I.01Congenital myasthenic syndromes.

Neuromuscular junction disorders are a heterogeneous group of acquired (Myasthenia Gravis, MG) and inherited (Congenital Myasthenic Syndromes, CMS) 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. 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. Next-generation sequencing and deep phenotyping, in combination with international data sharing, reveals new genetic causes of CMS, but also unusual, overlapping clinical phenotypes, which blur the boundaries with primary myopathies and motor neuropathies. Mitochondrial dysfunction has been implicated with both myopathies and neuromuscular transmission defects. TEFM is a nuclear gene that codes for a mitochondrial transcription elongation factor – the protein responsible for prolonging activity of RNA polymerase to ensure distal transcripts of the mitochondrial genome are transcribed. We identified the first human TEFM variants associated with mitochondrial respiratory chain deficiency in seven patients with varying clinical presentations. While symptoms included classical features of a mitochondrial disease, some patients also presented with a treatable neuromuscular transmission defect. 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. [ABSTRACT FROM AUTHOR]