Progressive Neuromuscular Disease Research Articles

Time-to-death in chronic respiratory failure on home mechanical ventilation: A cohort study.

Home mechanical ventilation (HMV) is used in heterogeneous conditions underlying chronic hypercapnic respiratory failure, but there are sparse data on long-term clinical outcomes. The aim was to systematically analyse the time and the circumstances of death on HMV. All-cause mortality data of HMV patients were prospectively collected between 2008 and 2018 in a large tertiary centre. Data were categorised into diagnostic groups including neuromuscular disease (NMD), chest wall disease (CWD), chronic obstructive pulmonary disease (COPD), obesity hypoventilation syndrome (OHS), overlap syndrome of COPD and OSA (overlap) and other group. The primary outcome was time-to-death from initiation of HMV. 1210 deaths were recorded over a 10-year period. Median time-to-death was 19.5 [6-55] months and differed between groups (Kruskal Wallis p<0.001). CWD (98.5 [23.5-120] months) and slowly progressive NMD (64.5 [28-120] months) had the longest time-to-death on HMV, while OHS (33 [13-75] months) and overlap syndrome (30.5 [14.5-68.5] months) had a longer median time-to-death than COPD (19.5 [7-42.5] months) and motor neurone disease (7 [3-14] months). Daily adherence to HMV of greater than 4h/night was associated with better outcomes (10 [3-24] vs. 30 [10-76] months; p<0.001). 43% with confirmed location of death died outside the hospital. The time-to-death on home mechanical ventilation varies widely across disease groups with chronic respiratory failure and seems to be associated with daily usage time. researchregistry.com UIN: researchregistry4122.

Systematization of methods of physical rehabilitation of children with inherited nervo-muscle diseases

Summary. Children with hereditary neuromuscular diseases constitute one of the main groups of patients in public and private rehabilitation institutions. Therefore, there is a need to develop a rational choice of physical rehabilitation means, their systematization depending on the level of functional capabilities, which is relevant when developing an individual rehabilitation program in the centres. Purpose. Formation of an integrated approach in the rational choice of methods of physical rehabilitation and orthopedic supply for patients with hereditary neuromuscular diseases. Tasks. Development of stages for the provision of rehabilitation services, determination of the composition of an individual rehabilitation program, development of an algorithm for choosing methods of physical rehabilitation and technical means, depending on the degree of limitation of the child's motor functions. Results. The study involved 46 children aged 2 to 15 years. Assessment of the functional status of children, in accordance with the recommendations of the International Committee for the Standards of Treatment of patients with SMA, was performed on the Hammersmith scale, the assessment of muscle strength - on the Lovett test. The rehabilitation course according to the developed algorithm consisted of 4 stages: the stage of diagnosis, the stage of drawing up an individual rehabilitation program in accordance with the patient's functional capabilities, the stage of the course of physical rehabilitation and the stage of assessing its effectiveness. The main principles of rehabilitation were: stretching of contracted tissues, positioning of segments of the limbs and spine, physical activity in a submaximal mode, verticalization with the use of aids, compensation of lost functions and orthopedic correction using orthoses of various designs. The course carried out helped to stabilize muscle strength and motor activity, increase the volume of passive movements in large joints, and fine motor dexterity. Technical means of rehabilitation made it possible to correct the deformity of the segments of the limbs and the spine, to increase the dexterity of movements when performing tasks for fine motor skills. Conclusions. Adequate rehabilitation measures aimed at maintaining the motor activity of patients, maintaining muscle tone (including the respiratory muscles), timely correction of pathological attitudes of the limbs and spine in children with progressive neuromuscular diseases, inhibit the development of deformities, prolong motor activity.

Deterioration of muscle force and contractile characteristics are early pathological events in spinal and bulbar muscular atrophy mice.

ABSTRACTSpinal and bulbar muscular atrophy (SBMA), also known as Kennedy's Disease, is a late-onset X-linked progressive neuromuscular disease, which predominantly affects males. The pathological hallmarks of the disease are selective loss of spinal and bulbar motor neurons, accompanied by weakness, atrophy and fasciculations of bulbar and limb muscles. SBMA is caused by a CAG repeat expansion in the gene that encodes the androgen receptor (AR) protein. Disease manifestation is androgen dependent and results principally from a toxic gain of AR function. There are currently no effective treatments for this debilitating disease. It is important to understand the course of the disease in order to target therapeutics to key pathological stages. This is especially relevant in disorders such as SBMA, for which disease can be identified before symptom onset, through family history and genetic testing. To fully characterise the role of muscle in SBMA, we undertook a longitudinal physiological and histological characterisation of disease progression in the AR100 mouse model of SBMA. Our results show that the disease first manifests in skeletal muscle, before any motor neuron degeneration, which only occurs in late-stage disease. These findings reveal that alterations in muscle function, including reduced muscle force and changes in contractile characteristics, are early pathological events in SBMA mice and suggest that muscle-targeted therapeutics may be effective in SBMA.This article has an associated First Person interview with the first author of the paper.

Processus dépressif chez l’adolescent déficient moteur avec troubles cognitifs associés, accueilli en Institut d’Éducation Motrice : étude qualitative et prospective

ObjectiveThe aim of the present study is to investigate the experience of adolescent life in young people affected by physical disability and cognitive disorders, in order to focus on the maturative or pathological depressive processes. This qualitative and exploratory study explores the subjective experience of these adolescents and aims to compensate for the lack of research into the understanding of depressive affects present in some young people with a disability at this particular period of their life. MethodsSix adolescents with physical disability and cognitive disorders (with cerebral palsy or progressive neuromuscular disease) in the care of a special school (Institut d’Éducation Motrice - IEM), a boarding school, participated in this study. Based on an inductive approach, tools used are identical to those used in clinical practice. A semi-directive interview, the DPI (Perron, 1969), a projective test on the development of self-image, and the MDI-C (Castro, 1999), providing data on elements from the depressive register and their signification, were used. ResultsThe results indicate the emergence of depressive feelings, a psychological distress, a sense of powerlessness and an insecure attachment. The results indicate also that these adolescents present an inhibition and search for scaffolding because they have difficulty to mobilize their resources. Projection in the future is also complex for them. They often have great loneliness, and exchanges with their peers, other adolescents, are infrequent. They only find support from professionals, not from other young people, whereas in adolescence the peer group is normally a resource. ConclusionThis study offers clinical perspectives in caring for young people and their family. It shows the need to take more into account the intrapsychic life of these adolescents, to detect their resources to help themselves and better take into account their psychics suffering. It is also necessary to help them to elaborate on their depressive position. Accompanied, the depressive affects can take a structuring dimension and can develop these adolescents’ abilities to talk about themselves, to think of themselves as a unique and autonomous person. It is also a question of favoring the deployment of their social relations. The methodology used confirms the need to conduct clinical research with this population, to understand better what is at stake at this period, and the importance of depressive affects.

Influence of \u03b22 adrenergic receptor genotype on risk of nocturnal ventilation in patients with Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease resulting in severe respiratory derangements. As such, DMD patients are at a high risk of nocturnal hypoventilation, thereby requiring nocturnal ventilation (NV). To this end, NV is an important clinical milestone in the management of DMD. Emerging evidence suggests that ß2 adrenergic receptors (ADRB2) may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function and respiratory muscle strength. These findings suggest that the more functional ADRB2 genotype may help to preserve respiratory function in patients with DMD. The purpose of this study was to identify the influence of ADRB2 genotype on the risk of NV use in DMD. Data from the CINRG Duchenne Natural History Study including 175 DMD patients (3–25 yrs) were analyzed focusing on ADRB2 genotype variants. Time-to-event analyses were used to examine differences in the age at prescription of full-time NV use between genotypes. There were no differences between genotype groups in age, height, weight, corticosteroid use, proportion of ambulatory patients, or age at loss of ambulation. DMD patients expressing the Gly16 polymorphism had a significantly (P < 0.05) lower mean age at NV prescription compared with those patients expressing the Arg16 polymorphism (21.80 ± 0.59 yrs. vs 25.91 ± 1.31 yrs., respectively). In addition, a covariate-adjusted Cox model revealed that the Gly16 variant group possessed a 6.52-fold higher risk of full-time NV use at any given age compared with the Arg16 polymorphism group. These data suggest that genetic variations in the ADRB2 gene may influence the age at which DMD patients are first prescribed NV, whereby patients with the Gly16 polymorphism are more likely to require NV assistance at an earlier age than their Arg16 counterparts.

P.363JEWELFISH: safety and pharmacodynamic data in patients with spinal muscular atrophy (SMA) receiving treatment with risdiplam (RG7916) that have previously been treated with nusinersen

Spinal muscular atrophy (SMA) is a severe, progressive neuromuscular disease caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations of the SMN1 gene. A second SMN gene, SMN2, produces only low levels of functional SMN protein. Risdiplam (RG7916; RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates SMN2 pre-mRNA splicing to increase SMN protein levels. JEWELFISH (NCT03032172) is an ongoing, multicenter, open-label study evaluating the safety, tolerability and pharmacokinetic/pharmacodynamic relationship of daily oral risdiplam in patients with all types of SMA. JEWELFISH participants, aged from 6 months to 60 years, previously participated in Study BP29420 (MOONFISH) with the splicing modifier RG7800 (RO6885247) or received previous treatment with nusinersen, olesoxime or AVXS-101 (following recent protocol amendments, participants that previously received olesoxime or AVXS-101 may now be included). We have previously presented data from 12 patients (data cut-off, 06 July 2018), with Type 2 or 3 SMA who received risdiplam for a minimum of 57 days up to 512 days (nine patients previously received RG7800 and three patients received nusinersen). No drug-related adverse events leading to withdrawal were reported. While patient numbers were limited, the magnitude of SMN protein increase (>2-fold) and safety observations were comparable to those in SUNFISH Part 1 (NCT02908685) in patients with Type 2 and 3 SMA who have not previously received an SMN2-targeting therapy. We will present updated data on safety and SMN protein levels in whole blood from a subgroup of patients who have previously received nusinersen. The JEWELFISH study is currently recruiting in sites in Europe and the US.

I.8Reversible formation of TDP-43 assemblies during skeletal muscle regeneration

Skeletal muscle maintenance and repair is dependent on the resident adult muscle stem cell. Following an injury and in diseased muscle, stem cells are engaged to replace or repair damaged tissue, which requires that the stem cells exit quiescence, expand, fuse and rebuild the contractile apparatus. Severe, progressive neuromuscular diseases manifest a constant injury, possibly disrupting the timing of regeneration, and coupled with attempts to continuously regenerate, may contribute to loss of muscle tissue and function. Proteostasis is disrupted in muscle during neuromuscular disease progression and often accompanied by the accumulation of irreversible protein aggregates in the cytoplasm, which are considered cytotoxic. Tar DNA binding Protein 43 (TDP-43), is a common component of these cytotoxic cytoplasmic cellular aggregates, even though TDP-43 is often not mutated. Unexpectedly, we observed cytoplasmic TDP-43 in amyloid assemblies or myo-granules during muscle regeneration following an induced muscle injury in normal mice. Myo-granules appear following an induced injury and dissipate during muscle regeneration. In regenerating muscle, TDP-43 is associated with transcripts encoding sarcomeric structural proteins as well as vasolin containing protein. We propose that cytoplasmic TDP-43-containing assemblies are not cytotoxic but are required for muscle formation, providing protection, transport and localized translation for TDP-43-associated transcripts. The relationship of cytoplasmic TDP-43-containing aggregates in diseased skeletal muscle to myo-granules in normal muscle is not known, however, myo-granules can seed the formation of insoluble amyloid fibrils. Thus, the formation of insoluble cytoplasmic aggregates occurring in progressive neuromuscular diseases may arise from altered myo-granule composition or from aberrant formation or clearance of myo-granules during continuous regeneration occurring in diseased muscle. Determining the relationship between cytotoxic TDP-43-containing cytoplasmic aggregates and myo-granules is essential to better understand disease progression and for the development of new therapies aimed at eliminating or preventing the accumulation of insoluble cytoplasmic aggregates arising during the progression of neuromuscular diseases.

Carboxyl-terminal modulator protein regulates Akt signaling during skeletal muscle atrophy in vitro and a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease involving motor neuron death, paralysis and, ultimately, respiratory failure. Motor neuron dysfunction leads to target skeletal muscle atrophy involving dysregulation of downstream cell survival, growth and metabolic signaling. Decreased Akt activity is linked to muscle atrophy in ALS and is associated with increased atrophy gene expression. Unfortunately, the regulating mechanism of Akt activity in atrophic muscle remains unclear. Recent research indicates a role of carboxyl-terminal modulator protein (CTMP) in Akt-signaling related neurologic dysfunction and skeletal muscle metabolism. CTMP is known to bind and reduce Akt phosphorylation and activation. We hypothesized that CTMP expression might progressively increase in ALS skeletal muscle as the disease progresses, downregulating Akt activity. We found that CTMP protein expression significantly increased in hindlimb skeletal muscle in the mSOD1G93A mouse model of ALS in late stages of the disease (P < 0.05), which negatively correlated with Akt phosphorylation over this period (R2 = −0.77). Co-immunoprecipitation of Akt revealed CTMP binding in pre-symptomatic and end-stage skeletal muscle, suggesting a possible direct role in reduced Akt signaling during disease progression. Inflammatory TNFα and downstream cellular degradation process markers for autophagy, lysosome production, and atrophy significantly increased in a pattern corresponding to increased CTMP expression and reduced Akt phosphorylation. In an in vitro model of skeletal muscle atrophy, differentiated C2C12 cells exhibited reduced Akt activity and decreased FOXO1 phosphorylation, a process known to promote transcription of atrophy genes in skeletal muscle. These results corresponded with increased Atrogin-1 expression compared to healthy control cells (P < 0.05). Transfection with CTMP siRNA significantly increased Akt phosphorylation in atrophic C2C12 cells, corresponding to significantly decreased CTMP expression. In conclusion, this is the first study to provide evidence for a link between elevated CTMP expression, downregulated Akt phosphorylation and muscle atrophy in ALS and clearly demonstrates a direct influence of CTMP on Akt phosphorylation in an in vitro muscle cell atrophy model.

Lower Extremity Functional Outcome Measures in Duchenne Muscular Dystrophy-A Delphi Survey.

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease characterized by progressive muscle weakness, multiple system involvement and premature mortality. Effective treatments for DMD through clinical trials and natural history studies are currently underway. Clinical trials in DMD typically include several outcome measures of motor function. Research sites and studies have been found to have slightly different operational definitions for a given functional outcome resulting in different procedures and protocols for these measurements. The goal of this study is to establish agreement among experts in the field around best practices in collecting functional outcome data in DMD providing researchers and clinicians with guidance on best practices. A group of 30 experts in Duchenne Muscular Dystrophy (DMD) with experience in the development and/ or execution of lower extremity outcome measures for this population met face to face to identify incongruences in the collection of this data. This effort was based in the United States (US) and sponsored by Parent Project Muscular Dystrophy. Several discrepancies were categorized for each outcome which included: 6-minute walk test, 10-meter walk/run, supine to stand, ascend 4 stairs, sit to stand, and the NorthStar Ambulatory Assessment. Following this meeting an additional 32 experts in DMD (28 from the United States and 11 international participants) consented to participate in a Delphi Survey to reach consensus on the protocols and execution of lower extremity outcomes. Round one: 70 operationally defined questions were surveyed with 45 (64%) reaching >70% consensus. Round two: 27 questions were operational, with 20 (74%) reaching >70% consensus. Those questions that did not reach consensus appear minor. With minor modifications in the collection of data across sites, outcomes could potentially be normalized across research studies. This would reduce excessive training for evaluators in trials and produce minimal differences between protocols. Consistency in protocols will promote more efficient study start up, less errors between administration of items across studies, and ultimately improve quality and reliability of the functional outcomes. The authors strongly advocate for the establishment of a "research network library" that could be utilized by all those performing clinical assessments and trials in DMD.

Cross-sectional and longitudinal assessment of the upper cervical spinal cord in motor neuron disease.

BackgroundAmyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease characterized by both upper and lower motor neuron degeneration. While neuroimaging studies of the brain can detect upper motor neuron degeneration, these brain MRI scans also include the upper part of the cervical spinal cord, which offers the possibility to expand the focus also towards lower motor neuron degeneration. Here, we set out to investigate cross-sectional and longitudinal disease effects in the upper cervical spinal cord in patients with ALS, progressive muscular atrophy (PMA: primarily lower motor neuron involvement) and primary lateral sclerosis (PLS: primarily upper motor neuron involvement), and their relation to disease severity and grey and white matter brain measurements.MethodsWe enrolled 108 ALS patients without C9orf72 repeat expansion (ALS C9–), 26 ALS patients with C9orf72 repeat expansion (ALS C9+), 28 PLS patients, 56 PMA patients and 114 controls. During up to five visits, longitudinal T1-weighted brain MRI data were acquired and used to segment the upper cervical spinal cord (UCSC, up to C3) and individual cervical segments (C1 to C4) to calculate cross-sectional areas (CSA). Using linear (mixed-effects) models, the CSA differences were assessed between groups and correlated with disease severity. Furthermore, a relationship between CSA and brain measurements was examined in terms of cortical thickness of the precentral gyrus and white matter integrity of the corticospinal tract.ResultsCompared to controls, CSAs at baseline showed significantly thinner UCSC in all groups in the MND spectrum. Over time, ALS C9– patients demonstrated significant thinning of the UCSC and, more specifically, of segment C3 compared to controls. Progressive thinning over time was also observed in C1 of PMA patients, while ALS C9+ and PLS patients did not show any longitudinal changes. Longitudinal spinal cord measurements showed a significant relationship with disease severity and we found a significant correlation between spinal cord and motor cortex thickness or corticospinal tract integrity for PLS and PMA, but not for ALS patients.DiscussionOur findings demonstrate atrophy of the upper cervical spinal cord in the motor neuron disease spectrum, which was progressive over time for all but PLS patients. Cervical spinal cord imaging in ALS seems to capture different disease effects than brain neuroimaging. Atrophy of the cervical spinal cord is therefore a promising additional biomarker for both diagnosis and disease progression and could help in the monitoring of treatment effects in future clinical trials.

Aerobic exercise in adult neuromuscular rehabilitation: A survey of healthcare professionals.

To evaluate the current application of aerobic exercise in adult neuromuscular rehabilitation. Cross-sectional survey. Dutch rehabilitation specialists and physical therapists in specialized centres for slowly progressive neuromuscular diseases and in primary care. Participants received a self-designed, web-based, questionnaire, including 27 close-ended questions covering 4 categories: respondent profile, application of aerobic exercise, barri-ers to prescribing aerobic exercise, and need for support to improve the application of aerobic exercise. All respondents (n = 52) prescribed aerobic exercise and in a wide variety of neuromuscular diseases, mostly applying sessions of more than 20 min, 2 days per week, over a period of 9-16 weeks, using different exercise modes and methods to target intensity. The majo-rity (81%) agreed that aerobic exercise should be incorporated into neuromuscular rehabilitation. However, all respon-dents perceived barriers to the application of aerobic exercise in one or more domains, and 77% of the respondents indicated needing support to improve application of this type of training, mostly with respect to screening procedures (54%) and dosing of exercise programmes (48%). Aerobic exercise is widely applied, yet our results raise awareness of the necessity of more evidence based knowledge, in order to develop and implement guidelines in adult neuromuscular rehabilitation.

Pluripotent Stem Cell-Based Drug Screening Reveals Cardiac Glycosides as Modulators of Myotonic Dystrophy Type 1

SummaryThere is currently no treatment for myotonic dystrophy type 1 (DM1), the most frequent myopathy of genetic origin. This progressive neuromuscular disease is caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors, resulting in alternative splicing misregulation. By combining human mutated pluripotent stem cells and phenotypic drug screening, we revealed that cardiac glycosides act as modulators for both upstream nuclear aggregations of DMPK mRNAs and several downstream alternative mRNA splicing defects. However, these occurred at different drug concentration ranges. Similar biological effects were recorded in a DM1 mouse model. At the mechanistic level, we demonstrated that this effect was calcium dependent and was synergic with inhibition of the ERK pathway. These results further underscore the value of stem-cell-based assays for drug discovery in monogenic diseases.

Prevalence of Amyotrophic Lateral Sclerosis - United States, 2015.

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a progressive and fatal neuromuscular disease; the majority of ALS patients die within 2-5 years of receiving a diagnosis (1). Familial ALS, a hereditary form of the disease, accounts for 5%-10% of cases, whereas the remaining cases have no clearly defined etiology (1). ALS affects persons of all races and ethnicities; however, whites, males, non-Hispanics, persons aged ≥60 years, and those with a family history of ALS are more likely to develop the disease (2). No cure for ALS has yet been identified, and the lack of proven and effective therapeutic interventions is an ongoing challenge. Treatments currently available, Edaravone and Riluzole, do not cure ALS, but slow disease progression in certain patients (3,4). This report presents National ALS Registry findings regarding ALS prevalence in the United States for the period January 1-December 31, 2015. In 2015, the estimated prevalence of ALS cases was 5.2 per 100,000 population with a total of 16,583 cases identified. Overall, these findings are similar to the 2014 ALS prevalence and case count (5.0 per 100,000; 15,927 cases) (2). Prevalence rates by patient characteristics (most common in whites, males, and persons aged ≥60 years) and U.S. Census regions are consistent with ALS demographics and have not changed from 2014 to 2015 calendar years. The algorithm used to identify cases from national administrative databases was updated from the International Classification of Diseases, Ninth Revision (ICD-9) to the ICD-10 codes for claims starting on October 1, 2015, with no apparent effect on case ascertainment. Data collected by the National ALS Registry are being used to better describe the epidemiology of ALS in the United States and to facilitate research on the genetics, potential biomarkers, environmental pollutants, and etiology for ALS.

Positive airway pressure devices for the management of breathlessness.

Breathlessness is a common symptom in many chronic diseases and may be refractory to pharmacotherapy. In this review, we discuss the pathophysiology of breathlessness and the role of positive airway pressure (PAP) devices to ameliorate it. Breathlessness is directly related to neural respiratory drive, which can be modified by addressing the imbalance between respiratory muscle load and capacity. Noninvasive PAP devices have been applied to patients limited by exertional breathless and, as the disease progresses, breathlessness at rest. The application of PAP is focussed on addressing the imbalance in load and capacity, aiming to reduce neural respiratory drive and breathlessness. Indeed, noninvasive bi-level PAP devices have been employed to enhance exercise capacity by enhancing pulmonary mechanics and reduce neural drive in chronic obstructive pulmonary disease (COPD) patients, and reduce breathlessness for patients with progressive neuromuscular disease (NMD) by enhancing respiratory muscle capacity. Novel continuous PAP devices have been used to maintain central airways patency in patients with excessive dynamic airway collapse (EDAC) and target expiratory flow limitation in severe COPD. PAP devices can reduce exertional and resting breathlessness by reducing the load on the system and enhancing capacity to reduce neural respiratory drive.

Study protocol for the MEXiletine hydrochloride administration trial: a placebo-controlled, randomised, double-blind, multicentre, crossover study of its efficacy and safety in spinal and bulbar muscular atrophy (MEXPRESS)

IntroductionSpinal and bulbar muscular atrophy (SBMA) is a slowly progressive neuromuscular disease. Cold exposure often leads to worsening of motor symptoms including paresis. Although mexiletine hydrochloride administration has been shown...

Validation of a Muscle-Specific Tissue Image Analysis Tool for Quantitative Assessment of Dystrophin Staining in Frozen Muscle Biopsies.

Duchenne muscular dystrophy is a rare, progressive, and fatal neuromuscular disease caused by dystrophin protein loss. Common investigational treatment approaches aim at increasing dystrophin expression in diseased muscle. Some clinical trials include assessments of novel dystrophin production as a surrogate biomarker of efficacy, which may predict a clinical benefit from treatment. To establish an immunofluorescent scanning and digital image analysis workflow that provides an objective approach for staining intensity assessment of the immunofluorescence dystrophin labeling and determination of the percentage of biomarker-positive fibers in muscle cryosections. Optimal and repeatable digital image capture was achieved by a rigorously qualified fluorescent scanning process. After scanning qualification, the MuscleMap (Flagship Biosciences, Westminster, Colorado) algorithm was validated by comparing high-power microscopic field total and dystrophin-positive fiber counts obtained by trained pathologists to data derived by MuscleMap. Next, the algorithm was tested on whole-slide images of immunofluorescent-labeled muscle sections from Duchenne muscular dystrophy, Becker muscular dystrophy, and control patients. When used under the guidance of a trained pathologist, the digital image analysis tool met predefined validation criteria and demonstrated functional and statistical equivalence with manual assessment. This work is the first, to our knowledge, to qualify and validate immunofluorescent scanning and digital tissue image-analysis workflow, respectively, with the rigor required to support the clinical trial environments. MuscleMap enables analysis of all fibers within an entire muscle biopsy section and provides data on a fiber-by-fiber basis. This will allow future clinical trials to objectively investigate myofibers' dystrophin expression at a greater level of consistency and detail.

BODY COMPOSITION AND ITS RELATIONSHIP WITH MOTOR PERFORMANCE IN NEUROMUSCULAR DISEASES

p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 26.0px 'Helvetica Neue'} Purpose: Increased fat mass and decreased muscle mass affect patient’s motor performance during slowly progressive neuromuscular diseases (NMDs). The purpose of this study was to investigate the effects of body composition on motor performance in adult patients with NMDs. Methods: Twenty-six patients and 26 age-matched healthy participants were included in this cross-sectional study. Body composition was assessed using a bioelectrical impedance analyzer, and the motor performance was determined using a manual muscle testing, and timed performance was evaluated using climbing ten stairs, walking 10 m, wearing a t-shirt, supine up tests, and functional level using Motor Function Measurement (MFM) scale. Results: There was no difference between the patients and the controls in terms of age, height, weight, and body composition (p>0.05). There was no correlation between body composition and timed performance tests for controls. In patients, the body mass index (BMI), fat mass (FM), and fat percentage (%FM) were correlated with the time of climbing 10 stairs (r=0.631, r=0.693, r=0.718, respectively) and supine up time (r=0.493, r=0.643, r=0.621, respectively) (p<0.05). Ten meter walking time was correlated with %FM (r=0.496) and fat free mass (r=-0.475, p<0.05). The MFM score was related with BMI (r=-0.425), FM (r=-0.503) and %FM (r=-0.586, p<0.05). Total lower extremity muscle strength was correlated with FM (r=-0.456) and %FM (r=-0.550) in patients (p<0.05). Conclusion: The results of the study showed that body composition might be a factor affecting motor performance in adult patients with NMDs. Preventive strategies should be considered from the early stages of the disease. 

Prevalence of Amyotrophic Lateral Sclerosis - United States, 2014.

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a progressive and fatal neuromuscular disease; the majority of ALS patients die within 2-5 years of receiving a diagnosis (1). Familial ALS, a hereditary form of the disease, accounts for 5%-10% of cases, whereas the remaining sporadic cases have no clearly defined etiology (1). ALS affects persons of all races and ethnicities; however, whites, males, non-Hispanics, persons aged >60 years, and those with a family history of ALS are more likely to develop the disease (1-3). No cure for ALS has yet been identified, and the lack of proven and effective therapeutic interventions is an ongoing challenge. Current treatments available do not cure ALS but have been shown to slow disease progression. Until recently, only one drug (riluzole) was approved to treat ALS; however, in 2017, the Food and Drug Administration approved a second drug, edaravone (4).

Correction of GSK3β at young age prevents muscle pathology in mice with myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is a progressive neuromuscular disease caused by expanded CUG repeats, which misregulate RNA metabolism through several RNA-binding proteins, including CUG-binding protein/CUGBP1 elav-like factor 1 (CUGBP1/CELF1) and muscleblind 1 protein. Mutant CUG repeats elevate CUGBP1 and alter CUGBP1 activity via a glycogen synthase kinase 3β (GSK3β)-cyclin D3-cyclin D-dependent kinase 4 (CDK4) signaling pathway. Inhibition of GSK3β corrects abnormal activity of CUGBP1 in DM1 mice [human skeletal actin mRNA, containing long repeats ( HSALR) model]. Here, we show that the inhibition of GSK3β in young HSALR mice prevents development of DM1 muscle pathology. Skeletal muscle in 1-yr-old HSALR mice, treated at 1.5 mo for 6 wk with the inhibitors of GSK3, exhibits high fiber density, corrected atrophy, normal fiber size, with reduced central nuclei and normalized grip strength. Because CUG-GSK3β-cyclin D3-CDK4 converts the active form of CUGBP1 into a form of translational repressor, we examined the contribution of CUGBP1 in myogenesis using Celf1 knockout mice. We found that a loss of CUGBP1 disrupts myogenesis, affecting genes that regulate differentiation and the extracellular matrix. Proteins of those pathways are also misregulated in young HSALR mice and in muscle biopsies of patients with congenital DM1. These findings suggest that the correction of GSK3β-CUGBP1 pathway in young HSALR mice might have a positive effect on the myogenesis over time.-Wei, C., Stock, L., Valanejad, L., Zalewski, Z. A., Karns, R., Puymirat, J., Nelson, D., Witte, D., Woodgett, J., Timchenko, N. A., Timchenko, L. Correction of GSK3β at young age prevents muscle pathology in mice with myotonic dystrophy type 1.

Outcomes of Primary Posterior Spinal Fusion for Scoliosis in Spinal Muscular Atrophy: Clinical, Radiographic, and Pulmonary Outcomes and Complications.

Spinal muscular atrophy (SMA) is a progressive neuromuscular disease commonly including progressive scoliosis resulting in severe deformity and negatively affecting pulmonary function. Surgical correction and stabilization of this progressive deformity is generally recommended; however, the timing and method of surgical fixation remains controversial. Retrospective review of clinical, radiographic, and pulmonary function data from 16 children with SMA and surgically treated scoliosis between 1985 and 2013. Radiographic data included direct measures of major curve, coronal balance, pelvic obliquity, T1-T12 height, T1-S1 height, and T1-rod length. Estimations of rib collapse, thoracic cavity shape, and space-available-for-lung (T6:T12, width ratio; T6:T10, rib-vertebral-angle difference ratios; and lung height) were determined. Eleven patients were able to complete pulmonary function testing. Results were compared with published outcomes for growing rod constructs. Posterior spinal fusion was performed at an average age of 9.8±3.6 years. The mean age at most recent follow-up was 19.4 years (range, 10 to 37 y), with a mean follow-up of 10.1 years (range, 3.1 to 26 y). Radiographic measurements improved from preoperative to latest follow-up as follows: major curve, 78±20 degrees to 27±24 degrees; coronal balance, 4.1±4.0 cm to 1.9±2.2 cm; pelvic obliquity (median), 23 to 5 degrees; T1-T12 height, 19±3 cm to 22±3 cm; T1-S1 height, 31±7 cm to 36±6 cm; T1-rod length, 0.8±1.1 cm (postop) to 2.8±1.6 cm (final); and space-available-for-lung ratio, 0.88±0.26 to 0.95±0.25. Rib collapse continued throughout the follow-up period in all but 1 patient. Pulmonary function testing demonstrated a decrease in rate of decline in forced vital capacity and forced expiratory volume when comparing preoperative with postoperative rates. Mean length of stay was 7.8±4.4 days. Complications included reintubation for low tidal volumes (n=1), pneumonia (n=1), superficial wound breakdown (n=1), and superficial infection (n=1). Definitive posterior spinal fusion for treatment of scoliosis associated with SMA is effective at controlling curve progression and pelvic obliquity without negatively impacting the space-available-for-lung ratio, trunk height, or pulmonary function at 10 years follow-up. Therapeutic Level IV.