Keywords spinal muscular atrophy - children - nusinersen - respiratory function - bulbar function
Introduction
Spinal muscular atrophy (SMA) stands as a significant autosomal recessive disorder that originates from mutations in the survival motor neuron gene 1 (SMN1 ).[1 ] These mutations result in a reduction of the SMN protein, which is ubiquitously expressed, with a particularly pronounced effect in the α-motor neurons located within the anterior horn of the spinal cord.[1 ] This specific vulnerability of motor neurons to the lack of SMN protein leads to neural death and progressive muscle weakness.[1 ] SMA manifests in varied forms, with classifications ranging from pediatric types SMA 0 to 3 to an adult-onset SMA 4.[2 ] These classifications revolve around the age at which symptoms emerge and the peak of motor achievements at presentation.[3 ]
Pivotal to the clinical presentation of SMA is the gamut of symptoms it elicits.[1 ] Common symptoms encompass progressive muscle weakness which, in severe forms, can impair mobility, respiration, and swallowing.[1 ] In children with SMA type 1, the ailment manifests as intense muscle weakness from an early age, affecting both the bulbar and respiratory systems. Such children are unable to sit without assistance, and in the absence of specialized drug treatments or ventilator and nutritional aid, their life expectancy rarely surpasses 2 years.[4 ] SMA's prevalence is concerning; studies estimate it affects 1 in 10,000 live births.[5 ]
Nusinersen, and two other novel drugs (onasemnogene abeparvovec and risdiplam) have surfaced as groundbreaking treatments of SMA.[3 ]
[6 ] Nusinersen, an antisense oligonucleotide administered intrathecally, acts on the pre-mRNA splicing of the SMN2 gene, facilitating an increase in the inclusion of exon 7 transcripts in the SMN2 mRNA, which in turn enhances the amount of functional SMN protein.[6 ] Following successful clinical trials, regulatory agencies, including the United States Food and Drug Administration and the European Medicines Agency, approved its use in 2016 and 2017, respectively.[7 ] While there are data from both clinical trials and real-world settings,[8 ]
[9 ]
[10 ]
[11 ]
[12 ]
[13 ]
[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ] orphan drugs, including nusinersen at the time of its authorization, often receive approval based on limited evidence.[26 ] Therefore, there is still a notable knowledge gap, especially concerning children treated outside of controlled trial environments. This study aims to evaluate the impact of nusinersen, in conjunction with standard care,[27 ] on bulbar function, respiratory function, and the need for respiratory support among pediatric SMA patients.
Methods
Study Design and Population
This prospective observational study involved pediatric SMA patients (types 1–3) treated with nusinersen at Spain's Hospital Universitario Virgen del Rocío (HUVR). Patient enrollment started in March 2017 via an “expanded access program” for the orphan drug and continued after a March 2018 reimbursement agreement. The last patient was included in May 2021. The study was closed and the results were analyzed when the last patient included had 25 months of follow-up, on June 30, 2023. All patients had confirmed SMN1 gene deletions or mutations and were enrolled in pretreatment, with a follow-up minimum of 24 months. No exclusion criteria were applied.
The research protocol was approved by the independent ethics committee at HUVR on November 29, 2017. This study followed the Helsinki Declaration principles and adhered to the EU General Data Protection Regulation, ensuring all personal identifiers were removed from the findings.
Objectives and Variables
For each patient, clinical status and SMA type were recorded, along with sex, SMN2 copy number, scoliosis, scoliosis surgery history, use of mechanical insufflation–exsufflation (MIE), and mechanical ventilation (MV). Key details such as age at SMA diagnosis and treatment initiation were also recorded. Scoliosis was diagnosed when a lateral deviation of the spine with concordant vertebral rotation was present (measured by means of the Cobb angle of at least 10 degrees in the supine position).
Using World Health Organization motor milestones,[28 ] functional status was assessed through the items “non-sitting,” “independent sitting” (no support needed at any time), and “walking” as peak states.
To assess primary respiratory characteristics, we evaluated the use of assisted ventilation, distinguishing between invasive and noninvasive types, and classified by duration (partial, <16 hours/day; permanent, ≥16 hours/day). For type 2/3 SMA patients over 6 years old, when feasible, respiratory tests including spirometry (measuring FVC and FEV1) were conducted, using the Global Lung Initiative Network's standardized lung function reference values.[29 ]
Additional clinical data on dysphagia, feeding support needs, and gastrostomy (for long-term feeding support) were collected. The Oral and Swallowing Abilities Tool (OrSAT),[30 ] a validated score specifically designed to record oral abilities, swallowing, and feeding in young type 1 SMA patients, was also utilized. In addition, a videofluoroscopic swallowing study (VFSS) was performed.
The safety analysis was descriptive, and no statistical tests were conducted.
Statistical Analysis
Qualitative variables were presented in tables and graphs with absolute and relative values, and quantitative variables were shown via central tendency and dispersion measures. Data normality was checked using the Shapiro–Wilk test. The Mann–Whitney U test compared independent samples for quantitative variables, while the chi-square test was used for categorical variables. Follow-up assessments employed Friedman's test for quantitative variables, Cochran's Q test for qualitative variables, and ordinal logistic regression for repeated measures. Statistical significance was set at p < 0.05. Analyses were conducted using RStudio (Posti; Boston, MA) and IBM SPSS version 29 (IBM; Armonk, NY).
Results
Baseline Clinical Characteristics
This study enrolled 28 pediatric patients, including 20 males ([Supplementary Table S1 ] [available in the online version only]). The cohort comprised 11 with SMA type 1 (6 type 1b and 5 type 1c), 12 with type 2, and 5 with type 3. Type 1 patients were diagnosed and treated significantly earlier than types 2 and 3 (p < 0.001), with a longer duration between diagnosis and treatment start in types 2 and 3 (p = 0.002).
Genetic profiling showed that 81.8% of type 1 patients and 11.8% of types 2 and 3 had two SMN2 gene copies (p < 0.001). In addition, 82.4% of types 2 and 3 and 18.2% in type 1 had three SMN2 copies. One type 3 patient had four SMN2 copies (5.8%); 63.6% of type 1 patients required MV compared with 23.5% in types 2 and 3 (p = 0.053; [Supplementary Table S1 ] [available in the online version only]), with 42.9% of type 1 and 0% of types 2 and 3 needing it for >16 hours daily (p = 0.236). One type 1b patient needed invasive permanent ventilation. No ventilation was required in type 3 patients.
Functional status analysis showed that all type 1 patients were unable to sit independently, while all type 2/3 patients could, and all type 3 patients could also walk unaided.
At baseline, scoliosis prevalence, spine surgery rates, use of MIE, and hospitalization for respiratory issues showed no statistically significant differences between type 1 and types 2 and 3 patients.
Peak Functional Status Evolution throughout the Study of All Populations
In evaluating peak functional status improvement at 6, 12, and 24 months posttreatment initiation, progress was noted at each time point ([Fig. 1 ]; [Supplementary Table S2 ] [available in the online version only]). At 6 months, one type 1b patient and three type 1c patients sat independently, while two type 2 patients walked unassisted. By 12 months, two type 1b and three type 2 patients improved in their functional status. By 24 months, three type 1b patients sat independently. No changes were seen in type 3 throughout the study.
Fig. 1 Functional status evolution throughout the study of all populations during the first 24 months of treatment with nusinersen.
Associated Parameters of Gain of Functional State
Odds of gain of functional state, adjusted for the “time between diagnosis and treatment initiation,” were observed at 2.30 (p = 0.030) at 6 months, 3.93 (p = 0.002) at 12 months, and 4.64 (p = 0.001) at 24 months ([Supplementary Table S3 ] [available in the online version only]). The analysis effect of the “time between diagnosis and treatment initiation” odds was 1.02 (p = 0.052).
When adjusted for the “age at first nusinersen administration,” the odds of gain of functional state were 1.63 (p = 0.052) at 6 months, 2.49 (p = 0.004) at 12 months, and 2.80 (p = 0.002) at 24 months. The “age at first nusinersen administration” onset contributed to an odds ratio (OR) of 1.02 (p = 0.042).
Respiratory Evolution Throughout the Study
Pulmonary Function Evolution in Types 2 and 3 Patients
Pulmonary functions were assessed with forced spirometry, analyzing FVC and FEV1 measurements when possible in type 2 patients ([Table 1 ]).
Table 1
Evolution of pulmonary function of spinal muscular atrophy type 2 patients
Mean (SD)
Variation
p -Value
SMA 2
FVC
Follow-up time
Baseline
−3.55 (1.8)
–
6 months
−1.07 (2.57)
2.48
0.002
12 months
−1.99 (2.18)
1.56
0.018
24 months
−1.69 (2.55)
1.86
0.013
FEV1
Follow-up time
Baseline
−3.52 (1.8)
–
6 months
−1.62 (2.54)
1.90
0.011
12 months
−2.04 (2.08)
1.48
0.035
24 months
−1.81 (2.52)
1.71
0.020
Abbreviations: SD, standard deviation; SMA, spinal muscular atrophy.
Analysis based on generalized linear equations (ordinal logistic regression of repeated measures).
In type 2 patients, there was a notable improvement in the mean FVC z-score at 6 months (p = 0.002), 12 months (p = 0.018), and 24 months (p = 0.013) throughout the 2-year period. Regarding FEV1 z-score, type 2 patients showed a significant improvement in the mean at 6 months (p = 0.011), 12 months (p = 0.035), and 24 months (p = 0.020).
Concerning type 3 patients FVC and FEV1 showed normal values and no significant changes through the follow-up ([Supplementary Tables S3 ] and [S4 ] [available in the online version only]).
Mechanical Insufflator–Exsufflator Evolution in Type 1c Patients
Usage of an MIE significantly rose in type 1c patients ([Supplementary Fig. S1 ] [available in the online version only]), with no variations in other groups.
Need for Mechanical Ventilation Evolution in All Patients
Throughout the study period, the requirement for MV among SMA patients demonstrated variability by type and over time ([Table 2 ]). Specifically, patients with type 1b and 1c SMA exhibited a predominant need for MV throughout the study duration, with type 1b patients presenting a higher proportion requiring ventilation ≥16 hours/day and a greater percentage necessitating MV overall. The majority of type 2 and 3 SMA patients did not require MV, a trend that remained consistent throughout the study.
Table 2
Need for mechanical ventilation in all patients throughout the study
Spinal muscular atrophy
1b
(n = 6)
1c
(n = 5)
2
(n = 12)
3
(n = 5)
Need of mechanic ventilation (none; invasive; noninvasive), n (%)
Baseline
1 (17.3); 1 (17.3); 4 (66.7)
3 (60.0); 0 (0.0); 2 (40.0)
9 (75.0); 0 (0.0); 3 (25.0)
4 (80.0); 0 (0.0); 1 (20.0)
6 months
1 (17.3); 2 (33.3); 3 (50.3)
2 (40.0); 0 (0.0); 3 (60.0)
8 (66.7); 0 (0.0); 4 (33.3)
4 (80.0); 0 (0.0); 1 (20.0)
12 months
0 (0.0); 2 (33.3); 4 (66.7)
2 (40.0); 0 (0.0); 3 (60.0)
8 (66.7); 0 (0.0); 4 (33.3)
4 (80.0); 0 (0.0); 1 (20.0)
24 months
0 (0.0); 2 (33.3); 4 (66.7)
2 (40.0); 0 (0.0); 3 (60.0)
9 (75.0); 0 (0.0); 3 (25.0)
4 (80.0); 0 (0.0); 1 (20.0)
Need of mechanic ventilation <16 hours/day, n (%)
Baseline
3 (50.0)
1 (20.0)
3 (25.0)
1 (20.0)
6 months
2 (33.3)
3 (60.0)
4 (33.3)
1 (20.0)
12 months
4 (66.7)
3 (60.0)
4 (33.3)
1 (20.0)
24 months
4 (66.7)
3 (60.0)
3 (25.0)
1 (20.0)
Need of permanent mechanic ventilation (≥16 hours/day), n (%)
Baseline
2 (33.3)
1 (20.0)
0 (0.0)
0 (0.0)
6 months
3 (50.0)
0 (0.0)
0 (0.0)
0 (0.0)
12 months
2 (33.3)
0 (0.0)
0 (0.0)
0 (0.0)
24 months
2 (33.3)
0 (0.0)
0 (0.0)
0 (0.0)
Factors Associated with the Need for Mechanical Ventilation in All Patients
SMA 1b (p < 0.001) and 1c (p = 0.018) patients showed a significantly higher rate of MV use than type 2/3 patients ([Table 3 ]).
Table 3
Factors associated with the need for mechanical ventilation in spinal muscular atrophy type 1 patients
Regression coefficient (β)
OR (95% CI)
p -Value
Need of mechanic ventilation
SMA[a ]
1b
5.60
271 (15 − 4832)
<0.001
1c
2.34
10.39 (1.49 − 72.61)
0.018
Follow-up time[b ]
Baseline
–
6 months
0.605
1.83 (0.99 − 3.36)
0.050
12 months
0.743
2.10 (0.90 − 4.93)
0.088
24 months
0.372
1.45 (0.56 − 3.75)
0.443
Age at first nusinersen administration (months)
0.020
1.02 (1.01 − 1.04)
0.012
Mechanic ventilation ≥16 months
SMA[a ]
1b
5.95
382 (23 − 6,364)
<0.001
1c
2.67
14.39 (1.85 − 112)
0.011
Follow-up time[b ]
Baseline
–
6 months
0.472
1.60 (0.84 − 3.08)
0.157
12 months
0.597
1.82 (0.77 − 4.27)
0.171
24 months
0.004
1.05 (0.37 − 2.97)
0.934
Age at first nusinersen administration (months)
0.025
1.03 (1.01 − 1.04)
0.002
Abbreviations: CI, confidence interval; OR, odds ratio; SMA, spinal muscular atrophy.
Analysis based on generalized linear equations (ordinal logistic regression of repeated measures).
a Versus SMA 2/3.
b Versus baseline.
Follow-up time indicated increasing ORs at 6 and 12 months, not reaching statistical significance, with the trend diminishing by 24 months (p = 0.443). Age at first nusinersen administration was significant (p = 0.012, OR 1.02), indicating a higher likelihood of needing MV with older age at treatment start.
SMA 1b (p < 0.001) and 1c (p = 0.011) also had a higher OR for needing ventilation ≥16 hours/day compared with type 2/3 ([Table 3 ]), with a decreasing trend at 6 (p = 0.157) and 12 months (p = 0.171), and minimal association at 24 months (p = 0.934). Age at first administration was again significant (p = 0.002, OR 1.03), suggesting a higher likelihood of requiring extended ventilation with older age at treatment start. Two type 1c patients never needed MV, while a type 1b patient, initially on invasive ventilation, had his tracheostomy removed 54 months posttreatment starting at 58 months of age.
Bulbar Function Evolution
Through the follow-up, SMA type 1c patients retained the ability to feed orally, whereas type 1b individuals gradually reduced their capability ([Table 4 ]). At 6 months, 16.67% of type 1b versus 100% of type 1c patients could feed orally (p = 0.015), dropping to none in type 1b by 12 months (p = 0.002). The oldest type 1c patient required supplemental feeding support, while all type 1b individuals transitioned to exclusive feeding support by the end of the study (p = < 0.001).
Table 4
Evolution of bulbar function between subgroups of spinal muscular atrophy type 1 patients
SMA
p -Value
1b
1c
Able to take food by mouth, n (%)
Baseline
2 (33.3)
5 (100)
0.061
6 months
1 (16.7)
5 (100)
0.015
12 months
0 (0.0)
5 (100)
0.002
24 months
0 (0.0)
5 (100)
0.002
Need of feeding support, n (%)
Baseline
–
No
2 (33.3)
4 (80.0)
0.157
Supplementary
2 (33.3)
1 (20.0)
Exclusive
2 (33.3)
0 (0.0)
6 months
No
0 (0.0)
4 (80.0)
0.002
Supplementary
1 (16.7)
1 (20.0)
Exclusive
5 (83.3)
0 (0.0)
12 months
No
0 (0.0)
4 (80.0)
<0.001
Supplementary
0 (0.0)
1 (20.0)
Exclusive
6 (100)
0 (0.0)
24 months
No
0 (0.0)
4 (80.0)
<0.001
Supplementary
0 (0.0)
1 (20.0)
Exclusive
6 (100)
0 (0.0)
Gastrostomy, n (%)
Baseline
1 (16.7)
1 (20.0)
1.00
6 months
5 (83.3)
1 (20.0)
0.800
12 months
6 (100)
1 (20.0)
0.015
24 months
6 (100)
1 (20.0)
0.015
OrSAT, n (%)
Baseline
–
Severe impairment
5 (83.3)
0 (0.0)
0.002
Moderate impairment
1 (16.7)
1 (20.0)
Normal
0 (0.0)
4 (80.0)
6 months
Severe impairment
5 (83.3)
0 (0.0)
0.002
Moderate impairment
1 (16.7)
1 (20.0)
Normal
0 (0.0)
4 (80.0)
12 months
Severe impairment
6 (100)
0 (0.0)
<0.001
Moderate impairment
0 (0.0)
1 (20.0)
Normal
0 (0.0)
4 (80.0)
24 months
Severe impairment
6 (100)
0 (0.0)
<0.001
Moderate impairment
0 (0.0)
1 (20.0)
Normal
0 (0.0)
4 (80.0)
Abbreviations: OrSAT, Oral and Swallowing Abilities Tool; SMA, spinal muscular atrophy.
Analysis based on generalized linear equations (ordinal logistic regression of repeated measures).
By 12 and 24 months, all type 1b patients underwent gastrostomy (p = 0.015), while only the eldest type 1c patient required pretreatment.
VFSS was performed on 8 of the 11 patients (4 type 1b and 4 type 1c). All type 1b patients presented findings compatible with severe dysphagia, and an alternative feeding route was recommended. In contrast, type 1c patients were classified as having mild or moderate dysphagia, and oral feeding was recommended, with adaptation of textures in some cases.
Type 1b patients showed a significantly higher prevalence of severe impairment on the OrSAT scale at baseline than type 1c (p = 0.002), worsening over 24 months, with all type 1b patients severely impaired by the end (p < 0.001 at 12 and 24 months).
Scoliosis
A notable increase in scoliosis was observed in type 1b patients (p = 0.036) and type 2 patients (p = 0.194; [Supplementary Fig. S2 ] [available in the online version only]). During follow-up, one type 1c patient underwent surgery, with no changes in other groups.
Safety
Two type 1c patients discontinued treatment after 36 and 48 months due to significant drug administration challenges and limited benefits, both having substantial scoliosis. One underwent spinal surgery before treatment and the other at 48 months, 11 months posttreatment start. Additionally, a type 1b patient required surgery for severe symptomatic hydrocephalus at 7 months. There were no other adverse events or deaths during the study.
Discussion
Although previous studies on SMA have been conducted in Spain,[31 ]
[32 ] including a real-world multicenter observational study of adult patients treated with nusinersen,[33 ] to our knowledge, this is the first publication to present real-world data on a pediatric SMA cohort in this country. Moreover, previous real-world studies of SMA children were mostly focused on type 1 patients. The present study extensively examines motor, respiratory, and bulbar functions in SMA types 1, 2, and 3 pediatric patients treated with nusinersen over a 60-month period.
Upon reviewing the demographics and baseline characteristics of our cohort, a distinct gender imbalance emerges, with males highly predominating. Notably, this trend deviates from findings in the published study on adult SMA nusinersen-treated patients in Spain.[33 ] While certain investigations have identified a male predominance in SMA, others have negated such findings.[34 ] A recent comprehensive review incorporating data from 17 diverse countries indicated no significant gender disparity in SMA prevalence.[34 ] Interestingly, this analysis also posited that the clinical presentation of SMA may differ between genders, potentially pointing toward a heightened vulnerability in males.[34 ] Such distinctions warrant consideration in the contextual analysis of our research outcomes when compared with similar studies.
The evaluation of functional status, often the most tangible outcome for both patients and their families, demonstrated improvements during the follow-up. Predominantly, there was an upward trajectory in functional capacities throughout the therapeutic intervention with nusinersen. Data delineation revealed a trend of improvement in functional status that reached statistical significance, suggesting that a younger age at the initiation of treatment may influence the gain of functional status. Notably, this change is greater in type 1 patients. Of the 11 patients, only 2 showed no improvement, and these were the type 1c patients who started treatment later, at 39 and 86 months, respectively. This finding resonates with the paradigm of early intervention posited in the extant real-world nusinersen literature.[8 ]
[9 ]
[10 ]
[11 ]
[12 ]
[13 ]
[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ] Such data further consolidate the hypothesis that delayed therapeutic intervention may not reciprocate the optimal outcomes anticipated from an early intervention trajectory.
In our cohort, we applied the standard of care that advocates for proactive respiratory support in type 1 patients.[27 ] This may contribute to a notably high number of patients with ventilatory support among SMA type 1 patients. This reliance on MV in certain situations underscores the profound respiratory challenges often encountered in this demographic, echoing findings from prior studies. Moreover, type 1b SMA patients required much more breathing assistance compared with type 1c patients. For context, older type 1c patients were already treated with ventilation before the start of their treatments, at ages 39 and 86 months. In our examination of respiratory function, it is noteworthy that the requirement for permanent ventilation (exceeding 16 hours/day) diminished during the study duration. This was maintained by two type 1b patients. One was the oldest type 1b patient, who was already on permanent ventilation at the study's commencement. The other required surgery for severe symptomatic hydrocephalus at the age of 7 months, as mentioned in the “Safety” section. Additionally, the need for ventilatory support showed a decline, with certain type 1c patients not necessitating any form of respiratory assistance. Remarkably, these patients could independently and adequately feed orally. Non-invasive ventilation (NIV) emerged as the preferred option for nearly all participants, barring instances where other comorbidities influenced the decision. This is in-line with the standard care considerations for SMA type 1 patients, though there may be instances where it is not routinely essential. Furthermore, one type 1b patient successfully transitioned from having a tracheostomy to relying on NIV. Type 3 patients showed no changes in pulmonary function tests, while for type 2 patients, pulmonary function seemed to show improvement up until the 24th month. Improvement in pulmonary function was accompanied by improvement in motor function soon after nusinersen initiation. Stability of mean pulmonary functions occurs despite an increasing number of scoliosis. Collectively, these findings underscore the potential of nusinersen treatment in enhancing the respiratory function of SMA patients. Additionally, the association between “age at first nusinersen administration” and both “need of mechanical ventilation” and “mechanical ventilation ≥16 hours” highlights the advantages of early intervention, a pattern also observed in the functional status evolution of this patient cohort.
This study confirms that in type 2/3 patients, there is no significant bulbar impairment and no nutritional support is needed. However, the baseline evaluation revealed a significantly deteriorated status in type 1 patients, as anticipated. Notably, type 1b patients exhibited more severe difficulties than type 1c in several parameters. Over 24 months of nusinersen treatment, type 1b patients showed progressive oral feeding decline, while type 1c patients maintained stability. This observation aligns with the findings of van der Heul and collaborators,[35 ] wherein bulbar function deteriorated between the ages of 8 and 12 months among patients under nusinersen treatment. Pechmann et al provided corroborative evidence, noting an increase in tube feeding in SMA pediatric patients undergoing nusinersen for a 38-month follow-up period.[18 ] While present real-world data suggest that nusinersen may not have a positive impact on bulbar function, there is still hope in ongoing research. The DEVOTE study is actively exploring the efficacy and safety of a higher nusinersen dosage.[36 ] This study will bring some light to ascertain if bulbar and respiratory outcomes might benefit from the potentially enhanced bioavailability in the bulbar or higher cervical motor nuclei with this increased dosage.[36 ] Future results will be crucial in determining whether a higher dose of nusinersen is both effective and safe for SMA patients.
In addressing SMA-related feeding and swallowing issues, our extended follow-up offers further insights. Children with SMA type 1b experiencing severe difficulties in these areas benefit significantly from speech and language therapies, especially those able to swallow voluntarily, usually around 5 to 6 years old. This emphasizes the value of specialized interventions for enhancing life quality in children with these developmental challenges.
In the context of nusinersen administration, it is pivotal to note its intrathecal delivery method. Recent literature indicates that nusinersen can reach the central nervous system, plasma, and systemic tissues.[37 ] However, its ability to achieve the necessary concentration across all neuromuscular junctions—to counteract or prevent the detrimental effects of SMA disease—remains unconfirmed. This could potentially explain the unresolved symptoms observed in several patients in our cohort. While nusinersen has made significant strides in reducing mortality rates and improving various clinical manifestations, the potential of alternative therapeutic strategies—either in combination or independently—or increased dosages of nusinersen should be explored in future research.[38 ]
Regarding safety data, adverse events reported were consistent with recognized side effects of lumbar puncture, linked to the underlying disease, or were not seen more frequently than in other infants of a similar age. Therefore, we identified no novel safety concerns regarding the treatment with nusinersen. However, it is important to note that two treatments were discontinued based on feedback from the patients' families and on objective clinical criteria. They observed no notable improvements in respiratory, motor, or bulbar function, and found the administration process to be both challenging and cumbersome for the child.
In reflecting on the findings of this study, it is important to emphasize that no fatalities were reported during its duration. This outcome is particularly significant in light of the severe symptoms associated with this disease.[4 ] From our clinical experience, such a result contrasts sharply with the outcomes observed prior to the introduction of nusinersen treatment in the clinical management of SMA patients. Notably, before nusinersen became available, survival beyond the age of 5 or 6 years was exceedingly rare for patients with SMA type 1 in our own experience. The advent of nusinersen has not only improved survival rates but also enabled the conduct of studies like this one, which can augment the data obtained from clinical trials. Clinical trials often occur under more controlled conditions than those encountered in real-world clinical settings.[39 ] Therefore, studies like ours are crucial for providing a more comprehensive understanding of the treatment's impact on everyday clinical practice.
Our study, like many real-world investigations of rare diseases, possesses inherent limitations.[40 ] One primary concern is the small sample size, which may lack the necessary statistical power to discern a genuine effect, possibly accounting for the absence of statistically significant findings across tested variables. The small size of the sample is especially pertinent given that the groups of different SMA types are not large enough to conduct analyses with adequate statistical power. This situation hinders the ability to draw definitive conclusions from the data, underscoring the need for larger sample sizes in future studies to ensure more robust and statistically significant results. Moreover, the single-center nature of our research further raises questions about the generalizability of our results to a broader population. Additionally, while our follow-up duration aligns with other real-world studies on SMA children, it remains brief relative to the entire course of the disease, offering only a limited view of its natural progression.
Conclusion
In conclusion, this study provides valuable insights into the real-world clinical history of pediatric patients with SMA and the treatment experience with nusinersen. Our findings add to the growing body of real-world evidence suggesting that nusinersen is an effective treatment for early-onset SMA. In addition to increased survival of type 1 patients, our results suggest that early use of nusinersen produces some improvement in the pulmonary function in type 2 patients, and reduces the need for respiratory support and permanent ventilation (≥16 hours/day) in the most severe phenotypes. However, it is vital to note that bulbar and respiratory functions need to be closely monitored, as these do not improve equivalently to motor function. Future research should build upon these insights, to offer a more definitive view of long-term outcomes and refine therapeutic approaches.
