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      Limb girdle muscular dystrophy type 2L presenting as necrotizing myopathy

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          Abstract

          Recessive mutations in the ANO5 gene, encoding anoctamin 5, cause proximal limb girdle muscular dystrophy (LGMD2L), Miyoshi-type distal myopathy (MM3) and asymptomatic hyper- CKemia.

          We report a woman with exertion-induced myalgia and weakness in the hip girdle manifesting at the age of 40. Creatine kinase (CK) was increased 20-fold. Histologically the dominating feature was necrotizing myopathy, but long-term immunosuppressive therapy did not change CK level or myopathic symptoms. Molecular genetic investigation led to the finding of the homozygous ANO5 c.191dupA mutation. This is a report of a muscular dystrophy due to ANO5 mutation presenting histologically as necrotizing myopathy. For this reason our finding extends the histological spectrum of myopathies due to ANO5 mutations as well as the possible differential diagnoses for necrotizing myopathy.

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          Most cited references 10

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          Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies.

          The recently described human anion channel Anoctamin (ANO) protein family comprises at least ten members, many of which have been shown to correspond to calcium-activated chloride channels. To date, the only reported human mutations in this family of genes are dominant mutations in ANO5 (TMEM16E, GDD1) in the rare skeletal disorder gnathodiaphyseal dysplasia. We have identified recessive mutations in ANO5 that result in a proximal limb-girdle muscular dystrophy (LGMD2L) in three French Canadian families and in a distal non-dysferlin Miyoshi myopathy (MMD3) in Dutch and Finnish families. These mutations consist of a splice site, one base pair duplication shared by French Canadian and Dutch cases, and two missense mutations. The splice site and the duplication mutations introduce premature-termination codons and consequently trigger nonsense-mediated mRNA decay, suggesting an underlining loss-of-function mechanism. The LGMD2L phenotype is characterized by proximal weakness, with prominent asymmetrical quadriceps femoris and biceps brachii atrophy. The MMD3 phenotype is associated with distal weakness, of calf muscles in particular. With the use of electron microscopy, multifocal sarcolemmal lesions were observed in both phenotypes. The phenotypic heterogeneity associated with ANO5 mutations is reminiscent of that observed with Dysferlin (DYSF) mutations that can cause both LGMD2B and Miyoshi myopathy (MMD1). In one MMD3-affected individual, defective membrane repair was documented on fibroblasts by membrane-resealing ability assays, as observed in dysferlinopathies. Though the function of the ANO5 protein is still unknown, its putative calcium-activated chloride channel function may lead to important insights into the role of deficient skeletal muscle membrane repair in muscular dystrophies. Copyright (c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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            A founder mutation in Anoctamin 5 is a major cause of limb-girdle muscular dystrophy.

            The limb-girdle muscular dystrophies are a group of disorders with wide genetic and clinical heterogeneity. Recently, mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel belonging to the Anoctamin family of proteins, were identified in five families with one of two previously identified disorders, limb-girdle muscular dystrophy 2L and non-dysferlin Miyoshi muscular dystrophy. We screened a candidate group of 64 patients from 59 British and German kindreds and found the truncating mutation, c.191dupA in exon 5 of ANO5 in 20 patients, homozygously in 15 and in compound heterozygosity with other ANO5 variants in the rest. An intragenic single nucleotide polymorphism and an extragenic microsatellite marker are in linkage disequilibrium with the mutation, suggesting a founder effect in the Northern European population. We have further defined the clinical phenotype of ANO5-associated muscular dystrophy. Patients show adult onset proximal lower limb weakness with highly raised serum creatine kinase values (average 4500 IU/l) and frequent muscle atrophy and asymmetry of muscle involvement. Onset varies from the early 20 s to 50 s and the weakness is generally slowly progressive, with most patients remaining ambulant for several decades. Distal presentation is much less common but a milder degree of distal lower limb weakness is often observed. Upper limb strength is only mildly affected and cardiac and respiratory function is normal. Females appear less frequently affected. In the North of England population we have identified eight patients with ANO5 mutations, suggesting a minimum prevalence of 0.27/100,000, twice as common as dysferlinopathy. We suggest that mutations in ANO5 represent a relatively common cause of adult onset muscular dystrophy with high serum creatine kinase and that mutation screening, particularly of the common mutation c.191dupA, should be an early step in the diagnostic algorithm of adult limb-girdle muscular dystrophy patients.
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              Frequency and characterisation of anoctamin 5 mutations in a cohort of Italian limb-girdle muscular dystrophy patients

              Limb-girdle muscular dystrophy (LGMD) 2L, caused by mutations in the anoctamin 5 (ANO5) gene, is the third most common LGMD in Northern and Central Europe, where the c.191dupA mutation causes the majority of cases. We evaluated data from 228 Italian LGMD patients to determine the prevalence of LGMD2L and the c.191dupA mutation, and to describe the clinical, muscle biopsy, and magnetic resonance imaging findings in these patients. Forty-three patients who lacked molecular diagnosis were studied for ANO5 mutations, and four novel mutations were found in three probands. Only one proband carried the c.191dupA mutation, which was compound heterozygous with c.2516T>G. Two probands were homozygous for the c.1627dupA and c.397A>T mutations, respectively, while a fourth proband had a compound heterozygous status (c.220C>T and c.1609T>C). Therefore occurrence and molecular epidemiology of LGMD2L in this Italian cohort differed from those observed in other European countries. ANO5 mutations accounted for ∼2% of our sample. Affected patients exhibited benign progression with variable onset and an absence of cardiac and respiratory impairment; muscle biopsy generally showed mild signs, except when performed on the quadriceps muscles; MRI showed predominant involvement of the posterior thigh. Overall these common clinical, morphological and imaging findings could be useful in differential diagnosis.
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                Author and article information

                Journal
                Acta Myol
                Acta Myol
                Pacini
                Acta Myologica
                Pacini Editore SpA
                1128-2460
                1128-2460
                May 2014
                : 33
                : 1
                : 19-21
                Affiliations
                [1 ] Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany;
                [2 ] Institute of Cell and Neurobiology, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Berlin, Germany;
                [3 ] Krankenhaus Rummelsberg, Schwarzenbruck, Germany
                Author notes
                Address for correspondence: Ilka Schneider, Department of Neurology, Martin-Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, D-06120 Halle (Saale), Germany. E-mail: ilka.schneider@ 123456medizin.uni-halle.de
                Article
                Pacini
                4021630
                The journal and the individual contributions contained in it are protected by the copyright of Gaetano Conte Academy, Naples, Italy

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License, which permits for noncommercial use, distribution, and reproduction in any digital medium, provided the original work is properly cited and is not altered in any way. For details, please refer to http://creativecommons.org/licenses/by-nc-nd/3.0/

                Categories
                Case Report

                Plant science & Botany

                anoctamin 5, limb girdle muscular dystrophy 2l, necrotizing myopathy

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