Investigation for RAPSN and DOK-7 mutations in a cohort of seronegative myasthenia gravis patients.

INTRODUCTION: Myasthenia gravis (MG) is an autoimmune disease. Patients without detectable antibodies against the nicotinic acetylcholine receptor or the muscle-specific tyrosine kinase are referred to as seronegative MG (SNMG). Because late-onset congenital myasthenic syndromes (CMSs) due to RAPSN or DOK7 mutations may be mistaken for SNMG, we investigated their frequency in a nationwide SNMG cohort. METHODS: We performed sequencing of RAPSN and DOK7 in all Norwegian SNMG patients (n = 74) and 37 healthy controls, examining for the N88K and c.1124_1127dupTGCC mutations, respectively. RESULTS: We found 1 patient homozygous for N88K and 2 carriers of the N88K mutation. Sequencing of DOK7 revealed no mutations. CONCLUSIONS: This study confirms that rapsn CMS can be mistaken for SNMG. In addition, the frequency of rapsn CMS in our nationwide SNMG cohort was found to be low. SNMG patients with an atypical clinical presentation and pediatric cases should be tested for the N88K mutation before initiation of immunosuppressive drug treatment or thymectomy.

Interleukin-10 promoter polymorphisms in myasthenia gravis.

Interleukin 10 (IL-10) is secreted by several hemopoietic cells and suppresses the Th1 mediated immune response, while stimulating B cell differentiation and the humoral immune response. IL-10 expression in Con A-stimulated peripheral blood mononuclear cells is related to three polymorphisms in the promoter region of the IL-10 gene; G/A at position -1082, T/C at position -819 and A/C at position -592. We analyzed the distribution of these IL-10 polymorphisms in 64 MG patients and 87 healthy blood donors to determine any influence on MG susceptibility. MG patients had a significantly higher frequency of the ACC/ACC haplotype (12.5% vs 3.4% in controls), as had the subgroups with late onset MG and thymomatous MG (20.0% and 21.4%, respectively). Early onset MG patients had a high frequency of the ATA/ATA haplotype (19.2% vs 3.4% in controls). Titin Ab-positive MG patients had high ACC/ACC (20.0%). This study indicates a direct link between IL-10 and MG pathogenesis, although the complex role of this multi-faceted cytokine in vivo is as yet not fully elucidated.