Genotype-phenotype correlation in Pompe disease, a step forward
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RESEARCH
Open Access
Genotype-phenotype correlation in Pompe disease, a step forward Paola De Filippi1*†, Kolsoum Saeidi1†, Sabrina Ravaglia2, Andrea Dardis3, Corrado Angelini4, Tiziana Mongini5, Lucia Morandi6, Maurizio Moggio7, Antonio Di Muzio8, Massimiliano Filosto9, Bruno Bembi3, Fabio Giannini10, Giovanni Marrosu11, Miriam Rigoldi12, Paola Tonin13, Serenella Servidei14, Gabriele Siciliano15, Annalisa Carlucci16, Claudia Scotti1, Mario Comelli17, Antonio Toscano18, Cesare Danesino1 and The Italian GSDII Group
Abstract Background: Pompe’s disease is a progressive myopathy caused by mutations in the lysosomal enzyme acid alphaglucosidase gene (GAA). A wide clinical variability occurs also in patients sharing the same GAA mutations, even within the same family. Methods: For a large series of GSDII patients we collected some clinical data as age of onset of the disease, presence or absence of muscular pain, Walton score, 6-Minute Walking Test, Vital Capacity, and Creatine Kinase. DNA was extracted and tested for GAA mutations and some genetic polymorphisms able to influence muscle properties (ACE, ACTN3, AGT and PPARα genes). We compared the polymorphisms analyzed in groups of patients with Pompe disease clustered for their homogeneous genotype. Results: We have been able to identify four subgroups of patients completely homogeneous for their genotype, and two groups homogeneous as far as the second mutation is defined “very severe” or “potentially less severe”. When disease free life was studied we observed a high significant difference between groups. The DD genotype in the ACE gene and the XX genotype in the ACTN3 gene were significantly associated to an earlier age of onset of the disease. The ACE DD genotype was also associated to the presence of muscle pain. Conclusions: We demonstrate that ACE and ACTN3 polymorphisms are genetic factors able to modulate the clinical phenotype of patients affected with Pompe disease. Keywords: Glycogen storage disease type II, Genetic polymorphisms, Modifier genes, GAA, ACE, ACTN3
Background Glycogen Storage Disease type II (GSDII) or Pompe disease (OMIM 232300) is a lysosomal storage disorder caused by mutations in the acid alpha-glucosidase (GAA) gene whose frequency is about 1 in 40000–50000 in European and US Populations and apparently much lower in Australia or Portugal [1]. A comprehensive review of clinical and genetic data was published by van der Ploeg and Reuser [2]. More than 300 different mutations have been described [3], without strict genotype-phenotype correlations [4]. Even within families large variations in * Correspondence: [email protected] † Equal contributors 1 Department of Molecular Medicine, University of Pavia, Pavia, Italy Full list of author information is available at the end of the article
disease severity can be observed; a recent report by Wens et al. [5] demonstrates as presenting symptoms were different in sibling in 8/22 (36%) families. The clinical heterogeneity of GSDII is more frequently observed among late-onset patients (i
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