Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disorder of upper and lower motor neurons. Genetic variants in the paraoxonase gene cluster have been associated with susceptibility to sporadic ALS. Because these studies have yielded conflicting results, we have further investigated this association in a larger data set. Twenty SNPs spanning the paraoxonase gene cluster were genotyped on a panel of 597 case and 692 control samples and tested for association with risk of sporadic ALS and with ALS sub-phenotypes. Our study revealed two SNPs, rs987539 and rs2074351, within the paraoxonase gene cluster that are associated with susceptibility to sporadic ALS (uncorrected p=6.47E-04 and 7.87E-04, respectively). None of the 20 SNPs displayed significant associations with age of onset, site of onset or disease survival. Using a sliding window approach, we have also identified a 5-SNP haplotype that is significantly associated with risk of sporadic ALS (p=2.75E-05). We conclude that a common haplotype within the PON1 promoter region is associated with susceptibility to sporadic ALS.
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PMID:A common haplotype within the PON1 promoter region is associated with sporadic ALS. 1861 3

Paraoxonase polymorphisms have been associated with amyotrophic lateral sclerosis (ALS). Paraoxonases are detoxifying enzymes involved in the metabolism of organophosphates. We tested the hypothesis that genetic variation within paraoxonase genes would interact with the environmental exposure to paraoxonase substrates. We used population density in the location of residence of ALS patients as a surrogate marker for environmental exposure. Paraoxonase genotypes at previously associated single nucleotide polymorphisms rs662, rs854560, rs6954345, and rs11981433 were studied in 98 patients from the South East England ALS population-based register. A case-only analysis was carried out and median population density was used to categorize patients into rural or urban environments. We found a significant interaction with population density for marker rs854560 (L55M) in ALS.
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PMID:Interaction between PON1 and population density in amyotrophic lateral sclerosis. 1910 60

The motor neuron diseases (MNDs) are a group of related neurodegenerative diseases that cause the relative selective progressive death of motor neurons. Exploring the molecular mechanisms underlying MND phenotypes has been hampered by their multifactorial nature and high incidence of sporadic cases, although genetic factors are considered to play a considerable role at present. However, environmental factors, especial exposure to neurotoxic substances, could induce neurotoxicity with the same phenotypes of specific MNDs. Organophosphate-induced delayed neuropathy (OPIDN) is a neurodegenerative disorder characterized by ataxia and progression to paralysis, with a concomitant distal axonal degeneration and secondary demyelination of central and peripheral axons. The inhibition and subsequent aging of neuropathy target esterase (NTE) by organophosphate has been proposed to be the initiating event in OPIDN. NTE is characterized to be a lysophospholipase/phospholipase B mostly in the nervous system to regulate phospholipid homeostasis. Brain-specific deletion of mouse NTE contributes to the behavioral defects characterized by neuronal loss. Recently, mutations in human NTE have also been shown to cause a hereditary spastic paraplegia called NTE-related motor neuron disorder with the same characteristics of OPIDN, which supported the role of NTE abnormalities in OPIDN, and raised the possibility that NTE pathway disturbances contribute to other MNDs. Together with the identified association of paraoxonase polymorphisms with amyotrophic lateral sclerosis, there is a possibility that neurotoxic substances contribute to MND in genetically vulnerable people by gene-environment interactions.
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PMID:Motor neuron diseases and neurotoxic substances: a possible link? 1949 9

Three clustered, homologous paraoxonase genes (PON1, PON2, and PON3) have roles in preventing lipid oxidation and detoxifying organophosphates. Recent reports describe a genetic association between the PON genes and sporadic amyotrophic lateral sclerosis (ALS). We now report that in genomic DNA from individuals with familial and sporadic ALS, we have identified at least 7 PON gene mutations that are predicted to alter PON function.
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PMID:Paraoxonase gene mutations in amyotrophic lateral sclerosis. 2058 42

Polymorphisms in the paraoxonase family (PON) have been reported in patients with amyotrophic lateral sclerosis (ALS), but a recent meta-analysis did not show a clear association. Recently, PON mutations have also been identified in ALS patients. In this study, we assessed the frequency of PON variants in 1118 sporadic ALS patients, 93 familial ALS patients, and 1240 control subjects of Dutch descent. We identified PON mutations in 1.4% of sporadic ALS patients, 2.1% of familial ALS patients, and 2.5% of control subjects. There were no significant differences in mutational burden for rare variants or in allele frequencies of polymorphisms between patients and control subjects. Thus, this study does not support the premise that mutations or polymorphisms in PON contribute to ALS susceptibility.
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PMID:Rare and common paraoxonase gene variants in amyotrophic lateral sclerosis patients. 2233 Jan 74

Single nucleotide polymorphisms (SNPs) of the paraoxonase gene family (ordered PON1, PON2, and PON3) have been associated with the risk of developing sporadic amyotrophic lateral sclerosis (SALS) in Caucasian populations. However, this association has yet to be confirmed in Chinese SALS patients. Nine SNPs across the PON gene cluster (i.e., rs662, rs705381, rs705382, rs854548, rs854560, rs7493, rs11981433, rs757158, and rs10487132) were analyzed in a large cohort consisting of 373 SALS patients and 248 controls from Southwest China. The data from the present study suggest that these SNPs of the PON gene cluster do not contribute to the risk for developing SALS in a Chinese population.
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PMID:Association analysis of PON polymorphisms in sporadic ALS in a Chinese population. 2288 47

Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive, and fatal neurodegenerative disease with unknown etiology. Recent evidence suggests an association between the exposure to toxic environmental factors and sporadic ALS. The flavin-containing monooxygenases (FMOs) and paraoxonase (PONs) genes encode enzymes involved in xenobiotic detoxication and are associated with ALS. FMO and PON gene expression has been examined in the human central nervous system including human brain subregions defined as the spinal cord, medulla, and cerebral cortex and in the peripheral tissues (lymphocytes, fibroblasts) in ALS patients and normal control subjects. FMO expression was generally higher in tissues from ALS subjects than in control tissues, with the largest increases in FMO expression detected in the spinal cord. In peripheral tissues, the FMO mRNA level was found to be lower compared with FMO expression in brain tissue, and no differences were detected between ALS patients and the control tissue. FMO and PON gene expression was low in peripheral tissues. In contrast to FMO5 expression, the PON2 gene was down-regulated in ALS patients compared to the controls. Because FMO and PON are involved in the detoxication processes and their functional activity to bioactivate chemicals to toxins has been documented, the data herein suggest that environmental toxin exposure may play a role in a subset of individuals who contract ALS by altering FMO and PON gene expression. Although the precise pathogenic link is presently unknown, these findings suggest a role at FMO and PON genes in the development of ALS.
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PMID:Regulation of FMO and PON detoxication systems in ALS human tissues. 2307 12

Organophosphorus (OP) compounds have been known as the most widely used pesticides during the past half century and there have been a huge body of literature regarding their association with human chronic diseases. Neurodegenerative and neurodevelopmental disorders including Alzheimer, Parkinson, amyotrophic lateral sclerosis (ALS), attention deficit hyperactivity disorder (ADHD), and autism are among the afflicting neurological diseases which overshadow human life and their higher risk in relation to OP exposures have been uncovered by epidemiological studies. In addition, experimental studies exploring the underlying mechanisms have provided some evidence for involvement of cholinergic deficit, oxidative stress, neuro-inflammation, and epigenetic modifications as the processes which are common in the toxicity of the OP and pathophysiology of the mentioned diseases. In addition, genetic mutations and polymorphisms of different variants of some genes like paraoxonase have been shown to be implicated in both susceptibility to OPs toxicity and neurological diseases. In this article, we reviewed the epidemiological as well as experimental studies evidencing the association of exposure to OPs and incidence of neurodegenerative and neurodevelopmental diseases.
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PMID:The link of organophosphorus pesticides with neurodegenerative and neurodevelopmental diseases based on evidence and mechanisms. 3005 94