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.

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.

Can the CHOP-INTEND be used as An Outcome Measure in the First Months of Age? Implications for Clinical Trials and Real World Data.

BACKGROUND: The CHOP-INTEND is an established outcome measure used to assess motor function in young and weak SMA patients previously validated in type I infants older than 3 months. OBJECTIVE: The aim of our study was to assess the maturation of the CHOP-INTEND scores in a group of healthy infants, establishing which items of the scale can be reliably used in individuals younger than 3 months. METHODS: This is a prospective observational study. The whole cohort was divided into 5 age groups. Each of the 16 CHOP-INTEND items was analyzed looking at the frequency distribution of the scores in each age subgroup. An item was considered developmentally appropriate when > 85% of the infants achieved a full score. RESULTS: our study includes 61 assessments collected < 2 weeks, 25 at 2-4 weeks, 20 at 5-8 weeks, 25 at 9-12 weeks and 20 at 13-17 weeks. Eight of the 16 items were developmentally appropriate already in the first week and another by the end of the first month. The remaining 7 items had more variable responses in the first three months and full scores were consistently achieved only after the third month. CONCLUSIONS: Our findings suggest that the CHOP-INTEND can be used before the age of 3 months, but the results should be interpreted with caution, considering which items are developmentally appropriate at the time of testing. This will also help to establish whether the changes observed following early treatments are a sign of efficacy or at least partly reflect maturational aspects.

Gain and loss of upper limb abilities in Duchenne muscular dystrophy patients: A 24-month study.

Duchenne muscular dystrophy (DMD) is a neuromuscular condition characterized by muscle weakness. The Performance of upper limb (PUL) test is designed to evaluate upper limb function in DMD patients across three domains. The aim of this study is to identify frequently lost or gained PUL 2.0 abilities at distinct functional stages in DMD patients. This retrospective study analyzed prospectively collected data on 24-month PUL 2.0 changes related to ambulatory function. Ambulant patients were categorized based on initial 6MWT distance, non-ambulant patients by time since ambulation loss. Each PUL 2.0 item was classified as shift up, no change, or shift down. The study's cohort incuded 274 patients, with 626 paired evaluations at the 24-month mark. Among these, 55.1 % had activity loss, while 29.1 % had gains. Ambulant patients showed the lowest loss rates, mainly in the shoulder domain. The highest loss rate was in the shoulder domain in the transitioning subgroup and in elbow and distal domains in the non-ambulant patients. Younger ambulant patients demonstrated multiple gains, whereas in the other functional subgroups there were fewer gains, mostly tied to singular activities. Our findings highlight divergent upper limb domain progression, partly linked to functional status and baseline function.

Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naïve patients with spinal muscular atrophy and following switch from other therapies.

Background: Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and <8.5 kg has been reported in clinical trials. This study examines efficacy and safety predictors in a wide age (22 days-72 months) and weight (3.2-17 kg) range, also including patients previously treated with other drugs. Methods: 46 patients were treated for 12 months between January 2020 and March 2022. Safety profile was also available for another 21 patients with at least 6 month follow-up after OA infusion. 19/67 were treatment naïve when treated with OA. Motor function was measured with the CHOP-INTEND. Findings: CHOP-INTEND changes varied among age groups. Baseline score and age at OA treatment best predicted changes. A mixed model post-hoc analysis showed that in patients treated before the age of 24 months the CHOP-INTEND changes were already significant 3 months after OA while in those treated after the age of 24 months the difference was only significant 12 months after OA. Adverse events occurred in 51/67. The risk for elevated transaminases serum levels was higher in older patients. This was also true for weight and for pre-treatment with nusinersen when analysed individually. A binomial negative regression analysis showed that only age at OA treatment had a significant effect on the risk of elevated transaminases. Interpretation: Our paper describes OA 12-month follow-up showing efficacy across various age and weight groups not targeted by clinical trials. The study identifies prognostic factors for safety and efficacy in treatment selection. Funding: None.

Longitudinal Analysis of PUL 2.0 Domains in Ambulant and Non-Ambulant Duchenne Muscular Dystrophy Patients: How do they Change in Relation to Functional Ability?

BACKGROUND: The performance of upper limb 2.0 (PUL) is widely used to assess upper limb function in DMD patients. The aim of the study was to assess 24 month PUL changes in a large cohort of DMD patients and to establish whether domains changes occur more frequently in specific functional subgroups. METHODS: The PUL was performed in 311 patients who had at least one pair of assessments at 24 months, for a total of 808 paired assessments. Ambulant patients were subdivided according to the ability to walk: >350, 250-350, ≤250 meters. Non ambulant patients were subdivided according to the time since they lost ambulation: <1, 1-2, 2-5 or >5 years. RESULTS: At 12 months, the mean PUL 2.0 change on all the paired assessments was -1.30 (-1.51--1.05) for the total score, -0.5 (-0.66--0.39) for the shoulder domain, -0.6 (-0.74--0.5) for the elbow domain and -0.1 (-0.20--0.06) for the distal domain.At 24 months, the mean PUL 2.0 change on all the paired assessments was -2.9 (-3.29--2.60) for the total score, -1.30 (-1.47--1.09) for the shoulder domain, -1.30 (-1.45--1.11) for the elbow domain and -0.4 (-1.48--1.29) for the distal domain.Changes at 12 and 24 months were statistically significant between subgroups with different functional abilities for the total score and each domain (p < 0.001). CONCLUSION: There were different patterns of changes among the functional subgroups in the individual domains. The time of transition, including the year before and after loss of ambulation, show the peak of negative changes in PUL total scores that reflect not only loss of shoulder but also of elbow activities. These results suggest that patterns of changes should be considered at the time of designing clinical trials.

Type I spinal muscular atrophy patients treated with nusinersen: 4-year follow-up of motor, respiratory and bulbar function.

BACKGROUND: We report the 4-year follow-up in type I patients treated with nusinersen and the changes in motor, respiratory and bulbar function in relation to subtype, age and SMN2 copy number. METHODS: The study included SMA 1 patients with at least one assessment after 12, 24 and 48 months from the first dose of nusinersen. The assessments used were Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination (HINE-II). RESULTS: Forty-eight patients, with ages ranging from 7 days to 12 years (mean 3.3 years, SD 3.6 years) were included in the study. The CHOP INTEND and HINE-II scores significantly increased between baseline and 48 months (p < 0.001). When age at starting treatment subgroups (<210 days, <2 years, 2-4 years, 5-11 years, ≥12 years) were considered, the CHOP INTEND increased significantly in patients younger than 4 years at treatment, while the HINE-2 increased significantly in patients younger than 2 years at treatment. In a mixed-model analysis, age, nutritional and respiratory status were predictive of changes on both scales while SMN2 copy number and decimal classification were not. CONCLUSIONS: Our results confirm the safety profile previously reported and support the durability of the efficacy of nusinersen at 4 years with an overall stability or mild improvement and no evidence of deterioration over a long period of time.

Needleless inhaled anesthesia with sevoflurane: Advantages of a simplified approach for children with spinal muscular atrophy undergoing intrathecal administration of nusinersen.

BACKGROUND: Intrathecal nusinersen administration, a fundamental step in the treatment of spinal muscular atrophy, is challenging in children. AIMS: This retrospective monocentric analysis of prospectively collected data evaluated the feasibility of needleless general anesthesia exclusively with sevoflurane, without imaging guidance, for children undergoing nusinersen administration in a 24-month period. METHODS: Clinical data included demographics, type of spinal muscular atrophy, presence and severity of scoliosis. Primary outcome was defined by the number of predefined sentinel adverse events related to anesthesia. Secondary outcomes were assessed by duration of the procedure, number of lumbar puncture attempts, and number of failures. Other measures included number and type of moderate, minor and minimal adverse events, as well as number and type of puncture-related adverse events. RESULTS: 116 patients (mean age: 8.7 (SD 6.9) years; with scoliosis: 49.1%) underwent 250 lumbar punctures; two cases of prolonged desaturation, considered as sentinel adverse events, (0.8%) were recorded during anesthesia (primary outcome). None of the patients underwent orotracheal intubation nor required an unplanned admission in the Pediatric Intensive Care Unit. No patient required an unplanned or prolonged hospitalization after the procedure. Mean number of puncture attempts was 1.6 (SD 1.3), and mean duration of the procedure was 14.1 (SD 8.3) minutes. No failure in the drug administration occurred (secondary outcomes). CONCLUSION: In this single-center experience, needleless general anesthesia with inhaled sevoflurane without imaging guidance has been shown to be feasible for children with spinal muscular atrophy undergoing lumbar puncture for nusinersen administration.

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.

Neurological assessment of newborns with spinal muscular atrophy identified through neonatal screening.

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.

Assessing floppy infants: a new module.

Our aim was to develop a new module for assessing the floppy infant, to describe the application of the module in a cohort of low-risk newborns and piloting the module in a cohort of floppy infants. The module was applied to a cohort of 143 low-risk newborns and piloted in in a cohort of 24 floppy infants. The new add-on module includes a neurological section and provides a section for recording information obtained by physical examination and antenatal history. For each item, column 1 reports abnormal findings, column 3 normal findings, and column 2 intermediate signs to be followed. Consistent with previous studies, in low-risk infants, none had definitely abnormal or mildly abnormal signs, with the exception of tendon reflexes that were not easily elicitable in 17.14% of term-born infants. CONCLUSION: Our study suggest that the module can be easily used in a clinical setting as an add-on to the regular neonatal neurological examination in newborns identified as hypotonic on routine examination. Larger cohorts are needed to establish the accuracy of the prognostic value of the module in the differential diagnosis of floppy infant. WHAT IS KNOWN: • Hypotonia is one of the key signs in newborns with neuromuscular disorders and can be associated with a wide range of other conditions (central nervous system involvement, genetic and metabolic diseases). • Weakness or/and contractures can identify infants with a neuromuscular disorder and help in the differential diagnosis of floppy infants. WHAT IS NEW: • To date, this is the first attempt to develop and apply a specific neurological module for the assessment of the floppy infant. • The module can be used in a routine clinical setting as an add-on to the regular neurological examination and has potential to differentiate the floppy infants from the low-risk infants.

Oral and Swallowing Abilities Tool (OrSAT) in nusinersen treated patients.

INTRODUCTION: The aim of the study was to longitudinally assess swallowing abilities in nusinersen-treated patients with type 1 spinal muscular atrophy. METHODS: Twenty infants with type 1 SMA (11 female and 9 male) treated with nusinersen between 3 weeks and 15 months of age, were assessed using the Oral and Swallowing Abilities Tool (OrSAT). The duration of the follow-up after treatment ranged between 12 months and 62 months. RESULTS: Twelve of the 20 infants had normal swallowing and there was no need for tube feeding at the time treatment started. Ten of the 12 had consistently normal swallowing with no need for tube feeding on follow-up. The other two required tube feeding but they regained the ability to eat some food by mouth.The remaining 8 infants already had tube feeding inserted at the time treatment started: 4 of them also had tracheostomy and they showed no changes on the OrSAT Scale. The other 4 who had tube feeding but no tracheostomy had partial functional improvement. CONCLUSION: Our results suggest that the degree of functional impairment at the time treatment is started can help to predict the progression of swallowing abilities. The use of a structured assessment also helped to detect partial improvements.

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.

Point-of-care lung and diaphragm ultrasound in a patient with spinal muscular atrophy with respiratory distress type 1.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1, OMIM #604,320), is a rare autosomal recessive disease resulting from degeneration of motor neurons in the anterior horns, which leads irreversible diaphragmatic palsy and progressive distal symmetrical muscular weakness. Respiratory distress is the main symptom and is severe, rapidly progressive, and frequently requiring invasive ventilation. Despite diaphragm being one of the target organ of the disease, no specific study has been done using ultrasound.We report diaphragm and lung ultrasound findings of a 13-month-old girl affected by SMARD1 (homozygosis c.1540G > A mutation in IGHMPB2 gene) with respiratory failure requiring permanent mechanical ventilation since birth and we discuss the role of diaphragmatic and lung ultrasound in this category of patients and its clinical implications.

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.

Oral and Swallowing Abilities Tool (OrSAT) for Type 1 SMA Patients: Development of a New Module.

We describe the development of a new tool specifically designed to record oral abilities, swallowing and, more generally, feeding in young type 1 SMA patients, to be used during the first 24 months of life.The tool is composed by a checklist and a separate section summarizing the functional abilities into levels of feeding/swallowing impairment. The checklist includes 12 questions assessing aspects thought to be clinically meaningful for a type 1 SMA population and developmentally appropriate for infants during the first months of life. Each item is graded with a score of 0 or 1, depending on the child's ability to perform the activity. As some items are age-dependent, the number of items to be used, and therefore the maximum score, changes with increasing age. The levels of feeding/swallowing impairment include four levels that can be identified using easily identifiable clinical criteria.In an attempt to validate the tool in an untreated population we applied it to 24 type 1 SMA patients (age range: 2.3-24.1 months, mean: 10.8) in whom the same information collected by the new tool had been previously recorded using a less-structured format.When patients were classified in three groups according to the Dubowitz decimal classification, there was a significant difference both at baseline and at follow-up (p < 0.001). The items assessing fatigue during the nursing sessions were the most frequently impaired even in infants who did not have any other obvious clinical sign of swallowing difficulties.

Type I SMA "new natural history": long-term data in nusinersen-treated patients.

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.