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IMPORTANCE: Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population. OBJECTIVE: To establish an updated natural history of ALSSOD1. DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000. MAIN OUTCOMES AND MEASURES: Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis. RESULTS: Mean age of disease onset was 49.7±12.3â years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7â years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7â years for SOD1A4V. SOD1A4V survival probability (median survival 1.2â years) was significantly decreased compared with SOD1non-A4V (median survival 6.8â years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1A4V compared with SOD1non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4V compared with SOD1non-A4V (p=0.02). CONCLUSIONS AND RELEVANCE: SOD1A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALSSOD1 patient population.
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Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/patología , Ensayos Clínicos como Asunto , Proyectos de Investigación , Superóxido Dismutasa/genética , Adulto , Edad de Inicio , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/fisiopatología , Progresión de la Enfermedad , Humanos , Persona de Mediana Edad , Mutación , Estudios Retrospectivos , Capacidad Vital/fisiologíaRESUMEN
OBJECTIVE: The corticospinal tract (CST) reveals progressive microstructural alterations in ALS measurable by DTI. The aim of this study was to evaluate fractional anisotropy (FA) along the CST as a longitudinal marker of disease progression in ALS. METHODS: The study cohort consisted of 114 patients with ALS and 110 healthy controls from the second prospective, longitudinal, multicentre study of the Canadian ALS Neuroimaging Consortium (CALSNIC-2). DTI and clinical data from a harmonized protocol across 7 centres were collected. Thirty-nine ALS patients and 61 controls completed baseline and two follow-up visits and were included for longitudinal analyses. Whole brain-based spatial statistics and hypothesis-guided tract-of-interest analyses were performed for cross-sectional and longitudinal analyses. RESULTS: FA was reduced at baseline and longitudinally in the CST, mid-corpus callosum (CC), frontal lobe, and other ALS-related tracts, with alterations most evident in the CST and mid-CC. CST and pontine FA correlated with functional impairment (ALSFRS-R), upper motor neuron function, and clinical disease progression rate. Reduction in FA was largely located in the upper CST; however, the longitudinal decline was greatest in the lower CST. Effect sizes were dependent on region, resulting in study group sizes between 17 and 31 per group over a 9-month interval. Cross-sectional effect sizes were maximal in the upper CST; whereas, longitudinal effect sizes were maximal in mid-callosal tracts. CONCLUSIONS: Progressive microstructural alterations in ALS are most prominent in the CST and CC. DTI can provide a biomarker of cerebral degeneration in ALS, with longitudinal changes in white matter demonstrable over a reasonable observation period, with a feasible number of participants, and within a multicentre framework.
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BACKGROUND: Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38ß MAPK) for the treatment of facioscapulohumeral muscular dystrophy. METHODS: We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. FINDINGS: Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. INTERPRETATION: Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. FUNDING: Fulcrum Therapeutics.
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Distrofia Muscular Facioescapulohumeral , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ciclopropanos/efectos adversos , Ciclopropanos/uso terapéutico , Método Doble Ciego , Piridinas/efectos adversos , Piridinas/uso terapéutico , Resultado del TratamientoRESUMEN
Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by motor neuron degeneration. Significant research has begun to establish brain magnetic resonance imaging (MRI) as a potential biomarker to diagnose and monitor the state of the disease. Deep learning has emerged as a prominent class of machine learning algorithms in computer vision and has shown successful applications in various medical image analysis tasks. However, deep learning methods applied to neuroimaging have not achieved superior performance in classifying ALS patients from healthy controls due to insignificant structural changes correlated with pathological features. Thus, a critical challenge in deep models is to identify discriminative features from limited training data. To address this challenge, this study introduces a framework called SF2Former, which leverages the power of the vision transformer architecture to distinguish ALS subjects from the control group by exploiting the long-range relationships among image features. Additionally, spatial and frequency domain information is combined to enhance the network's performance, as MRI scans are initially captured in the frequency domain and then converted to the spatial domain. The proposed framework is trained using a series of consecutive coronal slices and utilizes pre-trained weights from ImageNet through transfer learning. Finally, a majority voting scheme is employed on the coronal slices of each subject to generate the final classification decision. The proposed architecture is extensively evaluated with multi-modal neuroimaging data (i.e., T1-weighted, R2*, FLAIR) using two well-organized versions of the Canadian ALS Neuroimaging Consortium (CALSNIC) multi-center datasets. The experimental results demonstrate the superiority of the proposed strategy in terms of classification accuracy compared to several popular deep learning-based techniques.
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Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Canadá , Imagen por Resonancia Magnética/métodos , Neuroimagen , Encéfalo/diagnóstico por imagen , Encéfalo/patologíaRESUMEN
BACKGROUND: Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis. METHODS: This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed. FINDINGS: Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 [76%] male and 36 [24%] female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 [77%] and 70 [90%], respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (-3·26, 95% CI -4·15 to -2·36 in the arimoclomol group vs -2·26, -3·11 to -1·41 in the placebo group; mean difference -0·99 [95% CI -2·23 to 0·24]; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group. INTERPRETATION: Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design. FUNDING: US Food and Drug Administration Office of Orphan Products Development and Orphazyme.
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Miositis por Cuerpos de Inclusión , Estados Unidos , Adulto , Humanos , Animales , Femenino , Masculino , Ratones , Miositis por Cuerpos de Inclusión/tratamiento farmacológico , Proyectos Piloto , Método Doble Ciego , Progresión de la EnfermedadRESUMEN
Amyotrophic lateral sclerosis (ALS) is an unrelenting progressive neurodegenerative disease causing progressive weakness, ultimately leading to death. Despite aggressive research, the pathways leading to neuronal death are incompletely understood. Riluzole is the only drug clinically proven to enhance survival of ALS patients, but its mechanism of action is not clearly understood. In this article, the proposed pathophysiology of ALS is reviewed including glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, autoimmune mechanisms, protein aggregation, SOD1 accumulation, and neuronal death. Based on these mechanisms, past major ALS drug studies will be reviewed as well as promising current ALS drug studies, focusing on the advancement of these studies from the bench to the patient's bedside.
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/terapia , Antioxidantes/uso terapéutico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Terapia Genética , Humanos , Imidazoles/uso terapéutico , Inmunosupresores/uso terapéutico , Pirazinas/uso terapéutico , Trasplante de Células Madre , Superóxido Dismutasa/biosíntesis , Superóxido Dismutasa/genética , Superóxido Dismutasa-1RESUMEN
In 2011, a pathogenic hexanucleotide repeat expansion in the C9ORF72 gene was discovered to be the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Before this, the C9ORF72 gene and its protein were unknown. The repeat expansion was found to cause both haploinsufficiency and gain of toxicity through aggregating RNA products and dipeptide repeat proteins. A worldwide effort was then initiated to define C9ORF72 ALS/FTD and unravel the pathogenic mechanism for the development of therapeutic options. A decade later, C9ORF72 genetic testing is readily available. There is now an increasing appreciation that C9ORF72 not only is the leading genetic cause of ALS/FTD but may contribute to a spectrum of disorders. This article reviews what is currently known about the C9ORF72 expansion and how C9ORF72 expansion manifests in ALS, FTD, psychiatric disorders, and movement disorders. With therapeutic strategies fast approaching the clinic, earlier recognition of possible C9ORF72 expansion related disorders is even more paramount to improve patient care.
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4-Aminopiridina/análogos & derivados , Enfermedades de la Unión Neuromuscular/tratamiento farmacológico , Producción de Medicamentos sin Interés Comercial , Médicos/psicología , Bloqueadores de los Canales de Potasio/uso terapéutico , 4-Aminopiridina/uso terapéutico , Amifampridina , Humanos , Enfermedades de la Unión Neuromuscular/economía , Producción de Medicamentos sin Interés Comercial/economía , Producción de Medicamentos sin Interés Comercial/métodosRESUMEN
ABSTRACT: We describe an individual with slowly progressive amyotrophic lateral sclerosis who decided to enter the Talisker Whisky Atlantic Challenge, a rowing event across the Atlantic Ocean, and completes it in 51 days in a 5-man boat.
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Esclerosis Amiotrófica Lateral/psicología , Objetivos , Deportes Acuáticos/psicología , Humanos , Masculino , Calidad de VidaRESUMEN
OBJECTIVES: To describe prevalence rates of bowel, bladder, and sudomotor symptoms in patients with amyotrophic lateral sclerosis (ALS) in relation to disease onset and progression. Treatment strategies and efficacies were also assessed. METHODS: A pilot patient cohort revealed increased incidences of bowel/bladder and sudomotor symptoms. Questionnaires derived from formal bowel and bladder survey instruments were administered to a second cohort of patients during multidisciplinary ALS clinic visits. RESULTS: The pilot cohort of 30 patients reported an increase in bowel symptoms from 17% prior to 70% after the diagnosis of ALS, and an increase in urinary symptoms from 24% to 76%. In the second cohort of 66 patients an increase in constipation from 33% prior to 64.7% after the diagnosis of ALS was reported. 25.4% of patients reported bowel urgency initially, which increased to 33.3% over time. Constipation was most commonly treated with docusate, dietary fiber supplementation, fluid/exercise, and polyethylene glycol. In the second cohort the prevalence of overactive bladder symptoms increased from 3.1% prior to 25.0% after the diagnosis of ALS. Urinary symptoms are most commonly treated with catheters and oxybutynin. A sudomotor survey found stinging eyes in 17.2% of patients, oily/greasy skin in 14.1% of patients, and flaking of the skin in 29.7% of patients. CONCLUSIONS: Bowel and bladder symptoms are common in the ALS population and respond to treatment. Sudomotor symptoms are also common. Inquiring about these symptoms at clinic visits and initiating treatment can significantly improve the patients' quality of life.
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Esclerosis Amiotrófica Lateral , Vejiga Urinaria Hiperactiva , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/epidemiología , Estreñimiento/epidemiología , Estreñimiento/etiología , Humanos , Calidad de Vida , Vejiga Urinaria Hiperactiva/diagnóstico , Vejiga Urinaria Hiperactiva/epidemiología , Vejiga Urinaria Hiperactiva/etiologíaRESUMEN
OBJECTIVE: To identify novel disease associated loci for amyotrophic lateral sclerosis (ALS), we utilized sequencing data and performed in vitro and in vivo experiments to demonstrate pathogenicity of mutations identified in TP73. METHODS: We analyzed exome sequences of 87 sporadic ALS patients and 324 controls, with confirmatory sequencing in independent ALS cohorts of >2,800 patients. For the top hit, TP73, a regulator of apoptosis, differentiation, and a binding partner as well as homolog of the tumor suppressor gene TP53, we assayed mutation effects using in vitro and in vivo experiments. C2C12 myoblast differentiation assays, characterization of myotube appearance, and immunoprecipitation of p53-p73 complexes were perform in vitro. In vivo, we used CRISPR/Cas9 targeting of zebrafish tp73 to assay motor neuron number and axon morphology. RESULTS: Five heterozygous rare, nonsynonymous mutations in TP73 were identified in our sporadic ALS cohort. In independent ALS cohorts, we identified an additional 19 rare, deleterious variants in TP73. Patient TP73 mutations caused abnormal differentiation and increased apoptosis in the myoblast differentiation assay, with abnormal myotube appearance. Immunoprecipitation of mutant ΔN-p73 demonstrated that patient mutations hinder ΔN-p73's ability to bind p53. CRISPR/Cas9 knockout of tp73 in zebrafish led to impaired motor neuron development and abnormal axonal morphology, concordant with ALS pathology. CONCLUSION: Together, these results strongly suggest that variants in TP73 correlate with risk for ALS and indicate a novel role for apoptosis in ALS disease pathology.
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OBJECTIVE: Compare driving capacity of individuals with Amyotrophic Lateral Sclerosis (ALS) and healthy controls (HC) using a driving simulation program. METHODS: A prospective study was performed on individuals with ALS who reported they were still driving, and a group of HCs. Demographic data included age and gender. Assessment included cognitive assessments (Montreal cognitive assessment [MoCA] and ALS Cognitive Behavioral Scale [ALS-CBS]); gait speed (m/s); ALS Functional Rating Scale-revised total score (ALSFRS-R); and simulated driving assessment (Lane Change Task [LCT]). The LCT is a simple assessment tool which simulates the visual, cognitive, and motor demands of driving to detect at-risk drivers and uses distractions (secondary tasks) to quantify the performance loss on the primary task (lane changes). RESULTS: Twenty-eight individuals with ALS (22 males, mean age 64 years) and 20 HCs (7 males, mean age 59 years) were studied. Individuals with mild to moderate ALS (ALSFRS-R mean 36.2) were older, had mild cognitive difficulty (MoCA 24 vs 27; ALS-CBS 14.19 [SD 3.85]) and mobility decline (gait speed 1.1 vs 1.4 m/s) compared to HC. Driving assessment using the LCT found no differences in baseline scores or during motor, cognitive, or visually distracting conditions. CONCLUSIONS: Individuals with ALS with mild to moderate disease progression, with cognitive and motor weakness still demonstrate similar driving capacity to HCs using a driving simulation task. Driving assessment needs to be expanded longitudinally and perhaps with more robust measures to more precisely identify types of driving challenges that lead to cessation of driving in individuals with ALS.
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Esclerosis Amiotrófica Lateral , Conducción de Automóvil , Esclerosis Amiotrófica Lateral/complicaciones , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Importance: Many patients with generalized myasthenia gravis (gMG) have substantial clinical disability, persistent disease burden, and adverse effects attributable to chronic immunosuppression. Therefore, there is a significant need for targeted, well-tolerated therapies with the potential to improve disease control and enhance quality of life. Objective: To evaluate the clinical effects of zilucoplan, a subcutaneously (SC) self-administered macrocyclic peptide inhibitor of complement component 5, in a broad population of patients with moderate to severe gMG. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 2 clinical trial at 25 study sites across North America recruited participants between December 2017 and August 2018. Fifty-seven patients were screened, of whom 12 did not meet inclusion criteria and 1 was lost to follow-up after randomization but before receiving study drug, resulting in a total of 44 acetylcholine receptor autoantibody (AChR-Ab)-positive patients with gMG with baseline Quantitative Myasthenia Gravis (QMG) scores of at least 12, regardless of treatment history. Interventions: Patients were randomized 1:1:1 to a daily SC self-injection of placebo, 0.1-mg/kg zilucoplan, or 0.3-mg/kg zilucoplan for 12 weeks. Main Outcomes and Measures: The primary and key secondary end points were the change from baseline to week 12 in QMG and MG Activities of Daily Living scores, respectively. Significance testing was prespecified at a 1-sided α of .10. Safety and tolerability were also assessed. Results: The study of 44 patients was well balanced across the 3 treatment arms with respect to key demographic and disease-specific variables. The mean age of patients across all 3 treatment groups ranged from 45.5 to 54.6 years and most patients were white (average proportions across 3 treatment groups: 78.6%-86.7%). Clinically meaningful and statistically significant improvements in primary and key secondary efficacy end points were observed. Zilucoplan at a dose of 0.3 mg/kg SC daily resulted in a mean reduction from baseline of 6.0 points in the QMG score (placebo-corrected change, -2.8; P = .05) and 3.4 points in the MG Activities of Daily Living score (placebo-corrected change, -2.3; P = .04). Clinically meaningful and statistically significant improvements were also observed in other secondary end points, the MG Composite and MG Quality-of-Life scores. Outcomes for the 0.1-mg/kg SC daily dose were also statistically significant but slower in onset and less pronounced than with the 0.3-mg/kg dose. Rescue therapy (intravenous immunoglobulin or plasma exchange) was required in 3 of 15, 1 of 15, and 0 of 14 participants in the placebo, 0.1-mg/kg zilucoplan, and 0.3-mg/kg zilucoplan arms, respectively. Zilucoplan was observed to have a favorable safety and tolerability profile. Conclusions and Relevance: Zilucoplan yielded rapid, meaningful, and sustained improvements over 12 weeks in a broad population of patients with moderate to severe AChR-Ab-positive gMG. Near-complete complement inhibition appeared superior to submaximal inhibition. The observed safety and tolerability profile of zilucoplan was favorable. Trial Registration: ClinicalTrials.gov Identifier: NCT03315130.
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Complemento C5/antagonistas & inhibidores , Inactivadores del Complemento/administración & dosificación , Miastenia Gravis/tratamiento farmacológico , Método Doble Ciego , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , AutoadministraciónRESUMEN
OBJECTIVE: To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity. METHODS: Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls. RESULTS: Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls. CONCLUSIONS: Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates.
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Esclerosis Amiotrófica Lateral/genética , Predisposición Genética a la Enfermedad , Adulto , Ataxina-2/genética , Proteína C9orf72 , Estudios de Cohortes , Expansión de las Repeticiones de ADN , Exoma , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Modelos Genéticos , Oportunidad Relativa , Análisis de Componente Principal , Proteínas/genética , Análisis de Secuencia de ADN , Población Blanca/genéticaRESUMEN
OBJECTIVE: To estimate the risks for cancer (overall and site-specific) in an amyotrophic lateral sclerosis (ALS) cohort. METHODS: In this observational longitudinal study, ALS and cancer cases were identified in a computerized Utah genealogy database (Utah Population Database) linked to a statewide cancer registry and death certificates. Hazard ratios (HRs) were estimated as the ratio of observed to expected number of cancers. Site-specific rates for cancer were estimated within the Utah Population Database; sex, birth year (5-year range), and birth state (Utah or not) cohorts were used to estimate the expected number of cancers among ALS cases. To account for an overall shortened lifespan, Cox regression was used to include years at risk in estimation of cancer risks for ALS cases. RESULTS: An overall decreased hazard (hazard ratio [HR] 0.80, p = 0.014, 95% confidence interval [CI] 0.66-0.96) was found for cancer of any site in 1,081 deceased patients with ALS. A decreased hazard was found for lung cancer (HR 0.23, p = 0.002, CI 0.05-0.63). An increased hazard was found for salivary (HR 5.27, p = 0.041, 95% CI 1.09-15.40) and testicular (HR 3.82, p = 0.042, 95% CI 1.06-9.62) cancers. A nonsignificant hazard was observed for cutaneous malignant melanoma (HR 1.62, p = 0.12, 95% CI 0.88-2.71) for which increased risk has previously been reported. CONCLUSIONS: Using a unique population database, the overall risk of cancer of any site was found to be significantly reduced in cases with ALS, as was the risk of lung cancer. Significantly increased risk was observed for salivary and testicular cancers.
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Esclerosis Amiotrófica Lateral/epidemiología , Neoplasias/epidemiología , Anciano , Comorbilidad , Bases de Datos Factuales , Femenino , Humanos , Estudios Longitudinales , Masculino , Modelos de Riesgos Proporcionales , Factores de Riesgo , Utah/epidemiologíaRESUMEN
Our objective was to explore if creatine kinase (CK) levels correlate with survival in amyotrophic lateral sclerosis (ALS), and whether a correlation is independent of other well-studied predictors such as location of onset, gender, age, fat free mass, spasticity, cramps, and fasciculations. We analyzed data from 80 ALS patients from a 48-week non-interventional longitudinal multicenter nutrition study with long term follow-up. The overall mean CK was 214 ± 191.8 U/l (range 22-1992 U/l). Forty-five percent of patients had at least one high CK value (> 200 U/l), and about half maintained a high CK value, but there was no trend over the study period. Male gender and extremity onset were significantly associated with high CK. In univariate analysis, age, bioelectric impedance spectroscopy (BIS) fat free mass, spasticity, and fasciculations were not associated with CK level. There was an association between CK and muscle cramps (p < 0.001). In survival analysis, low CK (≤ 200 U/l) was associated with a longer overall survival (p = 0.02), when adjusting for location of onset, age, race, gender, BIS fat free mass, and study site. In conclusion, CK may be a useful marker for ALS survival, which has implications for clinical care and the design of future clinical trials.
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Esclerosis Amiotrófica Lateral/sangre , Composición Corporal , Creatina Quinasa/sangre , Fasciculación/sangre , Calambre Muscular/sangre , Espasticidad Muscular/sangre , Adulto , Anciano , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/mortalidad , Esclerosis Amiotrófica Lateral/fisiopatología , Biomarcadores/sangre , Progresión de la Enfermedad , Impedancia Eléctrica , Fasciculación/etiología , Fasciculación/fisiopatología , Femenino , Humanos , Estimación de Kaplan-Meier , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Calambre Muscular/etiología , Calambre Muscular/fisiopatología , Espasticidad Muscular/etiología , Espasticidad Muscular/fisiopatología , Pronóstico , Factores Sexuales , Adulto JovenRESUMEN
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.
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Esclerosis Amiotrófica Lateral/genética , Autofagia/genética , Exoma/genética , Predisposición Genética a la Enfermedad , Proteínas Serina-Treonina Quinasas/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Ciclo Celular , Femenino , Genes , Estudios de Asociación Genética , Humanos , Masculino , Proteínas de Transporte de Membrana , Persona de Mediana Edad , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Riesgo , Análisis de Secuencia de ADN , Proteína Sequestosoma-1 , Factor de Transcripción TFIIIA/genética , Factor de Transcripción TFIIIA/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: To determine the extent of an inherited contribution to amyotrophic lateral sclerosis (ALS) mortality. METHODS: Death certificates (DCs) from 1904 to 2009 were analyzed from patients with at least 3 generations recorded in the Utah Population Database, a genealogic and medical database of more than 2 million Utah residents. Among probands whose DCs listed ALS, the relative risk (RR) of death with ALS was determined among spouses and first- through fifth-degree relatives, using birth year-, sex-, and birthplace-matched cohorts. RESULTS: Eight hundred seventy-three patients with ALS met the inclusion criteria. Among 3,531 deceased first-degree relatives of probands, the RR of dying with ALS was increased compared with control cohorts (RR = 4.91, 95% confidence interval 3.36, 6.94). The RR of dying with ALS was also increased among 9,386 deceased second-degree relatives (RR = 2.85, 95% confidence interval 2.06, 3.84). The RR of dying with ALS was not increased among third- through fifth-degree relatives. More affected first-degree relatives were male (p = 0.014). No cases of conjugal ALS were observed. CONCLUSIONS: This study is suggestive of familial clustering in excess of expected for ALS. Our results confirm the results of prior studies of familial ALS, suggesting applicability of our findings to other mixed European populations. Furthermore, this work expands on previous studies by quantifying the RR of ALS among more distant relatives. The use of mortality data obtained from DCs reduces the ascertainment and recall bias of many previous studies. Finally, the excess of ALS among second-degree relatives and lack of conjugal ALS are strongly supportive of a genetic contribution.
Asunto(s)
Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/genética , Bases de Datos Factuales/tendencias , Vigilancia de la Población/métodos , Anciano , Análisis por Conglomerados , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Utah/epidemiologíaRESUMEN
Acute viral myositis is a rare condition that occurs during the recovery phase of an illness, most commonly influenza. It is characterized by muscle pain and weakness with an isolated laboratory finding of elevated serum creatine kinase (CK). We describe three previously healthy patients who were hospitalized after developing myositis following influenza-like illness during the 2009 influenza A (H1N1) virus pandemic. All experienced myalgias and weakness in all four extremities, including distal upper extremities, associated with an elevated CK level that resolved along with their myalgias and weakness within one week with supportive care. These cases serve as a reminder that influenza-related myositis may have atypical characteristics depending on the strain of influenza, and clinicians should be open to this possibility when new outbreaks occur.