Limb-girdle muscular dystrophy in the United States

University of Iowa, Iowa City, 52242, USA.
Journal of Neuropathology and Experimental Neurology (Impact Factor: 4.37). 11/2006; 65(10):995-1003. DOI: 10.1097/01.jnen.0000235854.77716.6c
Source: PubMed

ABSTRACT Limb-girdle muscular dystrophy (LGMD) has been linked to 15 chromosomal loci, 7 autosomal-dominant (LGMD1A to E) and 10 autosomal-recessive (LGMD2A to J). To determine the distribution of subtypes among patients in the United States, 6 medical centers evaluated patients with a referral diagnosis of LGMD. Muscle biopsies provided histopathology and immunodiagnostic testing, and their protein abnormalities along with clinical parameters directed mutation screening. The diagnosis in 23 patients was a disorder other than LGMD. Of the remaining 289 unrelated patients, 266 had muscle biopsies sufficient for complete microscopic evaluation; 121 also underwent Western blotting. From this combined evaluation, the distribution of immunophenotypes is 12% calpainopathy, 18% dysferlinopathy, 15% sarcoglycanopathy, 15% dystroglycanopathy, and 1.5% caveolinopathy. Genotypes distributed among 2 dominant and 7 recessive subtypes have been determined for 83 patients. This study of a large racially and ethnically diverse population of patients with LGMD indicates that establishing a putative subtype is possible more than half the time using available diagnostic testing. An efficient approach to genotypic diagnosis is muscle biopsy immunophenotyping followed by directed mutational analysis. The most common LGMDs in the United States are calpainopathies, dysferlinopathies, sarcoglycanopathies, and dystroglycanopathies.

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Available from: Katherine D Mathews, Aug 02, 2015
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    • "The mutation distribution was as follows: 50 FKRP cases (26 LGMD and 24 CMD); 7 FKTN cases (1 LGMD and the remaining CMDs, including 3 WWS); 3 POMT1 cases (all severe CMD/WWS); 5 POMT2 cases (all severe CMD/WWS), and 2 POMGnT1 cases (both MEB). (Some of the FKRP-LGMD cases were reported in Moore et al. [11] "
    Neuromuscular Disorders 03/2009; 19(3):229-34. DOI:10.1016/j.nmd.2008.11.008 · 3.13 Impact Factor
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    • "Cryosections of skeletal muscle were stained with hematoxylin and eosin (H&E) and underwent standard immunofluorescence staining using a panel of antibodies directed at muscular dystrophy-associated proteins [10]. Fluorescence microscopy was performed for dystrophin (Developmental Studies Hybridoma Bank, rod domain antibody 6A9), b-dystroglycan (Novocastra), and a-dystroglycan (glycoepitope antibody IIH6) [10]. Immunofluorescence was also performed with the core a-dystroglycan antibody, GT20ADG [11] "
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    ABSTRACT: The dystroglycanopathies comprise a clinically and genetically heterogeneous group of muscular dystrophies characterized by deficient glycosylation of alpha-dystroglycan. Mutations in the fukutin (FKTN) gene have primarily been identified among patients with classic Fukuyama congenital muscular dystrophy (FCMD), a severe form of dystroglycanopathy characterized by CMD, cobblestone lissencephaly and ocular defects. We describe two brothers of Caucasian and Japanese ancestry with normal intelligence and limb-girdle muscular dystrophy (LGMD) due to compound heterozygous FKTN mutations. Muscle biopsy showed a dystrophy with selectively reduced alpha-dystroglycan glycoepitope immunostaining. Immunoblots revealed hypoglycosylation of alpha-dystroglycan and loss of laminin binding. FKTN gene sequencing identified two variants: c.340G>A and c.527T>C, predicting missense mutations p.A114T and p.F176S, respectively. Our results provide further evidence for ethnic and allelic heterogeneity and the presence of milder phenotypes in FKTN-dystroglycanopathy despite a substantial degree of alpha-dystroglycan hypoglycosylation in skeletal muscle.
    Neuromuscular Disorders 03/2009; 19(5):352-6. DOI:10.1016/j.nmd.2009.03.001 · 3.13 Impact Factor
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    • "Limb girdle muscular dystrophies (LGMDs) are a heterogeneous group of inherited progressive muscle disorders affecting predominantly the shoulder and pelvic girdle muscles. There are at least 19 different subtypes of LGMD, seven with an autosomal dominant and 12 with an autosomal recessive pattern of inheritance [Bushby, 1999; Mathews and Moore, 2003; Starling et al., 2004; Guglieri et al., 2005; D'Amico et al., 2006; Jarry et al., 2007; Moore et al., 2006]. The autosomal dominant forms (LGMD1) are relatively rare and represent probably less than 10% of all LGMD cases. "
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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).
    Human Mutation 02/2008; 29(2):258-66. DOI:10.1002/humu.20642 · 5.05 Impact Factor
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