Spinal muscular atrophy with five SMN2 copies: Phenotypic heterogeneity and implications for newborn screening and treatment decisions.

BACKGROUND

The severity of spinal muscular atrophy (SMA) is partially influenced by SMN2 copy number, although this relationship becomes less reliable at higher copy numbers. The implementation of newborn screening has led to increasing identification of presymptomatic infants with five SMN2 copies, a subgroup for which long-term clinical outcomes remain poorly defined. Consequently, treatment decisions regarding immediate intervention versus careful clinical observation remain challenging.

METHODS

We describe three patients with genetically confirmed SMA (each with homozygous SMN1 deletion and five SMN2 copies).

RESULTS

Marked phenotypic variability was observed. Two siblings identified through family screening showed divergent clinical courses despite a shared genetic background, with one developing adult-onset proximal weakness; the other remains asymptomatic. A third patient had adolescent-onset disease progressing to severe motor impairment. These findings highlight the limited prognostic value of SMN2 copy number.

CONCLUSION

Patients with five SMN2 copies represent a clinically heterogeneous group requiring careful longitudinal monitoring. Our findings highlight the limitations of SMN2 copy number as an independent prognostic marker and illustrate the growing challenges of treatment decision-making and therapy timing in the era of newborn screening.