Limb-girdle congenital myasthenic syndrome (LG-CMS) is a genetically heterogeneous disease characterized by muscle weakness and fatigability. In LG-CMS patients linked to mutations in the DPAGT1 gene, a reduction in the localization of acetylcholine receptors (AChRs) at the neuromuscular junction (NMJ) is observed, due to a glycosylation deficit resulting in a decrease in neuromuscular transmission characterized by a decrement. In addition, analysis of muscle biopsies from LG-CMS patients shows the presence of tubular aggregates in their muscle, the origin and involvement of which in the pathology remain unclear at present.
French researchers, including experts from the Institute of Myology, report the observation of two unrelated patients (one from Guadeloupe and one from mainland France) diagnosed with congenital myasthenic syndrome (CMS):
- the clinical picture was limited to a deficit of the limb-girdle musculature that began in childhood and was accompanied by fatigability and decrement on repetitive stimulation,
- both patients responded positively to treatment with oral anticholinesterase agents,
- two distinct homozygous variants were identified in the DPAGT1 gene,
- tubular aggregates were present within the muscle cells,
- functional studies established a link between these aggregates and the hypoglycolysis induced by the DPAGT1 gene defect.
These two cases, in addition to the nine already reported in the literature, broaden the spectrum of DPAGT1 gene mutations responsible for LG-CMS forms, while providing a genotype/phenotype correlation. The discovery of ORAI1 hypoglycosylation in these two patients has also highlighted a pathophysiological link between LG-CMS and tubular aggregate myopathy due to ORAI1 overactivation at the plasma membrane.
