title: Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients.
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).
authors.affiliation: Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università degli Studi di Milano, Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Guglieri
authors.forename: Francesca
authors.initials: F
authors.lastname: Magri
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: D'Angelo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prelle
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.forename: Carmelo
authors.initials: C
authors.lastname: Rodolico
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.forename: Francesco
authors.initials: F
authors.lastname: Fortunato
authors.forename: Andreina
authors.initials: A
authors.lastname: Bordoni
authors.forename: Roberto
authors.initials: R
authors.lastname: Del Bo
authors.forename: Serena
authors.initials: S
authors.lastname: Ghezzi
authors.forename: Serena
authors.initials: S
authors.lastname: Pagliarani
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lucchiari
authors.forename: Sabrina
authors.initials: S
authors.lastname: Salani
authors.forename: Chiara
authors.initials: C
authors.lastname: Zecca
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.forename: Dario
authors.initials: D
authors.lastname: Ronchi
authors.forename: Mohammed
authors.initials: M
authors.lastname: Aguennouz
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ciscato
authors.forename: Claudia
authors.initials: C
authors.lastname: Di Blasi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ruggieri
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.forename: Anna
authors.initials: A
authors.lastname: Turconi
authors.forename: Antonio
authors.initials: A
authors.lastname: Toscano
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D002154:Calpain / Q000737:chemistry / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005799:Genes, Dominant; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007223:Infant; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D049288:Muscular Dystrophies, Limb-Girdle / Q000145:classification / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D044465:White People / Q000235:genetics*
chemical_list: D002154:Calpain