A case of severe spinal muscular atrophy type 1 resistant to specific treatment due to a missense variant in the Tudor domain of SMN1

Abstract

Introduction

Spinal muscular atrophy (SMA) is a genetic disorder characterized by muscle weakness and atrophy due to degeneration of anterior horn cells in the spinal cord. It typically results from the allele deletion of SMN1 alleles (null-SMN1). With the implementation of newborn screening for SMA (SMA-NBS), most null-SMN1 patients are diagnosed in a presymptomatic stage.

Case report

A full-term male infant initially had a negative SMA-NBS result but presented with muscle weakness within his first month. By two months, genetic testing identified a single allele deletion and a point variant in the Tudor domain of SMN1, along with three copies of SMN2, confirming SMA type I. The patient was treated with onasemnogene abeparvovec (OA) gene therapy. However, despite the presence of three SMN2 copies and OA treatment, he eventually required respiratory support, including tracheostomy and mechanical ventilation. At one year and seven months, risdiplam therapy was initiated.

Conclusion

SMA patients with SMN1 variants may bypass SMA-NBS and can develop severe SMA, depending on variant type, regardless of SMN2 copy number.