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
Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università degli Studi di Milano, Milano, Italy.
Hum Mutat. 2008 Feb;29(2):258-66. doi: 10.1002/humu.20642.
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).
肢带型肌营养不良症（LGMD）具有遗传和临床异质性：到目前为止，已确定了7个常染色体显性和12个常染色体隐性基因座。本研究的目的是评估181例以意大利人为主的LGMD患者（代表155个独立家庭）中不同类型LGMD的相对比例，描述不同形式的临床模式，并确定基因型、表型和蛋白质表达水平之间可能的相关性，作为预后因素。根据蛋白质数据，大多数先证者（n = 72）表现为钙蛋白酶-3缺乏；其他缺陷如下：肌膜蛋白（n = 31）、肌聚糖（n = 32）、α-抗肌萎缩蛋白聚糖（n = 4）和小窝蛋白-3（n = 2）。基因分析确定了111种不同的突变，其中包括47种新突变。LGMD的相对频率如下：LGMD1C（小窝蛋白-3）1.3%；LGMD2A（钙蛋白酶-3）28.4%；LGMD2B（肌膜蛋白）18.7%；LGMD2C（γ-肌聚糖）4.5%；LGMD2D（α-肌聚糖）8.4%；LGMD2E（β-肌聚糖）4.5%；LGMD2F（δ-肌聚糖）0.7%；LGMD2I（福库汀相关蛋白）6.4%；未确定的占27.1%。与北欧人群相比，意大利患者患LGMD2I的可能性较小。临床严重程度由高到低的顺序为：肌聚糖病、钙蛋白酶病、肌膜蛋白病和小窝蛋白病。LGMD2I患者表现出婴儿期非先天性和轻度晚发性症状。疾病发病年龄与LGMD2B中的基因型和蛋白质水平的变异性相关。截短突变比错义替代发病更早（20±5.1岁对36.7±11.1岁；P = 0.0037）。同样，与部分缺乏相比，肌膜蛋白缺乏与发病更早相关（20.2±标准差[SD]5.2岁对28.4±SD 11.2岁；P = 0.014）。
