scholarly journals Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

2015 ◽  
Vol 112 (26) ◽  
pp. 8100-8105 ◽  
Author(s):  
James C. Dodge ◽  
Christopher M. Treleaven ◽  
Joshua Pacheco ◽  
Samantha Cooper ◽  
Channa Bao ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Drug Targets ◽  
Muscular Atrophy ◽  
Neuromuscular Diseases ◽  
Sensory Neuropathy ◽  
Disease Course ◽  
Hereditary Sensory Neuropathy ◽  
Als Patients ◽  
Lateral Sclerosis

Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, α-galactosidase, and β-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1G93A mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets.

scholarly journals Utility of Transcranial Magnetic Simulation in Studying Upper Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (7) ◽  
pp. 906
Author(s):  
Nimeshan Geevasinga ◽  
Mehdi Van den Bos ◽  
Parvathi Menon ◽  
Steve Vucic
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cortical Excitability ◽  
Muscular Atrophy ◽  
Close Relationship ◽  
Bulbar Onset ◽  
Als Patients ◽  
Transcranial Magnetic Simulation ◽  
Cortical Dysfunction ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterised by progressive dysfunction of the upper and lower motor neurons. The disease can evolve over time from focal limb or bulbar onset to involvement of other regions. There is some clinical heterogeneity in ALS with various phenotypes of the disease described, from primary lateral sclerosis, progressive muscular atrophy and flail arm/leg phenotypes. Whilst the majority of ALS patients are sporadic in nature, recent advances have highlighted genetic forms of the disease. Given the close relationship between ALS and frontotemporal dementia, the importance of cortical dysfunction has gained prominence. Transcranial magnetic stimulation (TMS) is a noninvasive neurophysiological tool to explore the function of the motor cortex and thereby cortical excitability. In this review, we highlight the utility of TMS and explore cortical excitability in ALS diagnosis, pathogenesis and insights gained from genetic and variant forms of the disease.

scholarly journals Motor Unit Number Estimation in Neuromuscular Disease

2008 ◽  
Vol 35 (2) ◽  
pp. 153-159 ◽  
Author(s):  
Omid Rashidipour ◽  
K. Ming Chan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Unit ◽  
Neuromuscular Disease ◽  
Muscular Atrophy ◽  
Neuromuscular Diseases ◽  
Neuronal Loss ◽  
Response To Treatment ◽  
Motor Unit Number Estimation ◽  
Electrophysiological Method ◽  
Lateral Sclerosis

Motor unit number estimation (MUNE) is an electrophysiological method designed to quantify motor unit loss in target muscles of interest. Most of the techniques are noninvasive and are therefore well suited for longitudinal monitoring. In this brief review, we describe the more commonly used techniques and their applications in amyotrophic lateral sclerosis, poliomyelitis, spinal muscular atrophy and hereditary sensorimotor neuropathies. Findings in some of these studies offer important pathophysiological insights. Since conventional electrophysiologic methods are not sensible measures of motor neuronal loss, MUNE could play a potentially important role in the diagnosis, monitoring of disease progression and response to treatment in neuromuscular diseases in which motor unit loss is a major feature.

scholarly journals Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

2021 ◽  
Vol 8 (1) ◽  
pp. 25-38
Author(s):  
Marisa Cappella ◽  
Pierre-François Pradat ◽  
Giorgia Querin ◽  
Maria Grazia Biferi
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscular Atrophy ◽  
Monogenic Disease ◽  
Sporadic Als ◽  
Pathological Mechanism ◽  
Huge Impact ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease’s pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes clinical use of antisense oligonucleotides in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively.. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.

scholarly journals Transcriptional activator TAp63 is upregulated in muscular atrophy during ALS and induces the pro-atrophic ubiquitin ligase Trim63

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yannick von Grabowiecki ◽  
Paula Abreu ◽  
Orphee Blanchard ◽  
Lavinia Palamiuc ◽  
Samir Benosman ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Muscle Atrophy ◽  
Ubiquitin Ligase ◽  
Target Genes ◽  
Muscular Atrophy ◽  
Common Denominator ◽  
P53 Family ◽  
Protein Levels ◽  
Als Patients ◽  
Lateral Sclerosis

Mechanisms of muscle atrophy are complex and their understanding might help finding therapeutic solutions for pathologies such as amyotrophic lateral sclerosis (ALS). We meta-analyzed transcriptomic experiments of muscles of ALS patients and mouse models, uncovering a p53 deregulation as common denominator. We then characterized the induction of several p53 family members (p53, p63, p73) and a correlation between the levels of p53 family target genes and the severity of muscle atrophy in ALS patients and mice. In particular, we observed increased p63 protein levels in the fibers of atrophic muscles via denervation-dependent and -independent mechanisms. At a functional level, we demonstrated that TAp63 and p53 transactivate the promoter and increased the expression of Trim63 (MuRF1), an effector of muscle atrophy. Altogether, these results suggest a novel function for p63 as a contributor to muscular atrophic processes via the regulation of multiple genes, including the muscle atrophy gene Trim63.

Electrophysiological Characterization of C9ORF72-Associated Amyotrophic Lateral Sclerosis: A Retrospective Study

2019 ◽  
Vol 82 (4-6) ◽  
pp. 106-112 ◽  
Author(s):  
Antoine Pegat ◽  
Françoise Bouhour ◽  
Kevin Mouzat ◽  
Christophe Vial ◽  
Benoit Pegat ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Sensory Neuropathy ◽  
Mean Values ◽  
Cognitive Domains ◽  
Sensory Conduction ◽  
Significant Difference ◽  
The Mean ◽  
Electrophysiological Characterization ◽  
Als Patients ◽  
Lateral Sclerosis

Objective: C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS). The aim of the present study was to determine whether C9ORF72-associated ALS (C9-ALS) patients present distinctive electrophysiological characteristics that could differentiate them from non C9ORF72-associated ALS (nonC9-ALS) patients. Methods: Clinical and electrodiagnostic data from C9-ALS patients and nonC9-ALS patients were collected retrospectively. For electroneuromyography, the mean values of motor conduction, myography, and the mean values of sensory conduction were considered. Furthermore, the proportion of ALS patients with electrophysiological sensory neuropathy was determined. Results: No significant difference was observed between 31 C9-ALS patients and 22 nonC9-ALS patients for mean motor conduction and myography. For sensory conduction analyses, mean sensory conduction was not significantly different between both groups. In total, 38% of ­C9-ALS patient and 21% of nonC9-ALS patients presented electrophysiological sensory neuropathy (p = 0.33). In ­C9-ALS patients with electrophysiological sensory neuropathy, 80% (8/10) were male and 67% (6/9) presented spinal onset compare to 25% (4/16, p = 0.014) male and 25% (4/16, p = 0.087) with spinal onset in those without electrophysiological sensory neuropathy. Conclusion: Although not different from nonC9-ALS, these results suggest that sensory involvement is a frequent feature of C9-ALS patients, expanding the phenotype of the disease beyond the motor and cognitive domains.

scholarly journals Amyotrophic Lateral Sclerosis After Exposure to Manganese from Traditional Medicine Procedures in Kenya

2020 ◽  
Author(s):  
Elin Roos ◽  
Sebastian K.T.S. Wärmländer ◽  
Jeremy Meyer ◽  
Sabrina B. Sholts ◽  
Jüri Jarvet ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Muscular Atrophy ◽  
Systemic Exposure ◽  
Medical Procedure ◽  
Manganese Neurotoxicity ◽  
Causative Relationship ◽  
Genetic And Environmental Factors ◽  
Exposure Routes ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss and widespread muscular atrophy. Despite intensive investigations on genetic and environmental factors, the cause of ALS remains unknown. Recent data suggest a role for metal exposures in ALS causation. In this study we present a patient who developed ALS after a traditional medical procedure in Kenya. The procedure involved insertion of a black metal powder into several subcutaneous cuts in the lower back. Four months later, general muscle weakness developed. Clinical and electrophysiological examinations detected widespread denervation consistent with ALS. The patient died from respiratory failure less than a year after the procedure. Scanning electron microscopy and X-ray diffraction analyses identified the black powder as potassium permanganate (KMnO4). A causative relationship between the systemic exposure to KMnO4 and ALS development can be suspected, especially as manganese is a well-known neurotoxicant previously found to be elevated in cerebrospinal fluid from ALS patients. Manganese neurotoxicity and exposure routes conveying this toxicity deserve further attention.

scholarly journals Circulating miR-181a-5p is a prognostic biomarker for amyotrophic lateral sclerosis

2019 ◽  
Author(s):  
Iddo Magen ◽  
Anna Coenen-Stass ◽  
Nancy Yacovzada ◽  
Julian Grosskreutz ◽  
Ching-Hua Lu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Plasma Levels ◽  
Disease Course ◽  
Fold Reduction ◽  
System Variability ◽  
Als Patients ◽  
Clinical Phenotyping ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative disease affecting the motor neuron system. Variability in the rate of disease progression has limited the effectiveness of ALS clinical trials. Thus, better outcome measures are desperately needed in order to achieve therapeutic progress. Here, we investigate the potential of plasma cell-free microRNAs as biomarkers to predict ALS progression. We apply an unbiased high-throughput approach to define miRNA levels in a large cohort of ALS patients. Crucially, we conduct our analysis also on longitudinal samples reflecting disease progression, and are able to integrate detailed clinical phenotyping in our analysis. We find miR-181a-5p levels to be stable throughout the disease course and demonstrate that high miR-181a-5p plasma levels predict shortened survival in ALS patients, with a 2.5 fold reduction in median survival for patients with high miR-181a-5p plasma levels. We replicated this finding in an independent validation cohort, where an eight-fold (×8) difference in miR-181a-5p levels between the two prognosis subgroups was robustly measurable by quantitative real time PCR. In conclusion, miR-181a-5p plasma levels can predict disease course in ALS, identifying it as a novel biomarker for patient stratification with the potential to greatly enhance the effectiveness of clinical trials.One Sentence Summaryhigher plasma miR-181a-5p levels increase mortality risk in ALS patients.

scholarly journals Role of the nigrosome 1 absence as a biomarker in amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
María Isabel Moreno-Gambín ◽  
José I. Tembl ◽  
Miguel Mazón ◽  
Antonio José Cañada-Martínez ◽  
Luis Martí-Bonmatí ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Substantia Nigra ◽  
Muscular Atrophy ◽  
Brain Mri ◽  
Transcranial Sonography ◽  
Male Sex ◽  
Als Patients ◽  
Independent Marker ◽  
Lateral Sclerosis

Abstract Introduction The absence of nigrosome 1 on brain MRI and the hyperechogenicity of substantia nigra (SNh) by transcranial sonography are two useful biomarkers in the diagnosis of parkinsonisms. We aimed to evaluate the absence of nigrosome 1 in amyotrophic lateral sclerosis (ALS) and to address its meaning. Methods 136 ALS patients were recruited, including 16 progressive muscular atrophy (PMA) and 22 primary lateral sclerosis (PLS) patients. The SNh area was measured planimetrically by standard protocols. The nigrosome 1 status was qualitatively assessed by two blind evaluators in susceptibility weight images of 3T MRI. Demographic and clinical data were collected and the C9ORF72 expansion was tested in all patients. Results Nigrosome 1 was absent in 30% of ALS patients (36% of PLS, 29% of classical ALS and 19% of PMA patients). There was no relationship between radiological and clinical laterality, nor between nigrosome 1 and SNh area. Male sex (OR = 3.63 [1.51, 9.38], p = 0.005) and a higher upper motor neuron (UMN) score (OR = 1.10 [1.02, 1.2], p = 0.022) were independently associated to nigrosome 1 absence, which also was an independent marker of poor survival (HR = 1.79 [1.3, 2.8], p = 0.013). Conclusion In ALS patients, the absence of nigrosome 1 is associated with male sex, UMN impairment and shorter survival. This suggests that constitutional factors and the degree of pyramidal involvement are related to the substantia nigra involvement in ALS. Thus, nigrosome 1 could be a marker of a multisystem degeneration, which in turn associates to poor prognosis.

scholarly journals Cognitive Performance of Patients with Adult 5q-Spinal Muscular Atrophy and with Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 11 (1) ◽  
pp. 8
Author(s):  
Alma Osmanovic ◽  
Gary Wieselmann ◽  
Lucas Mix ◽  
Hannah Alexandra Siegler ◽  
Mareike Kumpe ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cognitive Function ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Disease Onset ◽  
Vocabulary Test ◽  
Cross Sectional ◽  
Physical Handicap ◽  
Als Patients ◽  
Lateral Sclerosis

Motor neuron diseases, such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), share several clinical similarities while differing substantially in etiology, disease onset and progression. Cognitive dysfunction, a clinically relevant non-motor feature in a substantial proportion of ALS patients, has been less frequently investigated in SMA. In this prospective multicenter cross-sectional study, cognitive function was assessed by the Edinburgh Cognitive (and Behavioural) ALS Screen (ECAS) and a German vocabulary test (Wortschatztest, WST) in 34 adult patients with SMA types 2–4 and in 34 patients with ALS. Demographic and clinical parameters were assessed to identify factors that potentially influence cognitive function. While SMA and ALS patients were comparable in the vocabulary test, on average, SMA patients performed better than ALS patients in the cognitive domains of memory, language and executive function. Better cognitive abilities in SMA patients seemed to be related to the early onset, rather than the extent or the duration, of their physical handicap. Future studies should focus on disease-specific cognitive functions in SMA.

scholarly journals Phosphorylated TDP-43 aggregates in skeletal and cardiac muscle are a marker of myogenic degeneration in amyotrophic lateral sclerosis and various conditions

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Fumiaki Mori ◽  
Mari Tada ◽  
Tomoya Kon ◽  
Yasuo Miki ◽  
Kunikazu Tanji ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cardiac Muscle ◽  
Skeletal Muscles ◽  
Neuromuscular Diseases ◽  
Iliopsoas Muscle ◽  
Vacuolar Degeneration ◽  
Cardiac Muscles ◽  
The Central Nervous System ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Background Amyotrophic lateral sclerosis (ALS) is characterized pathologically by the occurrence of phosphorylated TDP-43 (pTDP-43)-immunoreactive neuronal and glial inclusions in the central nervous system. Recent studies have shown that pTDP-43 aggregates also occur in the skeletal muscles in a certain proportion of ALS patients. Aim The aim of this study was to clarify the distribution and incidence of pTDP-43 aggregates in the skeletal and cardiac muscles of patients with ALS, and also those of patients with neuromuscular diseases (NMDs) and non-NMDs. Material and methods Five regions of muscle (tongue, cervical muscle, diaphragm, iliopsoas muscle and heart) were examined histologically and immunohistochemically in patients with ALS (n = 30), NMDs (n = 13) and non-NMDs (n = 7). Results Two types of pTDP-43 aggregates were distinguishable morphologically: dense filamentous and short linear inclusions. These inclusions were found in at least one of the five muscle regions in all 30 cases of ALS; skeletal muscles in 28 cases and myocardium in 12. pTDP-43 aggregates were also found in 9 of 13 patients with NMDs, including myositis, muscular dystrophy and mitochondrial myopathy, as well as in 3 of 7 patients with non-NMDs. In ALS, pTDP-43 aggregates were most frequent in the diaphragm (19 cases). The mean density of pTDP-43 aggregates in ALS was significantly higher than that in NMDs and non-NMDs. In contiguous sections stained with hematoxylin and eosin and anti-pTDP-43, muscle fibers with dense filamentous inclusions demonstrated single-fiber atrophy with vacuolar degeneration. Conclusion The present findings indicate that pTDP-43 aggregates in skeletal and cardiac muscle are a myogenic pathological marker in multiple diseases including ALS.

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