ABSTRACT
BACKGROUND: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. METHODS: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. RESULTS: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. CONCLUSIONS: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).
Subject(s)
Azo Compounds/administration & dosage , Neuromuscular Agents/administration & dosage , Pyrimidines/administration & dosage , Spinal Muscular Atrophies of Childhood/drug therapy , Survival of Motor Neuron 1 Protein/blood , Administration, Oral , Azo Compounds/adverse effects , Azo Compounds/pharmacokinetics , Dose-Response Relationship, Drug , Female , Humans , Infant , Male , Neuromuscular Agents/adverse effects , Neuromuscular Agents/pharmacokinetics , Progression-Free Survival , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , RNA Splicing , Respiratory Insufficiency/etiology , Respiratory Tract Infections/etiology , Spinal Muscular Atrophies of Childhood/complications , Spinal Muscular Atrophies of Childhood/mortality , Survival of Motor Neuron 1 Protein/geneticsABSTRACT
OBJECTIVE: The paucity of longitudinal natural history studies in MPZ neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ neuropathies across 13 sites of the Inherited Neuropathies Consortium. METHODS: Change in Charcot-Marie-Tooth Examination Score (CMTES) and Rasch modified CMTES (CMTES-R) were evaluated using longitudinal regression over a 5-year period in subjects with MPZ neuropathy. Data from 139 patients with MPZ neuropathy were examined. RESULTS: The average baseline CMTES and CMTES-R were 10.84 (standard deviation [SD] = 6.0, range = 0-28) and 14.60 (SD = 7.56, range = 0-32), respectively. A mixed regression model showed significant change in CMTES at years 2-5 (mean change from baseline of 0.87 points at 2 years, p = 0.008). Subgroup analysis revealed greater change in CMTES at 2 years in subjects with axonal as compared to demyelinating neuropathy (mean change of 1.30 points [p = 0.016] vs 0.06 points [p = 0.889]). Patients with a moderate baseline neuropathy severity also showed more notable change, by estimate, than those with mild or severe neuropathy (mean 2-year change of 1.14 for baseline CMTES 8-14 [p = 0.025] vs -0.03 for baseline CMTES 0-7 [p = 0.958] and 0.25 for baseline CMTES ≥ 15 [p = 0.6897]). The progression in patients harboring specific MPZ mutations was highly variable. INTERPRETATION: CMTES is sensitive to change over time in adult patients with axonal but not demyelinating forms of MPZ neuropathy. Change in CMTES was greatest in patients with moderate baseline disease severity. These findings will inform future clinical trials of MPZ neuropathies. ANN NEUROL 2023;93:563-576.
Subject(s)
Charcot-Marie-Tooth Disease , Adult , Humans , Charcot-Marie-Tooth Disease/genetics , Longitudinal Studies , Myelin P0 Protein/genetics , Mutation , Disease ProgressionABSTRACT
OBJECTIVE: Authors evaluated the performance of a commercially available next-generation sequencing assay kit; this was based on genomic content from Illumina's TruSight™ Oncology 500 research assay that identifies BRCA variants and proprietary algorithms licensed from Myriad and, with additional genomic content, measures the homologous recombination deficiency (HRD) genomic instability score (GIS) in tumor tissue (TSO 500 HRD assay). METHODS: Data from the TSO 500 HRD assay were compared with data from the Myriad MyChoice®CDx PLUS assay (Myriad assay). Prevalence rates for overall HRD status and BRCA mutations (a deleterious or suspected deleterious BRCA1 or BRCA2 mutation or both) and assay agreement rates for HRD GIS and BRCA analysis were assessed in ovarian tumor samples. Pearson correlations of the continuous HRD GIS and analytic sensitivity and specificity were evaluated. RESULTS: The prevalence of overall HRD positivity was 51.2% (TSO 500 HRD assay) versus 49.2% (Myriad assay) and the prevalence of BRCA mutations was 27.6% (TSO 500 HRD assay) versus 25.5% (Myriad assay). After post-processing optimization, concordance of the HRD GIS was 0.980 in all samples and 0.976 in the non-BRCA mutation cohort; the area under the receiver operating characteristic curve was 0.995 and 0.992, respectively. CONCLUSIONS: Comparison between the Illumina and Myriad assays showed that overall HRD status, the individual components of BRCA analysis, and HRD GIS detection results were highly concordant (>93%), suggesting the TSO 500 HRD assay will approach the analytical accuracy of the FDA-approved Myriad assay.
Subject(s)
Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/genetics , Ovarian Neoplasms/diagnosis , Homologous Recombination , High-Throughput Nucleotide Sequencing/methods , United States/epidemiology , Mutation , BRCA1 Protein/genetics , Genomic Instability , BRCA2 Protein/genetics , Reagent Kits, Diagnostic/standards , United States Food and Drug Administration , Middle Aged , Genes, BRCA1ABSTRACT
BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is a rare and progressive neuromuscular disorder with varying severity levels. The aim of the study was to calculate minimal clinically important difference (MCID), minimal detectable change (MDC), and values for the Hammersmith Functional Motor Scale Expanded (HFMSE) in an untreated international SMA cohort. METHODS: The study employed two distinct methods. MDC was calculated using distribution-based approaches to consider standard error of measurement and effect size change in a population of 321 patients (176 SMA II and 145 SMA III), allowing for stratification based on age and function. MCID was assessed using anchor-based methods (receiver operating characteristic [ROC] curve analysis and standard error) on 76 patients (52 SMA II and 24 SMA III) for whom the 12-month HFMSE could be anchored to a caregiver-reported clinical perception questionnaire. RESULTS: With both approaches, SMA type II and type III patients had different profiles. The MCID, using ROC analysis, identified optimal cutoff points of -2 for type II and -4 for type III patients, whereas using the standard error we found the optimal cutoff points to be 1.5 for improvement and -3.2 for deterioration. Furthermore, distribution-based methods uncovered varying values across age and functional status subgroups within each SMA type. CONCLUSIONS: These results emphasize that the interpretation of a single MCID or MDC value obtained in large cohorts with different functional status needs to be made with caution, especially when these may be used to assess possible responses to new therapies.
Subject(s)
Minimal Clinically Important Difference , Muscular Atrophy, Spinal , Humans , Male , Female , Child , Adolescent , Muscular Atrophy, Spinal/physiopathology , Muscular Atrophy, Spinal/diagnosis , Child, Preschool , Adult , Young Adult , Severity of Illness Index , Cohort Studies , Spinal Muscular Atrophies of Childhood/physiopathology , Spinal Muscular Atrophies of Childhood/diagnosis , Infant , Disability EvaluationABSTRACT
Neuromuscular disorders are a group of conditions that can result in weakness of skeletal muscles. Examples include fatal diseases such as amyotrophic lateral sclerosis and conditions associated with high morbidity such as myopathies (muscle diseases). Many of these disorders are known to have abnormal protein folding and protein aggregates. Thus, easy to apply methods for the detection of such changes may prove useful diagnostic biomarkers. Raman spectroscopy has shown early promise in the detection of muscle pathology in neuromuscular disorders and is well suited to characterising the conformational profiles relating to protein secondary structure. In this work, we assess if Raman spectroscopy can detect differences in protein structure in muscle in the setting of neuromuscular disease. We utilise in vivo Raman spectroscopy measurements from preclinical models of amyotrophic lateral sclerosis and the myopathy Duchenne muscular dystrophy, together with ex vivo measurements of human muscle samples from individuals with and without myopathy. Using quantitative conformation profiling and matrix factorisation we demonstrate that quantitative 'conformational fingerprinting' can be used to identify changes in protein folding in muscle. Notably, myopathic conditions in both preclinical models and human samples manifested a significant reduction in α-helix structures, with concomitant increases in ß-sheet and, to a lesser extent, nonregular configurations. Spectral patterns derived through non-negative matrix factorisation were able to identify myopathy with a high accuracy (79% in mouse, 78% in human tissue). This work demonstrates the potential of conformational fingerprinting as an interpretable biomarker for neuromuscular disorders.
Subject(s)
Biomarkers , Muscular Dystrophy, Duchenne , Spectrum Analysis, Raman , Spectrum Analysis, Raman/methods , Humans , Animals , Biomarkers/analysis , Muscular Dystrophy, Duchenne/pathology , Muscular Dystrophy, Duchenne/diagnosis , Muscle, Skeletal/chemistry , Muscle, Skeletal/pathology , Mice , Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/pathology , MaleABSTRACT
Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. These expanded repeats are transcribed and produce toxic CUG RNAs that sequester and inhibit activities of the MBNL family of developmental RNA processing factors. Although myotonic dystrophy is classified as a muscular dystrophy, the brain is also severely affected by an unusual cohort of symptoms, including hypersomnia, executive dysfunction, as well as early onsets of tau/MAPT pathology and cerebral atrophy. To address the molecular and cellular events that lead to these pathological outcomes, we recently generated a mouse Dmpk CTG expansion knock-in model and identified choroid plexus epithelial cells as particularly affected by the expression of toxic CUG expansion RNAs. To determine if toxic CUG RNAs perturb choroid plexus functions, alternative splicing analysis was performed on lateral and hindbrain choroid plexi from Dmpk CTG knock-in mice. Choroid plexus transcriptome-wide changes were evaluated in Mbnl2 knockout mice, a developmental-onset model of myotonic dystrophy brain dysfunction. To determine if transcriptome changes also occurred in the human disease, we obtained post-mortem choroid plexus for RNA-seq from neurologically unaffected (two females, three males; ages 50-70 years) and myotonic dystrophy type 1 (one female, three males; ages 50-70 years) donors. To test that choroid plexus transcriptome alterations resulted in altered CSF composition, we obtained CSF via lumbar puncture from patients with myotonic dystrophy type 1 (five females, five males; ages 35-55 years) and non-myotonic dystrophy patients (three females, four males; ages 26-51 years), and western blot and osmolarity analyses were used to test CSF alterations predicted by choroid plexus transcriptome analysis. We determined that CUG RNA induced toxicity was more robust in the lateral choroid plexus of Dmpk CTG knock-in mice due to comparatively higher Dmpk and lower Mbnl RNA levels. Impaired transitions to adult splicing patterns during choroid plexus development were identified in Mbnl2 knockout mice, including mis-splicing previously found in Dmpk CTG knock-in mice. Whole transcriptome analysis of myotonic dystrophy type 1 choroid plexus revealed disease-associated RNA expression and mis-splicing events. Based on these RNA changes, predicted alterations in ion homeostasis, secretory output and CSF composition were confirmed by analysis of myotonic dystrophy type 1 CSF. Our results implicate choroid plexus spliceopathy and concomitant alterations in CSF homeostasis as an unappreciated contributor to myotonic dystrophy type 1 CNS pathogenesis.
Subject(s)
Myotonic Dystrophy , Humans , Female , Mice , Animals , Myotonic Dystrophy/genetics , Choroid Plexus/metabolism , Choroid Plexus/pathology , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Alternative Splicing , RNA/genetics , Mice, Knockout , Trinucleotide Repeat ExpansionABSTRACT
Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness [change in CMTES (ΔCMTES) = 1.3 ± 2.6, P = 0.00016, SRM = 0.50]. Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, P = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.
Subject(s)
Charcot-Marie-Tooth Disease , Female , Humans , Male , Charcot-Marie-Tooth Disease/pathology , Connexins/genetics , Mutation/genetics , Mutation, Missense , Phenotype , Gap Junction beta-1 ProteinABSTRACT
Despite an increased drive over the past two decades in Western societies to promote children's physically active play to improve their health, there are concerns that childhood has become less physically active. There are also fears that a previously naturally occurring aspect of childhood has become less authentically playful. Both trends highlight changes over time in the amount and type of play practiced by children and are often cited as consequences of generational shifts. Yet, research which analytically employs the concept of generation to connect changes to childhood with relevant social transformations is lacking. Inspired by Mannheim's conceptualisation of generations, this paper draws on life history interviews with 28 United Kingdom residents born between 1950 and 1994 to propose a fracturing of naturally occurring physical activity from childhood play. As shifts in childhood and parenting have become inextricably linked, this argument illustrates the impact of an intensification to parenting upon greater parental surveillance of increasingly organised forms of childhood physical activity at the expense of spontaneous play. Future physical activity policy should be sensitive to the social climate in which recommendations for children are made, as this places expectations upon parents due to how childhood is currently understood within neoliberal contexts.
Subject(s)
Parenting , Parents , Child , Humans , Social Environment , United Kingdom , ExerciseABSTRACT
Heavy nuclides like uranium and their decay products are commonly found in nuclear industries and can pose a significant health risk to humans due to their alpha-emitting properties. Traditional alpha detectors require close contact with the contaminated surface, which can be time-consuming, labour-intensive, and put personnel at risk. Remote detection is urgently needed but very challenging. To this end, a candidate detection mechanism is alpha-induced radio-luminescence. This approach uses the emission of photons from radio-ionised excited nitrogen molecules to imply the presence of alpha emitters from a distance. Herein, the use of this phenomenon to remotely image various alpha emitters with unparalleled levels of sensitivity and spatial accuracy is demonstrated. Notably, the system detected a 29 kBq Am-241 source at a distance of 3 m within 10 min. Furthermore, it demonstrated the capability to discern a 29 kBq source positioned 7 cm away from a 3 MBq source at a 2 m distance. Additionally, a 'sandwich' filter structure is described that incorporates an absorptive filter between two interference filters to enhance the ambient light rejection. The testing of the system is described in different lighting environments, including room light and inside a glovebox. This method promises safer and more efficient alpha monitoring, with applications in nuclear forensics, waste management and decommissioning.
ABSTRACT
INTRODUCTION: Atrial Fibrillation (AF) is a common arrhythmia often comorbid with systolic or diastolic heart failure (HF). Catheter ablation is a more effective treatment for AF with concurrent left ventricular dysfunction, however, the optimal timing of use in these patients is unknown. METHODS: All patients that received a catheter ablation for AF(n = 9979) with 1 year of follow-up within the Intermountain Healthcare system were included. Patients with were identified by the presence of structural disease by ejection fraction (EF): EF ≤ 35% (n = 1024) and EF > 35% (n = 8955). Recursive partitioning categories were used to separate patients into clinically meaningful strata based upon time from initial AF diagnosis until ablation: 30-180(n = 2689), 2:181-545(n = 1747), 3:546-1825(n = 2941), and 4:>1825(n = 2602) days. RESULTS: The mean days from AF diagnosis to first ablation was 3.5 ± 3.8 years (EF > 35%: 3.5 ± 3.8 years, EF ≤ 35%: 3.4 ± 3.8 years, p = .66). In the EF > 35% group, delays in treatment (181-545 vs. 30-180, 546-1825 vs. 30-180, >1825 vs. 30-180 days) increased the risk of death with a hazard ratio (HR) of 2.02(p < .0001), 2.62(p < .0001), and 4.39(p < .0001) respectively with significant risks for HF hospitalization (HR:1.44-3.69), stroke (HR:1.11-2.14), and AF recurrence (HR:1.42-1.81). In patients with an EF ≤ 35%, treatment delays also significantly increased risk of death (HR 2.07-3.77) with similar trends in HF hospitalization (HR:1.63-1.09) and AF recurrence (HR:0.79-1.24). CONCLUSION: Delays in catheter ablation for AF resulted in increased all-cause mortality in all patients with differential impact observed on HF hospitalization, stroke, and AF recurrence risks by baseline EF. These data favor earlier use of ablation for AF in patients with and without structural heart disease.
Subject(s)
Atrial Fibrillation , Catheter Ablation , Heart Failure , Stroke , Humans , Atrial Fibrillation/surgery , Treatment Outcome , Catheter Ablation/adverse effectsABSTRACT
INTRODUCTION/AIMS: Electromyography (EMG) remains a key component of the diagnostic work-up for suspected neuromuscular disease, but it does not provide insight into the molecular composition of muscle which can provide diagnostic information. Raman spectroscopy is an emerging neuromuscular biomarker capable of generating highly specific, molecular fingerprints of tissue. Here, we present "optical EMG," a combination of EMG and Raman spectroscopy, achieved using a single needle. METHODS: An optical EMG needle was created to collect electrophysiological and Raman spectroscopic data during a single insertion. We tested functionality with in vivo recordings in the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS), using both transgenic (n = 10) and non-transgenic (NTg, n = 7) mice. Under anesthesia, compound muscle action potentials (CMAPs), spontaneous EMG activity and Raman spectra were recorded from both gastrocnemius muscles with the optical EMG needle. Standard concentric EMG needle recordings were also undertaken. Electrophysiological data were analyzed with standard univariate statistics, Raman data with both univariate and multivariate analyses. RESULTS: A significant difference in CMAP amplitude was observed between SOD1G93A and NTg mice with optical EMG and standard concentric needles (p = .015 and p = .011, respectively). Spontaneous EMG activity (positive sharp waves) was detected in transgenic SOD1G93A mice only. Raman spectra demonstrated peaks associated with key muscle components. Significant differences in molecular composition between SOD1G93A and NTg muscle were identified through the Raman spectra. DISCUSSION: Optical EMG can provide standard electrophysiological data and molecular Raman data during a single needle insertion and represents a potential biomarker for neuromuscular disease.
Subject(s)
Amyotrophic Lateral Sclerosis , Spectrum Analysis, Raman , Mice , Animals , Electromyography , Superoxide Dismutase-1/genetics , Muscle, Skeletal , Mice, Transgenic , Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/genetics , Disease Models, Animal , Superoxide DismutaseABSTRACT
BACKGROUND: Although Lesion size index (LSI) has been reported to highly predict radiofrequency lesion size in vitro, its accuracy in lesion size and steam pop estimation has not been well investigated for every possible scenario. METHODS: Initially, radiofrequency ablations were performed on porcine myocardial slabs at various power, CF, and time settings with blinded LSI. Subsequently, radiofrequency power at 20, 30, 40, 50, and 60 W was applied at CF values of 5, 10, 20, and 30 g to reach target LSIs of 4, 5, 6, and 7. Lesion size and steam pops were recorded for each ablation. RESULTS: Lesion size was positively correlated with LSI regardless of power settings (p < 0.001). The linear correlation coefficients of lesion size and LSI decreased at higher power settings. At high power combined with high CF settings (50 W/20 g), lesion depth and LSI showed an irrelevant correlation (p = 0.7855). High-power ablation shortened ablation time and increased the effect of resistive heating. LSI could predict the risk of steam pops at high-power settings with the optimal threshold of 5.65 (sensitivity, 94.1%; specificity, 46.1%). The ablation depth of the heavy heart was shallower than that of the light heart under similar ablation settings. CONCLUSIONS: LSI could predict radiofrequency lesion size and steam pops at high power settings in vitro, while synchronous high power and high CF should be avoided. Lighter hearts require relatively lower ablation settings to create appropriate ablation depth.
Subject(s)
Catheter Ablation , Steam , Swine , Animals , Myocardium/pathologyABSTRACT
DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis. Reverse transcription-polymerase chain reaction or high-throughput RNA sequencing methods identified 19 mutations with one of three pathogenic pseudoexon types: deep intronic point mutations, deletions or insertions, and translocations. In association with point mutations creating intronic splice acceptor sites, we observed the first examples of DMD pseudo 3'-terminal exon mutations causing high efficiency transcription termination within introns. This connection between splicing and premature transcription termination is reminiscent of U1 snRNP-mediating telescripting in sustaining RNA polymerase II elongation across large genes, such as DMD. We propose a novel classification of three distinct types of mutations identifiable by muscle RNA analysis, each of which differ in potential treatment approaches. Recognition and appropriate characterization may lead to therapies directed toward full-length dystrophin expression for some patients.
Subject(s)
Dystrophin , Muscular Dystrophy, Duchenne , Dystrophin/genetics , Humans , Introns/genetics , Muscular Dystrophy, Duchenne/diagnosis , Muscular Dystrophy, Duchenne/genetics , Muscular Dystrophy, Duchenne/pathology , Mutation , RNA Splice SitesABSTRACT
BACKGROUND: Class 1C antiarrhythmic drugs (AAD) have been associated with harm in patients treated for ventricular arrhythmias with a prior myocardial infarction. Consensus guidelines have advocated that these drugs not be used in patients with stable coronary artery disease (CAD). However, long-term data are lacking to know if unique risks exist when these drugs are used for atrial fibrillation (AF) in patients with CAD without a prior myocardial infarction. METHODS: In 24,315 patients treated with the initiation of AADs, two populations were evaluated: (1) propensity-matched AF patients with CAD were created based upon AAD class (flecainide, n = 1,114, vs class-3 AAD, n = 1,114) and (2) AF patients who had undergone a percutaneous coronary intervention or coronary artery bypass graft (flecainide, n = 150, and class-3 AAD, n = 1,453). Outcomes at 3 years for mortality, heart failure (HF) hospitalization, ventricular tachycardia (VT), and MACE were compared between the groups. RESULTS: At 3 years, mortality (9.1% vs 19.3%, P < .0001), HF hospitalization (12.5% vs 18.3%, P < .0001), MACE (22.9% vs 36.6%, P < .0001), and VT (5.8% vs 8.5%, P = .02) rates were significantly lower in the flecainide group for population 1. In population 2, adverse event rates were also lower, although not significantly, in the flecainide compared to the class-3 AAD group for mortality (20.9% vs 25.8%, P = .26), HF hospitalization (24.5% vs 26.1%, P = .73), VT (10.9% vs 14.7%, P = .28) and MACE (44.5% vs 49.5%, P = .32). CONCLUSIONS: Flecainide in select patients with stable CAD for AF has a favorable safety profile compared to class-3 AADs. These data suggest the need for prospective trials of flecainide in AF patients with CAD to determine if the current guideline-recommended exclusion is warranted.
Subject(s)
Atrial Fibrillation , Coronary Artery Disease , Anti-Arrhythmia Agents/therapeutic use , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Coronary Artery Disease/complications , Coronary Artery Disease/drug therapy , Flecainide/therapeutic use , Humans , Prospective StudiesABSTRACT
OBJECTIVE: Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD. METHODS: We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories. RESULTS: The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline. INTERPRETATION: The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967-978.
Subject(s)
Muscular Dystrophies, Limb-Girdle/diagnosis , Adolescent , Adult , Age of Onset , Aged , Aged, 80 and over , Child , Clinical Trials as Topic/methods , Cohort Studies , Disease Progression , Female , Humans , Longitudinal Studies , Male , Middle Aged , Muscular Dystrophies, Limb-Girdle/physiopathology , Muscular Dystrophies, Limb-Girdle/psychology , Psychometrics , Treatment Outcome , Young AdultABSTRACT
INTRODUCTION/AIMS: Raman spectroscopy is an emerging technique for the evaluation of muscle disease. In this study we evaluate the ability of in vivo intramuscular Raman spectroscopy to detect the effects of voluntary running in the mdx model of Duchenne muscular dystrophy (DMD). We also compare mdx data with muscle spectra from human DMD patients. METHODS: Thirty 90-day-old mdx mice were randomly allocated to an exercised group (48-hour access to a running wheel) and an unexercised group (n = 15 per group). In vivo Raman spectra were collected from both gastrocnemius muscles and histopathological assessment subsequently performed. Raman data were analyzed using principal component analysis-fed linear discriminant analysis (PCA-LDA). Exercised and unexercised mdx muscle spectra were compared with human DMD samples using cosine similarity. RESULTS: Exercised mice ran an average of 6.5 km over 48 hours, which induced a significant increase in muscle necrosis (P = .03). PCA-LDA scores were significantly different between the exercised and unexercised groups (P < .0001) and correlated significantly with distance run (P = .01). Raman spectra from exercised mice more closely resembled human spectra than those from unexercised mice. DISCUSSION: Raman spectroscopy provides a readout of the biochemical alterations in muscle in both the mdx mouse and human DMD muscle.
Subject(s)
Muscular Dystrophy, Duchenne , Animals , Disease Models, Animal , Humans , Mice , Mice, Inbred C57BL , Mice, Inbred mdx , Muscle, Skeletal/pathology , Muscular Dystrophy, Duchenne/diagnosis , Muscular Dystrophy, Duchenne/pathology , Spectrum Analysis, RamanABSTRACT
INTRODUCTION/AIMS: Myotonic dystrophy type 1 (DM1) is known to affect cognitive function, but the best methods to assess central nervous system involvement in multicenter studies have not been determined. In this study our primary aim was to evaluate the potential of computerized cognitive tests to assess cognition in DM1. METHODS: We conducted a prospective, longitudinal, observational study of 113 adults with DM1 at six sites. Psychomotor speed, attention, working memory, and executive functioning were assessed at baseline, 3 months, and 12 months using computerized cognitive tests. Results were compared with assessments of muscle function and patient reported outcomes (PROs), including the Myotonic Dystrophy Health Index (MDHI) and the 5-dimension EuroQol (EQ-5D-5L) questionnaire. RESULTS: Based on intraclass correlation coefficients, computerized cognitive tests had moderate to good reliability for psychomotor speed (0.76), attention (0.82), working memory speed (0.79), working memory accuracy (0.65), and executive functioning (0.87). Performance at baseline was lowest for working memory accuracy (P < .0001). Executive function performance improved from baseline to 3 months (P < .0001), without further changes over 1 year. There was a moderate correlation between poorer executive function and larger CTG repeat size (r = -0.433). There were some weak associations between PROs and cognitive performance. DISCUSSION: Computerized tests of cognition are feasible in multicenter studies of DM1. Poor performance was exhibited in working memory, which may be a useful variable in clinical trials. Learning effects may have contributed to the improvement in executive functioning. The relationship between PROs and cognitive impairment in DM1 requires further study.
Subject(s)
Myotonic Dystrophy , Adult , Cognition , Computers , Humans , Longitudinal Studies , Myotonic Dystrophy/complications , Myotonic Dystrophy/diagnosis , Prospective Studies , Reproducibility of ResultsABSTRACT
INTRODUCTION/AIMS: There is debate about whether and to what extent either respiratory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed to establish definitively whether dysfunction in either system is part of the dysferlinopathy phenotype. METHODS: As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3-y interval between tests, in 188 genetically confirmed patients aged 11-86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo). RESULTS: Mean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P-wave abnormalities indicative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population. DISCUSSION: These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings.
Subject(s)
Muscular Dystrophies, Limb-Girdle , Electrocardiography , Female , Humans , Longitudinal Studies , Male , Muscular Dystrophies, Limb-Girdle/genetics , PhenotypeABSTRACT
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease in urgent need of disease biomarkers for the assessment of promising therapeutic candidates in clinical trials. Raman spectroscopy is an attractive technique for identifying disease related molecular changes due to its simplicity. Here, we describe a fibre optic fluid cell for undertaking spontaneous Raman spectroscopy studies of human biofluids that is suitable for use away from a standard laboratory setting. Using this system, we examined serum obtained from patients with ALS at their first presentation to our centre (n = 66) and 4 months later (n = 27). We analysed Raman spectra using bounded simplex-structured matrix factorization (BSSMF), a generalisation of non-negative matrix factorisation which uses the distribution of the original data to limit the factorisation modes (spectral patterns). Biomarkers associated with ALS disease such as measures of symptom severity, respiratory function and inflammatory/immune pathways (C3/C-reactive protein) correlated with baseline Raman modes. Between visit spectral changes were highly significant (p = 0.0002) and were related to protein structure. Comparison of Raman data with established ALS biomarkers as a trial outcome measure demonstrated a reduction in required sample size with BSSMF Raman. Our portable, simple to use fibre optic system allied to BSSMF shows promise in the quantification of disease-related changes in ALS over short timescales.
Subject(s)
Amyotrophic Lateral Sclerosis , Neurodegenerative Diseases , Humans , Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/metabolism , Spectrum Analysis, Raman , Biomarkers , C-Reactive ProteinABSTRACT
The diagnosis of muscle disorders ("myopathies") can be challenging and new biomarkers of disease are required to enhance clinical practice and research. Despite advances in areas such as imaging and genomic medicine, muscle biopsy remains an important but time-consuming investigation. Raman spectroscopy is a vibrational spectroscopy application that could provide a rapid analysis of muscle tissue, as it requires no sample preparation and is simple to perform. Here, we investigated the feasibility of using a miniaturised, portable fibre optic Raman system for the rapid identification of muscle disease. Samples were assessed from 27 patients with a final clinico-pathological diagnosis of a myopathy and 17 patients in whom investigations and clinical follow-up excluded myopathy. Multivariate classification techniques achieved accuracies ranging between 71-77%. To explore the potential of Raman spectroscopy to identify different myopathies, patients were subdivided into mitochondrial and non-mitochondrial myopathy groups. Classification accuracies were between 74-89%. Observed spectral changes were related to changes in protein structure. These data indicate fibre optic Raman spectroscopy is a promising technique for the rapid identification of muscle disease that could provide real time diagnostic information. The application of fibre optic Raman technology raises the prospect of in vivo bedside testing for muscle diseases which would significantly streamline the diagnostic pathway of these disorders.