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.
