{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:35:45Z","timestamp":1792460145787,"version":"4.5.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:00:00Z","timestamp":1621555200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:00:00Z","timestamp":1621555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100010154","name":"FISEVI","doi-asserted-by":"crossref","award":["0826-N-15"],"award-info":[{"award-number":["0826-N-15"]}],"id":[{"id":"10.13039\/100010154","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Pompe disease (PD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the acid \u03b1-glucosidase gene (<jats:italic>GAA<\/jats:italic>) that produces defects in the lysosomal acid \u03b1-1,4-glucosidase. We aimed to identify genetic variations and clinical features in Spanish subjects to establish genotype\u2013phenotype correlation.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>A total of 2637 samples of patients who showed symptoms or susceptible signs of PD were enrolled in this observational study. Enzymatic activity was detected by fluorometric techniques and the genetic study was carried out using Next-Generation Sequencing.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Fourteen different variants from 17 diagnosed patients were identified, seven males and nine females with LOPD (mean age 36.07, SD 20.57, range 7\u201364) and a 2-day-old boy with IOPD, four genetic variants had not been described in the literature previously, including a homozygous variant. In all of them \u03b1-glucosidase activity was decreased. Muscle weakness, respiratory distress, exercise intolerance, hypotonia, dysphagia and myalgia were commonly observed in patients.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This study report four new genetic variants that contribute to the pathogenic variants spectrum of the <jats:italic>GAA<\/jats:italic> gene. We confirm that patients in Spain have a characteristic profile of a European population, with c.-32-13T&gt;G being the most prevalent variant. Furthermore, it was confirmed that the c.236_246delCCACACAGTGC pathogenic variant in homozygosity is associated with early disease and a worse prognosis.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-021-01864-8","type":"journal-article","created":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T07:02:55Z","timestamp":1621580575000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Genotype\u2013phenotype correlation of 17 cases of Pompe disease in Spanish patients and identification of 4 novel GAA variants"],"prefix":"10.1186","volume":"16","author":[{"given":"Paula","family":"Hern\u00e1ndez-Ar\u00e9valo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 D.","family":"Santotoribio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"Delarosa-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Gonz\u00e1lez-Meneses","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador","family":"Garc\u00eda-Morillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"Jim\u00e9nez-Arriscado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan M.","family":"Guerrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8622-1175","authenticated-orcid":false,"given":"Hada C.","family":"Macher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,21]]},"reference":[{"issue":"2","key":"1864_CR1","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1002\/ajmg.a.35662","volume":"161A","author":"D G\u00fcng\u00f6r","year":"2013","unstructured":"G\u00fcng\u00f6r D, Reuser AJ. How to describe the clinical spectrum in Pompe disease? Am J Med Genet A. 2013;161A(2):399\u2013400.","journal-title":"Am J Med Genet A"},{"issue":"9","key":"1864_CR2","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/s13023-014-0102-z","volume":"8","author":"P De Filippi","year":"2014","unstructured":"De Filippi P, Saeidi K, Ravaglia S, Dardis A, Angelini C, Mongini T, Morandi L, Moggio M, Di Muzio A, Filosto M, Bembi B, Giannini F, Marrosu G, Rigoldi M, Tonin P, Servidei S, Siciliano G, Carlucci A, Scotti C, Comelli M, Toscano A, Danesino C. Genotype-phenotype correlation in Pompe disease, a step forward. Orphanet J Rare Dis. 2014;8(9):102.","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"1864_CR3","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1002\/(SICI)1096-8628(19980827)79:1<69::AID-AJMG16>3.0.CO;2-K","volume":"79","author":"F Martiniuk","year":"1998","unstructured":"Martiniuk F, Chen A, Mack A, Arvanitopoulos E, Chen Y, Rom WN, et al. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet. 1998;79(1):69\u201372.","journal-title":"Am J Med Genet"},{"issue":"3","key":"1864_CR4","first-page":"80","volume":"154","author":"J Alonso-P\u00e9rez","year":"2020","unstructured":"Alonso-P\u00e9rez J, Segovia S, Dom\u00ednguez-Gonz\u00e1lez C, et al. Spanish Pompe registry: baseline characteristics of first 49 patients with adult onset of Pompe disease. Med Cl\u00edn (Engl Ed). 2020;154(3):80\u20135.","journal-title":"Med Cl\u00edn (Engl Ed)"},{"issue":"13","key":"1864_CR5","doi-asserted-by":"publisher","first-page":"278","DOI":"10.21037\/atm.2019.04.13","volume":"7","author":"P Peruzzo","year":"2019","unstructured":"Peruzzo P, Pavan E, Dardis A. Molecular genetics of Pompe disease: a comprehensive overview. Ann Transl Med. 2019;7(13):278.","journal-title":"Ann Transl Med"},{"issue":"3","key":"1864_CR6","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.ymgme.2011.06.010","volume":"104","author":"CC Yang","year":"2011","unstructured":"Yang CC, Chien YH, Lee NC, et al. Rapid progressive course of later-onset Pompe disease in Chinese patients. Mol Genet Metab. 2011;104(3):284\u20138.","journal-title":"Mol Genet Metab"},{"key":"1864_CR7","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1186\/s12881-014-0141-2","volume":"15","author":"X Liu","year":"2014","unstructured":"Liu X, Wang Z, Jin W, et al. Clinical and GAA gene mutation analysis in mainland Chinese patients with late-onset Pompe disease: identifying c.2238G > C as the most common mutation. BMC Med Genet. 2014;15:141.","journal-title":"BMC Med Genet"},{"issue":"1\u20132","key":"1864_CR8","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.cccn.2004.04.009","volume":"347","author":"NA Chamoles","year":"2004","unstructured":"Chamoles NA, Niizawa G, Blanco M, Gaggioli D, Casentini C. Glycogen storage disease type II: enzymatic screening in dried blood spots on filter paper. Clin Chim Acta. 2004;347(1\u20132):97\u2013102.","journal-title":"Clin Chim Acta"},{"issue":"5","key":"1864_CR9","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1097\/01.gim.0000217781.66786.9b","volume":"8","author":"H Zhang","year":"2006","unstructured":"Zhang H, Kallwass H, Young SP, et al. Comparison of maltose and acarbose as inhibitors of maltase-glucoamylase activity in assaying acid alpha-glucosidase activity in dried blood spots for the diagnosis of infantile Pompe disease. Genet Med. 2006;8(5):302\u20136.","journal-title":"Genet Med"},{"issue":"5","key":"1864_CR10","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1097\/01.gim.0000217785.19262.9e","volume":"8","author":"RM Jack","year":"2006","unstructured":"Jack RM, Gordon C, Scott CR, Kishnani PS, Bali D. The use of acarbose inhibition in the measurement of acid alpha-glucosidase activity in blood lymphocytes for the diagnosis of Pompe disease. Genet Med. 2006;8(5):307\u201312.","journal-title":"Genet Med"},{"issue":"3","key":"1864_CR11","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.ymgme.2013.08.005","volume":"110","author":"N Preisler","year":"2013","unstructured":"Preisler N, Lukacs Z, Vinge L, et al. Late-onset Pompe disease is prevalent in unclassified limb-girdle muscular dystrophies. Mol Genet Metab. 2013;110(3):287\u20139.","journal-title":"Mol Genet Metab"},{"issue":"2","key":"1864_CR12","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.ymgme.2013.03.002","volume":"109","author":"M Spada","year":"2013","unstructured":"Spada M, Porta F, Vercelli L, Pagliardini V, Chiad\u00f2-Piat L, Boffi P, Pagliardini S, Remiche G, Ronchi D, Comi G, Mongini T. Screening for later-onset Pompe\u2019s disease in patients with paucisymptomatic hyperCKemia. Mol Genet Metab. 2013;109(2):171\u20133.","journal-title":"Mol Genet Metab"},{"key":"1864_CR13","volume-title":"GeneReviews\u00ae","author":"N Leslie","year":"2007","unstructured":"Leslie N, Bailey L, et al. Pompe Disease. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews\u00ae. Seattle: University of Washington Seattle; 2007."},{"issue":"4","key":"1864_CR14","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1007\/s13311-018-0655-y","volume":"15","author":"L Kohler","year":"2018","unstructured":"Kohler L, Puertollano R, Raben N. Pompe disease: from basic science to therapy. Neurotherapeutics. 2018;15(4):928\u201342.","journal-title":"Neurotherapeutics"},{"issue":"Pt 3","key":"1864_CR15","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1093\/brain\/awh384","volume":"128","author":"ML Hagemans","year":"2005","unstructured":"Hagemans ML, Winkel LP, Van Doorn PA, et al. Clinical manifestation and natural course of late-onset Pompe\u2019s disease in 54 Dutch patients. Brain. 2005;128(Pt 3):671\u20137.","journal-title":"Brain"},{"issue":"2","key":"1864_CR16","doi-asserted-by":"publisher","first-page":"31","DOI":"10.3390\/ijns6020031","volume":"6","author":"T Sawada","year":"2020","unstructured":"Sawada T, Kido J, Nakamura K. Newborn screening for Pompe disease. Int J Neonatal Screen. 2020;6(2):31.","journal-title":"Int J Neonatal Screen"},{"issue":"9\u201310","key":"1864_CR17","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1016\/j.nmd.2007.06.002","volume":"17","author":"W M\u00fcller-Felber","year":"2007","unstructured":"M\u00fcller-Felber W, Horvath R, Gempel K, et al. Late onset Pompe disease: clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients. Neuromuscul Disord. 2007;17(9\u201310):698\u2013706.","journal-title":"Neuromuscul Disord"},{"issue":"5","key":"1864_CR18","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1007\/s00415-011-6293-5","volume":"259","author":"C Angelini","year":"2012","unstructured":"Angelini C, Semplicini C, Ravaglia S, et al. Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy for up to 4 years. J Neurol. 2012;259(5):952\u20138.","journal-title":"J Neurol"},{"issue":"13","key":"1864_CR19","doi-asserted-by":"publisher","first-page":"284","DOI":"10.21037\/atm.2019.07.24","volume":"7","author":"A Toscano","year":"2019","unstructured":"Toscano A, Rodolico C, Musumeci O. Multisystem late onset Pompe disease (LOPD): an update on clinical aspects. Ann Transl Med. 2019;7(13):284.","journal-title":"Ann Transl Med"},{"issue":"2","key":"1864_CR20","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1542\/peds.112.2.332","volume":"112","author":"HM van den Hout","year":"2003","unstructured":"van den Hout HM, Hop W, van Diggelen OP, et al. The natural course of infantile Pompe\u2019s disease: 20 original cases compared with 133 cases from the literature. Pediatrics. 2003;112(2):332\u201340.","journal-title":"Pediatrics"},{"issue":"10","key":"1864_CR21","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1002\/humu.20374","volume":"27","author":"AL Montalvo","year":"2006","unstructured":"Montalvo AL, Bembi B, Donnarumma M, et al. Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II. Hum Mutat. 2006;27(10):999\u20131006.","journal-title":"Hum Mutat"},{"issue":"4","key":"1864_CR22","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.ymgme.2007.07.006","volume":"92","author":"ME McCready","year":"2007","unstructured":"McCready ME, Carson NL, Chakraborty P, et al. Development of a clinical assay for detection of GAA mutations and characterization of the GAA mutation spectrum in a Canadian cohort of individuals with glycogen storage disease, type II. Mol Genet Metab. 2007;92(4):325\u201335.","journal-title":"Mol Genet Metab"},{"issue":"8","key":"1864_CR23","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1186\/1750-1172-8-182","volume":"19","author":"SC Wens","year":"2013","unstructured":"Wens SC, van Gelder CM, Kruijshaar ME, de Vries JM, van der Beek NA, Reuser AJ, van Doorn PA, van der Ploeg AT, Brusse E. Phenotypical variation within 22 families with Pompe disease. Orphanet J Rare Dis. 2013;19(8):182.","journal-title":"Orphanet J Rare Dis"},{"issue":"7","key":"1864_CR24","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/1750-1172-7-35","volume":"7","author":"A Herzog","year":"2012","unstructured":"Herzog A, Hartung R, Reuser AJ, Hermanns P, Runz H, Karabul N, G\u00f6kce S, Pohlenz J, Kampmann C, Lampe C, Beck M, Mengel E. A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations. Orphanet J Rare Dis. 2012;7(7):35.","journal-title":"Orphanet J Rare Dis"},{"issue":"4","key":"1864_CR25","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1007\/s00415-015-7664-0","volume":"262","author":"F Montagnese","year":"2015","unstructured":"Montagnese F, Barca E, Musumeci O, et al. Clinical and molecular aspects of 30 patients with late-onset Pompe disease (LOPD): unusual features and response to treatment. J Neurol. 2015;262(4):968\u201378.","journal-title":"J Neurol"},{"issue":"1","key":"1864_CR26","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.nmd.2006.09.004","volume":"17","author":"RE Palmer","year":"2007","unstructured":"Palmer RE, Amartino HM, Niizawa G, Blanco M, Pomponio RJ, Chamoles NA. Pompe disease (glycogen storage disease type II) in Argentineans: clinical manifestations and identification of 9 novel mutations. Neuromuscul Disord. 2007;17(1):16\u201322.","journal-title":"Neuromuscul Disord"},{"issue":"8","key":"1864_CR27","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1016\/j.nmd.2012.02.003","volume":"22","author":"LK Jones Jr","year":"2012","unstructured":"Jones LK Jr, Liewluck T, Gavrilova RH. Myalgic phenotype and preserved muscle strength in adult-onset acid maltase deficiency. Neuromuscul Disord. 2012;22(8):763\u20136.","journal-title":"Neuromuscul Disord"},{"issue":"1\u20132","key":"1864_CR28","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.jns.2006.09.012","volume":"251","author":"YE Park","year":"2006","unstructured":"Park YE, Park KH, Lee CH, Kim CM, Kim DS. Two new missense mutations of GAA in late onset glycogen storage disease type II. J Neurol Sci. 2006;251(1\u20132):113\u20137.","journal-title":"J Neurol Sci"},{"issue":"4","key":"1864_CR29","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1212\/01.WNL.0000048661.95327.BF","volume":"60","author":"CW Lam","year":"2003","unstructured":"Lam CW, Yuen YP, Chan KY, et al. Juvenile-onset glycogen storage disease type II with novel mutations in acid alpha-glucosidase gene. Neurology. 2003;60(4):715\u20137.","journal-title":"Neurology"},{"issue":"1","key":"1864_CR30","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1002\/ajmg.c.31319","volume":"160C","author":"DS Bali","year":"2012","unstructured":"Bali DS, Goldstein JL, Banugaria S, et al. Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience. Am J Med Genet C Semin Med Genet. 2012;160C(1):40\u20139.","journal-title":"Am J Med Genet C Semin Med Genet"},{"issue":"2","key":"1864_CR31","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1007\/s10545-014-9707-6","volume":"38","author":"CM van Gelder","year":"2015","unstructured":"van Gelder CM, Hoogeveen-Westerveld M, Kroos MA, Plug I, van der Ploeg AT, Reuser AJ. Enzyme therapy and immune response in relation to CRIM status: the Dutch experience in classic infantile Pompe disease. J Inherit Metab Dis. 2015;38(2):305\u201314. https:\/\/doi.org\/10.1007\/s10545-014-9707-6.","journal-title":"J Inherit Metab Dis"},{"issue":"3","key":"1864_CR32","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1007\/s13353-018-0444-7","volume":"59","author":"A Anna","year":"2018","unstructured":"Anna A, Monika G. Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet. 2018;59(3):253\u201368.","journal-title":"J Appl Genet"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-01864-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-021-01864-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-01864-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T07:03:54Z","timestamp":1621580634000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-021-01864-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,21]]},"references-count":32,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1864"],"URL":"https:\/\/doi.org\/10.1186\/s13023-021-01864-8","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,21]]},"assertion":[{"value":"21 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Informed consent was signed by all patients and the study was approved by the Ethics and Research Committee of the Virgen Macarena and Virgen del Roc\u00edo University Hospital (Code: 0826-N-15).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"233"}}