Progressive Neuromuscular Disorder Research Articles

Determining minimal clinically important differences in the Hammersmith Functional Motor Scale Expanded for untreated spinal muscular atrophy patients: An international study.

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. 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. 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. 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.

Monitoring spinal muscular atrophy with three-dimensional optoacoustic imaging

Spinal muscular atrophy is a progressive neuromuscular disorder and among the most frequent genetic causes of infant mortality. While recent advancements in gene therapy provide the potential to ameliorate the disease severity, there is currently no modality in clinical use to visualize dynamic pathophysiological changes in disease progression and regression after therapy. In this prospective diagnostic clinical study, ten pediatric patients with spinal muscular atrophy and ten age- and sex-matched controls have been examined with three-dimensional optoacoustic imaging and clinical standard examinations to compare the spectral profile of muscle tissue and correlate it with motor function (ClinicalTrials.gov: NCT04115475). We observed a reduced optoacoustic signal in muscle tissue of pediatric patients with spinal muscular atrophy. The reduction in signal intensity correlated with disease severity as assessed by grayscale ultrasound and standard motor function tests. In a cohort of patients who received disease-modifying therapy prior to the study, the optoacoustic signal intensity was similar to healthy controls. This translational study provides early evidence that three-dimensional optoacoustic imaging could have clinical implications in monitoring disease activity in spinal muscular atrophy. By visualizing and quantifying molecular changes in muscle tissue, disease progression and effects of gene therapy can be assessed in real time. The project was funded by ELAN Fonds (P055) at the University Hospital of the Friedrich-Alexander-Universität (FAU) Erlangen-Nurnberg to A.P.R.

Deficiency of skeletal muscle Agrin contributes to the pathogenesis of age-related sarcopenia in mice

Sarcopenia, a progressive and prevalent neuromuscular disorder, is characterized by age-related muscle wasting and weakening. Despite its widespread occurrence, the molecular underpinnings of this disease remain poorly understood. Herein, we report that levels of Agrin, an extracellular matrix (ECM) protein critical for neuromuscular formation, were decreased with age in the skeletal muscles of mice. The conditional loss of Agrin in myogenic progenitors and satellite cells (SCs) (Pax7 Cre:: Agrin flox/flox) causes premature muscle aging, manifesting a distinct sarcopenic phenotype in mice. Conversely, the elevation of a miniaturized form of Agrin in skeletal muscle through adenovirus-mediated gene transfer induces enhanced muscle capacity in aged mice. Mechanistic investigations suggest that Agrin-mediated improvement in muscle function occurs through the stimulation of Yap signaling and the concurrent upregulation of dystroglycan expression. Collectively, our findings underscore the pivotal role of Agrin in the aging process of skeletal muscles and propose Agrin as a potential therapeutic target for addressing sarcopenia.

Validation of the Patient-Reported Outcomes Measurement Information System (PROMIS®) physical function questionnaire in late-onset Pompe disease using PROPEL phase 3 data

BackgroundThe construct validity and interpretation of the Patient-Reported Outcome Measurement Information System (PROMIS®) Physical Function short form 20a (PF20a) questionnaire were evaluated for patients with late-onset Pompe disease (LOPD), a rare, autosomal recessive, progressive neuromuscular disorder treatable by enzyme replacement therapy (ERT).MethodsIn the phase 3 PROPEL study, adults with LOPD underwent testing of physical functioning and had PRO measurements at baseline and at weeks 12, 26, 38, and 52 while receiving experimental or standard-of-care ERT. All patients were pooled for analyses, without comparisons between treatment groups. Associations and correlations between PROMIS PF20a scores and the 6-minute walk distance (6MWD), % predicted forced vital capacity (FVC), manual muscle test (MMT) of the lower extremities, Gait, Stairs, Gowers’ maneuver, Chair (GSGC) score, and Rasch-built Pompe-specific Activity (R-PAct) scale were evaluated by calculating regression coefficients in linear regression models and Pearson correlation coefficients (R); patients’ age, sex, race, ERT prior to study, body mass index, and study treatment were included as covariables. The minimal clinically important difference (MCID) of PROMIS PF20a was determined using distribution- and anchor-based methods.Results123 patients received at least 1 dose of ERT. In multivariable analyses, PROMIS PF20a scores had strong correlations with R-PAct scores (R = 0.83 at baseline and R = 0.67 when evaluating changes between baseline and 52 weeks) and moderate correlations with the 6MWD (R = 0.57 at baseline and R = 0.48 when evaluating changes between baseline and 52 weeks). Moderate correlations were also observed between PROMIS PF20a and MMT (R = 0.54), GSGC (R=-0.51), and FVC (R = 0.48) at baseline. In multivariable linear regression models, associations were significant between PROMIS PF20a and 6MWD (P = 0.0006), MMT (P = 0.0034), GSGC (P = 0.0278), and R-PAct (P < 0.0001) at baseline, between PROMIS PF20a and 6MWD (P < 0.0001), FVC (P = 0.0490), and R-PAct (P < 0.0001) when combining all measurements, and between PF20a and 6MWD (P = 0.0016) and R-PAct (P = 0.0001) when evaluating changes in scores between baseline and 52 weeks. The anchor-based and distribution-based MCID for a clinically important improvement for PROMIS PF20a were 2.4 and 4.2, respectively.ConclusionsPROMIS PF20a has validity as an instrument both to measure and to longitudinally follow physical function in patients with LOPD.Trial registrationClinicalTrials.gov, NCT03729362. Registered 2 November 2018, https://www.clinicaltrials.gov/search?term=NCT03729362.

Tele-Rehabilitation for Boys with Duchenne Muscular Dystrophy in India Amidst the COVID-19 Pandemic: An Implementation Study

Purpose: Duchenne muscular dystrophy (DMD) is X-linked progressive neuromuscular disorder of childhood onset which leads to loss of ambulation, followed by respiratory and cardiac muscle weakness. Physiotherapy is integral to the multidisciplinary care plan for boys with DMD. During the COVID-19 pandemic, Tele-medicine was increasingly used to provide healthcare to patients. The study aimed to assess the efficacy and feasibility of Tele-rehabilitation among ambulatory boys with DMD. Materials and Methods: Ambulatory boys aged 5 to 12 years with DMD were recruited using purposive sampling. The Tele-rehabilitation program was designed by a neuromuscular team and provided by a physiotherapist through telephonic video calls twice a month for three months. A compliance diary was provided to fill out at home after each session. The outcome was measured with a change in Medical Research Council (MRC) sum score and gower's times at 12 weeks using paired t- test. Results: 92 boys with DMD were enrolled and 66 (71%) boys completed the program and had follow-up at 12 weeks. The baseline MRC sum score was 38.2±3.7, and the gower's time was 9.2±6.7 seconds. At 12 weeks MRC sum score was 38.8±4.2, and gower's time was 8.59±7.7 seconds (p-value- 0.03 and p-value- 0.001), respectively. The Vigno's and Brook's scores didn't show a significant change. Compliance of &amp;gt;50% to the Tele-rehabilitation exercise programs was present in 89% of subjects. Conclusion: A short-term Tele-rehabilitation program was feasible with a high compliance rate and efficacious in motor strengthening among boys with DMD.

Real-world outcomes from a series of patients with late onset Pompe disease who switched from alglucosidase alfa to avalglucosidase alfa.

Introduction: Pompe disease is an inherited, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase and accumulation of glycogen in tissues, resulting in cellular dysfunction, muscle damage, and functional disabilities. Enzyme replacement therapy with alglucosidase alfa (Myozyme/Lumizyme) has led to better outcomes, but many patients have plateaued or declined despite treatment. The second-generation ERT avalglucosidase alfa (Nexviazyme) was designed to have enhanced cellular uptake via the conjugation of additional bis-mannose-6-phosphate residues. There have been trials comparing the efficacy of alglucosidase and avalglucosidase, but there remains a need for more real-world data on patients who switched from alglucosidase to avalglucosidase. Methods: A chart review was conducted on n = 15 patients with late-onset Pompe disease followed at a single center who switched from alglucosidase to avalglucosidase and continued for at least 6months. Results: A total of n = 8/15 patients received alglucosidase for more than 3years prior to switching, and n = 7/15 received it for more than 5years prior to switching. There were statistically significant improvements in CK, Hex4, and AST with mean differences of -104.8U/L, -3.0mmol/molCr, and -14.7U/L, respectively, post-switch. 6-Minute Walk Test; comfortable gait speed; Gait, Stairs, Gower, Chair; and Quick Motor Function Test scores improved or stabilized in most patients post-switch (n = 8/12, n = 11/12, n = 9/12, n =7/11, respectively). Of n = 7 patients with pulmonary function testing, n = 4/7 had improved upright FVC. Patient-reported outcomes revealed improvements in dyspnea (n = 4/4), physical function (n = 3/4), fatigue (n = 2/3), and lower back pain (n = 3/3). Avalglucosidase was well tolerated without infusion-associated reactions, and all n = 7 patients on home infusions continued receiving ERT at home. Anti-drug antibodies were seen in n = 9/10 of patients on alglucosidase and n = 8/13 of those on avalglucosidase, with titers below 12,800 in a majority of patients. We also present the first outcome data for a patient with LOPD who is non-ambulatory and a full-time wheelchair user; she demonstrated meaningful improvements in quality of life and motor function with the switch. Discussion: In summary, improved outcomes were seen in most patients, with a subset whose decline persisted. This study presents evidence that switching from alglucosidase to avalglucosidase may be associated with improved outcomes in certain patients with LOPD.

Subjective oral health, malocclusions and oral health related quality of life in patients with Duchenne muscular dystrophy

Duchenne muscular dystrophy is a hereditary progressive neuromuscular disorder. Deterioration and weakening of the muscles is also present in orofacial muscles. Both weakness of the muscles and the fact that patients become more dependent of care, can make oral care more difficult. At this moment, it is unknown how patients with Duchenne muscular dystrophy experience their oral health and which problems regarding oral health and oral care may impact their oral health related quality of life. In this cross-sectional study, we found that, despite a high percentage of gingivitis, a high percentage of patients who experience halitosis and a high percentage of malocclusions, patients score their oral health related quality of life as good.

Aberrant evoked calcium signaling and nAChR cluster morphology in a SOD1 D90A hiPSC-derived neuromuscular model.

Familial amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is due to mutations in one of several target genes, including SOD1. So far, clinical records, rodent studies, and in vitro models have yielded arguments for either a primary motor neuron disease, or a pleiotropic pathogenesis of ALS. While mouse models lack the human origin, in vitro models using human induced pluripotent stem cells (hiPSC) have been recently developed for addressing ALS pathogenesis. In spite of improvements regarding the generation of muscle cells from hiPSC, the degree of maturation of muscle cells resulting from these protocols has remained limited. To fill these shortcomings, we here present a new protocol for an enhanced myotube differentiation from hiPSC with the option of further maturation upon coculture with hiPSC-derived motor neurons. The described model is the first to yield a combination of key myogenic maturation features that are consistent sarcomeric organization in association with complex nAChR clusters in myotubes derived from control hiPSC. In this model, myotubes derived from hiPSC carrying the SOD1 D90A mutation had reduced expression of myogenic markers, lack of sarcomeres, morphologically different nAChR clusters, and an altered nAChR-dependent Ca2+ response compared to control myotubes. Notably, trophic support provided by control hiPSC-derived motor neurons reduced nAChR cluster differences between control and SOD1 D90A myotubes. In summary, a novel hiPSC-derived neuromuscular model yields evidence for both muscle-intrinsic and nerve-dependent aspects of neuromuscular dysfunction in SOD1-based ALS.

Plasticity occurs in a specific phenotype of neurons in the nucleus tractus solitarius of dystrophin gene-mutated rats.

Duchenne muscular dystrophy (DMD) is a severe progressive neuromuscular disorder that causes cardiac and respiratory failure. Patients with DMD have tachycardia and autonomic nervous dysfunction at a young age, which can potentially worsen cardiorespiratory function. Therefore, we hypothesised that plasticity occurs in neurons of the cardiorespiratory brainstem nucleus (nucleus tractus solitarius [NTS]) due to DMD, thus affecting neuronal regulation because afferent information from cardiorespiratory organs changes with disease progression. Patch-clamp experiments were performed on second-order NTS neurons from Dmd-mutated (Dm) rats that showed no functional dystrophin protein expression, as confirmed by immunohistochemistry. NTS neurons are classified into two electrophysiological phenotypes: one showing a delayed onset of spiking from hyperpolarised membrane potentials, namely, delayed-onset spiking (DS)-type neurons, and the other showing a rapid onset, namely, rapid-onset spiking-type neurons. Neuroplasticity mainly occurs in DS-type neurons in Dm rats and is characterised by blunted neuronal excitability accompanied by reduced outward currents and a facilitatory effect on synaptic transmission, that is, an increased frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) without changes in the amplitude and an increased amplitude of tractus solitarius-evoked EPSCs without changes in the paired-pulse ratio. Although we cannot rule out the possibility that the neuroplastic changes observed in Dm rats were caused by dystrophin deficiency in the neurons themselves, the plasticity could be caused by cardiorespiratory deterioration and/or adaptation in DMD patients.

Twice-Weekly Outpatient Rehabilitation Intervention for Young Children With Spinal Muscular Atrophy Treated With Genetic-Based Therapies: Protocol for a Feasibility Study

Background Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder that causes muscle weakness and is the leading genetic cause of infant mortality worldwide. While no definitive cure exists, the approval of 3 genetic-based therapies in Canada since 2018 has led to significant improvements in muscle function for children with SMA. With that, there are no evidence-based rehabilitation interventions and minimal evidence on the combined effects of genetic-based therapies and rehabilitation. Objective This protocol describes the methodology to assess the feasibility of a twice-weekly outpatient rehabilitation intervention focusing on gross and fine motor function to inform the methodology and sample size of a definitive clinical trial. Methods We will conduct a single-center nonrandomized pilot and feasibility trial to explore an outpatient rehabilitation intervention for children aged 6 months to 3 years with SMA treated with genetic-based therapies. Participation in the study will occur over a 25-week period, with a baseline assessment visit followed by a 12-week intervention period and a 12-week nonintervention period. The rehabilitation intervention comprises weekly physical and occupational therapy for 11 weeks. Assessments will occur at baseline (week 0), end of intervention or early withdrawal (week 12), and follow-up (week 24). Predetermined feasibility indicators will evaluate study feasibility across process (recruitment rates, eligibility criteria, adherence rates, retention rates, questionnaire suitability, and acceptability), resource (time, implementation, and execution), management (materials and data), and scientific (safety, tolerability, and preliminary efficacy) domains. Results This project was funded in March 2022, and data will be collected between March 2023 and December 2023. Data analysis will occur between January 2024 and March 2024, with publication expected in the fall of 2024. The protocol for the feasibility trial will be considered successful if it meets the success criteria set out for the feasibility indicators. Indicators of specific interest include all process indicators, as well as time. Exploratory indicators will be reported. Pragmatically, the results of the feasibility trial will inform changes to the protocol and the start-up of a definitive multisite trial. Conclusions This novel twice-weekly outpatient rehabilitation intervention will be the first step toward filling the need for an evidence-based rehabilitation intervention for children with SMA treated with genetic-based therapies. It is expected that consistent and intensive rehabilitation therapy will augment functional gains being observed in this population. In the future, a definitive trial will measure the efficacy of the intervention. Trial Registration ClinicalTrials.gov NCT05638750; https://clinicaltrials.gov/study/NCT05638750 International Registered Report Identifier (IRRID) DERR1-10.2196/46363

Psychosocial factors and well-being among adults with Charcot-Marie-Tooth disease: A cross-sectional study.

The goal of the current study is to examine the relationships between psychosocial factors and well-being among adults with Charcot-Marie-Tooth (CMT) disease, a progressive neuromuscular disorder. Specifically, we aimed to examine associations between psychosocial factors and sense of purpose as well as the moderating role of sense of purpose on associations between psychosocial factors and two other measures of well-being (life satisfaction and health-related quality of life). In 2021, we recruited 263 U.S. adults with CMT (Mage = 60.15 years, 58.56% female, 92.40% White) to take part in a cross-sectional study. Participants were asked to complete an online survey assessing components of well-being as well as various psychosocial factors. Moderate-to-strong associations were found between most psychosocial factors assessed and sense of purpose in individuals with CMT. In addition, sense of purpose moderated the relationship between multiple psychosocial factors and other measures of well-being. Psychosocial factors may be important to consider when examining well-being among individuals with CMT. Furthermore, sense of purpose may be a beneficial tool for promoting well-being in this population. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Asymptomatic troponin I elevation and acute myocarditis in the late period of gene replacement therapy with onasemnogene aberpavovec for patients with spinal muscular atrophy: literature review and clinical case series

Introduction. Spinal muscular atrophy (SMA) 5q is a rare genetically determined progressive neuromuscular disorder, is the most frequent cause of infant death not long ago. Nowadays onasemnogen abeparvovec as pathogenetic therapy is successfully used in clinical practice to combat this disease. Gene replacement therapy (GRT) with onasemnogen abeparvovec for SMA patients may come amid non-target changes in the cardiovascular system that require early diagnosis and monitoring.&#x0D; Objective. To present clinical reports considering children with genetically confirmed SMA and elevated troponin I levels after onasemnogen abeparvovec gene replacement therapy.&#x0D; Materials and methods. We monitored forty two children with genetically confirmed SMA who received gene replacement therapy with onasemnogen abeparvovec in the pediatric neurology department. All patients were tested for troponin I before and after the infusion, additional tests of N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP), creatine phosphokinase-MB (CPK-MB), electrocardiogram, echocardiography were made if needed.&#x0D; Results. In 11 (26.2%) of 42 SMA children troponin I was elevated and detected up to the eighth week after drug administration. At the same time, an increased concentration of troponin I in the majority of cases (41 out of 42 children) was not associated with clinically significant manifestations. There was only one case when acute myocarditis, confirmed by clinical and instrumental methods of investigation occurred. It was a girl with a long-term (10 months) elevation of troponin I, who had an intercurrent infection.&#x0D; Conclusions. Troponin I elevations detected after GRT with onasomnogene abeparvovec in SMA patients are often asymptomatic. This myocarditis case highlights the importance of longer cardiac monitoring of troponin I elevations, especially in the presence of intercurrent bacterial and viral infections.

Management and Outcomes of Femur Fractures in Patients with Duchenne Muscular Dystrophy

Background: Duchenne muscular dystrophy (DMD) is a severe, progressive X-linked recessive neuromuscular disorder characterized by muscle weakness and atrophy. Additionally, patients with DMD have significant reductions in bone mineral density compared to age-matched controls, which is exacerbated by concomitant steroid use. These findings dramatically increase fracture risk, which may irreparably decrease functional status. The aim of this case series is to examine outcomes of operative versus nonoperative management of femur fractures in this patient population.Methods: An IRB-approved retrospective chart review was completed for patients with DMD treated at a single institution for a femur fracture between 2013-2022. Patients were excluded for incomplete documentation, treatment initiation at an outside hospital, or diagnosis of a different muscular dystrophy. Demographic variables, treatment information, functional status, and adverse events were collected for each patient. Descriptive statistics were used to summarize demographic and outcome variables.Results: A total of 10 patients with 11 femur fractures were included for analysis. All patients were male with an average age of 12.7 years and clinical follow-up of 286 days. Five fractures in five patients underwent operative fixation (Group A), and six fractures in five patients underwent nonoperative management (Group B). In Group A, three patients were short-distance ambulators prior to injury, and all patients regained a similar functional status postoperatively. All three patients were treated with a locked intramedullary nail. One patient in Group B was a short-distance ambulator prior to injury; the remainder were nonambulatory. All patients in Group B were primary wheelchair users at final follow-up. There were no adverse events as a result of treatment in either group.Conclusion: Nonoperative management with cast immobilization remains an acceptable option for nonambulatory patients and those with minimally displaced fractures not amenable to surgical intervention. Surgical intervention is recommended for higher-functioning patients with the goal of restoring ambulatory status. Regardless of treatment modality, patients should receive aggressive physical therapy directed at early weight-bearing, range of motion, and mobilization to preserve strength, muscle mass, and mobility.Level of Evidence: Level IV case series Key Concepts•Management of femur fractures in Duchenne muscular dystrophy should account for fracture morphology as well as patient functional status.•Surgical management is safe and effective in promoting fracture union and preserving functional status.•Nonoperative management is preferred in nonambulatory patients and for minimally displaced fractures.

Effect of Intensity of Home Noninvasive Ventilation in Individuals With Neuromuscular and Chest Wall Disorders: A Systematic Review and Meta-Analysis of Individual Participant Data

IntroductionHome noninvasive ventilation (NIV), targeting a reduction of carbon dioxide with a combination of sufficient inspiratory support and backup-rate improves outcomes in patients with chronic obstructive pulmonary disease. The aim of this systematic review with individual participant data (IPD) meta-analysis was to evaluate the effects of intensity of home NIV on respiratory outcomes in individuals with slowly progressive neuromuscular (NMD) or chest-wall disorders (CWD). MethodsControlled, non-controlled and cohort studies indexed between January-2000 and December-2020 were sought from Medline, Embase and the Cochrane Central Register. Outcomes were diurnal PaCO2, PaO2, daily NIV usage, and interface type (PROSPERO-CRD 42021245121). NIV intensity was defined according to the Z-score of the product of pressure support (or tidal volume) and backup-rate. Results16 eligible studies were identified; we obtained IPD for 7 studies (176 participants: 113-NMD; 63-CWD). The reduction in PaCO2 was greater with higher baseline PaCO2. NIV intensity per se was not associated with improved PaCO2 except in individuals with CWD and the most severe baseline hypercapnia. Similar results were found for PaO2. Daily NIV usage was associated with improvement in gas exchange but not with NIV intensity. No association between NIV intensity and interface type was found. ConclusionFollowing home NIV initiation in NMD or CWD patients, no relationship was observed between NIV intensity and PaCO2, except in individuals with the most severe CWD. The amount of daily NIV usage, rather than intensity, is key to improving hypoventilation in this population during the first few months after introduction of therapy.

Spinal astrocyte dysfunction drives motor neuron loss in late-onset spinal muscular atrophy

Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder caused by a loss of the survival of motor neuron 1 (SMN1) gene, resulting in a loss of spinal motor neurons (MNs), leading to muscle weakness and wasting. The pathogenesis of MN loss in SMA and the selective vulnerability in different cellular populations are not fully understood. To investigate the role of spinal astrocytes in the pathogenesis of late-onset SMA, we used a mouse model in addition to in vitro approaches. Immunostaining, Western blot analysis, small interfering ribonucleic acid (siRNA) transfections, functional assays, enzyme-linked immunosorbent assay (ELISA), behavioral tests, and electrophysiological measurements were performed. Early activation of spinal astrocytes and a reduction of the excitatory amino acid transporter 1 (EAAT1) on postnatal day (P) 20 preceded the loss of spinal MNs in SMA mice occurring on P42. EAAT1 reduction resulted in elevated glutamate levels in the spinal cord of SMA mice at P20 and P42. SMA-like astrocytes generated by siRNA and an ex vivo model of glutamate excitotoxicity involving organotypic spinal cord slice cultures revealed the critical role of glutamate homeostasis in the degeneration of MNs. The pre-emptive administration of arundic acid (AA), as an inhibitor of astrocyte activation, to SMA mice prior to the loss of motor neurons (P28) resulted in elevated EAAT1 protein levels compared to vehicle-treated SMA mice and prevented the increase of glutamate in the spinal cord and the loss of spinal MNs. Furthermore, AA preserved motor functions during behavioral experiments, the electrophysiological properties, and muscle alteration of SMA mice. In a translational approach, we transfected healthy human fibroblasts with SMN1 siRNA, resulting in reduced EAAT1 expression and reduced uptake but increased glutamate release. These findings were verified by detecting elevated glutamate levels and reduced levels of EAAT1 in cerebrospinal fluid of untreated SMA type 2 and 3 patients. In addition, glutamate was elevated in serum samples, while EAAT1 was not detectable. Our data give evidence for the crucial role of spinal astrocytes in the pathogenesis of late-onset SMA, a potential driving force for MN loss by glutamate excitotoxicity caused by EAAT1 reduction as an early pathophysiological event. Furthermore, our study introduces EAAT1 as a potential therapeutic target for additional SMN-independent therapy strategies to complement SMN-enhancing drugs.

Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population.

CAG repeat expansions in exon 1 of the AR gene on the X chromosome cause spinal and bulbar muscular atrophy, a male-specific progressive neuromuscular disorder associated with a variety of extra-neurological symptoms. The disease has a reported male prevalence of approximately 1:30 000 or less, but the AR repeat expansion frequency is unknown. We established a pipeline, which combines the use of the ExpansionHunter tool and visual validation, to detect AR CAG expansion on whole-genome sequencing data, benchmarked it to fragment PCR sizing, and applied it to 74 277 unrelated individuals from four large cohorts. Our pipeline showed sensitivity of 100% [95% confidence interval (CI) 90.8-100%], specificity of 99% (95% CI 94.2-99.7%), and a positive predictive value of 97.4% (95% CI 84.4-99.6%). We found the mutation frequency to be 1:3182 (95% CI 1:2309-1:4386, n = 117 734) X chromosomes-10 times more frequent than the reported disease prevalence. Modelling using the novel mutation frequency led to estimate disease prevalence of 1:6887 males, more than four times more frequent than the reported disease prevalence. This discrepancy is possibly due to underdiagnosis of this neuromuscular condition, reduced penetrance, and/or pleomorphic clinical manifestations.

A breakthrough effect of gene replacement therapy on respiratory outcomes in children with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an inherited progressive neuromuscular disorder characterized by generalized hypotonia, respiratory failure and early death. The introduction of gene replacement therapy (GRT) modified the natural history of the disease. However, more data is needed to understand the long-term effect of GRT on measurable respiratory outcomes. We report the respiratory outcomes in our cohort of patients with SMA post-GRT in 2-year period. A retrospective chart-review of genetically confirmed children with SMA who received GRT between 2019 and 2021 in Qatar. The evaluated respiratory outcomes were chronic respiratory support, respiratory hospitalizations, escalation of respiratory support and polysomnography results before and after GRT. Nonrespiratory outcomes; nutritional status, swallowing, and motor functions; were also assessed. A total of 11 patients (9 patients with SMA-1 and 2 patients with SMA-2) received GRT at a median age of 12 months and 22 months in patients with SMA-1 and SMA-2, respectively. All patients were successfully weaned off Noninvasive ventilation (NIV) except one patient who remained on mechanical ventilation through tracheostomy tube. The annualized hospitalization rate dropped by half after GRT. The average length of stay (LOS) in intensive care unit (ICU) decreased by 17.32 days/patient/year after GRT. Duration of required escalation of respiratory support during acute hospitalizations has dropped by 18.56 days/patient/year post-GRT. We report favorable respiratory outcomes of GRT in our cohort. GRT resulted in discontinuation of chronic respiratory support in majority of ventilated patients. GRT also resulted in decreased respiratory hospitalization rate, hospital-LOS, ICU-LOS, and need for escalation of ventilatory support.

Collaborative Therapist-Patient Decision Making: A Power-Based Exercise Program for an Adolescent With CMT1A.

The purpose of this case report is to describe an episode of care for an adolescent with Charcot Marie Tooth disease (CMT) using a power-based progressive resistance exercise (PRE) and balance program to improve performance of participant-defined goals with added description through the voice of the patient as "participant lived experience." Participant discussion demonstrates improvement of functional performance for an adolescent with CMT subtype 1A (CMT1A), a progressive neuromuscular disorder. Function and participation-specific movement observation, clinical evaluation, and resistance training fostered appropriate program design and intervention dosing. A power-based progressive resistance exercise and balance program with design based on participant-defined goals was feasible, well tolerated, and successful for an adolescent with CMT1A. Inclusion of viewpoints of the "lived experience" provides deeper insight into patient perspective and clinical outcomes. Outcomes may improve when intervention is specifically dosed to participant goals and individual muscle performance requirements for targeted tasks.

Newborn screening for Pompe disease in Italy: Long-term results and future challenges

Pompe disease (PD) is a progressive neuromuscular disorder caused by a lysosomal acid α-glucosidase (GAA) deficiency. Enzymatic replacement therapy is available, but early diagnosis by newborn screening (NBS) is essential for early treatment and better outcomes, especially with more severe forms. We present results from 7 years of NBS for PD and the management of infantile-onset (IOPD) and late-onset (LOPD) patients, during which we sought candidate predictive parameters of phenotype severity at baseline and during follow-up. We used a tandem mass spectrometry assay for α-glucosidase activity to screen 206,741 newborns and identified 39 positive neonates (0.019%). Eleven had two pathogenic variants of the GAA gene (3 IOPD, 8 LOPD); six carried variants of uncertain significance (VUS). IOPD patients were treated promptly and had good outcomes. LOPD and infants with VUS were followed; all were asymptomatic at the last visit (mean age 3.4 years, range 0.5–5.5). Urinary glucose tetrasaccharide was a useful and biomarker for rapidly differentiating IOPD from LOPD and monitoring response to therapy during follow-up. Our study, the largest reported to date in Europe, presents data from longstanding NBS for PD, revealing an incidence in North East Italy of 1/18,795 (IOPD 1/68,914; LOPD 1/25,843), and the absence of mortality in IOPD treated from birth. In LOPD, rigorous long-term follow-up is needed to evaluate the best time to start therapy. The high pseudodeficiency frequency, ethical issues with early LOPD diagnosis, and difficulty predicting phenotypes based on biochemical parameters and genotypes, especially in LOPD, need further study.

P.60 Is there correlation between North Star ambulatory assessments and performance upper limb module in ambulant boys with Duchenne muscular dystrophy?

Duchenne muscular dystrophy is a rapidly progressive X-linked neuromuscular disorder. The majority of boys, with and without treatments, lose ambulation by late teenage years. The North Star Ambulatory Assessment (NSAA) and the Performance of Upper Limb Module (PUL 2.0) are validated outcome measures used to assess change over time. The NSAA assesses gross motor function in ambulant boys (maximum score 34) while currently in the UK the PUL 2 is used predominantly to assess upper limb function in non-ambulant boys. The study aims to ascertain whether upper limb function starts to deteriorate in the ambulant population by applying both scales, and to assess which upper limb activities are most difficult in the younger age group. The PUL, which has a mixture of proximal and distal activities, has 22 items with a maximum achievable score of 42. It uses the Brook scale as an entry point. The boys engage well with this scale, finding it less challenging than some NSAA items (e.g standing from the floor, hopping). Cross sectional data was collected from 100 ambulant boys or those who recently lost ambulation (within 6 months of assessment) seen regularly in our neuromuscular service. Ages range from 4y 5m to 15y 2m for the ambulant boys. Ages for recently non-ambulant were 9y 7m to 13y 5m. In both ambulant and recently non-ambulant boys, scores for the North Star ambulatory assessment reduced with age. The corresponding scores for the PUL did not deteriorate with age and the majority of boys scored 35 or above. 20% scored maximum of 42, the youngest being 6y 4m. Four boys scored below 30 with NSAA below 6. Hardest items are lifting 1kg and 500g weights above shoulder level. This data shows that the majority of ambulant boys and recently non-ambulant boys with DMD maintain their upper limb function. Studies on older boys show a reduction in PUL 2.0. Further longitudinal studies are projected to show how function changes with loss of walking.