Spinal muscular atrophy: clinical aspects and genotype-phenotype correlations in the assessment of disease severity

Abstract

Introduction: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by biallelic pathogenic variants or deletions in SMN1. Although SMN2 copy number is a major modifier of disease severity, phenotypic variability remains important. In pediatric practice, integrating genotype with age at onset, motor development, and the diagnostic pathway may support a more realistic assessment of disease severity. Materials and Methods: We analyzed 96 individuals evaluated between 2019 and 2024: 36 patients with genetically confirmed SMA and 60 genetically tested individuals negative for SMA, who served as controls. Genotype data included SMN1 status, SMN2 copy number and, when available, NAIP copy-number status. Clinical analyses were limited to SMA-confirmed patients and focused on age at symptom onset, initial motor signs, motor milestones, feeding or respiratory involvement, age at genetic confirmation, and previous diagnostic evaluations. Clinical burden was estimated as the total number of documented manifestations per patient. CNV-defined genotype groups were compared descriptively using non-parametric tests. To illustrate genotype-phenotype variability, two representative SMA cases with different SMN2/NAIP profiles and diagnostic trajectories were comparatively analyzed. Results: Among SMA patients, mean clinical burden was 3.57±1.69 manifestations per patient (range 2-8). Burden varied descriptively across CNV-defined genotype groups; however, differences were not statistically significant (Kruskal-Wallis p=0.356; Spearman ρ=0.046, p=0.792), supporting relevant intra-group heterogeneity. Clinically, early-onset cases were mainly characterized by hypotonia, reduced spontaneous movements, feeding or respiratory vulnerability, and faster functional decline. Lateronset cases were more often associated with delayed motor acquisitions, proximal weakness, fatigue, and slower progression. The comparative analysis highlighted this variability. One child with four SMN2 copies and heterozygous NAIP deletion (HN5S4 genotype) presented in early infancy and was referred relatively rapidly for molecular testing because of evident hypotonia and functional impairment. A second child with three SMN2 copies and no NAIP deletion (NN5S3 genotype) had later onset, partial acquisition of motor milestones, and a longer diagnostic odyssey involving repeated orthopedic, neurologic, and rehabilitation assessments before genetic confirmation. Conclusions: SMA severity assessment in pediatric patients should integrate molecular findings with the chronology and intensity of clinical manifestations. The statistical data confirm heterogeneous clinical burden across CNV-defined groups, while the two-case comparison makes this variability easier to communicate in a pediatric context. Considering the diagnostic odyssey observed in some SMA cases, detailed system-based clinical assessment may not always ensure a timely diagnosis when the initial signs are nonspecific or slowly progressive. Therefore, early genetic testing should be considered in children with hypotonia, progressive weakness, or delayed motor development. SMN2 copy number remains an important severity modifier, but this modifier alone does not fully predict clinical expression or time to diagnosis. In highly heterogeneous diseases with potentially irreversible neuromuscular impairment, evaluation of multiple genetic targets, including SMN2 and NAIP, is essential for severity stratification, timely therapeutic decisions, and improved quality of life.