NM_000344.4(SMN1):c.801G>A (p.Trp267Ter)

For SMN1 c.801G>A (p.Trp267Ter), a pathogenic nonsense variant that abolishes SMN protein production from the SMN1 gene, nusinersen (Spinraza) represents the first and most extensively validated RNA therapy for spinal muscular atrophy. Rather than correcting the SMN1 mutation directly, nusinersen is an intrathecally delivered ASO that modifies SMN2 pre-mRNA splicing by blocking the intronic splicing silencer ISS-N1 in intron 7, thereby promoting exon 7 inclusion and increasing production of full-length functional SMN protein from the paralogous SMN2 gene. This elegant approach exploits the unique gene duplication biology of SMA: all patients retain at least one copy of SMN2, which differs from SMN1 by a single C-to-T transition in exon 7 that causes predominant exon 7 skipping. By correcting this splicing defect pharmacologically, nusinersen restores SMN protein without touching the mutant SMN1 locus.

The ENDEAR Phase 3 trial (PMID: 29091570, Finkel et al., NEJM 2017) in infantile-onset SMA (type 1) demonstrated 51% higher probability of motor milestone response vs sham, and 47% reduction in risk of death or permanent ventilation. The CHERISH Phase 3 trial in later-onset SMA showed significant improvement in HFMSE motor scores. Nusinersen received FDA approval in December 2016. Long-term follow-up data (>5 years, SHINE extension study) show sustained or continued motor function improvement with chronic intrathecal dosing. Pre-symptomatic treatment (NURTURE study) in infants identified by family history or newborn screening shows dramatic results: the majority achieve independent walking, approaching normal motor development. For p.Trp267Ter specifically, this nonsense variant produces zero functional SMN1 protein, making the patient entirely dependent on SMN2-derived SMN — the exact substrate that nusinersen augments. SMN2 copy number remains the strongest modifier: patients with 3-4 copies respond better than those with 2 copies.

Nusinersen requires lifelong intrathecal administration: 4 loading doses over 2 months followed by maintenance doses every 4 months via lumbar puncture. This is invasive, particularly in young children, and in patients with scoliosis or spinal fusion where lumbar access may be compromised. Treatment cost is substantial (~$750,000 first year, ~$375,000/year maintenance). While nusinersen improves outcomes, it does not fully restore normal motor function in most patients — the degree of motor neuron loss at treatment initiation is the key determinant of residual disability. Compared to onasemnogene abeparvovec (gene therapy, single IV dose), nusinersen requires chronic dosing but has a longer safety track record and broader age eligibility. Risdiplam (Evrysdi), an oral SMN2 splicing modifier with the same mechanism, now offers a less invasive alternative to intrathecal nusinersen. For p.Trp267Ter, SMN2 copy number should guide therapeutic strategy: low copy number (1-2) may warrant gene therapy rather than splicing modification alone.