Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG).

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1 (SMN1) genes with variable copies of partially functional SMN2 gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing.

Objective: STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients.

Step Activity Monitoring in Boys with Duchenne Muscular Dystrophy and its Correlation with Magnetic Resonance Measures and Functional Performance.

Background: Muscles of boys with Duchenne muscular dystrophy (DMD) are progressively replaced by fatty fibrous tissues, and weakness leads to loss of ambulation (LoA). Step activity (SA) monitoring is a quantitative measure of real-world ambulatory function. The relationship between quality of muscle health and SA is unknown in DMD.

Development of Contractures in DMD in Relation to MRI-Determined Muscle Quality and Ambulatory Function.

Background: Joint contractures are common in boys and men with Duchenne muscular dystrophy (DMD), and management of contractures is an important part of care. The optimal methods to prevent and treat contractures are controversial, and the natural history of contracture development is understudied in glucocorticoid treated individuals at joints beyond the ankle.

Objective: To describe the development of contractures over time in a large cohort of individuals with DMD in relation to ambulatory ability, functional performance, and muscle quality measured using magnetic resonance imaging (MRI) and spectroscopy (MRS).

MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline elevated serum creatine kinase.

Striated muscle needs to maintain cellular homeostasis in adaptation to increases in physiological and metabolic demands. Failure to do so can result in rhabdomyolysis. The identification of novel genetic conditions associated with rhabdomyolysis helps to shed light on hitherto unrecognized homeostatic mechanisms.

Psychometric properties of the PEDI-CAT for children and youth with spinal muscular atrophy.

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.

Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial.

Chronic activation of NF-κB is a key driver of muscle degeneration and suppression of muscle regeneration in Duchenne muscular dystrophy. Edasalonexent (CAT-1004) is an orally-administered novel small molecule that covalently links two bioactive compounds (salicylic acid and docosahexaenoic acid) that inhibit NF-κB. This placebo-controlled, proof-of-concept phase 2 study with open-label extension in boys ≥4-<8 years old with any dystrophin mutation examined the effect of edasalonexent (67 or 100 mg/kg/day) compared to placebo or off-treatment control.

Walking activity in a large cohort of boys with Duchenne muscular dystrophy.

Introduction: In this study we explored walking activity in a large cohort of boys with Duchenne muscular dystrophy (DMD).

Methods: Step activity (monitored for 7 days), functional ability, and strength were quantified in ambulatory boys (5-12.9 years of age) with DMD and unaffected boys.

Upper and Lower Extremities in Duchenne Muscular Dystrophy Evaluated with Quantitative MRI and Proton MR Spectroscopy in a Multicenter Cohort.

Background Upper extremity MRI and proton MR spectroscopy are increasingly considered to be outcome measures in Duchenne muscular dystrophy (DMD) clinical trials. Purpose To demonstrate the feasibility of acquiring upper extremity MRI and proton (H) MR spectroscopy measures of T2 and fat fraction in a large, multicenter cohort (ImagingDMD) of ambulatory and nonambulatory individuals with DMD; compare upper and lower extremity muscles by using MRI and H MR spectroscopy; and correlate upper extremity MRI and H MR spectroscopy measures to function. Materials and Methods In this prospective cross-sectional study, MRI and H MR spectroscopy and functional assessment data were acquired from participants with DMD and unaffected control participants at three centers (from January 28, 2016, to April 24, 2018).

Retrospective Analysis of Fractures and Factors Causing Ambulation Loss After Lower Limb Fractures in Duchenne Muscular Dystrophy.

Objective: Prevalence and characteristics of fractures and factors related to loss of ambulation after lower limb fractures were investigated.

Design: Chart review included height, weight, dual-energy x-ray absorptiometry, corticosteroid use, vitamin D, fracture history, muscle strength, range of motion, and timed performance tests (10 meter walk/run, Gowers, and four steps). Patients were grouped by fracture location and ambulation loss after fracture.

Modeling disease trajectory in Duchenne muscular dystrophy.

Objective: To quantify disease progression in individuals with Duchenne muscular dystrophy (DMD) using magnetic resonance biomarkers of leg muscles.

Methods: MRI and magnetic resonance spectroscopy (MRS) biomarkers were acquired from 104 participants with DMD and 51 healthy controls using a prospective observational study design with patients with DMD followed up yearly for up to 6 years. Fat fractions (FFs) in vastus lateralis and soleus muscles were determined with H MRS.

MR biomarkers predict clinical function in Duchenne muscular dystrophy.

Objective: To investigate the potential of lower extremity magnetic resonance (MR) biomarkers to serve as endpoints in clinical trials of therapeutics for Duchenne muscular dystrophy (DMD) by characterizing the longitudinal progression of MR biomarkers over 48 months and assessing their relationship to changes in ambulatory clinical function.

Methods: One hundred sixty participants with DMD were enrolled in this longitudinal, natural history study and underwent MR data acquisition of the lower extremity muscles to determine muscle fat fraction (FF) and MRI T biomarkers of disease progression. In addition, 4 tests of ambulatory function were performed.

Dominant collagen XII mutations cause a distal myopathy.

Objective: To characterize the natural history and clinical features of myopathies caused by mono-allelic, dominantly acting pathogenic variants in COL12A1.

Methods: Patients with dominant COL12A1-related myopathies were characterized by history and clinical examination, muscle imaging, and genetic analysis. Pathogenicity of the variants was assessed by immunostaining patient-derived dermal fibroblast cultures for collagen XII.

Phase 1 Study of Edasalonexent (CAT-1004), an Oral NF-κB Inhibitor, in Pediatric Patients with Duchenne Muscular Dystrophy.

Background: Edasalonexent is an orally administered small molecule designed to inhibit NF-κB, which is activated from infancy in Duchenne muscular dystrophy and is central to causing muscle damage and preventing muscle regeneration.

Objective: Evaluate the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of three doses of edasalonexent in ambulatory males ≥4 to <8 years of age with genetically confirmed Duchenne muscular dystrophy.

Methods: This was a 1-week, open-label, multiple-dose study with 3 sequential ascending doses (33, 67 and 100 mg/kg/day) of edasalonexent administered under different dietary conditions to 17 males with a mean age of 5.

Ambulatory function in spinal muscular atrophy: Age-related patterns of progression.

Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to evaluate whether age and SMA type 3 subtype are associated with decline in ambulatory function. Data from three prospective natural history studies were used.

Quantitative Evaluation of Lower Extremity Joint Contractures in Spinal Muscular Atrophy: Implications for Motor Function.

Purpose: To quantitatively describe passive lower extremity range of motion in participants with spinal muscular atrophy (SMA) types 2 and 3, and to establish preliminary thresholds to identify individuals at risk for performing poorly on disease-specific motor function outcome measures.

Methods: Eighty participants with SMA types 2 and 3, enrolled in an international multicenter natural history study, were evaluated with lower extremity range of motion testing and the Hammersmith Functional Motor Scale-Expanded.

Results: A hip extension joint angle of -7.

Evaluator Training and Reliability for SMA Global Nusinersen Trials1.

Background: Training methodology was established to optimize reliability of outcome measures in the nusinersen clinical trials. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), Hammersmith Functional Motor Scale Expanded (HFMSE), and Revised Upper Limb (RULM) were primary or secondary outcomes.

Methods: Video review, quarterly conference calls, and item scoring checks supported evaluator competence.

Longitudinal timed function tests in Duchenne muscular dystrophy: ImagingDMD cohort natural history.

Introduction: Tests of ambulatory function are common clinical trial endpoints in Duchenne muscular dystrophy (DMD). Using these tests, the ImagingDMD study has generated a large data set that can describe the contemporary natural history of DMD in 5-12.9-year-olds.

Two-Year Longitudinal Changes in Lower Limb Strength and Its Relation to Loss in Function in a Large Cohort of Patients With Duchenne Muscular Dystrophy.

Objective: The main objective of this study was to examine the effect of disease on strength in two functionally important lower limb muscles for a period of 2 yrs in children with Duchene muscular dystrophy.

Design: Seventy-seven Duchene muscular dystrophy children participated in this study. Plantar flexors, knee extensors, strength, and performance on timed tests (6-min walk, 4-stairs, 10-m walk, supine-up) were assessed yearly for 2 yrs.

Skeletal muscle magnetic resonance biomarkers correlate with function and sentinel events in Duchenne muscular dystrophy.

Objective: To provide evidence for quantitative magnetic resonance (qMR) biomarkers in Duchenne muscular dystrophy by investigating the relationship between qMR measures of lower extremity muscle pathology and functional endpoints in a large ambulatory cohort using a multicenter study design.

Methods: MR spectroscopy and quantitative imaging were implemented to measure intramuscular fat fraction and the transverse magnetization relaxation time constant (T2) in lower extremity muscles of 136 participants with Duchenne muscular dystrophy. Measures were collected at 554 visits over 48 months at one of three imaging sites.

Use of the Wilmington Robotic Exoskeleton to Improve Upper Extremity Function in Patients With Duchenne Muscular Dystrophy.

Patients with Duchenne muscular dystrophy in their second decade of life present with decreased upper extremity strength and active range of motion (AROM) that limit activities of daily living (ADLs). We evaluated the ability of the Wilmington Robotic Exoskeleton (WREX) to improve AROM and independence with ADLs. A retrospective chart review of 9 patients who trialed the WREX was performed.

Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool.

Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients.

Revised upper limb module for spinal muscular atrophy: Development of a new module.

Introduction: There is a growing need for a robust clinical measure to assess upper limb motor function in spinal muscular atrophy (SMA), as the available scales lack sensitivity at the extremes of the clinical spectrum. We report the development of the Revised Upper Limb Module (RULM), an assessment specifically designed for upper limb function in SMA patients.

Methods: An international panel with specific neuromuscular expertise performed a thorough review of scales currently available to assess upper limb function in SMA.

Rasch analysis of the Pediatric Evaluation of Disability Inventory-computer adaptive test (PEDI-CAT) item bank for children and young adults with spinal muscular atrophy.

Introduction: In this study we evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA).

Methods: PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types.

Physical therapy services received by individuals with spinal muscular atrophy (SMA).

Purpose: The consensus statement for standard of care in SMA recommends multidisciplinary medical care including physical therapy (PT) services. To date there are no reports regarding the implementation of these recommendations and the type of care or services received by individuals with SMA. The purpose of this study is to describe the PT services received by individuals with SMA.

Multicenter prospective longitudinal study of magnetic resonance biomarkers in a large duchenne muscular dystrophy cohort.

Objective: The aim of this study was to describe Duchenne muscular dystrophy (DMD) disease progression in the lower extremity muscles over 12 months using quantitative magnetic resonance (MR) biomarkers, collected across three sites in a large cohort.

Methods: A total of 109 ambulatory boys with DMD (8.7 ± 2.