Volume 4 • Issue 3 • 1000134 J Genet Syndr Gene Ther ISSN: 2157-7412 JGSGT, an open access journal Review Article Open Access Vernengo et al., J Genet Syndr Gene Ther 2013, 4:3 DOI: 10.4172/2157-7412.1000134 Keywords: Dysferlinopathies; LGMD2B; Miyoshi myopathy; DMAT; Dysferlin complex Introduction Primary dysferlinopathies are a rare heterogeneous group of autosomal recessive muscular dystrophies that are caused by mutations in the 55-exon gene encoding the protein dysferlin (DYSF, 2p13, MIM#603009) [1,2]. Tis 237 kDa protein belongs to a class of homologous proteins called “ferlins”. It is a protein located at the sarcolemma and the cytoplasm and, is not associated with the dystrophin-glycoprotein complex [3-5]. Te essential role of this protein seems to be the repair of the membrane of skeletal muscle fbers [6-9]. Te diferent presentations of these disorders have been described in various ethnic groups. Miyoshi myopathy (MM, MIM#254130), limb girdle muscular dystrophy 2B (LGMD2B, MIM#253601), distal myopathy with anterior tibial onset (DMAT, MIM#606678), and proximo-distal phenotypes are the most common disorders [10-14]. Tere are also other presentations ranging from isolated hyperCKemia to severe functional disability [13,15] and in elderly people, it can also be observed spinal muscle degeneration, with or without camptocormia [16]. Te case of dysferlinopathy with choreic movements has only been described once and this could have been only by sheer chance since it has never been described again [17]. Tere is signifcant phenotypic heterogeneity among the patients sharing the same mutation in the DYSF gene so MM, LGMD2B or DMAT can be observed within the same family [13,18,19]. Furthermore, there is intra and interfamilial variability among the patients [2,12,14,15,18-23]. Modifer genes are held responsible for this [20,24]. Te onset of LGMD2B and MM is generally in the teens or early adulthood. Tey usually have a normal life up to age 20 and they are ofen very good at sports. Te muscles primarily afected in MM are the soleus and the gastrocnemius muscles leading to weakness of the thigh and later the upper limb muscles [10,12,13,25]. Te early symptoms of these disorders are inability to stand on tip-toe, hop on one leg, run and difculty to climb stairs [10,13]. Tese dystrophies progress slowly [10,13]. DMAT begins with anterior tibial muscle weakness which rapidly progresses to the lower and upper proximal muscles [11]. Approximately 22 years afer onset, the patients are generally wheelchair-bound [13]. Creatine kinase (CK) levels are generally very high [10,12-15]. In many cases, it is common to fnd in the biopsies of the dysferlin defcient patients infammatory infltrates suggesting the misdiagnosis of infammatory myopathy [14,26-31]. It is believed that patients sufering from infammatory myopathy have a more rapid progression [14,27]. Te diagnosis is made by the absence or reduced dysferlin in muscle by immunohistochemistry or immunoblotting [13,32]. Te expression level of dysferlin protein can be either measured from blood monocytes [33,34] or Western blot analysis. When in the Western blot dysferlin is absent (0%) or reduced (up to 20%) it can be concluded that the DYSF gene is the only one to be held responsible for the variation [35]. Te molecular analysis of the dysferlin gene confrms the diagnosis [13]. Tere are no mutational hotspots and there is no genotype–phenotype correlation [36]. Clinical Features Common features Te patients have normal milestones. Te psychological *Corresponding author: Luis Vernengo, Clinical Unit, Department of Genetics, Faculty of Medicine, University of the Republic, Av. Gral. Flores 2125, CP 11800, Montevideo, Uruguay, Tel: +598 29015416; Fax: +598 24878132; E-mail: luvervi@gmail.com Received April 02, 2013; Accepted April 24, 2013; Published April 27, 2013 Citation: Vernengo L, Carrasco L, Angelini C, Rodriguez MM (2013) Dysferlinopathies. J Genet Syndr Gene Ther 4: 134. doi:10.4172/2157- 7412.1000134 Copyright: © 2013 Vernengo L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Dysferlinopathies Vernengo L 1,2 *, Carrasco L 3 , Angelini C 4,5 and Rodriguez MM 1,2 1 Faculty of Medicine, Clinical Unit, Department of Genetics, University of the Republic, Montevideo, Uruguay 2 ANII, Uruguay 3 Servicio de Neurología, Hospital Maciel, 25 de Mayo s/n, CP1100 Montevideo, Uruguay 4 Neurology Department, University of Padova, via Giustiniani 5, 35128 Padova, Italy 5 IRCCSS.Camillo, Lido, via Alberoni 70, Venice, Italy Abstract Primary dysferlinopathies are due to mutations in the 55-exon gene located on chromosome 2p13 which encodes the protein dysferlin. They are a group of autosomal recessive heterogeneous muscular disorders. Clinical presentations show heterogeneity, ranging from limb girdle muscular dystrophy 2B, Miyoshi myopathy and distal myopathy with anterior tibial onset to isolated hyperCKemia and severe functional disability. Miyoshi myopathy symptoms begin in the posterior muscle compartment of the calf, spreading later to the upper muscles. In limb girdle muscular dystrophy 2B the proximal muscles of the lower limbs are involved. The distal myopathy with anterior tibial onset shows anterior muscle weakness at onset, progressing rapidly to the lower and upper proximal muscles. The onset of these disorders is generally in the teens or early adulthood. The values of CK are always very high. The diagnosis is made by the reduction or absence of dysferlin in muscles of the affected patients performed by immunohistochemistry and immunoblotting with dysferlin monoclonal antibodies. The molecular analysis confrms the diagnosis. Journal of Genetic Syndromes & Gene Therapy J o u r n a l o f G e n e t i c S y n d r o m e s & G e n e T h e r a p y ISSN: 2157-7412