Search

Background and purpose: At 12 months in the phase 2 TOPAZ study, treatment with apitegromab was associated with both an improved motor function in patients with Type 2 or 3 spinal muscular atrophy (SMA) and with a favorable safety profile. This manuscript reports the extended efficacy and safety in the nonambulatory group of the TOPAZ study at 36 months. Methods: Patients who completed the primary study (NCT03921528) could enroll in an open-label extension, during which patients received apitegromab 20 mg/kg by intravenous infusion every 4 weeks. Patients were assessed periodically via the Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), World Health Organization (WHO) motor development milestones, Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) Daily Activities and Mobility domains, and Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire. Results: Of the 58 patients enrolled in TOPAZ, 35 were nonambulatory (mean age 7.3 years). The mean change at 36 months in HFMSE score from baseline was +4.0 (standard deviation [SD]: 7.54), and + 2.4 (3.24) for RULM score (excluding n = 7 after scoliosis surgery). Caregiver-reported outcomes (PEDI-CAT and PROMIS Fatigue) showed improvements from baseline over 36 months. In addition, most patients (28/32) improved or maintained WHO motor milestones achieved at baseline. The most frequently reported treatment-emergent adverse events were pyrexia (48.6%), nasopharyngitis (45.7%), COVID-19 infection (40.0%), vomiting (40.0%), and upper respiratory tract infection (31.4%). Conclusion: The benefit of apitegromab treatment observed at 12 months was sustained at 36 months with no new safety findings. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Eteplirsen, approved in the US for patients with Duchenne muscular dystrophy (DMD) with exon 51 skip‐amenable variants, is associated with attenuated ambulatory/pulmonary decline versus DMD natural history (NH). We report overall survival in a US cohort receiving eteplirsen and contextualize these outcomes versus DMD NH. Methods: US patients with DMD receiving eteplirsen were followed through a patient support program, with data collected on ages at eteplirsen initiation and death/end of follow‐up. Individual DMD NH data were extracted by digitizing Kaplan–Meier (KM) curves from published systematic and targeted literature reviews. Overall survival age was analyzed using KM curves and contextualized with DMD NH survival curves; subanalyses considered age groups and duration of eteplirsen exposure. Overall survival time from treatment initiation was also evaluated. Results: A total of 579 eteplirsen‐treated patients were included. During a total follow‐up of 2119 person‐years, median survival age was 32.8 years. DMD NH survival curves extracted from four publications (follow‐up for 1224 DMD NH controls) showed overall pooled median survival age of 27.4 years. Eteplirsen‐treated patients had significantly longer survival from treatment initiation versus age‐matched controls (age‐adjusted hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.44–0.98; p <.05). Longer treatment exposure was associated with improved survival (HR, 0.15; 95% CI, 0.05–0.41; p <.001). Comparisons using different DMD NH cohorts to address common risks of bias yielded consistent findings. Discussion: Data suggest eteplirsen may prolong survival in patients with DMD across a wide age range. As more data become available, the impact of eteplirsen on survival will be further elucidated. [ABSTRACT FROM AUTHOR]

Background: The natural history of spinal muscular atrophy (SMA) is well understood, with progressive muscle weakness resulting in declines in function. The development of contractures is common and negatively impacts function. Clinically, joint hypermobility (JH) is observed but is poorly described, and its relationship with function is unknown. Methods: Lower-limb ROM (range of motion) assessments of extension and flexion at the hip, knee, and ankle were performed. ROMs exceeding the published norms were included in the analysis. The functional assessments performed included the six-minute walk test (6 MWT) and the Hammersmith Functional Motor Scale—Expanded (HFMSE). Results: Of the 143 participants, 86% (n = 123) had at least one ROM measure that was hypermobile, and 22% (n = 32) had three or more. The HFMSE scores were inversely correlated with hip extension JH (r = −0.60, p = 0.21; n = 6) and positively correlated with knee flexion JH (r = 0.24, p = 0.02, n = 89). There was a moderate, inverse relationship between the 6 MWT distance and ankle plantar flexion JH (r = −0.73, p = 0.002; n = 15). Conclusions: JH was identified in nearly all participants in at least one joint in this study. Hip extension, knee flexion and ankle plantar flexion JH was associated with function. A further understanding of the trajectory of lower-limb joint ROM is needed to improve future rehabilitation strategies. [ABSTRACT FROM AUTHOR]

Nusinersen has been shown to improve or stabilize motor function in individuals with spinal muscular atrophy (SMA). We evaluated baseline scoliosis severity and motor function in nusinersen-treated non-ambulatory children with later-onset SMA. Post hoc analyses were conducted on 95 children initiating nusinersen treatment in the CHERISH study or SHINE long-term extension trial. Participants were categorized by baseline Cobb angle (first nusinersen dose): ≤10°, >10° to ≤20°, and >20° to <40° (no/mild/moderate scoliosis, respectively). Outcome measures included the Hammersmith Functional Motor Score—Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Regression analysis determined the relationships between baseline scoliosis severity and later motor function. For children with no, mild, and moderate scoliosis, the mean increase in HFMSE from baseline to Day 930 was 6.0, 3.9, and 0.7 points, and in RULM was 6.1, 4.6, and 2.3 points. In the linear model, a 10° increase in baseline Cobb angle was significantly associated with a −1.4 (95% CI −2.6, −0.2) point decrease in HFMSE (p = 0.02) and a −1.2 (95% CI −2.1, −0.4) point decrease in RULM (p = 0.006) at Day 930. Treatment with nusinersen was associated with improvements/stabilization in motor function in all groups, with greater response in those with no/mild scoliosis at baseline. [ABSTRACT FROM AUTHOR]

Background: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy with multisystem involvement, often requiring invasive ventilator support, gastrostomy tube feeding, and wheelchair use. Understanding healthcare resource utilization in patients with XLMTM is important for development of targeted therapies but data are limited. Methods: We analyzed individual medical codes as governed by Healthcare Common Procedure Coding System, Current Procedural Terminology, and International Classification of Diseases, 10th Revision (ICD-10) for a defined cohort of XLMTM patients within a US medical claims database. Using third-party tokenization software, we defined a cohort of XLMTM patient tokens from a de-identified dataset in a research registry of diagnostically confirmed XLMTM patients and de-identified data from a genetic testing company. After approval of an ICD-10 diagnosis code for XLMTM (G71.220) in October 2020, we identified additional patients. Results: A total of 192 males with a diagnosis of XLMTM were included: 80 patient tokens and 112 patients with the new ICD-10 code. From 2016 to 2020, the annual number of patients with claims increased from 120 to 154 and the average number of claims per patient per year increased from 93 to 134. Of 146 patients coded with hospitalization claims, 80 patients (55%) were first hospitalized between 0 and 4 years of age. Across all patients, 31% were hospitalized 1–2 times, 32% 3–9 times, and 14% ≥ 10 times. Patients received care from multiple specialty practices: pulmonology (53%), pediatrics (47%), neurology (34%), and critical care medicine (31%). The most common conditions and procedures related to XLMTM were respiratory events (82%), ventilation management (82%), feeding difficulties (81%), feeding support (72%), gastrostomy (69%), and tracheostomy (64%). Nearly all patients with respiratory events had chronic respiratory claims (96%). The most frequent diagnostic codes were those investigating hepatobiliary abnormalities. Conclusions: This innovative medical claims analysis shows substantial healthcare resource use in XLMTM patients that increased over the last 5 years. Most patients required respiratory and feeding support and experienced multiple hospitalizations throughout childhood and beyond for those that survived. This pattern delineation will inform outcome assessments with the emergence of novel therapies and supportive care measures. [ABSTRACT FROM AUTHOR]

Many individuals with muscular dystrophies remain genetically undiagnosed despite clinical diagnostic testing, including exome sequencing. Some may harbor previously undetected structural variants (SVs) or cryptic splice sites. We enrolled 10 unrelated families: nine had muscular dystrophy but lacked complete genetic diagnoses and one had an asymptomatic DMD duplication. Nanopore genomic long‐read sequencing identified previously undetected pathogenic variants in four individuals: an SV in DMD, an SV in LAMA2, and two single nucleotide variants in DMD that alter splicing. The DMD duplication in the asymptomatic individual was in tandem. Nanopore sequencing may help streamline genetic diagnostic approaches for muscular dystrophy. [ABSTRACT FROM AUTHOR]

Background: ANCHOVY was a global, multicenter, chart-review study that aimed to describe the natural history of Type 1 spinal muscular atrophy (SMA) from a broad geographical area and provide further contextualization of results from the FIREFISH (NCT02913482) interventional study of risdiplam treatment in Type 1 SMA.Methods: Data were extracted from medical records of patients with first symptoms attributable to Type 1 SMA between 28 days and 3 months of age, genetic confirmation of SMA, and confirmed survival of motor neuron 2 copy number of two or unknown. The study period started on 1 January 2008 for all sites; study end dates were site-specific due to local treatment availabilities. Primary endpoints were time to death and/or permanent ventilation and proportion of patients achieving motor milestones. Secondary endpoints included time to initiation of respiratory and feeding support.Results: Data for 60 patients from nine countries across Asia, Europe and North and South America were analyzed. The median age (interquartile range [IQR]) for reaching death or permanent ventilation was ~ 7.3 (5.9-10.5) months. The median age (IQR) at permanent ventilation was ~ 12.7 (6.9-16.4) months and at death was ~ 41.2 (7.3-not applicable) months. No patients were able to sit without support or achieved any level of crawling, standing or walking.Interpretation: Findings from ANCHOVY were consistent with published natural history data on Type 1 SMA demonstrating the disease's devastating course, which markedly differed from risdiplam-treated infants (FIREFISH Part 2). The results provide meaningful additions to the literature, including a broader geographical representation. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Data regarding weight, height/length, and growth status of patients with spinal muscular atrophy (SMA) who have received only supportive care are limited. This cross‐sectional study describes these measurements in patients with Type 1 and Types 2/3 SMA and compares them with reference values from typically developing children. Methods: Retrospective baseline data from three sites in the Pediatric Neuromuscular Clinical Research Network (Boston, New York, Philadelphia) were used. Descriptive statistics for weight, height/length, body mass index‐for‐age, as well as weight‐for‐length and absolute and relative deviations from reference values (ie, 50th percentile from World Health Organization/Centers for Disease Control growth charts) were calculated. Furthermore, growth status was reported. Results: A total of 91 genetically confirmed patients with SMA receiving optimal supportive care and without any disease‐modifying treatment were stratified into Types 1 (n = 28) and 2/3 SMA (n = 63). Patients with Type 1 SMA weighed significantly less (median = −7.5%) compared with reference values and patients with Types 2/3 SMA were significantly shorter (mean = −3.0%) compared with reference values. The median weight was considerably below the 50th percentile in both groups of patients, even if they received a high standard of care and proactive feeding support. Discussion: More research is needed to understand which factors influence growth longitudinally, and how to accurately capture growth in patients with SMA. Further research should investigate the best time to provide feeding support to avoid underweight, especially in patients with Type 1, and how to avoid the risk of overfeeding, especially in patients with Types 2/3 SMA. [ABSTRACT FROM AUTHOR]

The small sample sizes inherent in rare and pediatric disease settings offer significant challenges for clinical trial design. In such settings, Bayesian adaptive trial methods can often pay dividends, allowing the sensible incorporation of auxiliary data and other relevant information to bolster that collected by the trial itself. Previous work has also included the use of one-arm trials augmented by the participants' own natural history data, from which the future course of the disease in the absence of intervention can be predicted. Patient response can then be defined by the degree to which post-intervention observations are inconsistent with the predicted "natural" trajectory. While such trials offer obvious advantages in efficiency and ethical hazard (since they expose no new patients to a placebo, anathema to patients or their parents and caregivers), they can offer no protection against bias arising from the presence of any "placebo effect," the tendency of patients to improve merely by being in the trial. In this paper, we investigate the impact of both static and transient placebo effects on one-arm responder studies of this type, as well as two-arm versions that incorporate a small concurrent placebo group but still borrow strength from the natural history data. We also propose more traditional Bayesian changepoint models that specify a parametric functional form for the patient's post-intervention trajectory, which in turn allow quantification of the treatment benefit in terms of the model parameters, rather than semi-parametrically in terms of a response relative to some "null" model. We compare the operating characteristics of our designs in the context of an ongoing investigation of centronuclear myopathies (CNMs), a group of congenital neuromuscular diseases whose most common and severe form is X-linked, affecting approximately 1 in 50,000 newborn boys. Our results indicate our two-arm responder and changepoint methods can offer protection against placebo effects, improving power while protecting the trial's Type I error rate. However, further research into innovative trial designs as well as ongoing dialog with regulatory authorities remain critically important in rare disease research. [ABSTRACT FROM AUTHOR]

Since 2016, 3 innovative therapies for spinal muscular atrophy (SMA) have changed the face of the disease. Although these therapies often result in remarkable improvements in infants and children, benefits in adults are modest and treatment is not curative. Concerns have been raised about the enormous costs of these medications, the ultimate burden to taxpayers, and the costs to society of withholding treatments and sacrificing or disadvantaging some individuals. Physicians are best positioned to serve our patients by carefully considering the costs, benefits, implications for quality of life (QOL), and the interplay of these factors within the framework of core ethical principles that guide clinical care. ANN NEUROL 2022;91:305–316 [ABSTRACT FROM AUTHOR]

PURPOSE: The purpose of this study was to examine the psychometric properties of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) in children and youth with Spinal Muscular Atrophy (SMA). METHODS: In this prospective cross-sectional study, caregivers of children and youth with SMA completed the PEDI-CAT Daily Activities and Mobility domains. A subset of caregivers completed a questionnaire about the measure. RESULTS: Mean ranks of scaled scores for Daily Activities (n = 96) and Mobility (n = 95) domains were significantly different across the three SMA types and across the three motor classifications. Normative scores indicated that 85 participants (89.5%) had limitations in Mobility and 51 in Daily Activities (53.1%). Floor effects were observed in≤10.4% of the sample for Daily Activities and Mobility. On average, caregivers completed the Mobility domain in 5.4 minutes and the Daily Activities domain in 3.3 minutes. Most caregivers reported that they provided meaningful information (92.1%), were willing to use the PEDI-CAT format again (79%), and suggested adding content including power wheelchair mobility items. CONCLUSION: Convergent validity was demonstrated for the Daily Activities and Mobility domains. Normative scores detected limitations in Mobility and Daily Activity performance for most participants with SMA. The PEDI-CATwas feasible to administer and caregivers expressed willingness to complete the PEDI-CAT in the future. [ABSTRACT FROM AUTHOR]

Bi‐allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi‐allelic TECPR2‐variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross‐sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N‐ and C‐terminal regions containing β‐propeller repeats. Despite constituting nearly half of disease‐associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2‐associated disorder. This sets the stage for future prospective natural history studies. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to provide clinicians with an overview of literature relating to dysphagia in spinal muscular atrophy (SMA) to guide assessment and treatment. Method: In this clinical focus article, we review literature published in Scopus and PubMed between 1990 and 2020 pertaining to dysphagia in SMA across the life span. Original research articles that were published in English were included. Searches were conducted within four themes of inquiry: (a) etiology and phenotypes, (b) respiratory systemic deficits and management, (c) characteristics of natural history dysphagia and its treatment, and (d) dysphagia outcomes with disease-modifying therapies. Articles for the first two themes were selected by content experts who identified the most salient articles that would provide clinicians foundational background knowledge about SMA. Articles for the third theme were identified using search terms, including spinal muscular atrophy, swallow, dysphagia, bulbar, nutrition, g-tube, alternative nutrition, jaw, mouth, palate, OR mandible. Search terms for the fourth theme included spinal muscular atrophy AND nusinersen OR AVXS-101/onasemnogene abeparvovec-xioi. Review of Pertinent Literature: Twenty-nine articles were identified. Findings across identified articles support the fact that patients with SMA who do not receive diseasemodifying therapy exhibit clinically significant deficits in oropharyngeal swallow function. Few investigations provided systematic information regarding the underlying physiological deficits responsible for this loss in function, the timing of the degradation, or how disease-modifying therapies change these outcomes. Conclusion: Future research outlining the physiological and functional oropharyngeal swallowing deficits among patients with SMA who receive disease-modifying therapy is critical in developing standards of dysphagia care to guide clinicians. [ABSTRACT FROM AUTHOR]

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations. [ABSTRACT FROM AUTHOR]

Introduction: Duchenne muscular dystrophy (DMD) is a childhood onset muscular dystrophy leading to shortened life expectancy. There are gaps in published DMD care guidelines regarding recently approved DMD medications and alternative steroid dosing regimens. Methods: A list of statements about use of currently available therapies for DMD in the United States was developed based on a systematic literature review and expert panel feedback. Panelists' responses were collected using a modified Delphi approach. Results: Among corticosteroid regimens, either deflazacort or prednisone weekend dosing was preferred when payer requirements do not dictate choice. Most patients with exon 51 skip-amenable mutations should be offered eteplirsen, before or with a corticosteroid. Discussion: The options available for medical management of the motor symptoms of DMD are expanding rapidly. The choice of medical therapies should balance expected benefit with side effects. [ABSTRACT FROM AUTHOR]

Background: The advent of new therapies in spinal muscular atrophy (SMA) has highlighted the need to have natural history data for comparison. Natural history studies using structured assessments in type I however are very limited. We identified and reviewed all the existing longitudinal history data in infants with type I SMA first assessed before the age of 7 months with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND).Main Text: Three longitudinal natural history studies, two performed in the United States and one in Italy, were identified. The different study design of these three studies made it possible for the cumulative dataset to include the full spectrum of severity; from infants with neonatal onset to those with a milder phenotype that were not always included in the individual natural history studies. The cumulative analysis confirmed that, even in a larger cohort, there was never an improvement on the CHOP INTEND over time. This was true for all the infants, irrespective of their age or baseline CHOP INTEND scores. Infants with neonatal onset had low CHOP INTEND scores and a fast decline. The relatively large number of patients allowed us to calculate the rate of progression in subgroups identified according to SMN2 copy number and baseline CHOP INTEND scores.Conclusion: A detailed understanding of the existing data is important, as it will be difficult to acquire new systematic longitudinal history data because of the availability of disease modifying therapies. The cumulative findings in this review help to better understand the variability of natural history data in untreated patients and will be of use for comparison to the real world patients treated with the recently approved therapies that have shown encouraging results in clinical trials. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the sensitivity of electrical impedance myography (EIM) to disease progression in both ambulatory and non‐ambulatory boys with DMD. Methods and Participants: A non‐blinded, longitudinal cohort study of 29 ambulatory and 15 non‐ambulatory boys with DMD and age‐similar healthy boys. Subjects were followed for up to 1 year and assessed using the Myolex® mViewTM EIM system as part of a multicenter study. Results: In the ambulatory group, EIM 100 kHz resistance values showed significant change compared to the healthy boys. For example, in lower extremity muscles, the average change in EIM 100 kHz resistance values over 12 months led to an estimated effect size of 1.58. Based on these results, 26 DMD patients/arm would be needed for a 12‐month clinical trial assuming a 50% treatment effect. In non‐ambulatory boys, EIM changes were greater in upper limb muscles. For example, biceps at 100kHz resistance gave an estimated effect size of 1.92 at 12 months. Based on these results, 18 non‐ambulatory DMD patients/arm would be needed for a 12‐month clinical trial assuming a 50% treatment effect. Longitudinal changes in the 100 kHz resistance values for the ambulatory boys correlated with the longitudinal changes in the timed supine‐to‐stand test. EIM was well‐tolerated throughout the study. Interpretation: This study supports that EIM 100 kHz resistance is sensitive to DMD progression in both ambulatory and non‐ambulatory boys. Given the technology's ease of use and broad age range of utility it should be employed as an exploratory endpoint in future clinical therapeutic trials in DMD. Trial Registration: Clincialtrials.gov registration #NCT02340923 [ABSTRACT FROM AUTHOR]

Introduction: In this study we characterized disease progression over 48 weeks among boys receiving deflazacort vs prednisone/prednisolone placebo arm treatment in two recent Duchenne muscular dystrophy (DMD) clinical trials.Methods: Ambulatory boys with DMD receiving placebo in the phase 3 ataluren (N = 115) and tadalafil (N = 116) trials were included. The trials required at least 6 months of prior corticosteroid use and stable baseline dosing. Associations between corticosteroid use and 48-week changes in ambulatory function were estimated using mixed models. Adjusted differences between corticosteroid groups were pooled in a meta-analysis.Results: In the meta-analysis, deflazacort-treated patients vs prednisone/prednisolone-treated patients experienced, on average, lower declines of 28.3 meters on 6-minute walk distance (95% confidence interval [CI], 5.7, 50.9; 2.9 seconds on rise from supine [95% CI, 0.9, 4.9 seconds]; 2.3 seconds on 4-stair climb [95% CI, 0.5, 4.1 seconds]; and 2.9 [95% CI, 0.1, 5.8] points on the North Star Ambulatory Assessment linearized score).Discussion: Deflazacort-treated patients experienced significantly lower functional decline over 48 weeks. [ABSTRACT FROM AUTHOR]

Background: The neuromuscular disorders encountered in the pediatric intensive care unit (PICU) encompass a broad spectrum of pathologies. These include acute disorders (eg, Guillain-Barre syndrome), acute-on-chronic disorders (eg, myasthenia gravis), progressive disorders (eg, muscular dystrophy), and disorders that develop in the PICU (eg, critical illness myopathy/polyneuropathy). Familiarity with the presenting features of these disorders is of paramount importance in facilitating timely diagnosis. Methods: We conducted a retrospective review of the medical records of patients admitted to the PICU or Intermediate Care Program (ICP) at a single tertiary children's hospital from 2006 to 2017 with an acute or acute-on-chronic neuromuscular disorder. We did not include patients with a known progressive neuromuscular disorder or critical illness myopathy/polyneuropathy. Results: Twenty-four patients were admitted to the PICU/ICP with acute or acute-on-chronic neuromuscular disorders. Diagnosis and indication for ICU/ICP admission were Guillain-Barre syndrome (n = 6; respiratory failure: 3, respiratory monitoring: 2, autonomic instability: 1), myasthenia gravis (n = 5; airway clearance: 3, respiratory failure: 2), acute flaccid myelitis (n = 3; respiratory failure: 2, respiratory monitoring: 1), periodic paralysis (n = 3; intravenous potassium replacement), rhabdomyolysis (n = 3; monitoring for electrolyte derangements), infant botulism (n = 2; respiratory failure), chronic demyelinating polyneuropathy (n = 1; respiratory failure), and congenital myasthenic syndrome (n = 1; apnea). No patients were admitted to the PICU/ICP with a diagnosis of tick paralysis, acute intermittent porphyria, or inflammatory myopathy. Conclusions: Although acute and acute-on-chronic neuromuscular disorders are encountered relatively rarely in the PICU, familiarity with the presenting features of these disorders is important in facilitating timely diagnosis. This, in turn, enables the institution of effective management strategies, thereby avoiding complications associated with diagnostic delays. [ABSTRACT FROM AUTHOR]

As the drug development pipeline for Duchenne muscular dystrophy (DMD) rapidly advances, clinical trial outcomes need to be optimized. Effective assessment of disease burden, natural history progression, and response to therapy in clinical trials for Duchenne muscular dystrophy are critical factors for clinical trial success. By choosing optimal biomarkers to better assess therapeutic efficacy, study costs and sample size requirements can be reduced. Currently, functional measures continue to serve as the primary outcome for the majority of DMD clinical trials. Quantitative measures of muscle health, including magnetic resonance imaging and spectroscopy, electrical impedance myography, and ultrasound, sensitively identify diseased muscle, disease progression, and response to a therapeutic intervention. Furthermore, such non-invasive techniques have the potential to identify disease pathology prior to onset of clinical symptoms. Despite robust supportive evidence, non-invasive quantitative techniques are still not frequently utilized in clinical trials for Duchenne muscular dystrophy. Non-invasive quantitative techniques have demonstrated the ability to quantify disease progression and potential response to therapeutic intervention, and should be used as a supplement to current standard functional measures. Such methods have the potential to significantly accelerate the development and approval of therapies for DMD. [ABSTRACT FROM AUTHOR]

See article on pages 81–84 in this issue. [ABSTRACT FROM AUTHOR]

Introduction: Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments, and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with nusinersen, but its impact on fatigue has not been studied.Methods: Post hoc analyses were used to examine changes in 6-minute walk test (6MWT) distance and fatigue in children and adolescents with SMA type II and III who received their first dose of nusinersen in the phase Ib/IIa, open-label CS2 study and were ambulatory during CS2 or the extension study, CS12.Results: Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, whereas median fatigue changed by -3.8% (-19.7%, 1.4%).Discussion: These results support previous studies demonstrating clinically meaningful effects of nusinersen on motor function in children and adolescents with later-onset SMA. [ABSTRACT FROM AUTHOR]

Background: Treatment with nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA).Objective: The objective of this analysis was to characterize the safety of nusinersen across the clinical trial program in infants and children with symptomatic SMA.Methods: An integrated safety analysis evaluated end of study data from seven completed clinical trials that enrolled infants and children with symptomatic SMA who were treated with intrathecal nusinersen or underwent sham procedures. Two of the studies were conducted in symptomatic infants with infantile-onset SMA (most likely to develop SMA type I or II) and the remaining five in symptomatic children and adolescents with later-onset SMA (have or are most likely to develop SMA type II or III). Safety assessments included incidence of adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and electrocardiograms.Results: Data were analyzed from 323 infants and children, including 240 treated with nusinersen (100 with infantile-onset SMA and 140 with later-onset SMA) and 83 who underwent sham procedures (41 infantile-onset, 42 later-onset). Median (range) exposure to nusinersen was 449.0 (6-1538) days (375.9 participant-years). The most common AEs with nusinersen were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, headache, and constipation. The incidence of serious AEs was lower with nusinersen than with the sham procedure (41% vs. 61%). The overall incidence of respiratory, thoracic, and mediastinal AEs was higher in participants with symptomatic infantile-onset SMA than those with symptomatic later-onset SMA and similar in nusinersen- versus sham procedure-treated participants. Rates of post-lumbar puncture syndrome and related events were higher with nusinersen versus sham procedure in later-onset SMA participants. No abnormal patterns or trends in laboratory test results were observed.Conclusions: Nusinersen demonstrated a favorable safety profile in children with symptomatic infantile- and later-onset SMA. Most reported AEs and serious AEs were consistent with the nature and frequency of events typically seen with SMA or in the context of lumbar puncture procedures.Registration: NCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791. [ABSTRACT FROM AUTHOR]

Objective: To evaluate plasma phosphorylated neurofilament heavy chain (pNF‐H) as a biomarker in spinal muscular atrophy (SMA). Methods: Levels of pNF‐H were measured using the ProteinSimple® platform in plasma samples from infants with SMA enrolled in ENDEAR (NCT02193074) and infants/children without neurological disease. Results: Median pNF‐H plasma level was 167.0 pg/mL (7.46–7,030; n = 34) in children without SMA (aged 7 weeks–18 years) and was higher in those aged < 1 versus 1–18 years (P = 0.0002). In ENDEAR participants with infantile‐onset SMA, median baseline pNF‐H level (15,400 pg/mL; 2390–50,100; n = 117) was ~10‐fold higher than that of age‐matched infants without SMA (P < 0.0001) and ~90‐fold higher than children without SMA (P < 0.0001). Higher pretreatment pNF‐H levels in infants with SMA were associated with younger age at symptom onset, diagnosis, and first dose; lower baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders score; and lower peroneal compound muscle potential amplitude. Nusinersen treatment was associated with a rapid and greater decline in pNF‐H levels: nusinersen‐treated infants experienced a steep 71.9% decline at 2 months to 90.1% decline at 10 months; sham control–treated infants declined steadily by 16.2% at 2 months and 60.3% at 10 months. Interpretation: Plasma pNF‐H levels are elevated in infants with SMA. Levels inversely correlate with age at first dose and several markers of disease severity. Nusinersen treatment is associated with a significant decline in pNF‐H levels followed by relative stabilization. Together these data suggest plasma pNF‐H is a promising marker of disease activity/treatment response in infants with SMA. [ABSTRACT FROM AUTHOR]

Objective: We investigated the presence of non-neuromuscular phenotypes in patients affected by Spinal Muscular Atrophy (SMA), a disorder caused by a mutation in the Survival of Motor Neuron (SMN) gene, and whether these phenotypes may be clinically detectable prior to clinical signs of neuromuscular degeneration and therefore independent of muscle weakness. Methods: We utilized a de-identified database of insurance claims to explore the health of 1,038 SMA patients compared to controls. Two analyses were performed: (1) claims from the entire insurance coverage window; and (2) for SMA patients, claims prior to diagnosis of any neuromuscular disease or evidence of major neuromuscular degeneration to increase the chance that phenotypes could be attributed directly to reduced SMN levels. Logistic regression was used to determine whether phenotypes were diagnosed at significantly different rates between SMA patients and controls and to obtain covariate-adjusted odds ratios. Results: Results from the entire coverage window revealed a broad spectrum of phenotypes that are differentially diagnosed in SMA subjects compared to controls. Moreover, data from SMA patients prior to their first clinical signs of neuromuscular degeneration revealed numerous non-neuromuscular phenotypes including defects within the cardiovascular, gastrointestinal, metabolic, reproductive, and skeletal systems. Furthermore, our data provide evidence of a potential ordering of disease progression beginning with these non-neuromuscular phenotypes. Conclusions: Our data point to a direct relationship between early, detectable non-neuromuscular symptoms and SMN deficiency. Our findings are particularly important for evaluating the efficacy of SMN-increasing therapies for SMA, comparing the effectiveness of local versus systemically delivered therapeutics, and determining the optimal therapeutic treatment window prior to irreversible neuromuscular damage. [ABSTRACT FROM AUTHOR]

Recently, the splicing modulator risdiplam was approved by the US Food and Drug Administration (FDA) for spinal muscular atrophy (SMA) in adults and children 2 months of age and older. Neurologists should consider drug cell targets, efficacy, and durability of SMN protein augmentation, potential iatrogenic phenotypes, and financial/ethical issues when providing patients with informed consent for innovative therapies. Exploring neurotrophic factors can provide downstream treatment avenues for SMA and other motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and Kennedy's disease. [Extracted from the article]

Introduction: ACT DMD was a 48-week trial of ataluren for nonsense mutation Duchenne muscular dystrophy (nmDMD). Patients received corticosteroids for ≥6 months at entry and stable regimens throughout study. This post hoc analysis compares efficacy and safety for deflazacort and prednisone/prednisolone in the placebo arm.Methods: Patients received deflazacort (n = 53) or prednisone/prednisolone (n = 61). Endpoints included change from baseline in 6-minute walk distance (6MWD), timed function tests, estimated age at loss of ambulation (extrapolated from 6MWD).Results: Mean changes in 6MWD were -39.0 m (deflazacort; 95% confidence limit [CL], -68.85, -9.17) and -70.6 m (prednisone/prednisolone; 95% CL, -97.16, -44.02). Mean changes in 4-stair climb were 3.79 s (deflazacort; 95% CL, 1.54, 6.03) and 6.67 s (prednisone/prednisolone; 95% CL, 4.69, 8.64).Conclusions: This analysis, limited by its post hoc nature, suggests greater preservation of 6MWD and 4-stair climb with deflazacort vs. prednisone/prednisolone. A head-to-head comparison will better define these differences. Muscle Nerve 58: 639-645, 2018. [ABSTRACT FROM AUTHOR]

Elevated creatine kinase is a useful screening test in the diagnostic workup of patients with neuromuscular disorders. We did a retrospective study of children with hyperCKemia (>175 IU/L) who were followed in the neuromuscular program of a tertiary care pediatric center from 2005 to 2016. Patients with hyperCKemia were divided into 2 groups: myopathic and nonmyopathic. Within the myopathic group, there were 3 arbitrary subgroups based on creatine kinase values: A (creatine kinase >10 times normal), B (creatine kinase 5-10 times normal), and C (creatine kinase 1-5 times normal). The 3 major categories of myopathies across all the subgroups were muscular dystrophies (commonest) followed by metabolic myopathies and inflammatory myopathies. Among the nonmyopathic causes of hyperCKemia, spinal muscular atrophy was the commonest. Muscular dystrophies should be considered in children with hyperCKemia, muscle weakness, or calf hypertrophy, and metabolic myopathies to be considered in children with recurrent rhabdomyolysis. [ABSTRACT FROM AUTHOR]

Introduction: Muscle echo intensity has been shown to correlate with disease status in muscle disorders, including Duchenne muscular dystrophy (DMD). We report the effect of sonographer-applied load on measurements of muscle echo intensity.Methods: Quadriceps ultrasound scans were performed on 22 healthy boys and 16 boys with DMD between the ages of 2.2 and 15.3 years. Transducer contact force was increased linearly from 1.5 to 10 N, and echo intensity was measured throughout.Results: Echo intensity increased linearly with strain at a rate of 42 (95% confidence interval [CI]: 21-63) and 74 (95% CI: 49-98) in the healthy and DMD populations, respectively. Echo intensity reliability was moderate at low strain (intraclass correlation coefficient [ICC] = 0.82) and was improved at high strain (ICC = 0.92).Discussion: Sonographer-applied load introduces error in measurements of echo intensity, but it can be minimized by measuring echo intensity at near-maximal levels of compression. Muscle Nerve 57: 423-429, 2018. [ABSTRACT FROM AUTHOR]

Objective: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes.Methods: A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed.Results: Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17).Interpretation: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891. [ABSTRACT FROM AUTHOR]

Objective: We assessed changes in quantitative muscle ultrasound data in boys with Duchenne muscular dystrophy (DMD) and healthy controls to determine whether ultrasound can serve as a biomarker of disease progression. Two approaches were used: gray scale level (GSL), measured from the ultrasound image, and quantitative backscatter analysis (QBA), measured directly from the received echoes.Methods: GSL and QBA were obtained from 6 unilateral arm/leg muscles in 36 boys with DMD and 28 healthy boys (age = 2-14 years) for up to 2 years. We used a linear mixed effects model with random intercept and slope terms to compare trajectories of GSL, QBA, and functional assessments. We analyzed separately a subset of boys who initiated corticosteroids.Results: Compared to healthy boys, increasing GSL in DMD boys >7.0 years old was first identified at 6 months (eg, anterior forearm slope difference of 1.16 arbitrary units/mo, p = 0.004, 95% confidence interval [CI] = 0.38-1.94); in boys ≤ 7 years old, differences in GSL first appeared at 12 months (0.82 arbitrary units/mo, p = 0.04, 95% CI = 0.075-1.565, in rectus femoris). QBA performed similarly to GSL (eg, DMD boys > 7 years old: 0.41dB/mo, p = 0.01, 95% CI = 0.096-0.72, in anterior forearm at 6 months). Ultrasound identified differences earlier than functional measures including 6-minute walk and supine-to-stand tests. However, neither QBA nor GSL showed an effect of corticosteroid initiation.Interpretation: QBA performs similarly to GSL, and both appear more sensitive than functional assessments for detecting muscle deterioration in DMD. Additional studies will be required to determine whether quantitative muscle ultrasound can detect therapeutic efficacy. Ann Neurol 2017;81:633-640. [ABSTRACT FROM AUTHOR]

Objective: Sensitive, objective, and easily applied methods for evaluating disease progression and response to therapy are needed for clinical trials in Duchenne muscular dystrophy (DMD). In this study, we evaluated whether electrical impedance myography (EIM) could serve this purpose.Methods: In this nonblinded study, 36 boys with DMD and 29 age-similar healthy boys underwent multifrequency EIM measurements for up to 2 years on 6 muscles unilaterally along with functional assessments. A linear mixed-effects model with random intercept and slope terms was used for the analysis of multifrequency EIM values and functional measures. Seven DMD boys were initiated on corticosteroids; these data were analyzed using a piecewise linear mixed-effects model.Results: In boys > 7.0 years old, a significant difference in the slope of EIM phase ratio trajectories in the upper extremity was observed by 6 months of -0.074/month, p = 0.023, 95% confidence interval (CI) = -0.013, -0.14; at 2 years, this difference was -0.048/month, p < 0.0001, 95% CI = -0.028, -0.068. In boys ≤ 7.0 years old, differences appeared at 6 months in gastrocnemius (EIM phase slope = -0.83 °/kHz/mo, p = 0.007, 95% CI = -0.26, -1.40). EIM outcomes showed significant differences earlier than functional tests. Initiation of corticosteroids significantly improved the slope of EIM phase ratio (0.057/mo, p = 0.00019, 95% CI = 0.028, 0.086) and EIM phase slope (0.14 °/kHz/mo, p = 0.013, 95% CI = 0.028, 0.25), consistent with corticosteroids' known clinical benefit.Interpretation: EIM detects deterioration in muscles of both younger and older boys by 6 months; it also identifies the therapeutic effect of corticosteroid initiation. Because EIM is rapid to apply, painless, and requires minimal operator training, the technique deserves to be further evaluated as a biomarker in DMD clinical therapeutic trials. Ann Neurol 2017;81:622-632. [ABSTRACT FROM AUTHOR]

Introduction: Congenital hypomyelinating neuropathy (CHN) is a rare congenital neuropathy that presents in the neonatal period and has been linked previously to mutations in several genes associated with myelination. A recent study has linked 4 homozygous frameshift mutations in the contactin-associated protein 1 (CNTNAP1) gene with this condition.Methods: We report a neonate with CHN who was found to have absent sensory nerve and compound muscle action potentials and hypomyelination on nerve biopsy.Results: On whole exome sequencing, we identified a novel CNTNAP1 homozygous missense mutation (p.Arg388Pro) in the proband, and both parents were carriers. Molecular modeling suggests that this variant disrupts a β-strand to cause an unstable structure and likely significant changes in protein function.Conclusions: This report links a missense CNTNAP1 variant to the disease phenotype previously associated only with frameshift mutations. Muscle Nerve 55: 761-765, 2017. [ABSTRACT FROM AUTHOR]

Introduction: We studied patterns of nerve injury in pediatric common fibular (peroneal) neuropathy (CFN).Methods: A retrospective analysis was performed on data from 53 children with CFN at a pediatric electromyography laboratory.Results: Conduction block at the fibular head was present in 35% of patients. Deep fibular axonal loss was identified in 77%, while superficial fibular axonal loss was identified in 45%. The pathophysiology was predominantly axonal in 72%, mostly demyelinating in 6%, and mixed in 22%. Predominantly demyelinating lesions at the fibular head demonstrated sparing of the superficial fibular sensory nerve (P = 0.01, Fischer exact test). Predominantly axonal lesions had a moderate correlation between superficial and deep fibular axonal loss (Spearman r = 0.52; P = 0.0001).Conclusions: There is frequent axonal and fascicular injury in pediatric CFN, similar to adults. Deep and superficial fibular nerve involvements correlate in axonal lesions, whereas superficial fibular sensory fibers are often spared in demyelinating lesions. Muscle Nerve, 2016 Muscle Nerve 55: 693-697, 2017. [ABSTRACT FROM AUTHOR]

Introduction: Outcomes sensitive to change over time in non-ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well-established.Methods: Subjects (n = 91; 16.8 ± 4.5 years old) were assessed at baseline and 6-month intervals for 2 years. We analyzed all subjects using an intent-to-treat model and a subset of stronger subjects with Brooke Scale score ≤4, using repeated measures.Results: Eight patients (12-33 years old) died during the study. Sixty-six completed 12-month follow-up, and 51 completed 24-month follow-up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. Forced vital capacity percent predicted (FVC% predicted) declined significantly only after 2 years. However, Brooke and Egen Klassifikation (EK) Scale scores, elbow flexion, and grip strength declined significantly over both 1 and 2 years.Conclusion: Brooke and EK Scale scores, elbow flexion, and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non-ambulatory DMD subjects but did not affect decline rates of measures tested here. Muscle Nerve 54: 681-689, 2016. [ABSTRACT FROM AUTHOR]