Association of HLA-DQA1*0101/2 and DQB1*0502 with Myasthenia Gravis in Southern Iranian Patients

Background: Myasthenia gravis is an autoimmune disorder of neuromuscular junction characterized by skeletal muscle weakness and fatigability. Different genes may control the induction and clinical presentation of this disease. Various HLA alleles are reported as predisposing or protective genetic elements in myasthenia gravis. Objective: The aim of this study was to investigate the probable association between HLA-DQ alleles and myasthenia gravis in southern Iranian patients. Methods: HLA-DQA1 and DQB1 alleles were determined in 104 sporadic patients with myasthenia gravis using polymerase chain reaction - restriction fragment length polymorphism method and the results were compared to 816 healthy controls. Results: HLA-DQA1*0101/2 (39.4%) and DQB1*0502 (21.6%) were the most frequent alleles in southern Iranian patients with myasthenia gravis. These alleles revealed positive associations with the disease with relative risks of 1.69 and 2.41, respectively. The most common haplotype was DQA1*0101/2-DQB1*0502 in these patients. Conclusion: According to the results of this study, DQA1*0101/2 and DQB1*0502 alleles might be considered as predisposing genetic factors to myasthenia gravis while DQA1*0501, DQB1*0301 and *0602/3 show protective roles against this disease.     

Pleiotropic effects of the 8.1 HLA haplotype in patients with autoimmune myasthenia gravis and thymus hyperplasia

The 8.1 haplotype of the HLA complex has been reproducibly associated with several autoimmune diseases and traits, notably with thymus hyperplasia in patients with acquired generalized myasthenia gravis, an autoantibody-mediated disease directed at the muscle acetylcholine receptor. However, the strong linkage disequilibrium across this haplotype has prevented the identification of the causative locus, termed MYAS1. Here, we localized MYAS1 to a 1.2-Mb genome segment by reconstructing haplotypes and assessing their transmission in 73 simplex families. This segment encompasses the class III and proximal class I regions, between the BAT3 and C3-2-11 markers, therefore unambiguously excluding the class II loci. In addition, a case-control study revealed a very strong association with a core haplotype in this same region following an additive model (P=7 x 10(-11), odds ratio 6.5 for one copy and 42 for two copies of the core haplotype). Finally, we showed that this region is associated with a marked increase in serum titers of anti-acetylcholine receptor autoantibodies (P=8 x 10(-6)). Remarkably, this effect was suppressed by a second locus in cis on the 8.1 haplotype and located toward the class II region. Altogether, these data demonstrate the highly significant but complex effects of the 8.1 haplotype on the phenotype of myasthenia gravis patients and might shed light on its role in other autoimmune diseases.     

Steroids induce acetylcholine receptors on cultured human muscle: implications for myasthenia gravis.

Antibodies to the acetylcholine receptor (AChR), which are diagnostic of the human autoimmune disease myasthenia gravis, block AChR function and increase the rate of AChR degradation leading to impaired neuromuscular transmission. Steroids are frequently used to alleviate symptoms of muscle fatigue and weakness in patients with myasthenia gravis because of their well-documented immunosuppressive effects. We show here that the steroid dexamethasone significantly increases total surface AChRs on cultured human muscle exposed to myasthenia gravis sera. Our results suggest that the clinical improvement observed in myasthenic patients treated with steroids is due not only to an effect on the immune system but also to a direct effect on muscle. We propose that the identification and development of pharmacologic agents that augment receptors and other proteins that are reduced by human genetic or autoimmune disease will have broad therapeutic applications.     

Myasthenia in elderly patients: a series of 23 cases

PURPOSE: There is evidence that myasthenia gravis is substantially underdiagnosed in older people, for which diagnosis and treatment may be difficult. METHOD: We report on a series of 23 cases of myasthenia gravis diagnosed after the age of 65. Diagnosis was ascertained by compatible symptoms, associated with electrophysiological evidence and/or presence of antibodies to the acetylcholine receptor (AchRAb) and/or positive prostigmine test. RESULTS: Twelve female and 11 male patients were identified, with a mean age of 77 (range: 66-89). Initial symptoms were ocular in 8 cases (35%), bulbar and ocular in 9 cases (39%), generalized in 6 cases (26%). Diagnosis was delayed in many patients (mean delay 31+/-47 months). Prostigmine test was positive in 16 cases (100%), AchRAb were positive in 19/23 cases (83%). Only one thymoma was found. Other diagnoses than myasthenia gravis, mainly stroke, were often considered. Treatment with anticholinesterase drugs, prescribed in all cases, has been able to control symptoms in only 3 cases. Corticosteroids were used in 10 cases, azathioprine or mycophenolate mofetil in 14 cases, intravenous immunoglobulins in 8 cases, and plasma exchanges in 2 cases. Thymectomy was performed on one patient with thymoma. Three patients were hospitalized in intensive care units for several weeks, and 3 patients died from their myasthenia. CONCLUSION: Diagnosis of myasthenia gravis is often missed or delayed in the elderly, because of a broad differential diagnosis in older people, and because the high incidence of the disease in middle and old age is often overlooked. The outcome of myasthenia gravis in older people is far from simple, and immunomodulation proves to be necessary in most cases. However, quality of life of surviving patients appears good.     

Adult celiac disease with acetylcholine receptor antibody positive myasthenia gravis

Celiac disease has been associated with some autoimmune disorders. A 40-year-old competitive strongman with celiac disease responded to a glutenfree diet, but developed profound and generalized motor weakness with acetylcholine receptor antibody positive myasthenia gravis, a disorder reported to occur in about 1 in 5000. This possible relationship between myasthenia gravis and celiac disease was further explored in serological studies. Frozen stored serum samples from 23 acetylcholine receptor antibody positive myasthenia gravis patients with no intestinal symptoms were used to screen for celiac disease. Both endomysial and tissue transglutaminase antibodies were examined. One of 23 （or, about 4.3%） was positive for both IgA-endomysial and IgA tissue transglutaminase antibodies. Endoscopic studies subsequently showed duodenal mucosal scalloping and biopsies confirmed the histopathological changes of celiac disease. Celiac disease and myasthenia gravis may occur together more often than is currently appreciated. The presence of motor weakness in celiac disease may be a clue to occult myasthenia gravis, even in the absence of intestinal symptoms.     

Accelerated degradation of acetylcholine receptor from cultured rat myotubes with myasthenia gravis sera and globulins.

Altered geometry of the neuromuscular junction and a decreased number of acetylcholine receptors appear responsible for the defect of neuromuscular transmission in myasthenia gravis. We have used cultured rat myotubes as a model to study in vitro the potential role of myasthenic globulins in the pathological process. Acetylcholine receptor content was assayed by the extent of 125I-labeled alpha-bungarotoxin binding, and acetylcholine receptor function was assayed by the sensitivity to acetylcholine iontophoresis. The half-life of the acetylcholine receptor was 18.5 hr in the presence or absence of control sera. Myasthenic sera and globulins produced a gradual reduction in acetylcholine receptors, as assessed by biochemical and electrophysiological techniques. The half-life in the presence of myasthenic sera was 6 hr. The accelerated turnover was unaffected by puromycin but was slowed by lowered temperature (18-20 degrees), interference with energy metabolism (2,4-dinitrophenol), and interference with cytoskeletal structures (colchicine and cytochalasin B). We found no electrophysiological evidence to suggest globulin blockade of acetylcholine access to the acetylcholine receptor. Our observations suggest that circulating globulins in myasthenia gravis may contribute to the functional defects of neuromuscular transmission by accelerating the rate of internationalization and degradation of surface membrane acetylcholine receptors.     

Myasthenia gravis developing in a patient with CNS lymphoma

A patient was initially diagnosed with right basal ganglia lymphoma causing left hemiparesis. His disease was resistant to intravenous methotrexate, so he received radiation therapy with remarkable regression of the mass. However, 6 months after his initial diagnosis, he developed symmetric weakness of the proximal muscles. Electromyography was consistent with myasthenia gravis and anti-acetylcholine receptor antibodies were elevated. Treatment with pyridostigmine and corticosteroids improved his symptoms. The residual lymphoma was further treated with rituximab and temozolomide with complete resolution. Pyridostigmine and corticosteroids were stopped after 14 months of initiation with good results. Our case is the first case report of paraneoplastic myasthenia gravis developing in a patient with primary CNS lymphoma. The diagnosis of paraneoplastic myasthenia should be considered in patients with CNS lymphoma who develop muscle weakness and speech problems.     

A case of post-thymomectomy myasthenia gravis after extrapleural pneumonectomy for invasive thymoma which necessistated long-term mechanical ventilation]

The patient was a 58-year-old male with invasive thymoma which had disseminated in the left thorax and was histologically a polygonal cell type lesion. While the serum value of anti-acetylcholine receptor antibody was high before surgery, there were signs of myasthenia gravis. After preoperative chemotherapy, a thymectomy and left panpleuropneumonectomy were conducted. Forty days after surgery, the patients suffered post-thymomectomy myasthenia gravis, which necessitated mechanical ventilation for 6 months. Despite steroid therapy and 17 plasmapheresis procedures the tidal volume increased by little more than 200-250 ml during that time. The causes of ventilatory failure, therefore, were probably decreased pulmonary function due to extrapleural pneumonectomy and the myasthenia gravis. According to the literature, polygonal cell type thymomas with high serum levels of anti-acethycholine receptor antibody have higher incidences of post-thymomectomy myasthenia gragvis than other ones. Therefore, the risk of post-thymomectomy myasthenia gravis should be kept in mind when extrapleural pneumonectomy for invasive thymoma is being considered, especially in the cases of this type.     

Myasthenia gravis and hyperthyroidism: two cases

It is well known that hyperthyroidism occurs in approximately 2 to 17.5% of patients with myasthenia gravis. Hyperthyroidism may influence the clinical course of myasthenia gravis. We report the cases of two patients, a 53-year-old man and an 18-year-old woman, who had both severe myasthenia gravis and hyperthyroidism due to Graves' disease. Myasthenia gravis affected in particular facio-ocular areas with diffuse myopathy and signs of neuromuscular block on the electromyogram. In one patient, the diagnosis of thyroid disease was made three months before the diagnosis of myasthenia gravis while in the other, thyroid disease was recognized four months after myasthenia gravis. Myasthenia gravis worsened after the development of hyperthyroidism in the second patient. Both patients were given anti-cholinesterase drugs. One underwent thymectomy. Radioiodine used for the treatment of hyperthyroidism improved the symptoms of myasthenia gravis in the first patient. The association of myasthenia gravis and hyperthyroidism is more than a coincidence; our cases illustrate the difficult diagnosis and management of these diseases. Clinicians should look for myasthenia gravis in hyperthyroid patients and vice versa, especially when symptoms of myasthenia gravis or hyperthyroidism worsen.     

Current Trends in the Management of Myasthenia Gravis: Plasmapheresis and Immunosuppressive Therapy

Summary: Current trends in the management of myasthenia gravis: Plasmapheresis and immunosuppressive therapy. J. D. Pollard, A. Basten, J. E. Hassall, H. Kronenberg, R. Cobcroftand R. Dawkins, Aust. N.Z. J. Med ., 1980, 10, pp. 212–217.
In recent years a considerable body of evidence has accumulated to demonstrate autoimmune mechanisms in myasthenia gravis. This evidence has important implications for the aetiology, diagnosis and management of the disease
The primary abnormality in myasthenia gravis is related to the presence of antibody which reacts with the acetylcholine receptor. Measurement of this IgG antibody in the serum has become the most reliable diagnostic adjunct to the edrophonium test, and in an individual patient, the level of the serum antibody relates closely to the clinical indices. In cases of myasthenia where control with anticholinesterase drugs is unsatisfactory, methods to lower the antiacetylcholine receptor antibody are indicated: these may include thymectomy, immunosuppressive therapy or plasmapheresis
Two patients with very severe disease are described in whom all types of therapy were used and in whom survival depended ultimately on the use of plasmapheresis. These patients illustrate the importance of receptor antibody in the clinical manifestations of myasthenia gravis and in its management     

Acetylcholine receptors and myasthenia gravis

Recent years have seen considerable progress in understanding the nature of the molecular events involved in neuromuscular transmission. The acetylcholine receptor (AChR) has been purified to homogeneity and acetylcholine-induced ion transport has been reconstituted by incorporation of pure AChR into artificial membranes. Immunization against purified AChR induces a condition, clinically and physiologically similar to the human disease myasthenia gravis, which is due to circulating anti-AChR antibodies. This model, experimental autoimmune myasthenia gravis, is proving useful for investigating the role of genetic factors in determining the immune response to AChRs and for testing various experimental approaches to specific treatment. Myasthenia gravis is an autoimmune disease in which there is loss of acetylcholine receptors at the neuromuscular junction. Anti-AChR antibodies can be detected in the majority of patients and they cause loss of AChR by a variety of mechanisms. Anti-AChR antibody is heterogeneous and not restricted in idiotype. The role of the thymus in MG is still uncertain, but recent experiments implicate the presence of a cell type in MG thymus which may be involved in autosensitization to AChR.     

Myasthenia gravis in the elderly: report of 37 cases

The treatment of myasthenia gravis in the elderly is controversial. Thirty-seven myasthenic patients with onset of the disease after the age of 60 were followed for a period of 14 years. All of the 37 patients received anticholinesterase drugs during this period, ten underwent thymectomy, and 24 were treated with corticosteroids. At present, one patient is in remission, 28 are improved, one is unchanged, and seven have died. Only one death was directly related to myasthenia. In the authors' experience thymectomy can be an effective treatment of myasthenia gravis in elderly patients; corticosteroid therapy can also be useful in addition to or as an alternative to surgery. Using a "personalized" schedule the authors obtained good results in 78 per cent of their patients.     

Inhibitory effect of alpha-fetoprotein on the binding of myasthenia gravis antibody to acetylcholine receptor.

The binding of myasthenia gravis antibody acetylcholine receptor (AcChoR) as measured in vitro by Radioimmunoassay with 125I-labeled alpha-bungarotoxin (alpha-BuTx), can be blocked by amniotic fluid, maternal serum, and umbilical cord serum. This inhibitory effect is due to alpha-fetoprotein present in high concentrations in amniotic fluid and serum, as shown by: (i) selective removal of several components from amniotic fluid and serum; (ii) selective addition of different components present in amniotic fluid and serum, including alpha-fetoprotein, to be radioimmunoassay; (iii) correlation between the inhibitory effect of both amniotic fluid and serum and between the amounts of alpha-fetoprotein they contain; (iv) blocking of the alpha-fetoprotein in vitro suggests a similar effect in vivo in pregnant women with myasthenia gravis. This effect may explain in part the variability in the development of neonatal myasthenia gravis in the babies, due to transplacental transfer of maternal anti-AcChoR antibody, only after delivery and only in the minority of the cases. It also may explain the appearnace of remissions in females with myasthenia gravis during the second and third trimesters of pregnancy. Similar phenomena observed during pregnancy in other autoimmune and immunopathogenic diseases also might be attributed to activity of alpha-fetoprotein.     

Not all HLA DR3 DQ2 Haplotypes Confer Equal Susceptibility to Coeliac Disease: Transmission Analysis in Families

Background: HLA-DQ is the only established susceptibility factor for coeliac disease. We tested whether all HLA haplotypes with the known risk marker, HLA-DQ2, confer equal susceptibility to coeliac disease, i.e. whether haplotype transmission from DQ2 homozygous parents to patients is random. The random transmission would strengthen the importance of DQ2 as the only risk factor within the HLA region. Methods: Inheritance of DQ2-positive haplotypes from parent to patients was investigated in 14 of 127 Finnish coeliac families who had an HLA-DQ2 homozygous parent. HLA alleles and 18 HLA-linked microsatellite markers were used to determine the haplotypes, which were divided into those transmitted and those non-transmitted from DQ2-homozygous parents to patients. Results: Transmitted haplotypes differed clearly from those not transmitted. The alleles in the transmitted haplotypes were strongly conserved and predominantly consisted of the well-known HLA-A*01, B*08, DRB1*03, DQ2, DPB1*0101 haplotype. The non-transmitted haplotypes, on the other hand, were significantly more heterogeneous; in particular, markers near HLA-A and-B genes differed from the transmitted haplotypes. Conclusions: The results suggest that DQ2 is not the only HLA-linked genetic risk factor for coeliac disease but the conserved haplotype harbours at least one other risk gene.     

Not all HLA DR3 DQ2 haplotypes confer equal susceptibility to coeliac disease: transmission analysis in families

BACKGROUND: HLA-DQ is the only established susceptibility factor for coeliac disease. We tested whether all HLA haplotypes with the known risk marker, HLA-DQ2, confer equal susceptibility to coeliac disease, i.e. whether haplotype transmission from DQ2 homozygous parents to patients is random. The random transmission would strengthen the importance of DQ2 as the only risk factor within the HLA region. METHODS: Inheritance of DQ2-positive haplotypes from parent to patients was investigated in 14 of 127 Finnish coeliac families who had an HLA-DQ2 homozygous parent. HLA alleles and 18 HLA-linked microsatellite markers were used to determine the haplotypes, which were divided into those transmitted and those non-transmitted from DQ2-homozygous parents to patients: RESULTS: Transmitted haplotypes differed clearly from those not transmitted. The alleles in the transmitted haplotypes were strongly conserved and predominantly consisted of the well-known HLA-A*01, B*08, DRB1*03, DQ2, DPB1*0101 haplotype. The non-transmitted haplotypes, on the other hand, were significantly more heterogeneous; in particular, markers near HLA-A and -B genes differed from the transmitted haplotypes. CONCLUSIONS: The results suggest that DQ2 is not the only HLA-linked genetic risk factor for coeliac disease but the conserved haplotype harbours at least one other risk gene.     

The staircase phenomenon in myasthenia gravis and other neuromuscular disorders (author's transl)]

The isometric contractions with repetitive stimulation of 2/sec during 90 sec have been recorded in 39 patients with neuromuscular disorders other than myasthenia gravis. Seven patients had falling amplitudes of the contractions, in 14 cases the increase was below 12 per cent and 21 patients had a normal staircase phenomenon. It is recommended to take only a falling of the contraction amplitudes as an important indication for myasthenia gravis. This finding, however, is not specific and in the indivisual case it has to be considered in combination with the other clinical, electro-physiological and histological findings.     

Electrocardiographic findings in 24 patients with myasthenia gravis.

Twenty four myasthenia gravis patients, 14 females and 10 males, aged between 5 and 65 years (average 29) were studied electrocardiographically. The abnormalities found in the ECG were: prolonged "Q-T" intervals (10 cases, 44.1%), sinus tachycardias (5 cases, 20.8%), sinus arrhythmias (5 cases, 20.8%), right bundle branch block (4 cases, 16.6%), and non-specific "T" wave changes (2 cases, 8.3%). Among our 24 patients with myasthenia gravis, in contrast to previous reports, only two had non-specific "T" wave abnormalities. But prolonged "Q-T" intervals, right bundle branch block, sinus tachycardias and sinus arrhythmias, when compared to normal population incidence, were found to be quite significant. In pathogenesis, primary myocardial histo-pathological abnormalities, and the role of extracardiac factors in producing the changes were discussed.     

Thymectomy for myasthenia gravis: prognostic factors in 70 patients

Thymectomy has become increasingly accepted as an efficacious procedure for myasthenia gravis, with high rates of complete clinical remission. Predictors of the response to thymectomy for myasthenia gravis vary in the literature. We retrospectively reviewed the clinical records of 70 patients (63% female; mean age, 38 years) diagnosed with myasthenia gravis from August 1993 to August 2004, to determine the factors predicting outcome. Complications occurred in 20%, but there was no hospital mortality. Complete clinical remission was obtained postoperatively in 47%. Our results indicate that patients with less than 1 year's duration of disease have a better prognosis, and Osserman stages I, IIa, and IIb are also associated with higher clinical remission rates. Female patients have a better prognosis than males, and the younger the patient the better the outcome. Thymectomy is indicated for myasthenia gravis as early as possible in the course of the disease.     

Klinisch-pathologische Studie zur Klassifikation und Prognose von 57 Thymustumoren

Summary The most important prognostic determinants of the thymomas are the gross findings at operation (= the presence or absence of gross invasion of adjacent tissue) and the presence or absence of the thymoma-associated systemic disease, particulary myasthenia gravis. The histologic type of thymoma had no proof value in predicting prognosis with the exception of the so-called atypical thymomas.Thirty-four of 57 patients with thymomas were females and 23 males. The tumors in 40 cases were non-invasive thymomas, and in 17 cases the tumour were invasive of adjacent tissue. 35.1 percent of patients were asymptomatic, the tumours being discovered on roentgenograms done on a routine basis or for an unrelated porpose. 40.3 percent of patients have had a thymomaassociated systemic disease. The most common presenting symptoms were related to myasthenia gravis (26.3%). The 5-year survival rate was 90 percent for non-invasive thymomas without myastenia gravis and 50 percent for invasive thymomas. The 5-year survival rate for patients with myasthenia gravis and encapsulated (non-invasive) thymomas was approximately 60 percent, whereas that for invasive thymomas with myasthenia gravis was 40 percent. The primary form of therapy for all thymomas is the surgical excision. In cases with invasive and/or metastasizing thymomas, postoperative radiation and adjuvanted chemotherapy is indicated, but in most series, the longterm results of this form of therapy are discouraging.