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Spinal muscular atrophy with five SMN2 copies: Phenotypic heterogeneity and implications for newborn screening and
Olesja Parmova1,2, Blanka Adamova1,2
1Department of Neurology, Centre for Neuromuscular Diseases (Associated National Centre in the ERN EURO-NMD), University Hospital Brno, Brno, Czechia.
Insights
Spinal muscular atrophy (SMA) patients with five SMN2 copies show varied outcomes, challenging prognostic predictions. This highlights the need for careful monitoring and personalized treatment decisions in the era of newborn screening.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Spinal muscular atrophy (SMA) severity is linked to SMN2 gene copy number, but this correlation weakens with higher copies.
- Newborn screening identifies more presymptomatic SMA infants with five SMN2 copies, a group with undefined long-term outcomes.
- Treatment decisions for these infants are complex, balancing early intervention against watchful waiting.
Purpose of the Study:
- To investigate the clinical variability in spinal muscular atrophy (SMA) patients with five SMN2 copies.
- To assess the prognostic value of SMN2 copy number in genetically confirmed SMA cases.
- To inform treatment decision-making for presymptomatic infants identified through newborn screening.
Main Methods:
- Described three patients with genetically confirmed SMA, characterized by homozygous SMN1 deletion and five SMN2 copies.
- Analyzed clinical courses and outcomes in relation to genetic findings.
Main Results:
- Observed significant phenotypic heterogeneity among patients with five SMN2 copies.
- Two siblings with identical genetic profiles (five SMN2 copies) exhibited divergent clinical courses: one developed adult-onset weakness, while the other remained asymptomatic.
- A third patient presented with adolescent-onset SMA and severe motor impairment, underscoring the limited prognostic power of SMN2 copy number.
Conclusions:
- Patients with five SMN2 copies represent a clinically heterogeneous group requiring close longitudinal monitoring.
- SMN2 copy number alone is an insufficient prognostic marker for SMA.
- Newborn screening presents challenges in treatment timing and decision-making for SMA patients.
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.
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