Overview and Update of Congenital Myasthenic Syndromes

Neuromuscular junction disorders, also called Myasthenic Syndromes (MS), are a rare heterogeneous group of acquired (Myasthenia Gravis, MG) and inherited (Congenital Myasthenic Syndromes, CMS) neuromuscular disorders associated with distinctive clinical, electrophysiological, laboratory and ultrastructural abnormalities. The genetic defects in CMS either impair neuromuscular transmission directly or result in secondary impairments, which eventually compromise the safety margin of neuromuscular transmission. CMS are clinically characterized by fatigable weakness with an onset at birth or in the first 3 years of life. More than 15 different genetic causes of CMS have now been identified, with the majority inherited in autosomal recessive traits. The most frequent genetic defects causing CMS are loss-of-function mutations of the CHRNE gene, encoding the epsilon subunit of the acetylcholine receptor, which leads to receptor deficiency at the endplate. More recently, we have identified two genes (DOK7, GFPT1) that cause fatigable weakness of muscles in a limb-girdle distribution, but rarely affecting facial or eye muscles. While many patients with CMS respond favorably to pharmacological treatment with acetylcholine esterase inhibitors, some do not or even deteriorate. This can be largely attributed to the underlying genetic defect, and other drugs such as salbutamol and ephedrine have been used successfully I patients refractory to esterase inhibitors. We will cover the significant progress made in understanding the molecular pathogenesis of CMS, which is important for both patients and clinicians in terms of reaching a definite diagnosis and selecting the most appropriate treatment.