Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients |
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Authors: | Guglieri Michela Magri Francesca D'Angelo Maria Grazia Prelle Alessandro Morandi Lucia Rodolico Carmelo Cagliani Rachele Mora Marina Fortunato Francesco Bordoni Andreina Del Bo Roberto Ghezzi Serena Pagliarani Serena Lucchiari Sabrina Salani Sabrina Zecca Chiara Lamperti Costanza Ronchi Dario Aguennouz Mohammed Ciscato Patrizia Di Blasi Claudia Ruggieri Alessandra Moroni Isabella Turconi Anna Toscano Antonio Moggio Maurizio Bresolin Nereo Comi Giacomo P |
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Affiliation: | Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università degli Studi di Milano, Milano, Italy. |
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Abstract: | Limb girdle muscular dystrophies (LGMD) are characterized by genetic and clinical heterogeneity: seven autosomal dominant and 12 autosomal recessive loci have so far been identified. Aims of this study were to evaluate the relative proportion of the different types of LGMD in 181 predominantly Italian LGMD patients (representing 155 independent families), to describe the clinical pattern of the different forms, and to identify possible correlations between genotype, phenotype, and protein expression levels, as prognostic factors. Based on protein data, the majority of probands (n=72) presented calpain-3 deficiency; other defects were as follows: dysferlin (n=31), sarcoglycans (n=32), alpha-dystroglycan (n=4), and caveolin-3 (n=2). Genetic analysis identified 111 different mutations, including 47 novel ones. LGMD relative frequency was as follows: LGMD1C (caveolin-3) 1.3%; LGMD2A (calpain-3) 28.4%; LGMD2B (dysferlin) 18.7%; LGMD2C (gamma-sarcoglycan) 4.5%; LGMD2D (alpha-sarcoglycan) 8.4%; LGMD2E (beta-sarcoglycan) 4.5%; LGMD2F (delta-sarcoglycan) 0.7%; LGMD2I (Fukutin-related protein) 6.4%; and undetermined 27.1%. Compared to Northern European populations, Italian patients are less likely to be affected with LGMD2I. The order of decreasing clinical severity was: sarcoglycanopathy, calpainopathy, dysferlinopathy, and caveolinopathy. LGMD2I patients showed both infantile noncongenital and mild late-onset presentations. Age at disease onset correlated with variability of genotype and protein levels in LGMD2B. Truncating mutations determined earlier onset than missense substitutions (20+/-5.1 years vs. 36.7+/-11.1 years; P=0.0037). Similarly, dysferlin absence was associated with an earlier onset when compared to partial deficiency (20.2+/-standard deviation [SD] 5.2 years vs. 28.4+/-SD 11.2 years; P=0.014). |
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Keywords: | limb girdle muscular dystrophy LGMD genotype–phenotype |
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