Clinical and Genetic Features of MUSK-Related Congenital Myasthenic Syndrome: A Case Series and a Proposal for Clinical Classification

Abstract

MUSK-related congenital myasthenic syndrome (MUSK-CMS) is a rare neuromuscular disorder caused by pathogenic variants in the MUSK gene. The phenotypic spectrum varies significantly, ranging from mild, fatigable muscle weakness to severe neonatal onset with respiratory failure. This study is aimed at presenting a case series of MUSK-CMS, highlighting its clinical diversity and diagnostic challenges, and proposing a clinical classification into three distinct phenotypes. We conducted clinical and genetic analyses of six patients diagnosed with MUSK-CMS from three tertiary centers in Brazil. Clinical evaluations encompassed assessments of muscle strength, respiratory function, bulbar symptoms, and functional performance using the 6-min walk test (6MWT) and MG-ADL scale. Genetic testing was performed using whole exome sequencing (WES). Treatment responses were documented. Patients ranged in age from 19 to 58 years, with symptom onset varying from congenital to 32 years of age. All but one patient exhibited bilateral ptosis, extraocular muscle weakness, and gaze limitations. Based on our cohort and a review of previously reported cases, MUSK-CMS appears to exhibit three overlapping clinical patterns: early-onset severe disease, ocular-predominant involvement, and late-onset limb-girdle presentation. In our cohort, these phenotypes were distributed as follows: early-onset severe (n = 1), ocular (n = 4), and late-onset limb-girdle (n = 1). Early recognition and genetic testing are critical for optimal patient outcomes, especially in atypical or adult-onset cases.