Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. It is mostly sporadic, with the C9orf72 repeat expansion being the most common genetic cause. While the prevalence of ...C9orf72-ALS in patients from different populations has been studied, data regarding the yield of C9orf72 compared to an ALS gene panel testing is limited.We aimed to explore the application of C9orf72 versus a gene panel in the general Israeli population. A total of 140 ALS patients attended our Neurogenetics Clinic throughout 2018-2023. Disease onset was between ages 60 and 69 years for most patients (34%); however, a quarter had an early-onset disease (< 50 years). Overall, 119 patients (85%) were genetically evaluated: 116 (97%) were tested for the C9orf72 repeat expansion and 64 (54%) underwent gene panel testing. The C9orf72 repeat expansion had a prevalence of 21% among Ashkenazi Jewish patients compared to 5.7% in non-Ashkenazi patients, while the gene panel had a higher yield in non-Ashkenazi patients with 14% disease-causing variants compared to 5.7% in Ashkenazi Jews. Among early-onset ALS patients, panel testing was positive in 12% compared to 2.9% for C9orf72.We suggest a testing strategy for the Israeli ALS patients: C9orf72 should be the first-tier test in Ashkenazi Jewish patients, while a gene panel should be considered as the first step in non-Ashkenazi and early-onset patients. Tiered testing has important implications for patient management, including prognosis, ongoing clinical trials, and prevention in future generations. Similar studies should be implemented worldwide to uncover the diverse ALS genetic architecture and facilitate tailored care.
•There are few global estimates of depression prevalence and severity of depression among ALS patients.•We estimate the overall pooled prevalence of depression is 34% in ALS patients.•We estimate the ...overall pooled prevalence of mild depression is 29% in ALS patients.•We estimate the overall pooled prevalence of moderate depression is 16% in ALS patients.•We estimate the overall pooled prevalence of severe depression is 0.08% in ALS patients.
Amyotrophic lateral sclerosis (ALS) people have a high risk of severe mental disorders, like depression, which impacts their function, quality of life, and mobility. However, there are no estimates of depression based paper published. This study aimed conduct a systematic review and meta-analysis of the prevalence of depression in ALS patients around the world.
PubMed/Medline, Web of science, Scopus, Embase, and Ovid are searched to identify papers that reporting the prevalence of depression. Studies are included in random-effects meta-analyses of the prevalence of depression. Subgroup analyses are performed on the severity of depression, instruments of depression, type of studies, and study regions.
46 eligible studies reported prevalence of depression. The pooled prevalence of depression among ALS people was 34% (27%–41%). According to the severity of depression, mild, moderate, and severe depression were 29%, 16%, and 8%, respectively. For studies using BDI, PHQ, and HADS, the pooled prevalence of depression was 50%, 20%, and 15%, respectively.
ALS people have a high prevalence of depression. The high prevalence of depression causes a reduction of quality of life and mobility. The study identifies a population group at high risk needing special attention in clinical practice.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system, but in which extra‐motor manifestations are increasingly recognized. The loss of upper and ...lower motor neurons in the motor cortex, the brain stem nuclei and the anterior horn of the spinal cord gives rise to progressive muscle weakness and wasting. ALS often has a focal onset but subsequently spreads to different body regions, where failure of respiratory muscles typically limits survival to 2–5 years after disease onset. In up to 50% of cases, there are extra‐motor manifestations such as changes in behaviour, executive dysfunction and language problems. In 10%–15% of patients, these problems are severe enough to meet the clinical criteria of frontotemporal dementia (FTD). In 10% of ALS patients, the family history suggests an autosomal dominant inheritance pattern. The remaining 90% have no affected family members and are classified as sporadic ALS. The causes of ALS appear to be heterogeneous and are only partially understood. To date, more than 20 genes have been associated with ALS. The most common genetic cause is a hexanucleotide repeat expansion in the C9orf72 gene, responsible for 30%–50% of familial ALS and 7% of sporadic ALS. These expansions are also a frequent cause of frontotemporal dementia, emphasizing the molecular overlap between ALS and FTD. To this day there is no cure or effective treatment for ALS and the cornerstone of treatment remains multidisciplinary care, including nutritional and respiratory support and symptom management. In this review, different aspects of ALS are discussed, including epidemiology, aetiology, pathogenesis, clinical features, differential diagnosis, investigations, treatment and future prospects.
Alterations in RNA metabolism play an important role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. The literature has described, so far, a small number of long non coding RNAs (lncRNAs) ...associated to ALS demonstrating that how there is still much to do to identify and understand their role in ALS. This class of RNAs may offer numerous starting points for new investigations about pathogenic mechanism involved in ALS disease. In this review, we have collected all the presented data about lncRNAs and ALS to offer an overview about this class of non-coding RNAs and their possible role in ALS disease.
Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific ...treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = -1.96 per increase of one point in the ALSFRS-R score,
< 0.001). "Limb-onset" ALS (
ALS) was associated with a better QoL than "bulbar-onset" ALS (
ALS) (mean ALSAQ-5 total score 55.46 versus 60.99,
= 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = -7.60,
= 0.001), being tracheostomized (β = -14.80,
= 0.004) and using non-invasive ventilation (β = -5.71,
= 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95,
= 0.007), and increasing age (β = 0.18,
= 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.
Introduction: To date more than 180 different mutations in the SOD1 gene have been described in ALS; some of these mutations are associated to peculiar clinical features and have contributed to the ...understanding of disease heterogeneity. Only 5% of SOD1 mutations involve exon 3. Here we report a novel mutation c.197A > C in the exon 3 of the SOD1 gene in two apparently unrelated ALS families with early respiratory and cognitive impairment.
Case report: In the first family two brothers developed ALS in their seventies, with arm weakness followed by bulbar involvement and behavioral breakdown. An unrelated 57-year-old man presented with progressive leg weakness and mild compromised executive functions without known family history for ALS/FTD and underwent invasive ventilation in a few months. A novel missense mutation A to C at codon 197 in exon 3 causing aminoacid substitution of arginine by threonine (N66T) was found for all of them. Harmful consequences of c.197A > C mutation on SOD1 function were suggested by in silico prediction and homology with other known mutations at the same position.
Discussion and conclusion: Here, we report two apparently unrelated ALS families carrying a novel SOD1 mutation (N66T), supporting its pathogenic role by primary analysis, and characterized by early bulbar, respiratory, and cognitive involvement. Early cognitive impairment has been rarely described in ALS caused by SOD1 mutations, and mainly in the later phases of the disease. This report provides additional data on the SOD1 mutation spectrum and clinical presentation of ALS, widening phenotypical characterization of SOD1 ALS.
In this study, the effect of different error structures on psedounivariate and multivariate analytical figures of merit in simulated data of hyphenated chromatographic systems was investigated. ...Different error structures (e.g., homoscedastic, heteroscedastic, and correlated) were investigated. For this purpose, five components systems at five concentration levels with three replicates were simulated. Different types of error were added to the data. Multivariate Curve Resolution‐Alternating Least Squares (MCR‐ALS) and Maximum Likelihood Principal Component Analysis (MLPCA‐MCR‐ALS) methods were used. After resolution, pseudo‐univariate and multivariate analytical figures of merit were calculated and compared. As it expected, the detection limit for noisy datasets is higher than the noise‐free datasets, whereas the slopes of the calibration curves are not significantly different. Comparing the results generally showed that the detection limit values in multivariable mode were better than the univariate mode. The LODs of data (pseudo‐univariate and multivariate) with homoscedastic and correlated error structure by MCR‐ALS and MLPCA‐MCR‐ALS were the same. The analysis of data with heteroscedastic error structure by MLPCA‐MCR‐ALS had a lower detection limit than analysis with MCR‐ALS. The figures of merit obtained from WLS and OLS regression in heteroscedastic datasets were compared and better LODs were obtained after WLS method.
The effect of different error structures on psedounivariate and multivariate analytical figures of merit in simulated data of hyphenated chromatographic systems was investigated. Different error structures (e.g., homoscedastic, heteroscedastic, and correlated) were investigated. Multivariate Curve Resolution‐Alternating Least Squares (MCR‐ALS) and Maximum Likelihood Principal Component Analysis (MLPCA‐MCR‐ALS) methods were used. After resolution, pseudo‐univariate and multivariate analytical figures of merit were calculated and compared.
An intronic expansion of GGGGCC repeats within the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS‐FTD). Ataxin‐2 with intermediate ...length of polyglutamine expansions (Ataxin‐2 Q30x) is a genetic modifier of the disease. Here, we found that C9ORF72 forms a complex with the WDR41 and SMCR8 proteins to act as a GDP/GTP exchange factor for RAB8a and RAB39b and to thereby control autophagic flux. Depletion of C9orf72 in neurons partly impairs autophagy and leads to accumulation of aggregates of TDP‐43 and P62 proteins, which are histopathological hallmarks of ALS‐FTD. SMCR8 is phosphorylated by TBK1 and depletion of TBK1 can be rescued by phosphomimetic mutants of SMCR8 or by constitutively active RAB39b, suggesting that TBK1, SMCR8, C9ORF72, and RAB39b belong to a common pathway regulating autophagy. While depletion of C9ORF72 only has a partial deleterious effect on neuron survival, it synergizes with Ataxin‐2 Q30x toxicity to induce motor neuron dysfunction and neuronal cell death. These results indicate that partial loss of function of C9ORF72 is not deleterious by itself but synergizes with Ataxin‐2 toxicity, suggesting a double‐hit pathological mechanism in ALS‐FTD.
Synopsis
Expansion of GGGGCC repeats in the C9ORF72 gene is the major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS‐FTD). Here, we report that decreased expression of C9ORF72 impairs autophagy, but does not promote major neuronal cell death. In contrast, reduced levels of C9ORF72 enhance the aggregation and toxicity of the ALS‐linked factor Ataxin‐2 (ATXN2). A video synopsis is available online at http://embopress.org/video_EMBOJ-2015-93350
C9ORF72 forms a complex with SMCR8 and WDR41. This complex acts as a GDP/GTP exchange factors for RAB8a and RAB39b.
The kinase TBK1 phosphorylates and regulates SMCR8.
C9ORF72 in complex with SMCR8 and WDR41 regulates formation of the autophagosome.
Synergic toxicity between loss of C9ORF72 and expression of Ataxin‐2 with intermediate size of polyQ suggests a two‐hit mechanism in ALS‐FTD.
The ALS‐linked factor C9orf72 forms a novel complex with SMCR8 and WDR41 to regulate GEF activity for Rab8a and Rab39b and autophagy. Loss of function of C9ORF72 synergizes with Ataxin‐2 toxicity, suggesting a double‐hit pathological mechanism in ALS‐FTD.
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