P.12.4 Great phenotypic variability in two siblings affected by congenital myasthenic syndrome associated with mutations in MUSK

Abstract

Congenital myasthenic syndromes (CMS) are rare genetic diseases, in which neuromuscular transmission is impaired. To date 17 CMS disease genes have been identified with mutations in MUSK reported in only 8 patients. Here, we describe clinical, neurophysiological, and molecular features of two Italian siblings who carrying compound heterozygous mutations in MUSK. The first sibling is a 27-year-old woman. As a neonate, she had laryngeal stridor and respiratory failure requiring mechanical ventilation and tube feedings. Her subsequent clinical course was characterized by bilateral eyelid ptosis, paresis of lateral and vertical gaze, mild tongue weakness and atrophy, and severe weakness of the facial, neck flexor, and proximal limb muscles. Treatment with 3,4-diaminopyridine was of mild benefit, while pyridostigmine worsened her symptoms. The second sibling is a 29-year-old man. He had bilateral eyelid ptosis since birth but later only mild fatigable weakness of the proximal leg muscles which did not limit his daily activities and participation in sports. Examination at age of 28 years only revealed mild tongue weakness and atrophy, mild bilateral eyelid ptosis, limitation of lateral and vertical gaze, and mild facial and proximal leg muscle weakness. Mutation analysis of MUSK revealed 2 mutations: a previously identified c.2368G > A (p.Val790Met) mutation, reported by Chevassier et al., and a novel c.467delA (p.Lys156Argfsstop20) mutation. Thus, the phenotypic expression of the identical MUSK mutations was markedly different in the two siblings with the sister being more severely affected. To our knowledge a mild phenotype in one of two siblings harbouring the same mutations has never been documented in MuSK–MG.