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The Lancet. Neurology Jan 2018The disease course of amyotrophic lateral sclerosis (ALS) is rapid and, because its pathophysiology is unclear, few effective treatments are available. Genetic research... (Review)
Review
BACKGROUND
The disease course of amyotrophic lateral sclerosis (ALS) is rapid and, because its pathophysiology is unclear, few effective treatments are available. Genetic research aims to understand the underlying mechanisms of ALS and identify potential therapeutic targets. The first gene associated with ALS was SOD1, identified in 1993 and, by early 2014, more than 20 genes had been identified as causative of, or highly associated with, ALS. These genetic discoveries have identified key disease pathways that are therapeutically testable and could potentially lead to the development of better treatments for people with ALS.
RECENT DEVELOPMENTS
Since 2014, seven additional genes have been associated with ALS (MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF), all of which were identified by genome-wide association studies, whole genome studies, or exome sequencing technologies. Each of the seven novel genes code for proteins associated with one or more molecular pathways known to be involved in ALS. These pathways include dysfunction in global protein homoeostasis resulting from abnormal protein aggregation or a defect in the protein clearance pathway, mitochondrial dysfunction, altered RNA metabolism, impaired cytoskeletal integrity, altered axonal transport dynamics, and DNA damage accumulation due to defective DNA repair. Because these novel genes share common disease pathways with other genes implicated in ALS, therapeutics targeting these pathways could be useful for a broad group of patients stratified by genotype. However, the effects of these novel genes have not yet been investigated in animal models, which will be a key step to translating these findings into clinical practice. WHERE NEXT?: The identification of these seven novel genes has been important in unravelling the molecular mechanisms underlying ALS. However, our understanding of what causes ALS is not complete, and further genetic research will provide additional detail about its causes. Increased genetic knowledge will also identify potential therapeutic targets and could lead to the development of individualised medicine for patients with ALS. These developments will have a direct effect on clinical practice when genome sequencing becomes a routine and integral part of disease diagnosis and management.
Topics: Amyotrophic Lateral Sclerosis; Humans
PubMed: 29154141
DOI: 10.1016/S1474-4422(17)30401-5 -
The Lancet. Neurology Feb 2019Neuroinflammation is a common pathological feature of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and is characterised by activated... (Review)
Review
Neuroinflammation is a common pathological feature of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and is characterised by activated CNS microglia and astroglia, proinflammatory peripheral lymphocytes, and macrophages. Data from clinical studies show that multiple genetic mutations linked to ALS (eg, mutations in SOD1, TARDBP, and C9orf72) enhance this neuroinflammation, which provides compelling evidence for immune dysregulation in the pathogenesis of ALS. Transgenic rodent models expressing these mutations induce an ALS-like disease with accompanying inflammatory responses, confirming the immune system's involvement in disease progression. Even in the absence of known genetic alterations, immune dysregulation has been shown to lead to dysfunctional regulatory T lymphocytes and increased proinflammatory macrophages in clinical studies. Therefore, an improved understanding of the biological processes that induce this immune dysregulation will help to identify therapeutic strategies that circumvent or ameliorate the pathogenesis of ALS. Emerging cell-based therapies hold the promise of accomplishing this goal and, therefore, improving quality of life and extending survival in patients with ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Humans
PubMed: 30663610
DOI: 10.1016/S1474-4422(18)30394-6 -
Journal of Pain & Palliative Care... Mar 2015Questions from patients about pain conditions, analgesic pharmacotherapy, and responses from authors are presented to help educate patients and make them more effective...
Questions from patients about pain conditions, analgesic pharmacotherapy, and responses from authors are presented to help educate patients and make them more effective self-advocates. In reply to a question about benign fasciculation syndrome, the presentation, causes, treatment, and chances of developing amyotrophic lateral sclerosis will be discussed.
Topics: Amyotrophic Lateral Sclerosis; Fasciculation; Humans; Syndrome
PubMed: 25700216
DOI: 10.3109/15360288.2014.997856 -
Mayo Clinic Proceedings Nov 2018Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons and other neuronal cells, leading to severe disability and eventually death... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons and other neuronal cells, leading to severe disability and eventually death from ventilatory failure. It has a prevalence of 5 in 100,000, with an incidence of 1.7 per 100,000, reflecting short average survival. The pathogenesis is incompletely understood, but defects of RNA processing and protein clearance may be fundamental. Repeat expansions in the chromosome 9 open reading frame 72 gene (C9orf72) are the most common known genetic cause of ALS and are seen in approximately 40% of patients with a family history and approximately 10% of those without. No environmental risk factors are proved to be causative, but many have been proposed, including military service. The diagnosis of ALS rests on a history of painless progressive weakness coupled with examination findings of upper and lower motor dysfunction. No diagnostic test is yet available, but electromyography and genetic tests can support the diagnosis. Care for patients is best provided by a multidisciplinary team, and most interventions are directed at managing symptoms. Two medications with modest benefits have Food and Drug Administration approval for the treatment of ALS: riluzole, a glutamate receptor antagonist, and, new in 2017, edaravone, a free radical scavenger. Many other encouraging treatment strategies are being explored in clinical trials for ALS; herein we review stem cell and antisense oligonucleotide gene therapies.
Topics: Amyotrophic Lateral Sclerosis; C9orf72 Protein; Diagnosis, Differential; Edaravone; Female; Humans; Male; Mesenchymal Stem Cell Transplantation; Neuroprotective Agents; Riluzole
PubMed: 30401437
DOI: 10.1016/j.mayocp.2018.04.007 -
Continuum (Minneapolis, Minn.) Oct 2020This article reviews the clinical features, diagnostic approach, and treatments available for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. The... (Review)
Review
PURPOSE OF REVIEW
This article reviews the clinical features, diagnostic approach, and treatments available for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. The article also provides an update on the genetics and pathophysiology of ALS.
RECENT FINDINGS
ALS remains a clinical diagnosis without a unique biomarker. The areas of greatest progress include a large expansion in the number of genes associated with familial and sporadic ALS. The discovery of these genes, along with other work, has provided a deeper understanding of the mechanisms of motor neuron failure in ALS. Areas of particular interest include the role of transactive response DNA-binding protein 43 and other RNA-processing proteins in the development of disease.
SUMMARY
ALS remains a relentlessly progressive disorder with an elusive core pathophysiology. The current mainstay of treatment remains symptom management and palliation, particularly in the setting of a multidisciplinary clinic. The future holds potential for targeted therapies based on an ever-evolving understanding of the pathophysiology of both familial and sporadic ALS.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Female; Humans; Male; Middle Aged; Motor Neuron Disease; Young Adult
PubMed: 33003004
DOI: 10.1212/CON.0000000000000911 -
The Lancet. Neurology Oct 2016Amyotrophic lateral sclerosis is a progressive adult-onset neurodegenerative disease that primarily affects upper and lower motor neurons, but also frontotemporal and... (Review)
Review
Amyotrophic lateral sclerosis is a progressive adult-onset neurodegenerative disease that primarily affects upper and lower motor neurons, but also frontotemporal and other regions of the brain. The extent to which each neuronal population is affected varies between individuals. The subsequent patterns of disease progression form the basis of diagnostic criteria and phenotypic classification systems, with considerable overlap in the clinical terms used. This overlap can lead to confusion between diagnosis and phenotype. Formal classification systems such as the El Escorial criteria and the International Classification of Diseases are systematic approaches but they omit features that are important in clinical management, such as rate of progression, genetic basis, or functional effect. Therefore, many neurologists use informal classification approaches that might not be systematic, and could include, for example, anatomical descriptions such as flail-arm syndrome. A new strategy is needed to combine the benefits of a systematic approach to classification with the rich and varied phenotypic descriptions used in clinical practice.
Topics: Amyotrophic Lateral Sclerosis; Humans
PubMed: 27647646
DOI: 10.1016/S1474-4422(16)30199-5 -
International Journal of Molecular... Jun 2019Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness and incessant disease progression. While the presence of concomitant upper and lower motor neuron signs has been recognized as a pathognomonic feature of ALS, the pathogenic importance of upper motor neuron dysfunction has only been recently described. Specifically, transcranial magnetic stimulation (TMS) techniques have established cortical hyperexcitability as an important pathogenic mechanism in ALS, correlating with neurodegeneration and disease spread. Separately, ALS exhibits a heterogeneous clinical phenotype that may lead to misdiagnosis, particularly in the early stages of the disease process. Cortical hyperexcitability was shown to be a robust diagnostic biomarker if ALS, reliably differentiating ALS from neuromuscular mimicking disorders. The present review will provide an overview of key advances in the understanding of ALS pathophysiology and diagnosis, focusing on the importance of cortical hyperexcitability and its relationship to advances in genetic and molecular processes implicated in ALS pathogenesis.
Topics: Amyotrophic Lateral Sclerosis; Cortical Excitability; Electroencephalography; Humans; Transcranial Magnetic Stimulation
PubMed: 31185581
DOI: 10.3390/ijms20112818 -
Advances in Experimental Medicine and... 2020Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, characterized by inevitable progressive paralysis. To date, only two disease... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, characterized by inevitable progressive paralysis. To date, only two disease modifying therapeutic options are available for the patients with ALS, although they show very modest effect on disease course. The main reason of failure in the field of pharmacological correction of ALS is inability to untangle complex relationships taking place during ALS initiation and progression. Traditional methods of research, based on morphology or transgenic animal models studying provided lots of information about ALS throughout the years. However, translation of these results to humans was unsuccessful due to incomplete recapitulation of molecular pathology and overall inadequacy of the models used in the research.In this review we summarize current knowledge regarding ALS molecular pathology with depiction of novel methods applied recently for the studies. Furthermore we describe present and potential treatment strategies that are based on the recent findings in ALS disease mechanisms.
Topics: Amyotrophic Lateral Sclerosis; Animals; Biomedical Research; Disease Progression; Humans
PubMed: 32383122
DOI: 10.1007/978-3-030-41283-8_11 -
Atencion Primaria Dec 2021Amyotrophic Lateral Sclerosis (ALS) is a rare disease in primary care (PC), it represents a challenge for the family doctor, especially in home care. (Observational Study)
Observational Study
UNLABELLED
Amyotrophic Lateral Sclerosis (ALS) is a rare disease in primary care (PC), it represents a challenge for the family doctor, especially in home care.
OBJECTIVE
To know the incidence and prevalence of ALS in an area of ??PA management, the clinical characteristics and use of health resources.
DESIGN
Observational study.
LOCATION
PC-Direction Costa de Ponent, South Metropolitan Health Region, Barcelona, Catalonia, Spain.
PARTICIPANTS
Patients with ALS ≥18 years diagnosed until 03/01/2017. Main measurements Age, sex, characteristics: form of appearance (spinal, bulbar, others), interval between onset of symptoms and diagnosis, percutaneous gastrostomy carriers, ventilation non-invasive or invasive. Identification in PC as a Complex Chronic Patient or with palliative needs (CCP). Inclusion in home care programs (PAD). Model of attention hospitable.
RESULTS
81 patients, mean age 65.6 years (± 11.7), men 49.4%. Shape of onset: spinal 69%, bulbar 21%, another 4%. Interval between the onset of symptoms and diagnosis 12 months. Identified as a CCP 13.6%, 29 patients (35.8%) included in PAD. Attended in comprehensive hospital model 79 patients (97.5%). Prevalence 6.1/100,000 inhabitants in 2017. Annual incidence between 1.2 cases/100,000 inhabitants/year in 2012 and 3.5 cases/100,000 inhabitants/year in 2016.
CONCLUSIONS
The use of percutaneous gastrostomy in ALS favors the identification as CCP or with palliative needs and inclusion in PAD. The use of non-invasive ventilation favors inclusion in PAD. The incidence and prevalence data for ALS are higher than those described above in the same area. Early identification is necessary of these patients in the chronic care models in PC teams.
Topics: Aged; Amyotrophic Lateral Sclerosis; Female; Home Care Services; Humans; Male; Middle Aged; Primary Health Care; Spain
PubMed: 34509895
DOI: 10.1016/j.aprim.2021.102158 -
Nature Oct 2017
Topics: Amyotrophic Lateral Sclerosis; C9orf72 Protein; Clinical Trials as Topic; Fund Raising; Gene-Environment Interaction; Genetic Therapy; Humans; Male
PubMed: 29045369
DOI: 10.1038/550S105a