Early neurological signs in infants identified through neonatal screening for SMA: do they predict outcome?

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.

Communicative development inventory in type 1 and presymptomatic infants with spinal muscular atrophy: a cohort study.

OBJECTIVE: The aim of this study was to assess early language acquisitions in treated individuals with spinal muscular atrophy (SMA) type 1 and in infants identified by newborn screening (NBS). METHODS: Parents of SMA individuals aged between 8 and 36 months were asked to fill in the MacArthur-Bates Communicative Development Inventory (MB-CDI) that assesses comprehension, gesture and expressive skills. A follow-up assessment was performed in 21 of the 36. RESULTS: The MB-CDI was completed by parents of 24 type 1 and 12 infants identified by NBS. Comprehension skills were preserved in 81% of the type 1 SMA and in 87% infants identified by NBS. Gesture abilities were <5th centile in 55% of the type 1 SMA and in none of those identified by NBS. Lexical expressions were <5th centile in more than 80% type 1 SMA and in 50% of infants identified by NBS. At follow-up, despite an increase in lexical expression skills, the scores remained below the fifth centile in 43% type 1 SMA and in 86% of infants identified by NBS. CONCLUSIONS: These results suggest that language and communication development may follow a similar pattern to that observed in motor function with the possibility to develop skills (eg, ability to say clear words) that are not usually present in untreated infants but with a level of performance that does not reach that of their typically developing peers.

Early treatment of type II SMA slows rate of progression of scoliosis.

BACKGROUND: Type II spinal muscular atrophy (SMA) often leads to scoliosis in up to 90% of cases. While pharmacological treatments have shown improvements in motor function, their impact on scoliosis progression remains unclear. This study aims to evaluate potential differences in scoliosis progression between treated and untreated SMA II patients. METHODS: Treatment effect on Cobb's angle annual changes and on reaching a 50° Cobb angle was analysed in treated and untreated type II SMA patients with a minimum 1.5-year follow-up. A sliding cut-off approach identified the optimal treatment subpopulation based on age, Cobb angle and Hammersmith Functional Motor Scale Expanded at the initial visit. Mann-Whitney U-test assessed statistical significance. RESULTS: There were no significant differences in baseline characteristics between the untreated (n=46) and treated (n=39) populations. The mean Cobb angle variation did not significantly differ between the two groups (p=0.4). Optimal cut-off values for a better outcome were found to be having a Cobb angle <26° or an age <4.5 years. When using optimal cut-off, the treated group showed a lower mean Cobb variation compared with the untreated group (5.61 (SD 4.72) degrees/year vs 10.05 (SD 6.38) degrees/year; p=0.01). Cox-regression analysis indicated a protective treatment effect in reaching a 50° Cobb angle, significant in patients <4.5 years old (p=0.016). CONCLUSION: This study highlights that pharmacological treatment, if initiated early, may slow down the progression of scoliosis in type II SMA patients. Larger studies are warranted to further investigate the effectiveness of individual pharmacological treatment on scoliosis progression in this patient population.

Profile of cognitive abilities in spinal muscular atrophy type II and III: what is the role of motor impairment?

There has recently been some concern on possible cognitive impairment in patients with Spinal Muscular Atrophy (SMA). The aim of this study was to assess cognitive profiles in type II and III SMA with a focus on individual indexes and possible correlations with motor function. 57 type II and III individuals, aged 3.5-17 years, were consecutively enrolled in a prospective, multicentric study. Cognitive function was assessed using age-appropriate Weschler Scales. Motor function was concomitantly assessed using disease-specific functional scales. Only 2 individuals (3%) had a intellectual disability of mild degree while the others were within normal range, with no significant difference in relation to SMA type, gender or functional status. While the overall quotients were mostly within normal range, some indexes showed wider variability. A significant positive medium correlation was found between Processing Speed Index and motor functional scores. Working memory had lower scores in type III patients compared to type II. Intellectual disability is uncommon in type II and III SMA. Motor functional abilities may play a role in some of the items contributing to the overall cognitive profile.

Caregivers' Expectations on Possible Functional Changes following Disease-Modifying Treatment in Type II and III Spinal Muscular Atrophy: A Comparative Study.

Background: The primary aim of this study was to explore current caregivers' expectations on possible functional changes following treatment in comparison to data obtained in the pre-pharmacological era. Methods: A questionnaire, previously used in 2016, was administered to caregivers of type II and III SMA patients of age between 3 and 71 years, and to patients over the age of 13 years. The questionnaire focuses on (1) caregivers and patients expectations, (2) meaningfulness of the changes observed on the functional motor scales, and (3) their willingness to be enrolled in a clinical trial. A comparative study was performed with data obtained using the same questionnaire soon before the advent of disease-modifying therapies. Results: We administered the questionnaire to 150 caregivers. When comparing current caregiver data to those obtained in 2016, the most obvious differences were related to disease perception over the last year (stability: 16.5% in 2016 vs. 43.6% in 2022; deterioration 70.5% vs. 12.8%, and improvement: 12.9% vs. 43.6%) and expectations from clinical trials with higher expectations in 2022 compared to 2016 (p < 0.001). Forty-five of the 150 in the current study were caregivers of patients above the age of 13. In these 45 the questionnaire was also administered to the patient. No difference was found in responses between patients and their caregivers. Conclusions: Both carers and patients reported that even small changes on functional scales, similar to those reported by clinical studies and real-world data, are perceived as meaningful. Comparing the recent responses to those obtained in 2016, before pharmacological treatment was available, we found significant changes in caregivers' perception with increased expectations. These findings will provide a better understanding of the patients' expectations and facilitate discussion with regulators.

New therapies for spinal muscular atrophy: where we stand and what is next.

The natural history of spinal muscular atrophy has been radically changed by the advent of improved standards of care and the availability of disease-modifying therapies. The aim of this paper is to provide the current therapeutic scenario including new perspectives and to report the challenges related to new phenotypes a few years after the therapies have become available. The paper also includes a review of real-world data that provides information on safety and efficacy in individuals that were not included in clinical trials. Special attention is paid to future perspectives both in terms of new drugs that are currently investigated in clinical trials or providing details on current developments in the use of the available drugs, including combination therapies or new modalities of dose or administration.  Conclusion: Clinical trials and real world data support the efficacy and safety profiles of the available drugs. At the moment there is not enough published evidence about the superiority of one product compared to the others. What is Known: • Safety and efficacy results of clinical trials have led in the last 6 years to the marketing of three drugs for spinal muscular atrophy, with different mechanisms of action. What is New: • Since the drug's approval, real-world data allow us to have data on bigger and heterogeneous groups of patients in contrast with those included in clinical trials. • In addition to the new molecules, combinations of therapies are currently being evaluated.

Long term follow-up of scoliosis progression in type II SMA patients.

The aim of this study is to retrospectively assess onset and progression of scoliosis in type II SMA patients not treated with the approved disease modifying treatments. Scoliosis was evaluated by measuring the scoliosis angle on X-ray obtained in the anteroposterior view in sitting position (Cobb's angle method). Eighty-four patients had at least one assessment of scoliosis angle (287 assessments). There was a positive correlation between age and scoliosis angles (p<0.001) with a progressive increase of scoliosis with age. When subdividing the population by HFMSE score (<10; 11-22;> 22), there was a progressive increase in scoliosis angles with decreasing HFMSE scores. The difference between HFMSE categories was significant (p<0.001). Fifty-four patients had at least two assessments at 6-month distance and were retained for the longitudinal analysis. Using a mixed model, age, functional status and scoliosis angle at baseline were predictive on scoliosis progression. The mean annual rate of increase of scoliosis angle was 5.63 (95%CI: 4.74-6.52). Our results confirm the progression of scoliosis in untreated type II SMA providing details of the progression in relation to different variables. With different therapeutical options being available in many countries, our findings will provide reference data for establishing possible differences in the trajectories of progression with treated type II individuals.

Nusinersen efficacy data for 24-month in type 2 and 3 spinal muscular atrophy.

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.

Revised upper limb module in type II and III spinal muscular atrophy: 24-month changes.

The aim of the study was to establish 24-month changes in a large cohort of type II and III spinal muscular atrophy (SMA) patients assessed with the Revised Upper Limb Module (RULM), a tool specifically developed to assess upper limb function in SMA. We included 107 patients (54 type II and 53 type III) with at least 24-months follow up. The overall RULM 24-month changes showed a mean decline of -0.79 points. The difference between baseline and 24 months was significant in type II but not in type III patients. There was also a difference among functional subgroups but not in relation to age. Most patients had 24-month mean changes within 2 points, with 23% decreasing more than 2 points and 7% improving by >2 points. Our results suggest an overall progressive decline in upper limb function over 24 months. The negative changes were most notable in type II, in non-ambulant type III and with a different pattern of progression, also in non-sitter type II. In contrast, ambulant type III showed relative stability within the 24-month follow up. These findings will help in the interpretation of the real world data collected following the availability of new therapeutic approaches.

Motor function in type 2 and 3 SMA patients treated with Nusinersen: a critical review and meta-analysis.

BACKGROUND: There is an increasing number of papers reporting the real world use of Nusinersen in different cohorts of SMA patients. MAIN BODY: The aim of this paper was to critically review the literature reporting real world data on motor function in type 2 and 3 patients treated with Nusinersen, subdividing the results according to SMA type, age and type of assessment and performing a meta-analysis of the available results. We also report the available data collected in untreated patients using the same measures. Of the 400 papers identified searching for Nusinersen and spinal muscular atrophy, 19 reported motor function in types 2 and 3: 13 in adults, 4 in children and 2 included both. Twelve papers reported untreated patients' data. All studies reported positive changes on at least one of the functional measures and at every time point while all-untreated cohorts showed negative changes. CONCLUSION: Our review suggests that Nusinersen provides a favorable benefit in motor function across a wide range of SMA type 2 and 3 patients over a 10-14 month observation period. Although a direct comparison with studies reporting data from untreated patients cannot be made, the longitudinal changes in the treated cohorts (consistently positive) are divergent from those observed in the untreated cohorts (consistently negative). The difference could be observed both in the global cohorts and in smaller groups subdivided according to age, type or functional status.

Different trajectories in upper limb and gross motor function in spinal muscular atrophy.

INTRODUCTION: The Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM) have been widely used in natural history studies and clinical trials. Our aim was to establish how the scales relate to each other at different age points in spinal muscular atrophy (SMA) type 2 and 3, and to describe their coherence over 12 mo. METHODS: The study was performed by cross-sectional and longitudinal reanalysis of previously published natural history data. The longitudinal analysis of the 12-mo changes also included the analysis of concordance between scales with changes grouped as stable (±2 points), improved (>+2) or declined (>-2). RESULTS: Three hundred sixty-four patients were included in the cross-sectional analysis, showing different trends in score and point of slope change for the two scales. For type 2, the point of slope change was 4.1 y for the HFMSE and 5.8 for the RULM, while for type 3, it was 6 y for the HFMSE and 7.3 for the RULM. One-hundred-twenty-one patients had at least two assessments at 12 mo. Full concordance was found in 57.3% of the assessments, and in 40.4% one scale remained stable and the other changed. Each scale appeared to be more sensitive to specific age or functional subgroups. DISCUSSION: The two scales, when used in combination, may increase the sensitivity to detect clinically meaningful changes in motor function in patients with SMA types 2 and 3.

Nusinersen in pediatric and adult patients with type III spinal muscular atrophy.

OBJECTIVE: We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort. METHODS: Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83 years after nusinersen treatment. RESULTS: Over 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT. INTERPRETATION: Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.

Age related treatment effect in type II Spinal Muscular Atrophy pediatric patients treated with nusinersen.

Previous natural history studies suggest that type II SMA patients remain stable over one year but show some progression over two years. Since nusinersen approval, there has been increasing attention to identify more specific age-related changes. The aim of the study was to establish 12-month changes in a cohort of pediatric type II SMA treated with nusinersen and to establish possible patterns of treatment effect in relation to different variables such as age, baseline value and SMN2 copy number. The Hammersmith Functional Motor Scale Expanded and the Revised Upper Limb Module were performed at T0 and 12 months after treatment (T12). Data in treated patients were compared to available data in untreated patients collected by the same evaluators.Seventy-seven patients of age between 2.64 and 17.88 years (mean:7.47, SD:3.79) were included. On t-test there was an improvement, with increased mean scores between T0 and T12 on both scales (p < 0.001). Using multivariate linear regression analysis, age and baseline scores were predictive of changes on both scales (p < 0.05) while SMN2 copy number was not. Differences were also found between study cohort and untreated data on both scales (p < 0.001). At 12 months, an increase in scores was observed in all the age subgroups at variance with natural history data. Our real-world data confirm the treatment effect of nusinersen in pediatric type II SMA patients and that the data interpretation should take into account different variables. These data confirm and expand the ones already reported in the Cherish study.

Clinical Variability in Spinal Muscular Atrophy Type III.

OBJECTIVE: We report natural history data in a large cohort of 199 patients with spinal muscular atrophy (SMA) type III assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish the annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number, and functional status. METHODS: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments. RESULTS: A break point at age 7 years was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type, and ambulatory status were significantly associated with changes in mean HFMSE score, whereas gender and SMN2 copy number were not. The increase in response before the break point of age 7 years is significant only for SMA IIIA (ß = 1.79, p < 0.0001). After the break point, the change in the rate of HFMSE score significantly decrease for both SMA IIIA (ß = -1.15, p < 0.0001) and IIIB (ß = -0.69, p = 0.002). INTERPRETATION: Our findings contribute to the understanding of the natural history of SMA type III and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. ANN NEUROL 2020;88:1109-1117.

Diagnostic journey in Spinal Muscular Atrophy: Is it still an odyssey?

BACKGROUND: The advent of new therapies has increased the need to achieve early diagnosis in Spinal Muscular Atrophy (SMA). The aim of the present study was to define the age of diagnosis in the three main types of SMA with pediatric-onset and the timing between the recognition of clinical signs and confirmed genetic diagnosis. METHODS: All patients with a confirmed diagnosis of type I, II, III SMA followed in 5 Italian centers were included in this study, assessing age at symptoms onset, presenting sign or symptom, age at diagnosis, interval between clinical onset and diagnosis and type of medical investigations conducted in order to obtain the diagnosis. RESULTS: The cohort included 480 patients, 191 affected by SMA type I, 210 by type II and 79 by type III. The mean age at diagnosis was 4.70 months (SD ±2.82) in type I, 15.6 months (SD±5.88) in type II, and 4.34 years (SD±4.01) in type III. The mean time between symptom onset and diagnosis was 1.94 months (SD±1.84) in type I, 5.28 months (SD±4.68) in type II and 16.8 months (SD±18.72) in type III. CONCLUSIONS: Our results suggest that despite improved care recommendations there is still a marked diagnostic delay, especially in type III. At the time new therapies are becoming available more attention should be devoted to reducing such delay as there is consistent evidence of the benefit of early treatment.

MRI patterns of muscle involvement in type 2 and 3 spinal muscular atrophy patients.

Only few studies have reported muscle involvement in spinal muscular atrophy using muscle MRI but this has not been systematically investigated in a large cohort of both pediatric and adult patients with type 2 and type 3 spinal muscular atrophy. The aim of the present study was to define possible patterns of muscle involvement on MRI, assessing both fatty replacement and muscle atrophy, in a cohort of type 2 and type 3 spinal muscular atrophy children and adults (age range 2-45 years), including both ambulant and non-ambulant patients. Muscle MRI protocol consisted in T1-weighted sequences acquired on axial plane covering the pelvis, the thigh, and the leg with contiguous slices. Each muscle was examined through its whole extension using a grading system that allows a semiquantitative evaluation of fatty infiltration. Thigh muscles were also grouped in anterior, posterior, and medial compartment for classification of global atrophy. The results showed a large variability in both type 2 and type 3 spinal muscular atrophy, with a various degree of proximal to distal gradient. Some muscles, such us the adductor longus and gracilis were always selectively spared. In all patients, the involvement was a combination of muscle atrophy and muscle infiltration. The variability observed may help to better understand both natural history and response to new treatments.

A critical review of patient and parent caregiver oriented tools to assess health-related quality of life, activity of daily living and caregiver burden in spinal muscular atrophy.

The positive outcome of different therapeutic approaches for spinal muscular atrophy (SMA) in clinical trials and in clinical practice have highlighted the need to establish if functional changes are associated with possible changes of patient health-related quality of life or have an effect on activities of daily living and caregiver burden. The aim of this paper is to provide a critical review of the tools previously or currently used to measure quality of life, activity of daily living, and caregiver burden in SMA. We identified 36 measures. Only 6 tools were specifically developed for SMA while the others had been used and at least partially validated in wider groups of neuromuscular disorders including SMA. Twelve of the 36 focused on health-related quality of life, 5 on activities of daily living and 9 on caregiver burden. Ten included a combination of items. The review provides a roadmap of the different tools indicating their suitability for different SMA types or age groups. Scales assessing activities of daily living and care burden can provide patients and carers perspective on functional changes over time that should be added to the observer rated scales used in clinic.

Long-term progression in type II spinal muscular atrophy: A retrospective observational study.

OBJECTIVE: To report the long-term progression in a cohort of patients with type II spinal muscular atrophy (SMA) assessed with the Hammersmith Functional Motor Scale-Expanded. METHODS: Seventy-three patients (age 2.6-25 years) were included in the study. Twenty-eight of the 73 were first assessed before the age of 5 years and had been followed up for ≈5 years or longer. We observed an overall progression that was not linear. A piecewise regression analysis showed an improvement of scores in the younger patients with a point of slope change at ≈5 years of age, a decline between 5 and 13 years of age, and stability/slower decline after that. RESULTS: Patients with the lowest scores at baseline had the earliest onset of scoliosis and a higher need for noninvasive ventilation compared to those with higher scores. Our results confirm that on the long-term follow-up all patients with type II SMA show a clear and progressive decline. CONCLUSION: The severity of functional impairment at baseline can help to predict the magnitude of changes over time and the overall progression, including onset of scoliosis and need for noninvasive ventilation.

6MWT can identify type 3 SMA patients with neuromuscular junction dysfunction.

The aim of the study was to establish if the decrease in gait velocity on the 6 minute walk test relates to signs of neuromuscular junction dysfunction in spinal muscular atrophy type 3 patients. 6 minute walk test and low-rate repetitive nerve stimulation test were performed in fifteen ambulant patients with spinal muscular atrophy type 3 of age between 9 and 66 years. The 6 minute walk distance ranged between 66 and 575 m. The difference between the first and the 6th minute ranged between 0 and -69%. The low-rate repetitive nerve stimulation test measured in % of loss ranged between -31.7% to +4.2% to the axillary nerve. The correlation between 6 minute walk test changes and low-rate repetitive nerve stimulation test changes was 0.86. Our data suggest that the 6 minute walk test can identify fatigue in the ambulant type 3 patients who have a concurrent neuromuscular junction dysfunction. The identification of fatigue with a simple clinical test may help to target patients who may benefit from drugs that facilitate neuromuscular transmission.