A spontaneous missense mutation in the chromodomain helicase DNA-binding protein 8 (CHD8) gene: a novel association with congenital myasthenic syndrome.

AIMS: Congenital myasthenic syndromes (CMS) are characterized by muscle weakness, ptosis and episodic apnoea. Mutations affect integral protein components of the neuromuscular junction (NMJ). Here we searched for the genetic basis of CMS in female monozygotic twins. METHODS: We employed whole-exome sequencing for mutation detection and Sanger sequencing for segregation analysis. Immunohistology was done with antibodies against CHD8, rapsyn, ß-catenin (ßCAT) and golgin on fi-bro-blasts, human and mouse muscle. We recorded superresolution images of the NMJ using 3D-structured illumination microscopy. RESULTS: We discovered a spontaneous missense mutation in CHD8 [chr14:g.21,884,051G>A, GRCh37.p11 | c.1732C>T, NM_00117062 | p.(R578C)], the gene encoding chromodomain helicase DNA-binding protein 8. This is the first missense mutation affecting Duplin, the short 110 kDa isoform of CHD8. It is known that CHD8/Duplin negatively regulates ßCAT signalling in the WNT pathway and plays a role in chromatin remodelling. Inactivating CHD8 mutations are associated with autism spectrum disorder and intellectual disability in combination with facial dysmorphism, overgrowth and macrocephalus. No muscle-specific phenotype has been reported to date. Co-immunostaining with rapsyn on human and mouse muscle revealed a strong presence of CHD8 at the NMJ being located towards the sarcoplasmic side of the rapsyn cluster, where it co-localizes with ßCAT. CONCLUSION: We hypothesize CHD8 to have a role in the maintenance of the structural integrity and function of the NMJ. Both patients benefited from treatment with 3,4-diaminopyridine, a reversible blocker of voltage-gated potassium channels at the nerve terminal that prolongs the action potential and increases acetylcholine release.

[Neurological side effects of checkpoint inhibitors]. / Neurologische Nebenwirkungen von Checkpoint-Inhibitoren.

BACKGROUND: In recent years the treatment of many tumor entities has been revolutionized by the use of modern immunotherapies with checkpoint inhibitors; however, good response rates are contrasted by many immune-mediated side effects. Neurological immune-mediated side effects are rare but often severe complications of checkpoint inhibitor treatment. METHOD: A systematic search in the PubMed and Web of Sciences databases was carried out for case reports and studies on neurological side effects during checkpoint inhibitor treatment. RESULTS: A total of 42 articles on neurological side effects of checkpoint inhibitors with a total of 85 reported cases could be identified. The most frequently reported neurological side effects were myopathies, neuropathies, diseases of the neuromuscular endplates and encephalitides. Among those, encephalitides and myopathies with accompanying myocarditis were associated with the highest morbidity and mortality. CONCLUSION: Against the background of a rapidly increasing use of checkpoint inhibitors, this article provides an overview of currently available reports on the clinical courses of neurological side effects. Controlled studies on the treatment of neurological side effects are lacking. From case studies it can be assumed that early steroid treatment increases the probability of a complete remission of neurological symptoms. Typical symptom constellations must therefore be rapidly recognized and an immunosuppressive treatment must be initiated.