventilation and discharge to outpatient regimen, with reduction of steroid intake and biweekly maintenance with eculizumab. DISCUSSION: Eculizumab, a humanized monoclonal antibody that inhibits complement activation, is now approved as treatment for refractory generalized myasthenia gravis with anti-AChR antibodies. The use of eculizumab in myasthenic crisis is still investigational, but this case report suggests that it may be a promising treatment option for patients with severe clinical condition. Ongoing clinical trials will be needed to further evaluate the safety and efficacy of eculizumab in myasthenic crisis.

Complement activation profiles in anti-acetylcholine receptor positive myasthenia gravis.

BACKGROUND AND PURPOSE: Complement component 5 (C5) targeting therapies are clinically beneficial in patients with acetylcholine receptor antibody+ (AChR-Ab+ ) generalized myasthenia gravis (MG). That clearly implicates antibody-mediated complement activation in MG pathogenesis. Here, classical and alternative complement pathways were profiled in patients from different MG subgroups. METHODS: In a case-control study, concentrations of C3a, C5a and sC5b9 were simultaneously quantified, indicating general activation of the complement system, whether via the classical and lectin pathways (C4a) or the alternative pathway (factors Ba and Bb) in MG patients with AChR or muscle-specific kinase antibodies (MuSK-Abs) or seronegative MG compared to healthy donors. RESULTS: Treatment-naïve patients with AChR-Ab+ MG showed substantially increased plasma levels of cleaved complement components, indicating activation of the classical and alternative as well as the terminal complement pathways. These increases were still present in a validation cohort of AChR-Ab+ patients under standard immunosuppressive therapies; notably, they were not evident in patients with MuSK-Abs or seronegative MG. Neither clinical severity parameters (at the time of sampling or 1 year later) nor anti-AChR titres correlated significantly with activated complement levels. CONCLUSIONS: Markers indicative of complement activation are prominently increased in patients with AChR-Ab MG despite standard immunosuppressive therapies. Complement inhibition proximal to C5 cleavage should be explored for its potential therapeutic benefits in AChR-Ab+ MG.

Metformin inhibits the pathogenic functions of AChR-specific B and Th17 cells by targeting miR-146a.

Myasthenia gravis (MG) is characterized by fatigable skeletal muscle weakness with a fluctuating and unpredictable disease course and is caused by circulating autoantibodies and pathological T helper cells. Regulation of B-cell function and the T-cell network may be a potential therapeutic strategy for MG. MicroRNAs (miRNAs) have emerged as potential biomarkers in immune disorders due to their critical roles in various immune cells and multiple inflammatory diseases. Aberrant miR-146a signal activation has been reported in autoimmune diseases, but a detailed exploration of the relationship between miR-146a and MG is still necessary. Using an experimental autoimmune myasthenia gravis (EAMG) rat model, we observed that miR-146a was highly expressed in the spleen but expressed at low levels in the thymus and lymph nodes in EAMG rats. Additionally, miR-146a expression in T and B cells was also quite different. EAMG-specific Th17 and Treg cells had lower miR-146a levels, while EAMG-specific B cells had higher miR-146a levels, indicating that targeted intervention against miR-146a might have diametrically opposite effects. Metformin, a drug that was recently demonstrated to alleviate EAMG, may rescue the functions of both Th17 cells and B cells by reversing the expression of miR-146a. We also investigated the downstream target genes of miR-146a in both T and B cells using bioinformatics screening and qPCR. Taken together, our study identifies a complex role of miR-146a in the EAMG rat model, suggesting that more caution should be paid in targeting miR-146a for the treatment of MG.

Optimization of the cut-offs in acetylcholine receptor antibodies and diagnostic performance in myasthenia gravis patients.

OBJECTIVE: This study aims to establish an optimization procedure to define the cut-offs of quantitative assays for acetylcholine receptor antibody (AChRAb), evaluate their diagnostic performance in myasthenia gravis (MG), and explore the association with clinical features. METHODS: Samples from a representative cohort of 77 MG patients, 80 healthy controls (HC) and 80 other autoimmune diseases (OAD) patients were tested using competitive inhibition ELISA and RIA. Raw values (OD and cpm) and processed values (inhibition rate, binding rate and concentration) were used to define the cut-offs with statistical methods, a rough method, and receiver operating characteristic (ROC) curve. Optimal cut-offs were selected by comparing false positive rates in HC and OAD individuals. The diagnostic performance was evaluated in whole MG cohort and subgroups. Agreement between ELISA and RIA for AChRAb positivity were examined with Kappa test and McNemar test. Clinical association with AChRAb was explored by comparison among subgroups and with Spearman rank correlation. RESULTS: The optimal cut-offs for AChRAb positivity were determined as OD ≤ 1.79 for ELISA and cpm ≥ 1234.12 for RIA, which derived from statistical method and performed better than those derived from ROC curves. The sensitivity and specificity were 74.03%, 100% for ELISA, and 74.03%, 99.37% for RIA. There was good agreement between ELISA and RIA for AChRAb positivity in whole cohort and subgroups (weighted к ≥ 0.71, p < 0.01; McNemar test, p > 0.05). Levels of AChRAb were different in MG subgroups (p < 0.01). Correlation between Quantitative Myasthenia Gravis scores and AChRAb levels was moderate for ELISA and RIA (rs = -0.60 and 0.57, p < 0.01). CONCLUSION: The raw testing values of ELISA and RIA were found as optimal quantitative measures of AChRAb levels. There are good agreements on diagnostic performance between two assays. Quantitative values are more informative than positivity in association with clinical features.

How to manage MuSK antibody-positive myasthenic crisis during pregnancy?

Myasthenia gravis (MG) is an autoimmune disease that is characterised by the formation of antibodies against acetylcholine receptors in the postsynaptic membrane of the neuromuscular junction. The course of the disease cannot be predicted during pregnancy. A subtype of MG with positive muscle-specific receptor tyrosine kinase (anti-MuSK) antibodies exhibits more localised clinical characteristics and a poor response to treatment compared with the disease subtype that involves positivity for acetylcholine receptor antibodies. Myasthenic crisis is more frequently observed in anti-MuSK-positive myasthenia patients. Anti-MuSK-positive myasthenic crisis management is very difficult and a risky situation during pregnancy. The reported case was 30 years old, female, 9 weeks pregnant and musk antibody positive. She stopped her treatment without asking her doctor because she was planning pregnancy in the 6-month period before her hospitalization. She was intubated for a long time in the intensive care unit due to myasthenic crisis and was very resistant to treatment. During this period, her pregnancy was terminated due to fetal anomaly. Plasmapheresis, IVIg and immunosuppressive treatments were applied. Our patient was discharged after a period of about 10 weeks. We share our treatment management.

Subunit-specific autoantibodies in autoimmune autonomic ganglionopathy.

Autoimmune Autonomic Ganglionopathy (AAG) is a disorder that causes autonomic failure and is associated with alpha3-ganglionic acetylcholine-receptor (gnACHR) antibodies. Assays that detect antibodies to whole gnACHR or subunits are available. We compared in-house subunit-specific immunoassays using bacterially-expressed alpha3 and beta4 subunits against an immunomodulation assay to detect antibodies in patients with AAG or control groups in a novel 2-step clinical-characteristic unblinding protocol. Only 1/8 patients with seropositive-AAG had subunit-specific antibodies, with sensitivity, specificity, false-negative and positive rates of 12.5, 85.2, 78.6 and 13.4% respectively. Subunit-specific antibody-derived false-positive results can lead to misdiagnosis, as autonomic failure is not specific to AAG.

Comparison of fixed cell-based assay to radioimmunoprecipitation assay for acetylcholine receptor antibody detection in myasthenia gravis.

OBJECTIVE: To compare specificity and sensitivity of a commercially available fixed cell-based assay (F-CBA) to radioimmunoprecipitation assay (RIPA) for acetylcholine receptor antibody (anti-AChR) detection in myasthenia gravis (MG). METHODS: In this retrospective diagnostic cohort study we reviewed the clinical information of suspected MG patients evaluated at the London Health Sciences Centre MG clinic who had anti-AChR RIPA and then F-CBA performed, in order to classify them as MG or non-MG. Classification of each patient as anti-AChR F-CBA-negative/positive, RIPA-negative/positive, and MG/non-MG permitted specificity and sensitivity calculations for each assay. RESULTS: Six-hundred-eighteen patients were included in study analysis. The median patient age at time of sample collection was 45.8 years (range: 7.5-87.5 years) and 312/618 (50.5%) were female. Of 618 patients, 395 (63.9%) were classified as MG. Specificity of both F-CBA and RIPA was excellent (99.6% vs. 100%, P > 0.99). One F-CBA-positive patient was classified as non-MG, although in retrospect ocular MG with functional overlay was challenging to exclude. Sensitivity of F-CBA was significantly higher than RIPA (76.7% vs. 72.7%, P = 0.002). Overall, 20/97 (21%) otherwise seronegative MG (SNMG) patients after RIPA evaluation had anti-AChR detected by F-CBA. CONCLUSIONS: In our study anti-AChR F-CBA and RIPA both had excellent specificity, while F-CBA had 4% higher sensitivity for MG and detected anti-AChR in 21% of SNMG patients. Our findings indicate that F-CBA is a viable alternative to RIPA for anti-AChR detection. Prospective studies comparing F-CBA, RIPA and L-CBA are needed to determine optimal anti-AChR testing algorithms in MG.

Serum irisin levels in patients with myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is an autoimmune disorder whose main symptoms are muscle weakness and fatigue. Irisin is a novel skeletal muscle-derived myokine participating in several physiological and pathological processes. The initial objective of the project was to explore serum levels of irisin in patients with MG, as well as its correlation with disease severity. METHODS: We retrospectively evaluated serum levels of irisin in 77 MG patients and 57 healthy controls (HCs) by enzyme-linked immunosorbent assay. Further, clinical parameters were measured properly. RESULTS: Serum irisin levels were significantly elevated in MG patients compared with HCs (p < 0.001). Furthermore, serum irisin levels were associated with the myasthenia gravis activities of daily living score in ocular myasthenia gravis (OMG) patients (r = 0.476, p = 0.004), but there was no relationship to be considered of any relevant value in generalized myasthenia gravis (GMG) patients. Acetylcholine receptor antibody-positive MG patients had higher serum irisin levels compared with HCs. Thymoma, endotracheal intubation, or intensive care unit treatments subsequently were not found to have effect on serum levels of irisin, but tendencies of increase were observed in negative ones. CONCLUSIONS: Serum irisin levels were elevated in patients with MG, suggesting its possible involvement in MG. And irisin is expected to be a signal to evaluate the activities of daily living of OMG patients, while its effect needs further study.

Immunoadsorption apheresis versus intravenous immunoglobulin therapy for exacerbation of myasthenia gravis.

Immunoadsorption apheresis (IA) or intravenous immunoglobulin (IVIg) is used to treat exacerbation of myasthenia gravis (MG). This study aimed to compare the efficacy and safety between IA and IVIg for MG patients with anti-acetylcholine receptor (AChR) antibodies. We retrospectively studied 19 AChR antibody-positive generalized MG patients who underwent IA (n = 9) or IVIg treatment (n = 10). We reviewed the MG activities of daily living profile (MG-ADL) scores at baseline, 1 and 3 months after the treatment. Adverse events during the treatment period were also reviewed. The MG-ADL scores showed significantly greater improvement from the baseline in the IA group than in the IVIg group (1 month: -7 vs -3, P = .035; 3 months -9 vs -2.5, P = .016). An adverse event that led to the discontinuation of the treatment was observed in only one patient in the IVIg group (anaphylactic reaction). Our data suggest that the IA treatment is safe and more efficacious than the IVIg treatment for aggravation of anti-AChR-positive MG. Larger prospective studies are required to confirm the finding.

Effect of Buzhong Yiqi decoction on anti-acetylcholine receptor antibody and clinical status in juvenile ocular myasthenia gravis.

ABSTRACT: Ocular myasthenia gravis (MG) is the mainly widespread type of MG among juveniles. Buzhong Yiqi decoction (BZ) is a well-known traditional Chinese medicine prescription for treating MG. It has rarely been discussed whether the concentration of anti-acetylcholine receptor (AChR) antibodies is related to the clinical status of juvenile ocular myasthenia gravis (JOMG) treated with BZ.The patients with JOMG who had more than once AChR-antibody (ab) test and treated with BZ were retrospectively identified from June 2013 to January 2020 in the first hospital in Shijiazhuang. The presence or absence of ocular symptoms was used to grade the effectiveness of treatment. Generalized estimating equations logistic regression analysis was used to evaluate the effect of AChR ab concentration on the clinical status of MG.A total of 549 AChR-ab tests were performed in 135 patients, and the corresponding clinical status was recorded. One hundred two patients received treatment with BZ only and 33 combined with immunosuppressive drugs. In the group receiving only BZ treatment, the anti-acetylcholine receptor ab concentration was positively correlated with the clinical score after treatment.The results suggest that BZ could affect the AChR-ab. Repeated AChR-ab assays can provide information about the clinical status. For JOMG patients who only receive Buzhong Yiqi Decoction treatment, this can support treatment decisions.

The role of the cholinergic anti-inflammatory pathway in autoimmune rheumatic diseases.

The cholinergic anti-inflammatory pathway (CAP) is a classic neuroimmune pathway, consisting of the vagus nerve, acetylcholine (ACh)-the pivotal neurotransmitter of the vagus nerve-and its receptors. This pathway can activate and regulate the activities of immune cells, inhibit cell proliferation and differentiation, as well as suppress cytokine release, thereby playing an anti-inflammatory role, and widely involved in the occurrence and development of various diseases; recent studies have demonstrated that the CAP may be a new target for the treatment of autoimmune rheumatic diseases. In this review, we will summarize the latest progress with the view of figuring out the role of the cholinergic pathway and how it interacts with inflammatory reactions in several autoimmune rheumatic diseases, and many advances are results from a wide range of experiments performed in vitro and in vivo.

MuSK not MNGIE: Atypical MuSK-antibody myasthenia presenting as a genetic disorder.

Myasthenia gravis is a treatable autoimmune disease caused by autoantibodies directed against membrane proteins at the neuromuscular junction. While acetylcholine receptor antibodies are most common, a minority of patients have antibodies directed against muscle-specific kinase (MuSK-antibody). Differentiating features often include subacute onset and rapid progression of bulbar, respiratory and neck extensor muscles, with sparing of distal appendicular muscles, most commonly in middle-aged females. Here we present an atypical presentation of MuSK-antibody myasthenic syndrome in a young male consisting of a gradual-onset, insidiously-progressive, non-fatigable and non-fluctuating ocular, bulbar and oesophageal weakness, with a normal frontalis single fibre EMG. This case clinically resembled a mitochondrial myopathy (Mitochondrial Neurogastrointestinal Encephalopathy-MNGIE) with a poor prognosis. Because of the atypical presentation, MuSK antibodies were identified very late in the disease course, at which point the patient responded very well to immunotherapy. We report an unusual presentation of an uncommon but treatable condition, illustrating significant phenotypic heterogeneity possible in MuSK-antibody myasthenic syndrome.

Laboratory Investigation of Hybrid IgG4 k/λ in MuSK Positive Myasthenia Gravis.

Myasthenia gravis with antibodies (Abs) against the muscle-specific tyrosine kinase (MuSK) is a rare autoimmune disorder (AD) of the neuromuscular junction (NMJ) and represents a prototype of AD with proven IgG4-mediated pathogenicity. Thanks to the mechanism of Fab-arm exchange (FAE) occurring in vivo, resulting MuSK IgG4 k/λ Abs increase their interference on NMJ and pathogenicity. The characterization of hybrid MuSK IgG4 as a biomarker for MG management is poorly investigated. Here, we evaluated total IgG4, hybrid IgG4 k/λ, and the hybrid/total ratio in 14 MuSK-MG sera in comparison with 24 from MG with Abs against acetylcholine receptor (AChR) that represents the not IgG4-mediated MG form. In both subtypes of MG, we found that the hybrid/total ratio reflects distribution reported in normal individuals; instead, when we correlated the hybrid/total ratio with specific immune-reactivity we found a positive correlation only with anti-MuSK titer, with a progressive increase of hybrid/total mean values with increasing disease severity, indirectly confirming that most part of hybrid IgG4 molecules are engaged in the anti-MuSK pathogenetic immune-reactivity. Further analysis is necessary to strengthen the significance of this less unknown biomarker, but we retain it is full of a diagnostic-prognostic powerful potential for the management of MuSK-MG.

Differential Expression of miRNA in the Peripheral Blood Mononuclear Cells in Myasthenia Gravis with Muscle-Specific Receptor Tyrosine Kinase Antibodies.

To determine if differential profile of miRNAs in peripheral blood mononuclear cells (PBMCs) could be identified in muscle-specific receptor tyrosine kinase antibody positive myasthenia gravis (MuSK-MG) and linked to disease stage, a case-control method was used to compare the difference in miRNA expression profiles of PBMCs using next generation sequencing (NGS) in MuSK-MG patients and healthy controls (HCs). Six significant miRNAs from the discovery set were then validated using RT-qPCR in 11 MuSK-MG patients and 10 HCs. A unique miRNA prediction algorithm was used to predict the target genes of differentially expressed miRNAs and a network of miRNA gene pathways. Compared with HCs, 101 differentially expressed miRNAs were screened in MuSK-MG, of which 5 miRNAs were upregulated, and 96 miRNAs were downregulated. The top six differentially expressed molecules were selected for verification; four of them (miR-340-5p, miR-106b-5p, miR-27a-3p, and miR-15a-3p) were significantly different. The network analysis of miRNA gene pathways revealed that differentially expressed miRNAs were involved in a complex set of biological processes. Clinically, the four miRNAs that were validated are not correlated to MuSK antibody titers and quantitative myasthenia gravis score. Four miRNAs that were validated in this study have specificity to distinguish MuSK-MG from HCs.

Acquired Idiopathic Generalized Anhidrosis (AIGA) and Its Complications: Implications for AIGA as an Autoimmune Disease.

Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder in which systemic anhidrosis/hypohidrosis occurs without causative dermatological, metabolic or neurological disorder. Most cases of AIGA have been reported in Asia, especially in Japan, but there have been only a few reports in Europe and the United States. Severe AIGA may result in heatstroke and can reduce quality of life due to restriction of exercise and outdoor works. AIGA is often accompanied by cholinergic urticaria (CholU), and it is thought that AIGA and CholU with anhidrosis/hypohidrosis belong to the same spectrum of the disease. However, the pathophysiology of AIGA has not yet been clarified. Decreased expression of cholinergic receptor M3 on the epithelial cells of eccrine sweat glands is often accompanied by T cell infiltration around eccrine apparatus, suggesting an immunological mechanism of disordered perspiration. AIGA is occasionally associated with various complications indicative of autoimmune disorders. The association of autoimmune complications further suggests that AIGA is an autoimmune disorder. Studies on complications may lead to a better understanding of the pathophysiology of AIGA.

Evaluation of commercially available antibodies and fluorescent conotoxins for the detection of surface ganglionic acetylcholine receptor on the neuroblastoma cell line, IMR-32 by flow cytometry.

Commercially available antibodies that bind to the human muscle acetylcholine receptor (ACHR) have been validated previously for flow cytometric use (Keefe et al., 2009; Leite et al., 2008; Lozier et al., 2015). Despite a multitude of commercially available antibodies to other nicotinic ACHRs, validation in a wide variety of immunoassay formats is lacking; when studied, a large proportion of these antibodies have been deemed not fit for most research purposes (Garg and Loring, 2017). We have recently described a flow cytometric immunomodulation assay for the diagnosis of Autoimmune Autonomic Ganglionopathy (AAG) (Urriola et al., 2021) that utilises the monoclonal antibody mab35(Urriola et al., 2021) which is specific for ganglionic ACHR (gnACHR) that contain α3 subunits (Vernino et al., 1998). Other fluorescent ligands for α3-gnACHR have not been validated for flow cytometric use. We investigated 7 commercially sourced antibodies and 3 synthetic fluorescent novel conotoxins purported to specifically bind to the extracellular domains of the gnACHR, and compared the results to staining by mab35, using flow cytometry with the neuroblastoma cell line IMR-32. We also evaluated the degree of non-specific binding by depleting the cell membrane of the relevant acetylcholine receptor with a pre-incubation step involving the serum from a patient with Autoimmune Autonomic Ganglionopathy containing pathogenic antibodies to the ganglionic acetylcholine receptor. None of the assessed conotoxins, and only one antibody (mab35) was found to perform adequately in flow cytometric staining of the native ganglionic acetylcholine receptor.

Age at sampling and sex distribution of AChRAb vs. MuSKAb myasthenia gravis in a large Greek population.

OBJECTIVE: Myasthenia gravis (MG) is a typical B-cell-mediated neuromuscular junction disease that can be classified into seropositive and seronegative subtypes. Association of patients' age at sampling and sex with the two major seropositive MG subcategories, i.e., MGs linked to antibodies directed against the acetylcholine receptor (AChRAb) and against the muscle-specific kinase (MuSKAb), has not been compared in a large population. METHODS: We performed a retrospective analysis of samples from patients with MG in Greece who underwent neurochemical diagnostic evaluation between January 2, 2013, and August 31, 2016. RESULTS: Overall, 1620 adult (623 male and 997 female patients; male-to-female ratio = 0.62) and 51 pediatric patients were found to be seropositive for MG. The distributions in both male and female patients were bimodal in the total and AChRAb MG cases but not in the total MuSKAb MG cases. Significant differences in the age at sampling distribution between the male and female adult patients were observed only in the AChRAb MG subtype. Significant differences between the AChRAb and MuSKAb MG categories were noted in the mean age values (60.10 and 51.49 years, respectively, for female and 65.69 and 56.19 years, respectively, for male adult patients). CONCLUSION: Our findings confirm an uneven profile of age at sampling and sex between the AChRAb and MuSKAb MG cases in a large population. Future mechanistic studies can elucidate the cause of these differences. Moreover, clinical studies can explore how such differences can affect MG treatment and prognosis.

Acetylcholine receptor antibodies in a patient with sensory neuropathy.

Antibodies to acetylcholine receptor (AChR) are detected in the vast majority of patients with generalized myasthenia gravis (MG) and are rarely detected in significant titer in other autoimmune diseases. We report a patient with an axonal predominately sensory neuropathy for over 12 years with persistent binding and modulating AChR antibodies as well as striational muscle antibodies with no evidence of MG or any neoplastic disease.

Whole-exome sequencing and human leukocyte antigen analysis in familial myasthenia gravis with thymoma: Case report and literature review.

Myasthenia gravis (MG) is an autoimmune disease characterized by impaired neurotransmission at the neuromuscular junction. MG is generally non-inherited but is rarely inherited. Here, we report two patients with MG in the same pedigree: a 62-year-old Japanese man and his 46-year-old daughter who were positive for anti-acetylcholine receptor antibodies and had thymoma. We performed whole-exome sequencing (WES) and human leukocyte antigen (HLA) analyses to investigate the genetic contribution to familial onset. WES analysis of both patients showed no known variations in candidate genes for familial MG, and HLA analysis failed to detect HLA haplotypes seen in early-onset and late-onset MG. These findings suggest the presence of an unknown genetic background. Previous genetic studies on familial MG have identified ENOX1 and IFNGR1 as candidate genes in patients without thymoma, whereas no studies have identified candidate genes in patients with thymoma. To explore causative genes, it may be necessary to consider whether the genetic background differs between patients with and without thymoma in familial autoimmune MG.