Myasthenia Gravis

Tola et al. (1994) examined HLA antigens in 47 Italian patients with sporadic myasthenia gravis. The frequency of B8 and DR3 in patients was 19.1 and 27.3%, respectively, compared to 9.7 and 14.1% in controls. There was also an association between the B8 allele and early onset of generalized myasthenia gravis sustained by thymic hyperplasia. The DR1 antigen was found in 55% of patients with ocular myasthenia and in only 2.8% of patients with generalized myasthenia. DR3 was present in 50% of patients with concurrent autoimmune conditions and in only 4.54% of patients without a more generalized disorder of autoimmunity.

According to Celesia (1965), the disease has been limited to one generation in 18 of the 22 reported families with multiple cases. In the other 4 families, 2 generations were affected. The familial form usually affects young children or adolescents and onset in adulthood is rare. The familial form is, furthermore, static or only slowly progressive. Affected brother-sister pairs have been reported by Teng and Osserman (1956) and Celesia (1965), among others. Affected parent and offspring were reported by Foldes and McNall (1960), among others. Kurland and Alter (1961) reviewed the reports of familial aggregation and twin cases and concluded that 'there is as yet insufficient evidence to suggest that genetic factors are of significance in the etiology of myasthenia gravis.' Bundey (1972) concluded that there are 2 forms of childhood myasthenia. A form with onset before 2 years of age and milder though persistent course may be autosomal recessive. Cases with onset between ages 2 and 20 years resemble adult myasthenia, which is associated with autoimmunity and increased incidence of thyroid dysfunction. Noyes (1930) noted myasthenia gravis in a father and 2 daughters. Herrmann (1966) reported affected father and son. The familial aggregation, although definite, does not conform to a simple mendelian pattern. In a sample of 70 patients with myasthenia gravis, Jacob et al. (1968) found no instance of familial occurrence. They provided a comprehensive survey of the reported familial cases and pointed out differences from their own series, particularly earlier onset in the familial cases. Namba et al. (1971) pointed out, on the basis of 85 families with multiple cases (excluding transient neonatal myasthenia in offspring of myasthenic mothers), that the familial cases most often involved sibs.

In Finland, Pirskanen (1977) found 264 patients with MG of whom 19 (17 females and 2 males) were familial cases from 8 families: 11 sibs, 2 mother-offspring and 6 cousins. Clinically, familial and nonfamilial cases were closely similar. No concordance was found among 45 sets of twins. No definite clustering of grandparental birthplaces, such as occurs in Finland for many mendelian disorders, was observed. Parental consanguinity was found in 7 of 192 families. An increase in 'connective tissue disease' and thyroid disease was observed in the families of both familial and nonfamilial MG. The author concluded that the familial predisposition may be due to autoimmunity in general (see 109100). Nakao et al. (1980) found association between myasthenia gravis and a particular Gm type. Cases with thymoma showed an especially strong association. Provenzano et al. (1988) described father and son with myasthenia gravis. The father had typical antibodies against the acetylcholine receptor, whereas the son seemed to have antibodies directed against some other antigen. Both patients showed the HLA-DR2 antigen, which is found in increased frequency in patients with myasthenia gravis. Bergoffen et al. (1992, 1994) described a family in which the parents were first cousins and 5 of 10 sibs had autoimmune myasthenia gravis with onset ranging from age 50 to 72 years. Three sibs had elevated antiacetylcholine receptor antibody titers. One affected sister had a history of thyroid disease. Two affected brothers and 1 unaffected brother had diabetes. By molecular analysis, Bergoffen et al. (1994) excluded the major histocompatibility complex, the beta subunit of the acetylcholine receptor (CHRNB1; 100710), and the alpha (see 186880) and beta (see 186930) subunits of the T-cell receptor as candidate genes for the disorder in this family; different alleles at these loci were demonstrated by the patients. The results were uninformative concerning CHRNA1 (100690), CHRNG (100730), and CHRND. Usually a sporadic disorder, autoimmune myasthenia gravis has a frequency of about 1 in 30,000. The proportion of cases that are familial is estimated to be between 1.2 and 4.3%.

Several mothers with clinically diagnosed myasthenia gravis have given birth to infants with the Pena-Shokeir syndrome (208150), which is characterized by pulmonary hypoplasia, multiple ankyloses, and facial abnormalities. Brueton et al. (1994) reported 2 mothers with no neurologic symptoms of myasthenia gravis but with increased titers of antiacetylcholine receptor antibody who gave birth to 8 infants with the Pena-Shokeir phenotype. Myasthenia gravis was diagnosed in these mothers. In the case of maternal myasthenia gravis, the recurrence risk for Pena-Shokeir syndrome is high, and there has been no instance of a normal child being born following the affected pregnancy.

Mullaney et al. (2000) reviewed the natural history and ophthalmic involvement in childhood myasthenia gravis in 34 patients. Among the 7 children with congenital myasthenic syndromes, severity varied. The diagnosis in severe cases was often obscured by apnea attacks, aspiration, and failure to thrive. Ophthalmic signs and symptoms (strabismus, ophthalmoplegia, and ptosis) were more prominent in mild cases and did not resolve during remissions.

Croxen et al. (2002) reported 2 sisters diagnosed in childhood with congenital myasthenic syndrome, each of whom was found to carry 2 mutations in the AChR epsilon-subunit gene, near the N terminus. Serum anti-AChR antibody levels were negative in both patients. At the age of 34 years, the younger sister's condition deteriorated, with respiratory failure necessitating tracheostomy and assisted ventilation. Serum anti-AChR titers were elevated, indicating autoimmune myasthenia gravis, and the patient was successfully treated with plasmapheresis, immunosuppression, and thymectomy. Croxen et al. (2002) suggested that the epsilon-AChR gene mutations may predispose to later development of anti-AChR antibodies. The authors also noted that the younger sister had recently had 3 children and, unlike her sister, was homozygous for the HLA-DR3-B8-A1 phenotype, which is known to associate with autoimmune myasthenia gravis.

Using microarray analysis, Feferman et al. (2005) found increased expression of Cxl10 (147310) and its receptor, Cxcr3 (300574), in lymph node cells of rats with experimental autoimmune MG. Real-time RT-PCR, FACS, and immunohistochemistry analyses confirmed these findings and revealed upregulated expression of another Cxcr3 chemoattractant, Cxcl9 (601704), and of Tnf (191160) and Il1b (147720), which act synergistically with Ifng (147570) to induce Cxcl10, in both lymph node cells and muscle of myasthenic rats. Upregulation of these genes was reduced after mucosal tolerance induction with an AChR fragment. Using RT-PCR, flow cytometric, and fluorescence microscopy analyses, Feferman et al. (2005) found increased expression of CXL10 and CXCR3 in thymus and muscle of MG patients compared with age-matched controls, validating their findings in the rat model of MG. They concluded that CXCL10/CXCR3 signaling is associated with MG pathogenesis and proposed that CXCL10 and CXCR3 may serve as novel drug targets to treat MG.

The CHRNA1 gene (100690) encodes the alpha subunit of the muscle acetylcholine receptor, which is the main target of pathogenic autoantibodies in autoimmune myasthenia gravis. Giraud et al. (2007) identified a functional biallelic variant in the CHRNA1 promoter (16862847) that was associated with early onset of autoimmune myasthenia gravis in 2 independent human populations (France and U.K.). They showed that this variant prevented binding of interferon regulatory factor-8 (IRF8; 601565) and abrogated CHRNA1 promoter activity in thymic epithelial cells in vitro. Notably, both the CHRNA1 promoter variant and AIRE (607358) modulated CHRNA1 mRNA levels in human medullary thymic epithelial cells ex vivo and also in a transactivation assay. Giraud et al. (2007) concluded that their findings revealed a critical function of AIRE and the interferon signaling pathway in regulating quantitative expression of this autoantigen in the thymus, suggesting that together they set the threshold for self-tolerance versus autoimmunity.

In an attempt to develop an antigen-specific therapy for myasthenia gravis as an autoimmune disorder, Im et al. (1999) administered a nonmyasthenogenic recombinant fragment of AChR orally to rats. This fragment, corresponding to the extracellular domain of the human AChR alpha subunit, protected rats from subsequently induced experimental autoimmune myasthenia gravis (EAMG) and suppressed ongoing EAMG when treatment was initiated during either the acute or chronic phases of disease. Prevention and suppression of EAMG were accompanied by a significant decrease in AChR-specific humoral and cellular responses. The underlying mechanism for the oral tolerance induced by the agent seemed to be active suppression, mediated by a shift from a T-helper-1 (Th1) to a Th2/Th3 response. The results in experimental myasthenia suggested that oral administration of AChR-specific recombinant fragments should be considered for antigen-specific immunotherapy of myasthenia gravis.

Lin et al. (2002) demonstrated enhanced susceptibility to experimental autoimmune myasthenia gravis in mice lacking decay-accelerating factor (DAF; 125240), an intrinsic complement regulator. Following anti-AChR Ab injection, Daf1 -/- mice (devoid of neuromuscular DAF protein) showed dramatically greater muscle weakness than their Daf1 +/+ littermates. Reversal of the weakness by edrophonium was consistent with a myasthenic disorder. Immunohistochemistry revealed greatly augmented C3b deposition localized at postsynaptic junctions, and radioimmunoassays showed more profound reductions in AChR levels. Electron microscopy demonstrated markedly greater junctional damage in the Daf1 -/- mice compared with the Daf1 +/+ littermates.