Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients

Michela Guglieri, Francesca Magri, Maria Grazia D'Angelo, Alessandro Prelle, Lucia Morandi, Carmelo Rodolico, Rachele Cagliani, Marina Mora, Francesco Fortunato, Andreina Bordoni, Roberto Del Bo, Serena Ghezzi, Serena Pagliarani, Sabrina Lucchiari, Sabrina Salani, Chiara Zecca, Costanza Lamperti, Dario Ronchi, Mohammed Aguennouz, Patrizia CiscatoClaudia Di Blasi, Alessandra Ruggieri, Isabella Moroni, Anna Turconi, Antonio Toscano, Maurizio Moggio, Nereo Bresolin, Giacomo P. Comi

Research output: Contribution to journalArticle

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), α-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 (γ-sarcoglycan) 4.5%; LGMD2D (α-sarcoglycan) 8.4%; LGMD2E (β-sarcoglycan) 4.5%; LGMD2F (δ-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).

Original languageEnglish
Pages (from-to)258-266
Number of pages9
JournalHuman Mutation
Volume29
Issue number2
DOIs
Publication statusPublished - Feb 2008

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Keywords

  • Genotype-phenotype
  • LGMD
  • Limb girdle muscular dystrophy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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