Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients.
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).
Guglieri
Michela
M
Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università degli Studi di Milano, Milano, Italy.
Magri
Francesca
F
D'Angelo
Maria Grazia
MG
Prelle
Alessandro
A
Morandi
Lucia
L
Rodolico
Carmelo
C
Cagliani
Rachele
R
Mora
Marina
M
Fortunato
Francesco
F
Bordoni
Andreina
A
Del Bo
Roberto
R
Ghezzi
Serena
S
Pagliarani
Serena
S
Lucchiari
Sabrina
S
Salani
Sabrina
S
Zecca
Chiara
C
Lamperti
Costanza
C
Ronchi
Dario
D
Aguennouz
Mohammed
M
Ciscato
Patrizia
P
Di Blasi
Claudia
C
Ruggieri
Alessandra
A
Moroni
Isabella
I
Turconi
Anna
A
Toscano
Antonio
A
Moggio
Maurizio
M
Bresolin
Nereo
N
Comi
Giacomo P
GP
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*
D002154:Calpain