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The aim of this retrospective study was to review body mass index (BMI) in a large cohort of Italian pediatric type 2 spinal muscular atrophy (SMA) patients, aged between 0 and 20 years and to establish possible differences in relation to a number of variables such as ventilation, motor function, and survival motor neuron 2 gene copies. Cross-sectional data were collected from 102 patients for a total of 344 visits. Standard growth charts for height and weight were used as reference, with age adjusted BMI calculated using the Center for Disease and Prevention Children’s BMI Tool. In the 344 visits, weight ranged between 3.90 and 83 kg, and the BMI between 8.4 and 31.6 with a BMI/age z-scores <  − 2SD present in 28% and BMI/age z-scores >  + 2SD in 9% of the measurements. The BMI/age z-scores were relatively stable < 5 years of age with an increasing number of patients <  − 2SD after the age of 5, and a wider range of BMI/age z-scores after the age of 13. A difference on the BMI/age z-scores was found among the different age subgroups (< 5, 5–12, ≥ 13 years). A multivariate analysis in 58 patients with longitudinal assessments showed that baseline BMI/age z-scores and gender were significantly contributing to the changes while other variables were not.Conclusion: Our results confirm that careful surveillance of weight and BMI/age z-scores is needed in type 2 SMA. Further studies, including assessments of chewing and swallowing and of lean/fat body mass, will help to better understand the possible mechanisms underlying weight issues.What is Known:• Feeding difficulties have been reported in a few studies and were invariably found in patients with type 1 SMA.• Type 2 SMA patients often have low BMI with a relevant number of patients requiring tube feeding.What is New:• Reduction in BMI/age z-score overtime appeared to depend on baseline BMI/age z-score and gender.• Patients with a low BMI/age z-score were at higher risk of developing further reduction.

Objective The aim of this paper was to report the 2‐year follow‐up in type I patients treated with Nusinersen and to assess whether possible changes in motor function are related to the subtype, age, or SMN2 copy number. Methods Sixty‐eight patients, with ages ranging from 0.20 to 15.92 years (mean: 3.96; standard deviation: +3.90) were enrolled in the study. All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the developmental section of the Hammersmith Infant Neurological Examination (HINE‐2) at the time they started treatment and 12 and 24 months after that. Results For both CHOP and HINE‐2 repeated measures analysis of variance showed a significant difference (P < 0.001) between baseline and 12 months, 12 months and 24 months, and baseline and 24‐month scores for the whole group. When age subgroups (<210 days, <2 years, 2–4 years, 5–11 years, 12–18 years) were considered, on the CHOP INTEND the difference was significant between baseline and 24 months in all age subgroups. On the HINE‐2, the difference between baseline and 24 months was significant in all the subgroups before the age of 4 years. Age was predictive of changes on both scales (P < 0.05), whereas SMN2 copy number and decimal classification were not. Interpretation Our results suggest that some improvement of motor function can be observed even after the first year of treatment. This is more obvious in the infants treated in the first 2 years but some improvement can also be found in older children.

The study reports real world data in type 2 and 3 SMA patients treated for at least 2 years with nusinersen. Increase in motor function was observed after 12 months and during the second year. The magnitude of change was variable across age and functional subgroup, with the largest changes observed in young patients with higher function at baseline. When compared to natural history data, the difference between study cohort and untreated patients swas significant on both Hammersmith Functional Motor Scale and Revised Upper Limb Module both at 12 months and at 24 months.

Objective This study investigated myostatin levels in SMA patients receiving disease‐modifying therapies (DMTs) to understand their relationship with treatment duration and functional status. Methods Our study includes both cross‐sectional and longitudinal analyses of myostatin levels in treated SMA patients. The longitudinal cohort included 46 treatment‐naive patients assessed at baseline and 12 months post‐treatment. Myostatin levels were measured using ELISA. Age‐matched controls (n = 89) were included for comparison. The cross‐sectional study included 128 patients with variable durations of treatment (from 0.4 to 7.2 years). In both cohorts, myostatin levels were correlated with SMA type, functional status, and clinical outcomes. Results Baseline myostatin levels were significantly lower than controls (p < 0.001), except during the neonatal period in presymptomatic patients. After 12 months of treatment, there were no significant changes compared to baseline levels (p = 0.1652). The only substantial changes were observed in presymptomatic neonates, who showed a reduction of myostatin despite treatment intervention. There was a significant correlation between myostatin levels, functional status, and SMA type both in the cross‐sectional and longitudinal groups. Interpretation This study demonstrates lower myostatin levels in SMA patients compared to controls. The association between myostatin levels, functional status, and SMA type suggests its possible role as a disease severity biomarker. The utility of myostatin as a biomarker for DMT response remains controversial; while we observed no significant increase in myostatin levels following treatment, we also did not observe the progressive reduction previously reported in untreated patients.

Abstract The possibility to identify patients with spinal muscular atrophy through neonatal screenings has highlighted the need for clinical assessments that may systematically evaluate the possible presence of early neurological signs. The aim of this study was to use the Hammersmith Neonatal Neurological Examination (HNNE) and a module specifically designed for floppy infants to assess the possible variability of neurological findings in infants identified through neonatal screening. The infants included in this study were identified as part of a pilot study exploring neonatal screening in two Italian regions. A neurological examination was performed using the HNNE and an additional module developed for the assessment of floppy infants. Seventeen infants were identified through the screening. One patient had 1 SMN2 copy, 9 had 2 copies, 3 had 3, and 4 had more than 3 copies. Nine of the 17 infants (53%) had completely normal results on both scales, 3 had minimal signs, and the other 5 had more obvious clinical signs. The number of SMN2 copies was related to the presence of abnormal neurological signs (p = 0.036) but two SMN2 copies were associated with variable clinical signs as they were found in some infants with respectively normal examination or obvious severe early signs.Conclusions: Our results suggest that the combination of both scales increases the possibility to detect neonatal neurological signs and to define different early patterns of involvement also identifying paucisymptomatic patients. What is Known:• The use of new therapeutic options in presymptomatic SMA patients leads to a dramatic reduction of the onset and severity of the diesease.• The already existing tools commonly used in Type I SMA (HINE and CHOP-intend) may not be suitable to identify minor neurological signs in the neonatal period.What is New:• Combining the HNNE and the floppy infant module, we were able to identify early neurological signs in SMA infants identified through newborn screening and may help to predict the individual therapeutic outcome of these patients.• Iinfants with 2 SMN2 copies identified through the screening had a more variable neonatal examination compared to those with three or more copies, in agreement with similar findings in older infants.

Background and purpose Spinal muscular atrophy (SMA) is a rare and progressive neuromuscular disorder with varying severity levels. The aim of the study was to calculate minimal clinically important difference (MCID), minimal detectable change (MDC), and values for the Hammersmith Functional Motor Scale Expanded (HFMSE) in an untreated international SMA cohort. Methods The study employed two distinct methods. MDC was calculated using distribution‐based approaches to consider standard error of measurement and effect size change in a population of 321 patients (176 SMA II and 145 SMA III), allowing for stratification based on age and function. MCID was assessed using anchor‐based methods (receiver operating characteristic [ROC] curve analysis and standard error) on 76 patients (52 SMA II and 24 SMA III) for whom the 12‐month HFMSE could be anchored to a caregiver‐reported clinical perception questionnaire. Results With both approaches, SMA type II and type III patients had different profiles. The MCID, using ROC analysis, identified optimal cutoff points of −2 for type II and −4 for type III patients, whereas using the standard error we found the optimal cutoff points to be 1.5 for improvement and −3.2 for deterioration. Furthermore, distribution‐based methods uncovered varying values across age and functional status subgroups within each SMA type. Conclusions These results emphasize that the interpretation of a single MCID or MDC value obtained in large cohorts with different functional status needs to be made with caution, especially when these may be used to assess possible responses to new therapies.

Neonatal screening for SMA has allowed the identification of infants who may present with early clinical signs. Our aim was to establish whether the presence and the severity of early clinical signs have an effect on the development of motor milestones. Infants identified through newborn screening were prospectively assessed using a structured neonatal neurological examination and an additional module developed for the assessment of floppy infants. As part of the follow-up, all infants were assessed using the HINE-2 to establish developmental milestones. Only infants with at least 24 months of follow-up were included. Normal early neurological examination ( n  = 11) was associated with independent walking before the age of 18 months while infants with early clinical signs of SMA ( n  = 4) did not achieve ambulation (duration follow-up 33.2 months). Paucisymptomatic patients ( n  = 3) achieved ambulation, one before the age of 18 months and the other 2 between 22 and 24 months.   Conclusion : Our findings suggest that early clinical signs may contribute to predict motor milestones development. What is Known: • There is increasing evidence of heterogeneity among the SMA newborns identified via NBS. • The proposed nosology describes a clinically silent disease, an intermediate category (‘paucisymptomatic’) and ‘symptomatic SMA’. What is New: • The presence of minimal clinical signs at birth does not prevent the possibility to achieve independent walking but this may occur with some delay. • The combination of genotype at SMN locus and clinical evaluation may better predict the possibility to achieve milestones.

The aim of this study was to assess the need for tube feeding in a cohort of treated infants with type I SMA and to identify predictive factors. All patients were classified at baseline, when treatment started, and at follow-up according to their functional level and the need for tube feeding. Fisher’s exact test was used to examine the associations between the outcome at the last follow-up and SMA type, SMN2 copy number, and baseline nutritional status. ANOVA was performed to compare CHOP INTEND scores and age at treatment initiation with outcomes. The cohort includes 75 type I SMA infants treated between 0.1 and 5 years of age. At the last follow-up, 34 had no need for tube feeding, 9 had tube feeding but were also able to be fed by mouth, and 32 had tube feeding and were unable to be fed by mouth. Thirty of the 41 infants with tube feeding at follow-up already had feeding difficulties when treatment was started. The need for tube feeding at follow-up was associated with the level of feeding involvement at baseline and with CHOP INTEND scores [ p  < 0.001] but not with SMN2 copy number, SMA type 1 subtypes or age at treatment. The results of this study suggest that the need for tube feeding is not frequent in treated infants with type I SMA and, when occurring, can be predicted by the level of feeding involvement and low CHOP INTEND scores at baseline. What is Known: • The advent of disease-modifying therapies is increasingly changing the approach to swallowing and nutritional management in type I SMA. • Clinical trials and real-world data using all three disease-modifying therapies report a rather wide variability of feeding outcome and need for tube feeding that is often related to different cohorts that makes comparison between studies very difficult. What is New: • The real-world findings of this study, including all the children treated since treatments became available, confirmed that the need for tube feeding is not an invariable finding. • The level of feeding involvement at baseline appears to be a reliable prognostic indicator of bulbar outcome. • The results highlight the need for interventional studies with structured Speech and Language Therapist protocols that will help to better understand the extent to which bulbar function can be maintained or regained even in children requiring tube feeding.

Background The aim of this international retrospective study was to assess 4‐year change using the Hammersmith Functional Motor Scale Expanded (HFMSE) in individuals with type II and III spinal muscular atrophy (SMA) treated with nusinersen and to establish predictors of HFMSE changes. Methods Individuals with type II or III SMA, and at least 4 years of nusinersen‐only treatment were included. All were assessed using the HFMSE. Age at baseline, sex, motor function, SMN2 copy number, and age of onset were also retrospectively collected. Linear mixed effect models were used to calculate yearly changes and trajectory predictors. Results We included 73 individuals with SMA type II (mean age 8.58 years, SD 7.91, IQR 3.04–10.70) and 111 type III (mean age 7.91 years, SD 17.83, IQR 8.15–34.42). Over 4 years, mean changes were + 4.18 (95% CI: 2.85–5.50) for SMA II and + 1.08 (95% CI: 0.12–2.04) for SMA III. Age (SMA II: −0.34\\[−0.51 to −0.17]; SMA III: −0.13\\[−0.20 to −0.06], p < 0.001) and baseline HFMSE (SMA II: 1.02\\[0.70–1.34]; SMA III: 0.79\\[0.71–0.87], p < 0.001) were the strongest predictors of progression, with younger age and higher baseline scores associated with better outcomes. Functional status was only predictive for type III (6.96\\[4.26–9.66]). Conclusion Our results confirm that, given a follow up of 4 years, there is a persistent impact of nusinersen on clinical progression that is better observed in younger patients with higher HFMSE scores at baseline, especially during the first 2 years of treatment. Four‐year trajectories of HMFSE‐related motor function in SMA II and III patients treatment with nusinersen.

Background and purpose Spinal muscular atrophy (SMA) is a genetic disorder caused by SMN1 gene mutations. Although studies on available disease‐modifying treatments have reported their efficacy and safety, long‐term natural history data are lacking for comparison. The aim of this prospective study was to report 4‐year changes on the Hammersmith Functional Motor Scale Expanded (HFMSE) in type II and III SMA in relation to several variables such as age, functional status and SMN2 copy number. Methods The study involves retrospective analysis of prospectively collected data from international datasets (Belgium, Italy, Spain, USA, UK). HFMSE longitudinal changes were analyzed using linear mixed effect models, examining annualized HFMSE change and its association with variables such as age at baseline, sex, motor function, SMN2 copy number. Results In SMA type II (n = 226), the 4‐year mean change was −2.20 points. The largest mean changes were observed in sitters aged 5–14 years and the lowest in those who lost the ability to sit unsupported. In SMA type III (n = 162), the 4‐year mean change was −2.75 points. The largest mean changes were in those aged 7–15 years, whilst the lowest were in those below 7 and in the SMA type IIIa subgroup over 15. Age and score at baseline were predictive of 4‐year changes. Conclusions Our findings provide natural history reference data for comparison with long‐term follow‐up of clinical trials or real‐world data, highlighting the need to define patterns of changes in smaller SMA subgroups instead of reporting mean changes across an entire SMA cohort.