Use of next-generation sequencing as a diagnostic tool for congenital myasthenic syndrome

The clinical presentation of congenital myasthenic syndromes is similar to many other neuromuscular disorders of infancy, and with 12 known discrete genetic forms of congenital myasthenic syndromes, both the diagnosis and treatment decisions present clinical challenges.

We report a 20-month-old boy with rapsyn deficiency. At birth, he presented with a weak cry, hypotonia, joint contractures, and facial deformity. Because of respiratory difficulty associated with muscle fatigue, he spent a total of 71 days in the neonatal intensive care unit and 47 days in the pediatric intensive care unit. Imaging study results were normal, along with a battery of metabolic tests and electrodiagnostic studies. A limited genetic evaluation for reversible cytochrome c oxidase deficiency was negative, as was the oligonucleotide microarray. A muscle biopsy demonstrated myofiber atrophy in a pattern consistent with early denervation. Based on nonspecific and nondiagnostic results, whole-exome (next generation) sequencing was performed. This study identified two confirmed pathogenic mutations in the RAPSN gene that are associated with congenital myasthenic syndrome (OMIM 608931). The patient was treated with pyridostigmine at 16 months of age, which resulted in a dramatic improvement in muscle tone and strength and a steady resolution of joint contractures. Four months after treatment was initiated, he was beginning to bear weight and was able to sit unsupported and vocalize full words.

This patient serves to highlight next-generation sequencing as an important diagnostic tool that can result in life-saving treatment.