Genetic factors for survival in amyotrophic lateral sclerosis: an integrated approach combining a systematic review, pairwise and network meta-analysis

Su, Wei‐Ming; Gu, Xiaojing; Duan, Qing-Qing; Jiang, Zheng; Gao, Xia; Shang, Huifang; Chen, Yongping

doi:10.1186/s12916-022-02411-3

Cited by 8 publications

(3 citation statements)

References 132 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most common familial ALS cases include mutation of the chromosome 9 open reading frame 72 (C9orf72, present in 7.7% of ALS cases), followed by Cu/Zn-superoxide dismutase 1 (SOD1, 2.0%), never in mitosis A (NIMA)related kinase 1 (NEK1, 1.8%), TAR DNA binding protein (TARDBP) (1.4%), and kinesin family member 5A ( KIF5A, 0.8%) [11]. For risk factor and prognostic variants, compared to the above gene mutations, ataxin-2 gene (ATXN2) intermediate trinucleotide expansion in 3.9% of ALS subjects and increased ALS risk [11,16,17]. In spite of the fact that the disease was first described almost 200 years ago [18] and the simultaneous involvement of both the UMN and LMN has been identified as the disease's distinctive hallmark, the diagnosis of ALS is still mostly a clinical one.…”

Section: Introductionmentioning

confidence: 99%

Diffusion magnetic resonance imaging-based surrogate marker in amyotrophic lateral sclerosis

Saito

2023

Explor Neuroprot Ther

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is the most prevalent type of motor neuron disease (MND) and is diagnosed with a delay from the first appearance of symptoms. Surrogate markers that may be used to detect pathological changes before a significant neuronal loss occurs and allow for early intervention with disease-modifying therapy techniques are desperately needed. Using water molecules that diffuse within the tissue and experience displacement on the micron scale, diffusion magnetic resonance imaging (MRI) is a promising technique that can be used to infer microstructural characteristics of the brain, such as microstructural integrity and complexity, axonal density, order, and myelination. Diffusion tensor imaging (DTI) is the primary diffusion MRI technique used to evaluate the pathogenesis of ALS. Neurite orientation dispersion and density imaging (NODDI), diffusion kurtosis imaging (DKI), and free water elimination DTI (FWE-DTI) are only a few of the approaches that have been developed to overcome the shortcomings of the diffusion tensor technique. This article provides a summary of these methods and their potential as surrogate markers for detecting the onset of ALS at an early stage.

show abstract

Section: Introductionmentioning

confidence: 99%

Diffusion magnetic resonance imaging-based surrogate marker in amyotrophic lateral sclerosis

Saito

2023

Explor Neuroprot Ther

View full text Add to dashboard Cite

show abstract

“…Yet, this association was only nominally significant, which — in addition to the absence of further oligogenic associations with ALS age of onset — results in a lack of clarity regarding the validity of this relationship. We only observed an association between singleton carriers and survival period when the C9orf72 repeat expansion was included in the analysis, which may be explained by the C9orf72 pathogenic repeat expansion being associated with a decreased survival period individually 43,44 . Overall, consistent with recent reports 11,45,46 , these results suggest the genetic architecture underlying ALS risk is decoupled from that underlying survival.…”

Section: Discussionmentioning

confidence: 65%

The oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling, and therapeutic implications

Iacoangeli,

Dilliott,

Al Khleifat

et al. 2024

Preprint

View full text Add to dashboard Cite

Recently, large-scale case-control analyses have been prioritized in the study of ALS. Yet the same effort has not been put forward to investigate additive moderate phenotypic effects of genetic variants in genes driving ALS risk, despite case-level evidence suggesting a potential oligogenic risk model. Considering its direct clinical and therapeutic implications, a large-scale robust investigation of oligogenicity in ALS is greatly needed. Here, we leveraged the Project MinE ALS Sequencing Consortium genome sequencing datasets of individuals with ALS (n = 6711) and controls (n = 2391) to identify signals of association between oligogenicity in known ALS genes (n=26) and disease risk, as well as clinical outcomes. Applying regression models to a discovery and replication cohort, we observed that the risk imparted from carrying rare variants in multiple known ALS genes was significant and was greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes, such as C9orf72. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, might not follow the same pattern as we did not observe any associations. Our findings represent the first large-scale, case-control assessment of oligogenic associations in ALS to date and confirm that oligogenic events involving known ALS risk genes are indeed relevant for the risk of disease in approximately 6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring the use of comprehensive gene panels even when a potential pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need of a complete genetic profile for the correct choice of therapy in all ALS patients.

show abstract

“…The heterogeneity of ALS means, despite all the best stratification strategies, the risk of having groups that are not perfectly comparable. This challenges trialists to categorize patients in homogeneous subgroups based on phenotype characteristics, such as age, clinical type, comorbidities, respiratory function, stage of disease progression, disease management [8], and even genotype [17], all possible predictors of disease course also related to aging [18][19][20]. Furthermore, the stage of neurodegeneration is not the same in all neurons, and different biological manifestations might be active in different regional groups of motor neurons.…”

Section: Disease Heterogeneity and Inclusion Criteriamentioning

confidence: 99%

Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A Systematic Review

Pupillo,

Al-Chalabi,

Sassi

et al. 2024

Journal of Neuromuscular Diseases

View full text Add to dashboard Cite

Background: More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found. Objective: To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022. Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses. Results: 213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55–65% in 21.6%, between 70–80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was < 6-months in 6 studies, 7–36 months in 68, 37–60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was ≥20% in 30.5% trials, while it was not reported for 8.5% . Conclusion: The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting.

show abstract

Genetic factors for survival in amyotrophic lateral sclerosis: an integrated approach combining a systematic review, pairwise and network meta-analysis

Cited by 8 publications

References 132 publications

Diffusion magnetic resonance imaging-based surrogate marker in amyotrophic lateral sclerosis

Diffusion magnetic resonance imaging-based surrogate marker in amyotrophic lateral sclerosis

The oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling, and therapeutic implications

Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A Systematic Review

Contact Info

Product

Resources

About