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.

Monoamine Oxidase-B Inhibition Facilitates α-Synuclein Secretion In Vitro and Delays Its Aggregation in rAAV-Based Rat Models of Parkinson's Disease.

Cell-to-cell transmission of α-synuclein (α-syn) pathology is considered to underlie the spread of neurodegeneration in Parkinson's disease (PD). Previous studies have demonstrated that α-syn is secreted under physiological conditions in neuronal cell lines and primary neurons. However, the molecular mechanisms that regulate extracellular α-syn secretion remain unclear. In this study, we found that inhibition of monoamine oxidase-B (MAO-B) enzymatic activity facilitated α-syn secretion in human neuroblastoma SH-SY5Y cells. Both inhibition of MAO-B by selegiline or rasagiline and siRNA-mediated knock-down of MAO-B facilitated α-syn secretion. However, TVP-1022, the S-isomer of rasagiline that is 1000 times less active, failed to facilitate α-syn secretion. Additionally, the MAO-B inhibition-induced increase in α-syn secretion was unaffected by brefeldin A, which inhibits endoplasmic reticulum (ER)/Golgi transport, but was blocked by probenecid and glyburide, which inhibit ATP-binding cassette (ABC) transporter function. MAO-B inhibition preferentially facilitated the secretion of detergent-insoluble α-syn protein and decreased its intracellular accumulation under chloroquine-induced lysosomal dysfunction. Moreover, in a rat model (male Sprague Dawley rats) generated by injecting recombinant adeno-associated virus (rAAV)-A53T α-syn, subcutaneous administration of selegiline delayed the striatal formation of Ser129-phosphorylated α-syn aggregates, and mitigated loss of nigrostriatal dopaminergic neurons. Selegiline also delayed α-syn aggregation and dopaminergic neuronal loss in a cell-to-cell transmission rat model (male Sprague Dawley rats) generated by injecting rAAV-wild-type α-syn and externally inoculating α-syn fibrils into the striatum. These findings suggest that MAO-B inhibition modulates the intracellular clearance of detergent-insoluble α-syn via the ABC transporter-mediated non-classical secretion pathway, and temporarily suppresses the formation and transmission of α-syn aggregates.SIGNIFICANCE STATEMENT The identification of a neuroprotective agent that slows or stops the progression of motor impairments is required to treat Parkinson's disease (PD). The process of α-synuclein (α-syn) aggregation is thought to underlie neurodegeneration in PD. Here, we demonstrated that pharmacological inhibition or knock-down of monoamine oxidase-B (MAO-B) in SH-SY5Y cells facilitated α-syn secretion via a non-classical pathway involving an ATP-binding cassette (ABC) transporter. MAO-B inhibition preferentially facilitated secretion of detergent-insoluble α-syn protein and reduced its intracellular accumulation under chloroquine-induced lysosomal dysfunction. Additionally, MAO-B inhibition by selegiline protected A53T α-syn-induced nigrostriatal dopaminergic neuronal loss and suppressed the formation and cell-to-cell transmission of α-syn aggregates in rat models. We therefore propose a new function of MAO-B inhibition that modulates α-syn secretion and aggregation.

[An autopsy case of nivolumab-induced myasthenia gravis and myositis].

An 84-year-old woman developed blepharoptosis, diplopia, weakness of extremities, and dysphagia with elevation of serum CK levels after treatment with nivolumab against renal cell carcinoma. 3 Hz repetitive stimulation showed waning in the trapezius muscle, leading to the diagnosis of myasthenia gravis. Laboratory examination showed that anti-acetylcholine receptor antibody was negative. We performed IVIg and steroid therapy. However, her symptoms did not improve, and she died of respiratory failure, although serum CK levels ameliorated to the normal range. The results of autopsy showed atrophy of muscle fibers and massive infiltration of inflammatory cells in the endomysium of the iliopsoas muscle and diaphragm, indicating occurrence of myositis. Immunohistochemical analysis showed that CD8-positive T cells mainly infiltrates in the endomysium with a small number of CD4-potive T cells. Here, we report an autopsy case of nivolumab-induced myasthenia gravis and myositis.