The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research

Gentile, Francesco; Scarlino, Stefania; Falzone, Yuri Matteo; Lunetta, Christian; Tremolizzo, Lucio; Quattrini, Angelo; Riva, Nilo

doi:10.3389/fnins.2019.00601

Cited by 36 publications

(34 citation statements)

References 274 publications

(267 reference statements)

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“…An interesting finding is that 28% of the variants were identified in CMT2/dSMA genes. These data confirm the emerging genetic pleiotropy of ALS [1,2,9,58]. More specifically, in relation to the specific design of our panel, our data suggest an overlap with other diseases sharing degeneration of motor axons and neurons as a common feature, such as the axonal hereditary neuropathies [9].…”

Section: Discussionsupporting

confidence: 84%

“…However, genetic heterogeneity, pleiotropy, and nonpenetrance are incompletely understood issues in ALS [1,2,4,6]. Furthermore, some aspects of the ALS phenotype, are shared with other neurodegenerative, neuropsychiatric, and neuromuscular diseases, such as axonal hereditary Charcot-Marie-Tooth neuropathy (CMT2), distal hereditary motor neuropathy (dHMN), or hereditary spastic paraplegia (HSP), which could implicate similar genes in their pathology [1,2,[9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

Scarlino¹,

Domi²,

Pozzi³

et al. 2020

IJMS

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Although the genetic architecture of amyotrophic lateral sclerosis (ALS) is incompletely understood, recent findings suggest a complex model of inheritance in ALS, which is consistent with a multistep pathogenetic process. Therefore, the aim of our work is to further explore the architecture of ALS using targeted next generation sequencing (NGS) analysis, enriched in motor neuron diseases (MND)-associated genes which are also implicated in axonal hereditary motor neuropathy (HMN), in order to investigate if disease expression, including the progression rate, could be influenced by the combination of multiple rare gene variants. We analyzed 29 genes in an Italian cohort of 83 patients with both familial and sporadic ALS. Overall, we detected 43 rare variants in 17 different genes and found that 43.4% of the ALS patients harbored a variant in at least one of the investigated genes. Of note, 27.9% of the variants were identified in other MND- and HMN-associated genes. Moreover, multiple gene variants were identified in 17% of the patients. The burden of rare variants is associated with reduced survival and with the time to reach King stage 4, i.e., the time to reach the need for percutaneous endoscopic gastrostomy (PEG) positioning or non-invasive mechanical ventilation (NIMV) initiation, independently of known negative prognostic factors. Our data contribute to a better understanding of the molecular basis of ALS supporting the hypothesis that rare variant burden could play a role in the multistep model of disease and could exert a negative prognostic effect. Moreover, we further extend the genetic landscape of ALS to other MND-associated genes traditionally implicated in degenerative diseases of peripheral axons, such as HMN and CMT2.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

Scarlino¹,

Domi²,

Pozzi³

et al. 2020

IJMS

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“…The imbalance between mitochondrial fission and fusion leads to abnormal mitochondrial morphology, underlies axonal damage, and is a potential therapeutic target for treating SPG15 and SPG48 (Denton et al, 2018). The ER and mitochondria form complex sites of interactions known as mitochondria-associated membranes (Gentile et al, 2019). Decreased ER-mitochondria association can occur as a result of loss-of-function mutations in SIGMAR1, leading to impaired retrograde transport and, ultimately, to axonal degeneration and MN death (Bernard-Marissal et al, 2015;Watanabe et al, 2016).…”

Section: Axonal Energy Supplymentioning

confidence: 99%

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is an intractable adult-onset neurodegenerative disease that leads to the loss of upper and lower motor neurons (MNs). The long axons of MNs become damaged during the early stages of ALS. Genetic and pathological analyses of ALS patients have revealed dysfunction in the MN axon homeostasis. However, the molecular pathomechanism for the degeneration of axons in ALS has not been fully elucidated. This review provides an overview of the proposed axonal pathomechanisms in ALS, including those involving the neuronal cytoskeleton, cargo transport within axons, axonal energy supply, clearance of junk protein, neuromuscular junctions (NMJs), and aberrant axonal branching. To improve understanding of the global changes in axons, the review summarizes omics analyses of the axonal compartments of neurons in vitro and in vivo, including a motor nerve organoid approach that utilizes microfluidic devices developed by this research group. The review also discusses the relevance of intra-axonal transcription factors frequently identified in these omics analyses. Local axonal translation and the relationship among these pathomechanisms should be pursued further. The development of novel strategies to analyze axon fractions provides a new approach to establishing a detailed understanding of resilience of long MN and MN pathology in ALS.

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“…This disorder manifests in the form of progressive painless weakness of several muscle groups including those involved in respiratory movements, which invariably leads to respiratory failure and death (1). In addition, an increasing number of studies have recently reported sensory and autonomic symptoms in ALS patients, supporting an involvement of the peripheral nervous system in the pathogenic mechanisms of this disease (2).…”

Section: Introductionmentioning

confidence: 85%

A Retrospective Study of the Clinical Phenotype and Predictors of Survival in non-Caucasian Hispanic Patients with Amyotrophic Lateral Sclerosis.

Sánchez-Martínez

Choreño-Parra

Núñez-Orozco

et al. 2019

Preprint

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Background. Little is known about the clinical phenotype of amyotrophic lateral sclerosis (ALS) in non-Caucasian populations. Here, we aimed to describe the clinical characteristics, prognostic factors and survival of Mexican patients with ALS. Methods. We conducted a retrospective study by reviewing the medical records of patients with ALS that attended and were regularly followed at a third level hospital in Mexico City from 2000 to 2015. We calculated absolute and relative frequencies of the clinical characteristics from all the participants. We also estimated correlation coefficients between clinical features and overall survival. Additionally, survival rates were compared for all participants grouped according to different clinical features using the Kaplan-Meier method and the log-rank test. Results. We enrolled 45 ALS patients, 53.33% had spinal-onset ALS and 46.66% presented bulbar ALS. The male/female ratio was 0.8. The mean age at onset of symptoms was 58.11 years. Mean survival time from onset was 64.73 ± 34.83 months. Cumulative survival rate after 5 years of disease onset was 44.44%. Age at onset and age at diagnosis inversely correlated with overall survival time. Also, we found that bulbar-onset, short diagnostic delay, percutaneous endoscopic gastrostomy, mechanical ventilation, and lower total cholesterol serum levels were associated with short survival. Conclusions. The clinical characteristics of Mexican ALS patients differ from the disease phenotype observed in Caucasians. Nonetheless, the predictive value of certain well-recognized prognostic factors remains consistent in our population. The current study provides relevant information for a better understanding of prognostic factors in ALS patients from Mexico and other Latin American countries.

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The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research

Cited by 36 publications

References 274 publications

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

Burden of Rare Variants in ALS and Axonal Hereditary Neuropathy Genes Influence Survival in ALS: Insights from a Next Generation Sequencing Study of an Italian ALS Cohort

Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

A Retrospective Study of the Clinical Phenotype and Predictors of Survival in non-Caucasian Hispanic Patients with Amyotrophic Lateral Sclerosis.

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