Characterization of swallowing biomechanics and function in untreated infants with spinal muscular atrophy: A natural history dataset.

Background: Spinal Muscular Atrophy (SMA) is a progressive neuromuscular disorder that in its most severe form, causes profound swallowing deficits. There remains a paucity of research systematically elucidating the biomechanical and functional correlates. This void limits the ability to evaluate the effects of disease-modifying treatments on swallowing.

Eteplirsen Treatment for Duchenne Muscular Dystrophy: A Qualitative Patient Experience Study.

Introduction: Duchenne muscular dystrophy (DMD) is characterized by rapid functional decline. Current available treatment options aim to delay disease progression or stabilize physical function. To aid in healthcare providers' understanding of the symptoms of disease that impact patients' experience, this study explored children's physical functioning, activities of daily living (ADLs), and health-related quality of life (HRQoL) after receiving eteplirsen, a weekly infusion indicated for individuals with DMD with exon 51 skip-amenable mutations.

Assessing the Assisted Six-Minute Cycling Test as a Measure of Endurance in Non-Ambulatory Patients with Spinal Muscular Atrophy (SMA).

Assessing endurance in non-ambulatory individuals with Spinal Muscular Atrophy (SMA) has been challenging due to limited evaluation tools. The Assisted 6-Minute Cycling Test (A6MCT) is an upper limb ergometer assessment used in other neurologic disorders to measure endurance. To study the performance of the A6MCT in the non-ambulatory SMA population, prospective data was collected on 38 individuals with SMA (13 sitters; 25 non-sitters), aged 5 to 74 years (mean = 30.

Major Adverse Dystrophinopathy Events (MADE) Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy.

Background: Overlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy confound assessment of heart failure in Duchenne Muscular Dystrophy. We developed an ordinal scale of multiorgan clinical variables that reflect cumulative disease burden-the ajor dverse ystrophinopathy vent ) Score. We hypothesized that a higher MADE score would be associated with increased mortality in boys with Duchenne Muscular Dystrophy.

Cerebrospinal Fluid Proteomic Changes after Nusinersen in Patients with Spinal Muscular Atrophy.

Disease-modifying treatments have transformed the natural history of spinal muscular atrophy (SMA), but the cellular pathways altered by SMN restoration remain undefined and biomarkers cannot yet precisely predict treatment response. We performed an exploratory cerebrospinal fluid (CSF) proteomic study in a diverse sample of SMA patients treated with nusinersen to elucidate therapeutic pathways and identify predictors of motor improvement. Proteomic analyses were performed on CSF samples collected before treatment (T0) and at 6 months (T6) using an Olink panel to quantify 1113 peptides.

Knee Strength and Ankle Range of Motion Impacts on Timed Function Tests in Duchenne Muscular Dystrophy: In the Era of Glucocorticoids.

Background: Duchenne Muscular Dystrophy (DMD) is a neuromuscular disorder that presents in childhood and is characterized by slowly progressive proximal weakness and lower extremity contractures that limit ambulatory ability [1, 2]. Contractures develop in the ankles, knees, and hips due to muscle imbalances, fibrotic changes, loss of strength, and static positioning [2, 5]. Currently, standards of care guidelines emphasize the importance of maintaining good musculoskeletal alignment through stretching, bracing, and glucocorticoid (GC) therapy to preserve strength and function.

Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study.

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).

Assessment of disease progression in dysferlinopathy: A 1-year cohort study.

Objective: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.

Methods: One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry.

Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials.

Background And Objective: Dysferlinopathies are a group of muscle disorders caused by mutations in the gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests.

Methods: We present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies.

Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita.

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons.

Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases.

Background: Molecular diagnostics in the genetic myopathies often requires testing of the largest and most complex transcript units in the human genome (DMD, TTN, NEB). Iteratively targeting single genes for sequencing has traditionally entailed high costs and long turnaround times. Exome sequencing has begun to supplant single targeted genes, but there are concerns regarding coverage and needed depth of the very large and complex genes that frequently cause myopathies.

The Clinical Outcome Study for dysferlinopathy: An international multicenter study.

Objective: To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy.

Methods: The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments.

Exome Sequencing Identifies DYNC1H1 Variant Associated With Vertebral Abnormality and Spinal Muscular Atrophy With Lower Extremity Predominance.

Background: Molecular diagnosis of the distal spinal muscular atrophies or distal hereditary motor neuropathies remains challenging because of clinical and genetic heterogeneity. Next generation sequencing offers potential for identifying de novo mutations of causative genes in isolated cases.

Patient Description: We present a 3.

Novel large deletion in the ACTA1 gene in a child with autosomal recessive nemaline myopathy.

Nemaline myopathy (NM) is a genetically and clinically heterogeneous disorder resulting from a disruption of the thin filament proteins of the striated muscle sarcomere. The disorder is typically characterized by muscle weakness including the face, neck, respiratory, and limb muscles and is clinically classified based on the age of onset and severity. Mutations in the ACTA1 gene contribute to a significant proportion of NM cases.

'Double trouble': diagnostic challenges in Duchenne muscular dystrophy in patients with an additional hereditary skeletal dysplasia.

Duchenne muscular dystrophy (DMD) is caused by mutations in Dystrophin and affects 1 in 3600-6000 males. It is characterized by progressive weakness leading to loss of ambulation, respiratory insufficiency, cardiomyopathy, and scoliosis. We describe the unusual phenotype of 3 patients with skeletal dysplasias in whom an additional diagnosis of DMD was later established.

CINRG pilot trial of coenzyme Q10 in steroid-treated Duchenne muscular dystrophy.

Introduction: Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin-deficient muscle.

Methods: We performed an open-label, "add-on" pilot study of CoQ10 in thirteen 5-10-year-old DMD patients on steroids.

Liquid formulation of pentoxifylline is a poorly tolerated treatment for duchenne dystrophy.

Introduction: In this study we performed an open-label, pilot study of an orally administered liquid formulation of immediate-release pentoxifylline (PTX) on patients with Duchenne muscular dystrophy (DMD). Treatment efficacy, safety, and tolerability were assessed.

Methods: The tolerability and safety of PTX and measures of muscle strength and function were evaluated during 12 months of treatment.

Limb-girdle and congenital muscular dystrophies: current diagnostics, management, and emerging technologies.

The muscular dystrophies show muscle degeneration and regeneration (necrotizing myopathy) on muscle biopsy, typically associated with elevated serum creatine kinase, and muscle weakness. In 1986, the first causative gene was identified for the most prevalent and best-characterized form of muscular dystrophy, Duchenne muscular dystrophy. Over the past 25 years, the number of other genes determined to cause different subtypes has grown rapidly.