ATXN2 polyQ intermediate repeats are a modifier of ALS survival
OBJECTIVE:To analyze the frequency and clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) with intermediate-length (CAG) expansion (encoding 27–33 glutamines, polyQ) in the ATXN2 gene, in a population-based cohort of Italian patients with ALS (discovery cohort), and to rep...
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| Veröffentlicht in: | Neurology 2015-01, Vol.84 (3), p.251-258 |
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| creator | Chiò, Adriano Calvo, Andrea Moglia, Cristina Canosa, Antonio Brunetti, Maura Barberis, Marco Restagno, Gabriella Conte, Amelia Bisogni, Giulia Marangi, Giuseppe Moncada, Alice Lattante, Serena Zollino, Marcella Sabatelli, Mario Bagarotti, Alessandra Corrado, Lucia Mora, Gabriele Bersano, Enrica Mazzini, Letizia DʼAlfonso, Sandra |
| description | OBJECTIVE:To analyze the frequency and clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) with intermediate-length (CAG) expansion (encoding 27–33 glutamines, polyQ) in the ATXN2 gene, in a population-based cohort of Italian patients with ALS (discovery cohort), and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort).
METHODS:PolyQ repeats were assessed in 672 patients with incident ALS in Piemonte and Valle dʼAosta regions, Italy, in the 2007–2012 period (discovery cohort); controls were 509 neurologically healthy age- and sex-matched subjects resident in the study area. The validation cohort included 661 patients with ALS consecutively seen between 2001 and 2013 in the ALS Clinic Center of the Catholic University in Rome, Italy.
RESULTS:In the discovery cohort, the frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs 1 control, p = 0.0001; odds ratio 14.8, 95% confidence interval 1.9–110.8). Patients with an increased number of polyQ repeats had a shorter survival than those with |
| doi_str_mv | 10.1212/WNL.0000000000001159 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1712577054</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1652405300</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4359-47612dab9f9bd82839934f00d89ddd950612271741c291ebe9ca8fdc8e0ae4293</originalsourceid><addsrcrecordid>eNqFkN9LwzAQx4Mobk7_A5E8-tKZpE2TPMkQf0GZiBP3VtLmyqrtWpN2Y_-9kU0RH_Re7uA-3zv4IHRKyZgyyi5epsmY_ChKudpDQ8pZHMQhm--jISFMBqEUcoCOnHv1DGdCHaIB435gMR-iy8lsPmW4barNIy6XHdgaTKk7wBZa0J3D2gLWuG5MWZRgcVPgSfKEXW9X5UpXx-ig0JWDk10foeeb69nVXZA83N5fTZIgj0KugkjElBmdqUJlRjIZKhVGBSFGKmOM4sSvmaAiojlTFDJQuZaFySUQDRFT4Qidb--2tnnvwXVpXbocqkovoeldSgVlXAjCo__RmLOI8JAQj0ZbNLeNcxaKtLVlre0mpST9tJx6y-lvyz52tvvQZ17Xd-hLqwfkFlg3lVfq3qp-DTZdgK66xd-3PwDEYYZO</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1652405300</pqid></control><display><type>article</type><title>ATXN2 polyQ intermediate repeats are a modifier of ALS survival</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><source>Journals@Ovid Complete</source><creator>Chiò, Adriano ; Calvo, Andrea ; Moglia, Cristina ; Canosa, Antonio ; Brunetti, Maura ; Barberis, Marco ; Restagno, Gabriella ; Conte, Amelia ; Bisogni, Giulia ; Marangi, Giuseppe ; Moncada, Alice ; Lattante, Serena ; Zollino, Marcella ; Sabatelli, Mario ; Bagarotti, Alessandra ; Corrado, Lucia ; Mora, Gabriele ; Bersano, Enrica ; Mazzini, Letizia ; DʼAlfonso, Sandra</creator><creatorcontrib>Chiò, Adriano ; Calvo, Andrea ; Moglia, Cristina ; Canosa, Antonio ; Brunetti, Maura ; Barberis, Marco ; Restagno, Gabriella ; Conte, Amelia ; Bisogni, Giulia ; Marangi, Giuseppe ; Moncada, Alice ; Lattante, Serena ; Zollino, Marcella ; Sabatelli, Mario ; Bagarotti, Alessandra ; Corrado, Lucia ; Mora, Gabriele ; Bersano, Enrica ; Mazzini, Letizia ; DʼAlfonso, Sandra ; PARALS ; For PARALS</creatorcontrib><description>OBJECTIVE:To analyze the frequency and clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) with intermediate-length (CAG) expansion (encoding 27–33 glutamines, polyQ) in the ATXN2 gene, in a population-based cohort of Italian patients with ALS (discovery cohort), and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort).
METHODS:PolyQ repeats were assessed in 672 patients with incident ALS in Piemonte and Valle dʼAosta regions, Italy, in the 2007–2012 period (discovery cohort); controls were 509 neurologically healthy age- and sex-matched subjects resident in the study area. The validation cohort included 661 patients with ALS consecutively seen between 2001 and 2013 in the ALS Clinic Center of the Catholic University in Rome, Italy.
RESULTS:In the discovery cohort, the frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs 1 control, p = 0.0001; odds ratio 14.8, 95% confidence interval 1.9–110.8). Patients with an increased number of polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 1.8 years, interquartile range [IQR] 1.3–2.2; polyQ <31, 2.7 years, IQR 1.6–5.1; p = 0.001). An increased number of polyQ repeats remained independently significant at multivariable analysis. In the validation cohort, patients with ≥31 polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 2.0 years, IQR 1.5–3.4; polyQ <31, 3.2 years, IQR 2.0–6.4; p = 0.007).
CONCLUSIONS:ATXN2 polyQ intermediate-length repeat is a modifier of ALS survival. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS.</description><identifier>ISSN: 0028-3878</identifier><identifier>EISSN: 1526-632X</identifier><identifier>DOI: 10.1212/WNL.0000000000001159</identifier><identifier>PMID: 25527265</identifier><language>eng</language><publisher>United States: American Academy of Neurology</publisher><subject>Aged ; Amyotrophic Lateral Sclerosis - diagnosis ; Amyotrophic Lateral Sclerosis - genetics ; Amyotrophic Lateral Sclerosis - mortality ; Ataxins ; Case-Control Studies ; Cohort Studies ; Female ; Genetic Testing ; Humans ; Italy ; Male ; Middle Aged ; Nerve Tissue Proteins - genetics ; Peptides - genetics</subject><ispartof>Neurology, 2015-01, Vol.84 (3), p.251-258</ispartof><rights>2015 American Academy of Neurology</rights><rights>2014 American Academy of Neurology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4359-47612dab9f9bd82839934f00d89ddd950612271741c291ebe9ca8fdc8e0ae4293</citedby><cites>FETCH-LOGICAL-c4359-47612dab9f9bd82839934f00d89ddd950612271741c291ebe9ca8fdc8e0ae4293</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25527265$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chiò, Adriano</creatorcontrib><creatorcontrib>Calvo, Andrea</creatorcontrib><creatorcontrib>Moglia, Cristina</creatorcontrib><creatorcontrib>Canosa, Antonio</creatorcontrib><creatorcontrib>Brunetti, Maura</creatorcontrib><creatorcontrib>Barberis, Marco</creatorcontrib><creatorcontrib>Restagno, Gabriella</creatorcontrib><creatorcontrib>Conte, Amelia</creatorcontrib><creatorcontrib>Bisogni, Giulia</creatorcontrib><creatorcontrib>Marangi, Giuseppe</creatorcontrib><creatorcontrib>Moncada, Alice</creatorcontrib><creatorcontrib>Lattante, Serena</creatorcontrib><creatorcontrib>Zollino, Marcella</creatorcontrib><creatorcontrib>Sabatelli, Mario</creatorcontrib><creatorcontrib>Bagarotti, Alessandra</creatorcontrib><creatorcontrib>Corrado, Lucia</creatorcontrib><creatorcontrib>Mora, Gabriele</creatorcontrib><creatorcontrib>Bersano, Enrica</creatorcontrib><creatorcontrib>Mazzini, Letizia</creatorcontrib><creatorcontrib>DʼAlfonso, Sandra</creatorcontrib><creatorcontrib>PARALS</creatorcontrib><creatorcontrib>For PARALS</creatorcontrib><title>ATXN2 polyQ intermediate repeats are a modifier of ALS survival</title><title>Neurology</title><addtitle>Neurology</addtitle><description>OBJECTIVE:To analyze the frequency and clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) with intermediate-length (CAG) expansion (encoding 27–33 glutamines, polyQ) in the ATXN2 gene, in a population-based cohort of Italian patients with ALS (discovery cohort), and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort).
METHODS:PolyQ repeats were assessed in 672 patients with incident ALS in Piemonte and Valle dʼAosta regions, Italy, in the 2007–2012 period (discovery cohort); controls were 509 neurologically healthy age- and sex-matched subjects resident in the study area. The validation cohort included 661 patients with ALS consecutively seen between 2001 and 2013 in the ALS Clinic Center of the Catholic University in Rome, Italy.
RESULTS:In the discovery cohort, the frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs 1 control, p = 0.0001; odds ratio 14.8, 95% confidence interval 1.9–110.8). Patients with an increased number of polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 1.8 years, interquartile range [IQR] 1.3–2.2; polyQ <31, 2.7 years, IQR 1.6–5.1; p = 0.001). An increased number of polyQ repeats remained independently significant at multivariable analysis. In the validation cohort, patients with ≥31 polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 2.0 years, IQR 1.5–3.4; polyQ <31, 3.2 years, IQR 2.0–6.4; p = 0.007).
CONCLUSIONS:ATXN2 polyQ intermediate-length repeat is a modifier of ALS survival. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS.</description><subject>Aged</subject><subject>Amyotrophic Lateral Sclerosis - diagnosis</subject><subject>Amyotrophic Lateral Sclerosis - genetics</subject><subject>Amyotrophic Lateral Sclerosis - mortality</subject><subject>Ataxins</subject><subject>Case-Control Studies</subject><subject>Cohort Studies</subject><subject>Female</subject><subject>Genetic Testing</subject><subject>Humans</subject><subject>Italy</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Peptides - genetics</subject><issn>0028-3878</issn><issn>1526-632X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkN9LwzAQx4Mobk7_A5E8-tKZpE2TPMkQf0GZiBP3VtLmyqrtWpN2Y_-9kU0RH_Re7uA-3zv4IHRKyZgyyi5epsmY_ChKudpDQ8pZHMQhm--jISFMBqEUcoCOnHv1DGdCHaIB435gMR-iy8lsPmW4barNIy6XHdgaTKk7wBZa0J3D2gLWuG5MWZRgcVPgSfKEXW9X5UpXx-ig0JWDk10foeeb69nVXZA83N5fTZIgj0KugkjElBmdqUJlRjIZKhVGBSFGKmOM4sSvmaAiojlTFDJQuZaFySUQDRFT4Qidb--2tnnvwXVpXbocqkovoeldSgVlXAjCo__RmLOI8JAQj0ZbNLeNcxaKtLVlre0mpST9tJx6y-lvyz52tvvQZ17Xd-hLqwfkFlg3lVfq3qp-DTZdgK66xd-3PwDEYYZO</recordid><startdate>20150120</startdate><enddate>20150120</enddate><creator>Chiò, Adriano</creator><creator>Calvo, Andrea</creator><creator>Moglia, Cristina</creator><creator>Canosa, Antonio</creator><creator>Brunetti, Maura</creator><creator>Barberis, Marco</creator><creator>Restagno, Gabriella</creator><creator>Conte, Amelia</creator><creator>Bisogni, Giulia</creator><creator>Marangi, Giuseppe</creator><creator>Moncada, Alice</creator><creator>Lattante, Serena</creator><creator>Zollino, Marcella</creator><creator>Sabatelli, Mario</creator><creator>Bagarotti, Alessandra</creator><creator>Corrado, Lucia</creator><creator>Mora, Gabriele</creator><creator>Bersano, Enrica</creator><creator>Mazzini, Letizia</creator><creator>DʼAlfonso, Sandra</creator><general>American Academy of Neurology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TK</scope></search><sort><creationdate>20150120</creationdate><title>ATXN2 polyQ intermediate repeats are a modifier of ALS survival</title><author>Chiò, Adriano ; Calvo, Andrea ; Moglia, Cristina ; Canosa, Antonio ; Brunetti, Maura ; Barberis, Marco ; Restagno, Gabriella ; Conte, Amelia ; Bisogni, Giulia ; Marangi, Giuseppe ; Moncada, Alice ; Lattante, Serena ; Zollino, Marcella ; Sabatelli, Mario ; Bagarotti, Alessandra ; Corrado, Lucia ; Mora, Gabriele ; Bersano, Enrica ; Mazzini, Letizia ; DʼAlfonso, Sandra</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4359-47612dab9f9bd82839934f00d89ddd950612271741c291ebe9ca8fdc8e0ae4293</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Aged</topic><topic>Amyotrophic Lateral Sclerosis - diagnosis</topic><topic>Amyotrophic Lateral Sclerosis - genetics</topic><topic>Amyotrophic Lateral Sclerosis - mortality</topic><topic>Ataxins</topic><topic>Case-Control Studies</topic><topic>Cohort Studies</topic><topic>Female</topic><topic>Genetic Testing</topic><topic>Humans</topic><topic>Italy</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Peptides - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chiò, Adriano</creatorcontrib><creatorcontrib>Calvo, Andrea</creatorcontrib><creatorcontrib>Moglia, Cristina</creatorcontrib><creatorcontrib>Canosa, Antonio</creatorcontrib><creatorcontrib>Brunetti, Maura</creatorcontrib><creatorcontrib>Barberis, Marco</creatorcontrib><creatorcontrib>Restagno, Gabriella</creatorcontrib><creatorcontrib>Conte, Amelia</creatorcontrib><creatorcontrib>Bisogni, Giulia</creatorcontrib><creatorcontrib>Marangi, Giuseppe</creatorcontrib><creatorcontrib>Moncada, Alice</creatorcontrib><creatorcontrib>Lattante, Serena</creatorcontrib><creatorcontrib>Zollino, Marcella</creatorcontrib><creatorcontrib>Sabatelli, Mario</creatorcontrib><creatorcontrib>Bagarotti, Alessandra</creatorcontrib><creatorcontrib>Corrado, Lucia</creatorcontrib><creatorcontrib>Mora, Gabriele</creatorcontrib><creatorcontrib>Bersano, Enrica</creatorcontrib><creatorcontrib>Mazzini, Letizia</creatorcontrib><creatorcontrib>DʼAlfonso, Sandra</creatorcontrib><creatorcontrib>PARALS</creatorcontrib><creatorcontrib>For PARALS</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><jtitle>Neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chiò, Adriano</au><au>Calvo, Andrea</au><au>Moglia, Cristina</au><au>Canosa, Antonio</au><au>Brunetti, Maura</au><au>Barberis, Marco</au><au>Restagno, Gabriella</au><au>Conte, Amelia</au><au>Bisogni, Giulia</au><au>Marangi, Giuseppe</au><au>Moncada, Alice</au><au>Lattante, Serena</au><au>Zollino, Marcella</au><au>Sabatelli, Mario</au><au>Bagarotti, Alessandra</au><au>Corrado, Lucia</au><au>Mora, Gabriele</au><au>Bersano, Enrica</au><au>Mazzini, Letizia</au><au>DʼAlfonso, Sandra</au><aucorp>PARALS</aucorp><aucorp>For PARALS</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ATXN2 polyQ intermediate repeats are a modifier of ALS survival</atitle><jtitle>Neurology</jtitle><addtitle>Neurology</addtitle><date>2015-01-20</date><risdate>2015</risdate><volume>84</volume><issue>3</issue><spage>251</spage><epage>258</epage><pages>251-258</pages><issn>0028-3878</issn><eissn>1526-632X</eissn><abstract>OBJECTIVE:To analyze the frequency and clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) with intermediate-length (CAG) expansion (encoding 27–33 glutamines, polyQ) in the ATXN2 gene, in a population-based cohort of Italian patients with ALS (discovery cohort), and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort).
METHODS:PolyQ repeats were assessed in 672 patients with incident ALS in Piemonte and Valle dʼAosta regions, Italy, in the 2007–2012 period (discovery cohort); controls were 509 neurologically healthy age- and sex-matched subjects resident in the study area. The validation cohort included 661 patients with ALS consecutively seen between 2001 and 2013 in the ALS Clinic Center of the Catholic University in Rome, Italy.
RESULTS:In the discovery cohort, the frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs 1 control, p = 0.0001; odds ratio 14.8, 95% confidence interval 1.9–110.8). Patients with an increased number of polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 1.8 years, interquartile range [IQR] 1.3–2.2; polyQ <31, 2.7 years, IQR 1.6–5.1; p = 0.001). An increased number of polyQ repeats remained independently significant at multivariable analysis. In the validation cohort, patients with ≥31 polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 2.0 years, IQR 1.5–3.4; polyQ <31, 3.2 years, IQR 2.0–6.4; p = 0.007).
CONCLUSIONS:ATXN2 polyQ intermediate-length repeat is a modifier of ALS survival. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS.</abstract><cop>United States</cop><pub>American Academy of Neurology</pub><pmid>25527265</pmid><doi>10.1212/WNL.0000000000001159</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Neurology, 2015-01, Vol.84 (3), p.251-258 |
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| language | eng |
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| source | MEDLINE; Alma/SFX Local Collection; Journals@Ovid Complete |
| subjects | Aged Amyotrophic Lateral Sclerosis - diagnosis Amyotrophic Lateral Sclerosis - genetics Amyotrophic Lateral Sclerosis - mortality Ataxins Case-Control Studies Cohort Studies Female Genetic Testing Humans Italy Male Middle Aged Nerve Tissue Proteins - genetics Peptides - genetics |
| title | ATXN2 polyQ intermediate repeats are a modifier of ALS survival |
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