Exploring the Trajectory of Swallowing Within Psychomotor Development in Spinal Muscular Atrophy: Moving Toward Integrated Care

ObjectiveSpinal Muscular Atrophy linked to chromosome 5q (SMA) is an autosomal recessive neurodegenerative disease characterized by progressive proximal muscle atrophy and weakness. This study addresses the scarcity of research on novel disease-modifying therapies for SMA in Latin America by reporting a real-world experience in Southern Brazil. MethodologyThis is a single-center historical cohort that included all patients diagnosed with spinal muscular atrophy at a Regional Reference Service for rare diseases. ResultsEighty-one patients were included, of whom 7 died during follow-up. Of the remaining 74 patients, 5.4 % were classified as pre-symptomatic, 24.3 % with SMA type 1, 28.4 % with type 2, 36.5 % with type 3, and 5.4 % with type 4. The mean follow-up time ranged from 1.8 years for pre-symptomatic cases to 8.7 years for SMA types 2 and 3. Approximately 42 % of these patients received specific disease-modifying therapy, of these, 96.8 % received Nusinersen, with 19.4 % transitioning to gene therapy using Onasemnogene Abeparvovec, and 6.4 % starting Risdiplam. Most patients with SMA type 1 were on disease-modifying treatment, whereas only slightly over a third of patients with type 2 and about 10 % of type 3 were receiving such treatments. Among treated patients, 80 % demonstrated improvement in motor performance during the follow-up, with a lesser therapeutic response being associated with late initiation of treatment and low motor function scores at baseline. ConclusionThis real-world study reinforces the effectiveness of disease-modifying therapies for SMA in Brazil within the context of low- and middle-income countries, which is greater the earlier and the better the patient's functional status.

Bifunctional RNAs Targeting the Intronic Splicing Silencer N1 Increase SMN Levels and Reduce Disease Severity in an Animal Model of Spinal Muscular Atrophy

Background Spinal muscular atrophy (SMA-5q) is a neurodegenerative disease characterized by progressive muscle atrophy, hypotonia, and weakness, with SMA 1 presenting symptoms within the first 6 months of life. Disease-modifying therapies have been approved, with better outcomes with earlier treatment.Objective To describe the safety and clinical efficacy of disease-modifying therapies based onSMN1andSMN2gene strategies concerning motor, respiratory, and bulbar function. Patients with SMA 1 were divided into 2 groups: those exclusively on nusinersen (group 1) and those transitioning to onasemnogene abeparvovec (OA) (group 2).Methods Over 18 months, patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scale, developmental milestones, ventilation needs and duration, nutritional support needs, consistency of food, and signs of dysphagia. There were ten patients, divided between the groups; in group 1, the average age for starting nusinersen was 53.6 (12–115) months, and, in group 2, the age was 7 (1–12) months for nusinersen and 15.2 (10–19) months for OA.Results Our results indicate that 70% of patients reached some motor milestones, with group 1 increasing by 10.2 points on the CHOP-INTEND scale, while group 2 increased by 33 points. Additionally, 90% of the patients experienced no respiratory decline, and 30% maintained oral feeding. No serious adverse effects or deaths were recorded.Conclusion Both groups showed improvement in motor function and stabilization of respiratory and bulbar function, with the difference between the groups possibly being related to the earlier treatment initiation. Thus, the present study provides valuable insights into the real-world safety and clinical efficacy of disease-modifying therapies for SMA 1 patients.

BackgroundSpinal muscular atrophy (SMA) is a severe genetic neuromuscular disorder characterized by muscle atrophy and weakness due to motor neuron loss. It results from mutations in the SMN1 gene, leading to insufficient SMN protein, which is essential for motor neuron survival. SMA manifests in varying degrees of severity, with subtypes classified based on the age of symptom onset and motor function impairment. SMA type 1 is the most severe, with early onset and significant respiratory and motor complications, while SMA types 2 and 3 have later onset and less severe symptoms. Recent advancements, such as the approval of Nusinersen, offer new hope in altering the disease’s progression and improving motor functions, respiratory outcomes, and survival rates across SMA types.ResultsThis systematic review included 10 studies. Significant improvements in motor function were observed, particularly in patients with SMA types 1, 2, and 3, as measured by scales, such as CHOP INTEND, HFMSE, and 6MWT. Respiratory function and survival outcomes were mixed, with some patients requiring ongoing ventilation support despite motor function improvements. The safety profile of Nusinersen was generally favorable, with mild to moderate adverse events such as headaches and back pain being the most common. Severe adverse events, though rare, included cases of aseptic meningitis and increased intracranial pressure, highlighting the need for careful monitoring during treatment.ConclusionsThis review confirms that Nusinersen is safe and effective for treating SMA across different types and severities. It improves motor and respiratory functions with manageable side effects. The findings support Nusinersen’s role in SMA treatment and provide valuable guidance for both clinical practice and future research. Early treatment initiation and attention to individual patient needs are emphasized to achieve the best outcomes.

IntroductionInfants with spinal muscular atrophy (SMA) type 1 typically face a decline in motor function and a severely shortened life expectancy. Clinical trials for SMA type 1 therapies, onasemnogene abeparvovec (AVXS-101) and nusinersen, demonstrated meaningful improvements in efficacy (e.g., overall survival) but there were no head-to-head clinical trials assessing comparative efficacy. This study estimated the treatment effects of AVXS-101 relative to nusinersen for the treatment of SMA type 1.MethodsOverall survival, event-free survival (no death or need to use permanent assisted ventilation), improvement in motor function [increase of ≥ 4 points in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score from baseline], and motor milestone achievements (head control, rolling over, and sitting unassisted) reported in the onasemnogene abeparvovec (AVXS-101-CL-101; NCT02122952) and nusinersen (ENDEAR; NCT02193074) clinical trials were indirectly compared using frequentist and Bayesian approaches.ResultsAmong symptomatic infants with SMA type 1, the number needed to treat (NNT) to prevent one more death with AVXS-101 instead of nusinersen was 6.2 [95% confidence intervals (CI) = 4.1–12.2], and the probability of preventing death was 20% higher for patients treated with AVXS-101 than nusinersen [risk ratio (RR) = 1.2, 95% CI 1.1–1.3]. For event-free survival, the NNT to prevent one more event was 2.6 (95% CI 2.0–3.6) and RR was 1.6 (95% CI 1.4–1.9). For improvement in motor function, NNT was 3.5 (95% CI 2.6–5.3) and RR was 1.4 (95% CI 1.2–1.6). For milestone achievements, the NNTs were 1.4 (95% CI 1.1–1.9), 1.5 (95% CI 1.1–2.5), and 1.2 (95% CI 1.0–1.5); RRs 4.2 (95% CI 2.6–6.7), 7.8 (95% CI 3.6–17.0), and 11.2 (95% CI 5.1–24.5) for head control, rolling over, and sitting unassisted, respectively. Results were similar using the Bayesian approach.ConclusionThis indirect comparison (AVXS-101-CL-101 vs. ENDEAR) among symptomatic SMA type 1 infants suggests that AVXS-101 may have an efficacy advantage relative to nusinersen for overall survival, independence from permanent assisted ventilation, motor function, and motor milestones.FundingAveXis.

BackgroundSpinal muscular atrophy (SMA) is a genetic neuromuscular disease caused by mutations of the SMN1 gene. Deficient SMN protein causes irreversible degeneration of alpha motor neurons characterized by progressive muscle weakness and atrophy. Considering that SMA is a multi-systemic disorder and SMN protein was found to be expressed in cortical structures, the cognitive profile of adult patients with SMA has recently been of particular interest. With nusinersen, a novel, disease-modifying drug has been established, but its effects on neuropsychological functions have not been validated yet. Aim of this study was to investigate the cognitive profile of adult patients with SMA during treatment initiation with nusinersen and to reveal improvement or deterioration in cognitive performance.MethodsThis monocentric longitudinal study included 23 patients with SMA type 2 and 3. All patients were assessed with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) before and after 14 months of treatment initiation with nusinersen. Additionally, motor function was evaluated by Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) and Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R).ResultsOf the treatment-naive patients, only three were below the age- and education-matched cut-off for cognitive impairment in the ECAS total score. Significant differences between SMA type 2 and 3 were only detected in the domain of Language. After 14 months of treatment, patients showed significant improvement of absolute scores in all three ALS-specific domains, in the non-ALS-specific domain of Memory, in both subscores and in the ECAS total score. No associations were detected between cognitive and functional outcome measures.ConclusionsIn some adult patients with SMA abnormal cognitive performance in ALS-specific functions of the ECAS was evident. However, the presented results suggest no clinically significant cognitive changes during the observed treatment period with nusinersen.

Patient and parent oriented tools to assess health-related quality of life, activity of daily living and caregiver burden in SMA. Rome, 13 July 2019

The aim of the study was to explore the effect of acupuncture combined with rehabilitation on cognitive and motor functions in poststroke patients. All patients were divided into Group A and Group B based on different interventions (Group A: acupuncture + conventional rehabilitation, Group B: conventional rehabilitation alone). Acupuncture was conducted once a day, five times a week for 8 weeks, and rehabilitation (including physical therapy and occupational therapy) was conducted for 2 hr per session, once a day, five times a week for 8 weeks. Mini-mental State Examination (MMSE) and Fugl-Meyer Assessment (FMA) were used to assess the motor and cognitive functions at baseline and the end of 8 weeks. After the intervention, FMA and MMSE scores were improved significantly in the two groups (p <.05), compared with the scores prior to intervention. After 8 weeks of intervention, a statistically significant difference in the FMA and MMSE scores was observed between the Group A and the Group B. The results suggested that the combined intervention is more effective than the conventional rehabilitation alone in improving cognitive and motor functions in poststroke patients.

Background &amp; Objectives: Motor function and cognition are crucial for performing daily activities in patients with stroke. However, it remains unclear whether measures of motor function in patients with subacute hemiplegic stroke are related to baseline overall cognitive domains or to specific domains. The aim of this study is to determine which baseline cognitive domains are associated with improvements in motor function in patients with subacute hemiplegic stroke after 4 weeks of rehabilitation. Method: We retrospectively analyzed data of 129 hemiplegic patients with a first-ever stroke, who were admitted or transferred to the rehabilitation department within 3 months of stroke onset. We assessed patient demographics, baseline cognitive function using Mini-Mental Status Examination (MMSE), Wechsler Adult Intelligence Scale-IV, and Motor-Free Visual Perceptual Test-Revised (MVPT-R). Motor function was evaluated using the Berg Balance Scale, Timed Up and Go Test (TUG), 10 m gait time, and functional reach at baseline and after 4 weeks of rehabilitation. Pearson’s correlation coefficient was used to analyze the correlation between improvements in motor and cognitive functions. Results: No significant correlation was observed between improvements in motor function and baseline MMSE, full-scale IQ, and MVPT total scores. However, subscale analysis of baseline MVPT demonstrated significant correlations between visual discrimination and all outcome effects. Additionally, visual closure and visual-spatial relationship exhibited significant correlation with TUG and 10 m gait velocity. Conclusions: This study highlighted the association between improvement in motor function, including balance and gait speed, and initial visual perception skills. Thus, evaluating and enhancing visual perception skills are essential for improving motor function in patients with subacute hemiplegic stroke.

BackgroundSpinal muscular atrophy (SMA) is a rare neuromuscular disease that affects motor neurons, resulting in progressive skeletal muscle weakness and atrophy.ObjectiveThe aim of this study was to examine treatment preferences of patients and caregivers of patients with Type 2 and non-ambulatory Type 3 SMA in the Netherlands, Belgium, Finland, Ireland and Portugal.MethodsA discrete choice experiment (DCE) survey was developed to elicit the preferences of adult patients and caregivers regarding different treatment aspects of SMA. This survey built on the design of a similar study undertaken in the UK. The DCE described choice questions in terms of attributes and levels combined using a D-efficient design. The attributes described improvements or worsening in motor and breathing function. The mode of treatment administration (intrathecal injection, single intravenous infusion or regular oral therapy) was described. Treatment risks and side effects related to currently available treatments including risk of liver injury, fatigue, headache, nausea, diarrhoea and rash were described. Lastly, an attribute described whether a treatment had evidence of treatment effectiveness in different SMA types. Participants were recruited via patient advocacy associations to complete an online survey. A clustered conditional logit model was used to estimate treatment preferences.ResultsParticipants (n = 65) were 4.8 times and 8.1 times more likely to choose a treatment with stable or improved (vs worse) motor function, respectively. Similarly, participants were 4.3 times and 5.8 times more likely to choose stable or improved (vs worse) breathing function, respectively. Treatments with a risk of liver injury, fatigue, headache and nausea were 1.6 times less likely to be chosen than treatments with a risk of diarrhoea and rash. Treatments with demonstrated effectiveness in Type 1 SMA only were 2.3 times less likely to be chosen than those with demonstrated effectiveness in Types 1–3 SMA. Treatments administered via intrathecal injections were also 1.8 times less likely to be chosen than daily oral treatments.DiscussionStudy results show the importance of improvement as well as stabilisation of motor and breathing function to patients and caregivers, and a preference for oral treatments, treatments with demonstrated effectiveness in Types 2–3 SMA, and avoidance of liver injury risk.

ObjectiveTo evaluate the effectiveness and safety of nusinersen for the treatment of 5q-spinal muscular atrophy (SMA) among Chinese pediatric patients.MethodsUsing a longitudinal, multi-center registry, both prospective and retrospective data were collected from pediatric patients with 5q-SMA receiving nusinersen treatment across 18 centers in China. All patients fulfilling the eligibility criteria were included consecutively. Motor function outcomes were assessed post-treatment by SMA type. Safety profile was evaluated among patients starting nusinersen treatment post-enrollment. Descriptive analyses were used to report baseline characteristics, effectiveness, and safety results.ResultsAs of March 2nd, 2023, 385 patients were included. Most patients demonstrated improvements or stability in motor function across all SMA types. Type II patients demonstrated mean changes [95% confidence interval (CI)] of 4.4 (3.4–5.4) and 4.1 (2.8–5.4) in Hammersmith Functional Motor Scale-Expanded (HFMSE), and 2.4 (1.7–3.1) and 2.3 (1.2–3.4) in Revised Upper Limb Module (RULM) scores at months 6 and 10. Type III patients exhibited mean changes (95% CI) of 3.9 (2.5–5.3) and 4.3 (2.6–6.0) in HFMSE, and 2.1 (1.2–3.0) and 1.5 (0.0–3.0) in RULM scores at months 6 and 10. Of the 132 patients, 62.9% experienced adverse events (AEs). Two patients experienced mild AEs (aseptic meningitis and myalgia) considered to be related to nusinersen by the investigator, with no sequelae.ConclusionsThese data underscore the significance of nusinersen in Chinese pediatric patients with SMA regarding motor function improvement or stability, and support recommendations on nusinersen treatment by Chinese SMA guidelines and continuous coverage of nusinersen by basic medical insurance.

Respiratory and bulbar dysfunctions (including swallowing, feeding, and speech functions) are key symptoms of spinal muscular atrophy (SMA), especially in its most severe forms. Demonstrating the long-term efficacy of disease-modifying therapies (DMTs) necessitates an understanding of SMA natural history. This study summarizes published natural history data on respiratory, swallowing, feeding, and speech functions in patients with SMA not receiving DMTs. Electronic databases (Embase, MEDLINE, and Evidence-Based Medicine Reviews) were searched from database inception to June 27, 2022, for studies reporting data on respiratory and/or bulbar function outcomes in Types 1-3 SMA. Data were extracted into a predefined template and a descriptive summary of these data was provided. Ninety-one publications were included: 43 reported data on respiratory, swallowing, feeding, and/or speech function outcomes. Data highlighted early loss of respiratory function for patients with Type 1 SMA, with ventilatory support typically required by 12 months of age. Patients with Type 2 or 3 SMA were at risk of losing respiratory function over time, with ventilatory support initiated between the first and fifth decades of life. Swallowing and feeding difficulties, including choking, chewing problems, and aspiration, were reported in patients across the SMA spectrum. Swallowing and feeding difficulties, and a need for non-oral nutritional support, were reported before 1 year of age in Type 1 SMA, and before 10 years of age in Type 2 SMA. Limited data relating to other bulbar functions were collated. Natural history data demonstrate that untreated patients with SMA experience respiratory and bulbar function deterioration, with a more rapid decline associated with greater disease severity. This study provides a comprehensive repository of natural history data on bulbar function in SMA, and it highlights that consistent assessment of outcomes in this area is necessary to benefit understanding and approval of new treatments.

Experience of nusinersen treatment in advanced spinal muscular atrophy type 1: Characteristics of late responders with delayed treatment efficacy.

ObjectivesThis study aimed to evaluate the mediational role of change in psychosocial abilities, adjustment and participation on change in motor and cognitive function from admission to discharge from a staged community-based brain injury rehabilitation (SCBIR) service in Western Australia, 2011–2020.MethodsA retrospective cohort study of n = 324 adults with ABI enrolled in SCBIR using routinely collected rehabilitation outcome measures data. Motor and cognitive function were assessed with the UK Functional Independence and Assessment Measure and psychosocial function with the Mayo-Portland Adaptability Inventory-4. Six multilevel mediation regression analyses were conducted to determine whether change in psychosocial function (abilities, adjustment and participation) mediated change in motor and cognitive function from admission to discharge.ResultsParticipants demonstrated clinically significant improvements in both motor (+ 11.8, p < 0.001) and cognitive (+ 9.5, p < 0.001) functioning from admission to discharge. Statistically significant improvements in psychosocial abilities (− 4.8, p < 0.001), adjustment (− 2.9, p = 0.001) and participation (− 2.5, p < 0.001) were also seen but were not clinically significant. Mediation analyses showed that participation accounted for 81% of improvements in motor function at discharge and 71% of cognitive function improvements. Adjustment accounted for 26% and 32% of change in motor and cognitive function, respectively. Abilities accounted for 60% of change in cognitive function but did not significantly influence change in motor function. Changes in psychosocial participation fully mediated change in motor function during neurorehabilitation.ConclusionsPsychosocial function, particularly participation, is an important driver of motor and cognitive recovery throughout neurorehabilitation. Functional rehabilitation programs should target psychosocial improvement as an important mechanism of change.

Risdiplam and nusinersen in spinal muscular atrophy: a descriptive real-world study on motor function outcomes in northwestern Iran.