Adult-onset Myasthenia Gravis Research Articles

Comparison of anti-acetylcholine receptor profiles between Chinese cases of adult- and juvenile-onset myasthenia gravis using cell-based assays

ObjectiveJuvenile-onset myasthenia gravis (JOMG) is a unique clinical subtype in China, featured by a higher prevalence of ocular myasthenia gravis (OMG), higher seronegativity of acetylcholine receptor (AChR) antibodies, and better prognosis than that in adult-onset myasthenia gravis (AOMG). We previously identified low-affinity AChR antibodies in Chinese JOMG patients using cell-based assays (CBAs), indicating a predominantly AChR antibody-positive profile. Here, we further screened AChR antibodies in both Chinese AOMG and JOMG patients by CBAs. Materials and methodsWe recruited patients with MG who had not received prednisone or immunosuppressive therapies between June 2015 and June 2019, and divided them into AOMG and JOMG subgroups according to their ages at the time of recruitment. Clinical information and blood samples were collected. Serum AChR antibodies were detected by CBAs in HEK293T cells expressing clustered adult and fetal AChRs, as well as by enzyme-linked immunosorbent assays (ELISAs). Differences in AChR antibody profiles between AOMG and JOMG subgroups were determined. ResultsA total of 239 patients with MG were enrolled in the present study, including 121 AOMG and 118 JOMG patients. Based on ELISAs, 74.4% of AOMG (90/121) and 59.3% of JOMG (70/118) patients were anti-AChR positive (p = 0.02). However, CBAs yielded equal anti-AChR positivities (p = 0.64), as indicated by 80.2% of AOMG patients (97/121) and 77.1% of JOMG patients (91/118). Furthermore, among AOMG patients, 67.8% (82/121) were positive for both adult and fetal AChR antibodies, 5.8% (7/121) were positive for only adult AChR antibodies, and 6.6% (8/121) were positive for only fetal AChR antibodies, while these rates were 50.8% (60/118), 21.2% (25/118), and 5.1% (6/118), respectively, in JOMG cohorts (p < 0.01). Twenty-nine AOMG patients and 10 JOMG patients underwent IgG subclassification of AChR antibodies, which were all confirmed to be predominantly IgG1. ConclusionsThe positive rates of AChR antibodies did not differ between Chinese AOMG and JOMG patients, as revealed by CBAs. Furthermore, the screened AChR antibodies were predominantly IgG1 in both AOMG and JOMG patients.

Cell-Based Versus Enzyme-Linked Immunosorbent Assay for the Detection of Acetylcholine Receptor Antibodies in Chinese Juvenile Myasthenia Gravis

BackgroundPatients in China with juvenile-onset myasthenia gravis present early, with a high prevalence of purely ocular symptoms, spontaneous remission rates, and low antibody seropositivity. Antibody detection using a cell-based assay has been reported to increase the diagnostic sensitivity in adult-onset myasthenia gravis. However, this method in patients with juvenile-onset myasthenia gravis has not been investigated. MethodsPatients with juvenile-onset myasthenia gravis who had not received prednisone or immunosuppressive therapy were recruited between June 2015 and April 2018 at the Huashan Hospital. Clinical information was collected. Serum anti-acetylcholine receptor antibodies were detected via cell-based assay with HEK293T cells expressing acetylcholine receptor subunits and rapsyn. Additionally, the IgG antibody subclass was identified. ResultsEighty-two patients with juvenile-onset myasthenia gravis were enrolled in the current study. Among them, 48 patients were anti-acetylcholine receptor positive (58.5%) and 34 were seronegative (41.5%), as assessed via enzyme-linked immunosorbent assay. Cell-based assay yielded 63 positive subjects (76.8%) and 19 seronegative subjects (23.2%). All the enzyme-linked immunosorbent assay-positive samples showed robust immunofluorescence in the cell-based assay, whereas 15 of 34 enzyme-linked immunosorbent assay-negative patients (44.1%) were found to have low-affinity acetylcholine receptor antibodies. Among all the cell-based assay-positive patients, 41 were positive for both adult and fetal acetylcholine receptor antibodies (50.0%), 18 were found positive for only adult acetylcholine receptor antibodies (21.9%), and four were found to possess only fetal acetylcholine receptor antibodies (4.9%). Fifteen antibody-positive samples underwent subclassification and were confirmed to be IgG1 subclass predominant (n = 15, including eight adult and fetal acetylcholine receptor antibody positive, five only adult acetylcholine receptor antibody positive, and two only fetal acetylcholine receptor antibody positive). There were no significant differences in clinical features among patients with different antibody profiles. ConclusionsThe cell-based assay showed increased sensitivity in acetylcholine receptor antibody detection in Chinese patients with juvenile-onset myasthenia gravis, and most cases of Chinese juvenile-onset myasthenia gravis are still acetylcholine receptor autoantibody mediated. Furthermore, the antibodies detected are predominately of the IgG1 subclass.

HLA typing using next-generation sequencing for Chinese juvenile- and adult-onset myasthenia gravis patients

To compare HLA typing between juvenile- and adult-onset myasthenia gravis (MG), we enrolled 101 children (age ≤12 years) and 168 adults (age ≥20 years) with MG. We excluded patients with histories of thymoma, thyroid disease, or other autoimmune disease. We selected 41 seronegative juvenile-onset patients with ocular symptoms only, and 41 seropositive adult-onset patients with generalized symptoms. We used next-generation sequencing for typing and analysis of HLA genes (Loci: A, B, C, DPA1, DPB1, DQA1, DQB1 and DRB1). Haplotypes HLA-A∗02:07:01-B∗46:01:01-C∗01:02:01-DQA1∗01:01:01-DQB1∗03:03:02-DRB1∗09:01:02, HLA-A∗11:01:01, HLA-A∗24:02:01, and HLA-DPA1∗02:02:02 were found to be related to juvenile-onset MG and HLA-A∗01:01:01, HLA-A∗02:03:01, HLA-C∗03:04:01, and HLA-DQB1∗06:02:01 to adult-onset MG. Therefore, our findings suggested that HLA typing might determine the heterogeneity between AChR-Ab negative juvenile-onset and AChR-Ab positive adult-onset Chinese MG patients.

Survival and mortality of adult-onset myasthenia gravis in the population of Belgrade, Serbia.

The objective of this study was to estimate mortality and survival in a large cohort of myasthenia gravis (MG) patients from Belgrade, Serbia, during the period 1979-2008. Data for all patients with MG were collected from hospital records and the Belgrade MG Registry. Within the 30-year study period, death occurred in 107 (20%) of 562 patients with MG, with MG-related fatality below 2%. The average MG mortality rate was 1.76 per 1,000,000 population (1.26/1,000,000 women, 2.45/1,000,000 men). A statistically significant increase was recorded for the average standardized mortality rate for all patients (P < 0.01). The mean survival from disease onset was 34.3 ± 2.0 years. Significantly shorter survival was observed in men compared with women and in patients older than 50 years compared with younger ones (P < 0.01). We observed long survival and low frequency of MG-related fatalities but increasing average standardized mortality rate, most notably in older men with MG. Muscle Nerve 58: 708-712, 2018.

Epidemiological Study of Adult-Onset Myasthenia Gravis in the Area of Belgrade (Serbia) in the Period 1979–2008

Background: The aim of this study was to analyze the prevalence and incidence of adult-onset myasthenia gravis (MG) in the Belgrade population from 1979 to 2008. Methods: Data on the number of MG patients and their basic demographic and clinical characteristics were collected from hospital records (1979–1992) and the Belgrade MG Registry (1993–2008). Incidence and prevalence were standardized by the direct method (using the world standard population). A time-trend analysis of MG incidence was performed using a linear regression model. Results: During the study period 562 cases (316 women, 246 men) were registered. On December 31st, 2008, the standardized prevalence (according to the world standard population) was 188.3/1,000,000 (women: 237.8/1,000,000; men: 139.4/1,000,000). The average annual standardized incidence rate was 13.3/1,000,000 (women: 14.1/1,000,000; men: 12.2/1,000,000). The incidence rates tended to increase significantly in both sexes during the study period (y = 3.299 + 14.363x, p = 0.002). Age-specific incidence rates for women demonstrated a bimodal pattern, with the first peak in the 20- to 29-year age group and the second one in the ≥70-year group. For both genders, an increase in age-specific incidence rates was registered for all age groups, although this was significant (p = 0.001) only for an MG onset of ≥60 years of age. Conclusions: The study confirms an increase in the incidence of MG in the area of Belgrade during the study period, especially for those with MG onset after 60 years of age.

Myasthenia gravis: presentation and outcome in 104 patients managed in a single institution

BACKGROUND AND OBJECTIVESFew studies have attempted to delineate the clinical profile of myasthenia gravis (MG) among people of Arab ancestry. Therefore, we sought to clarify the clinical profile, the outcome of treatment and the role of thymectomy in non-thymomatous MG in Saudi Arabia.PATIENTS AND METHODSWe retrospectively studied 104 patients followed over a mean period of 7.2 years (range, 1 to 22 years) at the King Khaled University Hospital, Riyadh, Saudi Arabia. Disease outcomes were compared among thymectomized and non-thymectomized patients according to the post-intervention status criteria of the Myasthenia Gravis Foundation of America (MGFA).RESULTSAge of onset was 22.5±9.3 years (mean±SD) in females and 28.2±15.9 years in males, with peaks in the second and third decades among females and the third and fourth decades among males. At diagnosis, a majority of patients had moderate generalized weakness, equivalent to MGFA class III severity. After medical treatment with or without thymectomy, 9.6% of all patients had achieved complete stable remission, 3.8% had pharmacological remission, 27.9% had minimal manifestations, 23.1% were improved, 20.2% were unchanged and 15.4% were worse. Only thymectomized patients without a thymoma achieved remission, a significant benefit over those who had no thymectomy (P=.02).CONCLUSIONMG presents at a younger age among Saudi Arabs compared to other racial groups. Thymectomy conferred significant benefits towards achievement of remission.

Juvenile form of myasthenia gravis presenting as recurrent pulmonary infection with atelectasis

Myasthenia gravis (MG), a chronic disease characterized by unusual fatigability of voluntary muscles, was first described by Willis. Three forms of MG are seen in childhood: juvenile MG, congenital MG and transient neonatal MG. Aside from age of onset, there is no difference in terms of pathology and pathogenesis between juvenile MG and adult-onset MG. Juvenile MG, like adult MG, appears to result from T-cell-initiated antibodies directed against end-plate Ach receptor protein. The onset of juvenile myasthenia can be insidious, although at times it is rapid, often a sequel to an acute febrile illness. Generally, muscles innervated by the cranial nerves are affected first, with bilateral ptosis being the most common presenting sign. Generalized weakness and dysphagia are less common presenting symptoms, while the clinical course is highly variable.

HLA antigens in Japanese patients with myasthenia gravis.

HLA antigens in 104 Japanese patients and 41 families with myasthenia gravis (MG) were investigated. The frequencies of DR9 and DRw13 were significantly increased in the patients who developed MG before 3 yr of age. The DQw3 antigen was positive for all the patients that developed MG before 15 yr with only one exception. All the examined cases that developed MG before 3 yr (including this DQw3 negative patient) had the same DQA and DQB DNA restriction fragments. These HLA frequencies decreased as the age of onset increased, and no significant association was observed in adult-onset MG. No patients had B8, DR3, and DQw2. The relative risk was higher for the DR9/DRw13 heterozygotes (37.4) than for DR9 (16.4) or DRw13 (7.1) in the childhood-onset MG. Statistical analysis suggested that DR9 and DRw13 (or DQw1 and DQw3) act synergistically in the disease development. Family study revealed diverse DR9 haplotypes. The most frequent DRw13 haplotype was Bw44-BFF-C4A3B1-DRw13-DQw1, which may be evolutionarily related to the caucasian B8-DR3-DQw2 haplotype. These results showed that MG in early childhood in Japanese individuals is genetically different from that in adulthood and that in caucasians.

Acetylcholine receptor antibody in myasthenia gravis.

Radioimmunoassay techniques were used to detect antibodies to the acetylcholine receptor (AAChR) in 164 patients with adult-onset myasthenia gravis. AAChR levels above 0.6 nM/l were considered pathological and were found in 67% of the patients with an average value of 58.99 +/- 125.02 nM/l (0.6-900.0). Correlation, with clinical functional status, the histopathological thymus alterations and the different therapeutics used did not disclose any statistically significant differences.

Myasthenia gravis and HLA antigens in American blacks and other races

The association of HLA B8 and DR3 with generalised adult onset myasthenia gravis (GMG) in European Caucasoids is now well established. Studies of the HLA association with myasthenia gravis (MG) in other races might help to determine the location of a critical disease locus. Some previous studies in Japanese, Thais, Asian Indians and Filipinos have been reported. In this study HLA A, B, C and DR typing on 28 American blacks with either GMG or ocular myasthenia gravis (OMG) is reported. A significant increase in both HLA A1 and B8 was detected but there was an increase in DR5 rather than DR3. A review of the HLA antigen frequencies in other races and in D-penicillamine (D-Pen) induced MG suggests that prior claims implicating immune response genes marked by DR3 require review. It seems unlikely that any particular HLA allele is involved directly. Other possibly relevant combinations of alleles or supratypes are suggested. These may provide the basis for future studies of the immunogenetic basis for MG.

The diagnostic significance of autoantibodies to the acetylcholine receptor

The predictive value of the assay for antibodies to the acetylcholine receptor (anti-AChR) is dependent upon the reference range used and the question being asked by the clinician. A reference range has been established after assaying sera from 200 healthy individuals, 314 patients with diseases often considered in the differential diagnosis of myasthenia gravis (MG) or found in association with MG, and 72 patients with active adult onset MG. If the assay is to be used to screen at unselected population for MG a conservative cut off point (2 units) should be used. After establishment of a differential diagnosis more significant may be attributed to a lower result (1 unit or greater). A negative result does not exclude MG. In patients with Systemic Lupus Erythematosus, Graves' disease or thymoma anti-AChR has been demonstrated in the absence of signs of MG. Such patients may have latent or subclinical MG. Two such patients subsequently developed clinically evident MG concomitant with a rise in anti AChR titre above their particular ‘biological threshold’.