Article

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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    • "Dysferlinopathies are autosomal recessive muscular dystrophies caused by mutations in the gene encoding dysferlin (DYSF; Online Mendelian Inheritance in Man [OMIM] gene number 603009, Chr 2p13, GenBank NM_003494.2) [1,2]. Dysferlinopathies are rare muscular dystrophies, as the number of adult patients is estimated between 1/100,000 to 1/200,000 [3]. Miyoshi myopathy [4] (MM) and distal anterior compartment myopathy [5] (DMAT), both allelic distal muscle disorders that preferentially affect the gastrocnemius or tibial muscle, and limb girdle muscular dystrophy (LGMD) type 2B with characteristic proximal weakness at onset [1,2] represent different phenotypic presentations of dysferlinopathy. "
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    ABSTRACT: BACKGROUND: Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). METHODS: We assessed the one-year-natural course of dysferlinopathy, and the safety and efficacy of deflazacort treatment in a double-blind, placebo-controlled cross-over trial. After one year of natural course without intervention, 25 patients with genetically defined dysferlinopathy were randomized to receive deflazacort and placebo for six months each (1 mg/kg/day in month one, 1 mg/kg every 2nd day during months two to six) in one of two treatment sequences. RESULTS: During one year of natural course, muscle strength declined about 2% as measured by CIDD (Clinical Investigation of Duchenne Dystrophy) score, and 76 Newton as measured by hand-held dynamometry. Deflazacort did not improve muscle strength. In contrast, there is a trend of worsening muscle strength under deflazacort treatment, which recovers after discontinuation of the study drug. During deflazacort treatment, patients showed a broad spectrum of steroid side effects. CONCLUSION: Deflazacort is not an effective therapy for dysferlinopathies, and off-label use is not warranted. This is an important finding, since steroid treatment should not be administered in patients with dysferlinopathy, who may be often misdiagnosed as polymyositis.Trial registration: This clinical trial was registered at www.ClincalTrials.gov, identifier: NCT00527228, and was always freely accessible to the public.
    Orphanet Journal of Rare Diseases 02/2013; 8(1):26. DOI:10.1186/1750-1172-8-26 · 3.96 Impact Factor
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    • "Because of the success of Alloca et al., it was our intent to take advantage of the transduction capabilities of AAV5 for skeletal muscle [30]. We targeted the dysferlin gene because of its relative frequency amongst the LGMDs [5], [40]. Our findings are supportive of the unique properties of AAV5 to express a 6.5 kb cDNA producing full length protein but the mechanism for expression of the dysferlin gene pointed in a different direction than reported for the series of retinal genes protecting against blindness [30]. "
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    ABSTRACT: The dysferlinopathies comprise a group of untreatable muscle disorders including limb girdle muscular dystrophy type 2B, Miyoshi myopathy, distal anterior compartment syndrome, and rigid spine syndrome. As with other forms of muscular dystrophy, adeno-associated virus (AAV) gene transfer is a particularly auspicious treatment strategy, however the size of the DYSF cDNA (6.5 kb) negates packaging into traditional AAV serotypes known to express well in muscle (i.e. rAAV1, 2, 6, 8, 9). Potential advantages of a full cDNA versus a mini-gene include: maintaining structural-functional protein domains, evading protein misfolding, and avoiding novel epitopes that could be immunogenic. AAV5 has demonstrated unique plasticity with regards to packaging capacity and recombination of virions containing homologous regions of cDNA inserts has been implicated in the generation of full-length transcripts. Herein we show for the first time in vivo that homologous recombination following AAV5.DYSF gene transfer leads to the production of full length transcript and protein. Moreover, gene transfer of full-length dysferlin protein in dysferlin deficient mice resulted in expression levels sufficient to correct functional deficits in the diaphragm and importantly in skeletal muscle membrane repair. Intravascular regional gene transfer through the femoral artery produced high levels of transduction and enabled targeting of specific muscle groups affected by the dysferlinopathies setting the stage for potential translation to clinical trials. We provide proof of principle that AAV5 mediated delivery of dysferlin is a highly promising strategy for treatment of dysferlinopathies and has far-reaching implications for the therapeutic delivery of other large genes.
    PLoS ONE 06/2012; 7(6):e39233. DOI:10.1371/journal.pone.0039233 · 3.23 Impact Factor
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    • "This heterogeneity was observed even in the same family with the same mutation (8, 9). It is well-known that LGMD2B is one of the most common forms of limb girdle muscular dystrophy (10, 11). However, there are few reports of patients with dysferlinopathy in Korea (12-14). "
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    ABSTRACT: Dysferlinopathy is caused by mutations in the DYSF gene. To characterize the clinical spectrum, we investigated the characteristics of 31 Korean dysferlinopathy patients confirmed by immunohistochemistry. The mean age of symptom onset was 22.23 ± 7.34 yr. The serum creatine kinase (CK) was highly increased (4- to 101-fold above normal). The pathological findings of muscle specimens showed nonspecific dystrophic features and frequent inflammatory cell infiltration. Muscle imaging studies showed fatty atrophic changes dominantly in the posterolateral muscles of the lower limb. The patients with dysferlinopathy were classified by initial muscle weakness: fifteen patients with Miyoshi myopathy phenotype (MM), thirteen patients with limb girdle muscular dystrophy 2B phenotype (LGMD2B), two patients with proximodistal phenotype, and one asymptomatic patient. There were no differences between LGMD2B and MM groups in terms of onset age, serum CK levels and pathological findings. Dysferlinopathy patients usually have young adult onset and high serum CK levels. However, heterogeneity of clinical presentations and pathologic findings upon routine staining makes it difficult to diagnose dysferlinopathy. These limitations make immunohistochemistry currently the most important method for the diagnosis of dysferlinopathy.
    Journal of Korean medical science 04/2012; 27(4):423-9. DOI:10.3346/jkms.2012.27.4.423 · 1.25 Impact Factor
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