Foundations · Year 1 · from Foundations
Case 1: Spinal Muscular Atrophy (Splicing Defect and Therapy)
Clinical Image
Source: Wikipedia - Spinal muscular atrophy - CC BY-SA 3.0
Case Presentation
A 4-month-old infant is brought for evaluation of progressive weakness and poor feeding. The parents note she has become "floppy" and has difficulty lifting her head. She was born full-term and initially seemed normal but has progressively lost motor milestones. Physical examination reveals severe hypotonia, absent deep tendon reflexes, tongue fasciculations, and paradoxical breathing (abdominal breathing with chest wall retraction due to intercostal weakness). Genetic testing confirms homozygous deletion of the SMN1 gene, consistent with spinal muscular atrophy type 1 (Werdnig-Hoffmann disease). The parents ask why she has disease when she still has the SMN2 gene. The physician explains that SMN2 is nearly identical to SMN1, but a single nucleotide difference creates a weak exon 7 splice site, causing most SMN2 transcripts to skip exon 7 and produce unstable, non-functional protein. She is started on nusinersen (Spinraza), an antisense oligonucleotide administered intrathecally that binds to an intronic splicing silencer in SMN2 pre-mRNA, promoting exon 7 inclusion and restoring functional SMN protein production. Alternatively, she could receive onasemnogene abeparvovec (Zolgensma), a gene therapy delivering functional SMN1. With early treatment, her prognosis is dramatically better than the historical natural history of SMA type 1.
Key Learning Points
- SMA results from loss of SMN1; the nearly identical SMN2 gene cannot compensate because a C-to-T transition weakens exon 7 splicing, causing it to be frequently skipped
- Nusinersen is an antisense oligonucleotide that blocks an intronic splicing silencer (ISS-N1), promoting exon 7 inclusion in SMN2 transcripts and restoring functional SMN protein
- This represents a triumph of understanding splicing biology to develop a disease-modifying therapy; gene therapy (Zolgensma) provides an alternative approach by delivering functional SMN1