Do MTHFR C677T Genetic Polymorphism Influence in the Pathogenesis of Amyotrophic Lateral Sclerosis?

Abstract Amyotrophic Lateral Sclerosis (ALS) is a progressive and lethal neurodegenerative disease without a definitive diagnostic test and effective treatment. A plethora of studies suggest that genetic factors play an important role in ALS development, and potentially link folate pathway dysregulation to disease pathogenesis. This study aims to evaluate folate dysregulation due to MTHFR C677T polymorphism and other factors such as sociodemographic and clinical, to better elucidate the involvement of these factors in ALS pathogenesis, and to investigate possible biomarkers for use as disease diagnostics or prognostics. This hospital-based case-control study analyzed 101 patients diagnosed with ALS and 119 considered healthy, with no suspicion or diagnosis of neurodegenerative disease. Blood samples were collected, stored, and underwent DNA extraction. Clinical and sociodemographic data from patients were collected through a questionnaire, as well as consultation of medical records. Genotypic analyses were performed using PCR-RFLP, and statistical analysis of clinical and genotypic data was conducted with SPSS software, version 23. The results show a higher presence of the mutant genotype (p = 0.02) in the case group, and suggest that mutant allele (T) is a risk factor for ALS susceptibility (OR = 1.54; 95% CI = 1.05–2.29; p = 0.03). Mutant genotype (T/T) interacts with both demographics (White p = 0.005 / Brown p = 0,001) and clinical factors (Physical activity p = 0.006) as risk factors for ALS. Also, a significant difference in alcohol consumption (p = 0.001) between the case and control group was observed. Moreover, a statistical trend towards faster disease progression and death was observed for patients with the mutant allele (T) (p = 0.06). Thus, the results of this study suggest that folate deficiency due to MTHFR C677T polymorphism is implicated in ALS through pathogenic mechanisms and interaction with other risk factors, resulting in faster disease progression and early death.

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Open Randomized Clinical Trial on JWSJZ Decoction for the Treatment of ALS Patients

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/347525 ◽

2013 ◽

Vol 2013 ◽

pp. 1-5 ◽

Cited By ~ 6

Author(s):

Weidong Pan ◽

Xiaojing Su ◽

Jie Bao ◽

Jun Wang ◽

Jin Zhu ◽

...

Keyword(s):

Clinical Trial ◽

Amyotrophic Lateral Sclerosis ◽

Rating Scale ◽

Control Group ◽

Efficacy And Safety ◽

Significant Difference ◽

Als Patients ◽

And Control ◽

Lateral Sclerosis ◽

Basic Treatment

Objective. To investigate the efficacy and safety of the traditional Chinese medicine Jiawei Sijunzi (JWSJZ) decoction for the treatment of patients with amyotrophic lateral sclerosis (ALS).Methods. Forty-eight patients with ALS were divided into a JWSJZ group (n=24) and a control group (n=24) using a randomized number method. Together with the basic treatment for ALS, JWSJZ decoction was added to the treatment regimen of patients in the JWSJZ group or Riluzole was administered to the control group for 6 months. Neurologists evaluated the treated and control patients using the ALS functional rating scale (ALSFRS) before, 3 and 6 months after starting the additional treatments.Results. The ALSFRS scores in both groups were lower 3 and 6 months after treatment than before. There was a significant difference at 6 months after treatment between the subgroups of patients with ALS whose limbs were the initial site of attack. No serious adverse effects were observed in the JWSJZ group.Conclusion. JWSJZ decoction may be a safe treatment for ALS, and may have delayed the development of ALS, especially in the subgroup of patients in whom the limbs were attacked first when compared with Riluzole treatment.

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What causes amyotrophic lateral sclerosis?

F1000Research ◽

10.12688/f1000research.10476.1 ◽

2017 ◽

Vol 6 ◽

pp. 371 ◽

Cited By ~ 31

Author(s):

Sarah Martin ◽

Ahmad Al Khleifat ◽

Ammar Al-Chalabi

Keyword(s):

Risk Factors ◽

Amyotrophic Lateral Sclerosis ◽

Respiratory Failure ◽

Neurodegenerative Disease ◽

Motor Neurons ◽

Environmental Risk ◽

Age Of Onset ◽

Genetic Associations ◽

Male Predominance ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disease predominantly affecting upper and lower motor neurons, resulting in progressive paralysis and death from respiratory failure within 2 to 3 years. The peak age of onset is 55 to 70 years, with a male predominance. The causes of amyotrophic lateral sclerosis are only partly known, but they include some environmental risk factors as well as several genes that have been identified as harbouring disease-associated variation. Here we review the nature, epidemiology, genetic associations, and environmental exposures associated with amyotrophic lateral sclerosis.

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Effects of environmental enrichment on the amyotrophic lateral sclerosis mouse model

Laboratory Animals ◽

10.1258/la.2008.005090 ◽

2009 ◽

Vol 43 (2) ◽

pp. 182-190 ◽

Cited By ~ 5

Author(s):

A D Sorrells ◽

K Corcoran-Gomez ◽

K A Eckert ◽

A G Fahey ◽

B L Hoots ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Disease Progression ◽

Environmental Enrichment ◽

Mouse Strains ◽

Control Group ◽

Copper Zinc Superoxide Dismutase ◽

Exercise Regime ◽

Copper Zinc ◽

Lateral Sclerosis

The manner in which an animal's environment is furnished may have significant implications for animal welfare as well as research outcomes. We evaluated four different housing conditions to determine the effects of what has been considered standard rodent enrichment and the exercise opportunities those environments allow on disease progression in the amyotrophic lateral sclerosis mouse model. Forty-eight copper/zinc superoxide dismutase mice (strain: B6SJL-TgN [SOD1-G931]1Gur) (SOD1) and 48 control (C) (strain: B6SJL-TgN[SOD1]2Gur) male mice were randomly assigned to four different conditions where 12 SOD1 and 12 C animals were allotted to each condition ( n = 96). Conditions tested the effects of standard housing, a forced exercise regime, access to a mouse house and opportunity for ad libitum exercise on a running wheel. In addition to the daily all-occurrence behavioural sampling, mice were weighed and tested twice per week on gait and Rotor-Rod™ performance until the mice reached the age of 150 days (C) or met the criteria for our humane endpoint (SOD1). The SOD1 mice exposed to the forced exercise regime and wheel access did better in average lifespan and Rotor-Rod™ performance, than SOD1 mice exposed to the standard cage and mouse house conditions. In SOD1 mice, stride length remained longest throughout the progression of the disease in mice exposed to the forced exercise regime compared with other SOD1 conditions. Within the control group, mice in the standard cage and forced exercise regime conditions performed significantly less than the mice with the mouse house and wheels on the Rotor-Rod™. Alpha motor neuron counts were highest in mice with wheels and in mice exposed to forced exercise regime in both mouse strains. All SOD1 mice had significantly lower alpha neuron counts than controls ( P < 0.05). These data show that different enrichment strategies affect behaviour and disease progression in a transgenic mouse model, and may have implications for the effects of these strategies on experimental outcomes.

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Metabolic Abnormalities, Dietary Risk Factors and Nutritional Management in Amyotrophic Lateral Sclerosis

Nutrients ◽

10.3390/nu13072273 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2273

Author(s):

Emanuele D’Amico ◽

Giuseppe Grosso ◽

Jeri W. Nieves ◽

Aurora Zanghì ◽

Pam Factor-Litvak ◽

...

Keyword(s):

Risk Factors ◽

Amyotrophic Lateral Sclerosis ◽

Survival Time ◽

Disease Progression ◽

Nutritional Assessment ◽

Dietary Factors ◽

Metabolic Abnormalities ◽

Dietary Risk Factors ◽

Dietary Risk ◽

Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects motor neurons, leading to a relentless paralysis of skeletal muscles and eventual respiratory failure. Although a small percentage of patients may have a longer survival time (up to 10 years), in most cases, the median survival time is from 20 to 48 months. The pathogenesis and risk factors for ALS are still unclear: among the various aspects taken into consideration, metabolic abnormalities and nutritional factors have been the focus of recent interests. Although there are no consistent findings regarding prior type-2 diabetes, hypercholesterolemia and ALS incidence, abnormalities in lipid and glucose metabolism may be linked to disease progression, leading to a relatively longer survival (probably as a result of counteract malnutrition and cachexia in the advanced stages of the disease). Among potential dietary risk factors, a higher risk of ALS has been associated with an increased intake of glutamate, while the consumption of antioxidant and anti-inflammatory compounds, such as vitamin E, n-3 polyunsaturated fatty acids, and carotenoids, has been related to lower incidence. Poor nutritional status and weight loss in ALS resulting from poor oral intake, progressive muscle atrophy, and the potential hypermetabolic state have been associated with rapid disease progression. It seems important to routinely perform a nutritional assessment of ALS patients at the earliest referral: weight maintenance (if adequate) or gain (if underweight) is suggested from the scientific literature; evidence of improved diet quality (in terms of nutrients and limits for pro-inflammatory dietary factors) and glucose and lipid control is yet to be confirmed, but it is advised. Further research is warranted to better understand the role of nutrition and the underlying metabolic abnormalities in ALS, and their contribution to the pathogenic mechanisms leading to ALS initiation and progression.

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Therapeutic Nanocatalysis to Slow Disease Progression of Amyotrophic Lateral Sclerosis (ALS)

Case Medical Research ◽

10.31525/ct1-nct04098406 ◽

2019 ◽

Author(s):

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Slow Disease Progression ◽

Lateral Sclerosis

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Mitophagy Modulation, a New Player in the Race against ALS

International Journal of Molecular Sciences ◽

10.3390/ijms22020740 ◽

2021 ◽

Vol 22 (2) ◽

pp. 740

Author(s):

Enrique Madruga ◽

Inés Maestro ◽

Ana Martínez

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Protein Aggregation ◽

Neurodegenerative Disease ◽

Effective Treatment ◽

Unknown Etiology ◽

Drug Candidates ◽

Relevant Evidence ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.

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Improved Long-Term Survival with Edaravone Therapy in Patients with Amyotrophic Lateral Sclerosis: A Retrospective Single-Center Study in Japan

Pharmaceuticals ◽

10.3390/ph14080705 ◽

2021 ◽

Vol 14 (8) ◽

pp. 705

Author(s):

Hideki Houzen ◽

Takahiro Kano ◽

Kazuhiro Horiuchi ◽

Masahiro Wakita ◽

Azusa Nagai ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Rank Test ◽

Positive Pressure ◽

Control Group ◽

Single Center ◽

Term Survival ◽

Long Term Survival ◽

Kaplan Meier ◽

Lateral Sclerosis

Reports on the long-term survival effect of edaravone, which was approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2015 in Japan, are rare. Herein, we report our retrospective analysis of 45 consecutive patients with ALS who initially visited our hospital between 2013 and 2018. Of these, 22 patients were treated with edaravone for an average duration of 26.6 (range, 2–64) months, whereas the remaining patients were not treated with edaravone and comprised the control group. There were no differences in baseline demographics between the two groups. The primary endpoint was tracheostomy positive-pressure ventilation (TPPV) or death, and the follow-up period ended in December 2020. The survival rate was significantly better in the edaravone group than in the control group based on the Kaplan–Meier analysis, which revealed that the median survival durations were 49 (9–88) and 25 (8–41) months in the edaravone and control groups, respectively (p = 0.001, log-rank test). There were no serious edaravone-associated adverse effects during the study period. Overall, the findings of this single-center retrospective study suggest that edaravone might prolong survival in patients with ALS.

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Clinical Determinants of Disease Progression in Amyotrophic Lateral Sclerosis—A Retrospective Cohort Study

Journal of Clinical Medicine ◽

10.3390/jcm10081623 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1623

Author(s):

Maria Viktoria Requardt ◽

Dennis Görlich ◽

Torsten Grehl ◽

Matthias Boentert

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Disease Progression ◽

Rating Scale ◽

Rapid Decline ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Hazard Ratios ◽

Sum Score ◽

Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is ultimately fatal but characterized by substantial phenotypic heterogeneity, which is known to impact long-term course and survival. This study investigated clinical determinants of disease progression and outcome in a large cohort of patients with ALS. Methods: Retrospective analysis included comprehensive data from 625 patients who attended a tertiary ALS centre at least twice. Patients were stratified according to five distinct clinical phenotypes: classical ALS; bulbar ALS; ALS with frontotemporal dementia (ALS-FTD); upper motor neuron predominant (UMNP); and lower motor neuron predominant (LMNP). Results: This study confirmed higher age at symptom onset, shorter latency to diagnosis and more rapid decline in the revised ALS Functional Rating Scale sum score as predictors of poor prognosis. Hazard ratios for shorter survival were higher in patients with ALS-FTD versus classical ALS, and in patients with versus without chronic obstructive pulmonary disease (COPD). Mean survival was longest in the UMNP phenotype group. Conclusions: This study confirmed established predictors of shorter survival in ALS and showed that concomitant COPD in particular relates to poor outcome.

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