Abstract
Amyotrophic lateral sclerosis (ALS) is a rare degenerative condition of the motor neurons. Over 10% of ALS cases are linked to monogenic mutations, with the remainder thought to be due to other risk factors, including environmental factors, genetic polymorphisms, and possibly gene-environmental interactions. We examined the association between ALS and an intermediate CAG repeat expansion in the ATXN2 gene using a meta-analytic approach. Observational studies were searched with relevant disease and gene terms from MEDLINE, EMBASE, and PsycINFO from January 2010 through to January 2014. All identified articles were screened using disease terms, gene terms, population information, and CAG repeat information according to PRISMA guidelines. The final list of 17 articles was further evaluated based on the study location, time period, and authors to exclude multiple usage of the same study populations: 13 relevant articles were retained for this study. The range 30–33 CAG repeats in the ATXN2 gene was most strongly associated with ALS. The meta-analysis revealed that the presence of an intermediate CAG repeat (30-33) in the ATXN2 gene was associated with an increased risk of ALS [odds ratio (OR) = 4.44, 95%CI: 2.91–6.76)] in Caucasian ALS patients. There was no significant difference in the association of this CAG intermediate repeat expansion in the ATXN2 gene between familial ALS cases (OR = 3.59, 1.58–8.17) and sporadic ALS cases (OR = 3.16, 1.88–5.32). These results indicate that the presence of intermediate CAG repeat expansion in the ATXN2 gene is a specific genetic risk factor for ALS, unlike monogenic mutations with an autosomal dominant transmission mode, which cause a more severe phenotype of ALS, with a higher prevalence in familial ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a rare neurological degenerative condition of the motor neurons leading to paralysis of skeletal muscles, characterized by rapid irreversible progression in most cases [1]
We synthesized data from published articles related to intermediate CAG repeat expansions in the ATXN2 gene in individuals with ALS, and found that an intermediate CAG expansion with a range of 30–33 repeats was associated with an increased risk of ALS
Since significant differences with respect to the prevalence of these expansions among familial ALS (fALS) cases compared to sporadic ALS (sALS) cases were not identified, heritability is unlike the dominant autosomal transmission mode of inheritance of spinocerebellar ataxia type 2 (SCA2) observed for CAG expansions greater than 34 repeats in the ATXN2 gene
Summary
Amyotrophic lateral sclerosis (ALS) is a rare neurological degenerative condition of the motor neurons leading to paralysis of skeletal muscles, characterized by rapid irreversible progression in most cases [1]. We know that the most common monogenic mutated gene in Caucasians with ALS is the GGGGCC hexanucleotide repeat expansion in the C9orf72 [13,14], which is responsible for over 30% of fALS cases, and about 6.0% of sALS in Caucasian populations [7,15,16] This repeat mutation arose in Northern Europe a few thousand years ago [17], and occurs with a much lower frequency in Asian ALS populations [18,19,20], in particular, the mutation frequency has been shown to be extremely low in Chinese, Indian, Japanese and Korean ALS patients [16,19,20,21,22,23]. Extensive studies have not revealed a definitive, universally accepted environmental risk factor for ALS, many environmental risk factors, such as exposure to heavy metals, exposure to pesticides, exposure to solvent, intake of biological toxicants, history of head injury, smoking, and military service have been reported to be associated with ALS in some studies [30,31,32,33,34,35]
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