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Muscular Dystrophy Diseases
Published in Maher Kurdi, Neuromuscular Pathology Made Easy, 2021
It is impossible to distinguish DMD or BMD from other muscular dystrophies on the basis of histology alone. Histochemical reaction and genetic testing are mandating. The dystrophin gene is considered one of the largest gene defects in the MD group. Its protein is located in the sarcoplasmic membrane interacting with sarcoglycans and dystroglycans (see Figure 1.3inChapter 1, Part I). The gene has four domains with exons, illustrated in Figure 16.2. About two-thirds of identified mutations in the dystrophin gene are deletions, about one-third are point mutations, and a small proportion are duplications (Table 16.1). Point mutations are difficult to identify with a polymerase chain reaction (PCR) but immunohistochemistry (IHC) can easily identify all mutations that led to a stop codon and result in protein absence.
Muscle Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Kourosh Rezania, Peter Pytel, Betty Soliven
The LGMDs are a group of clinically as well as genetically heterogeneous diseases that share an autosomal inheritance pattern and predominant weakness of the proximal limb-girdle muscles. Some of the associated genes have been linked to other allelic diseases. The overall incidence is around 1:25,000–1:50,000. Cases with mutations in calpain3, dysferlin, FKRP, or one of the sarcoglycans are the most common forms.
Neurology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Fenella Kirkham, Adnan Manzur, Stephanie Robb
Limb girdle dystrophies (LGMD) (Figs 8.55, 8.60): dominant and recessive forms, many subtypes, some present in adulthood.abnormalities of: – lamin A/C (Emery–Dreifuss dystrophy (EDMD)) (Figs 8.60 C,D 8.26 C,D).– calpain 3 (Figs 8.60 E,F).– sarcoglycans (Figs 8.60 A,B,G,D).– FKRP.– collagen VI (Bethlem myopathy).
Proteomic profiling of fatty acid binding proteins in muscular dystrophy
Published in Expert Review of Proteomics, 2020
Paul Dowling, Stephen Gargan, Margit Zweyer, Dieter Swandulla, Kay Ohlendieck
X-linked muscular dystrophy is a progressive neuromuscular disorder with a high caregiver burden [17]. Primary abnormalities in the largest gene in the human genome, the 79-exon spanning DMD gene [18], cause the almost complete loss of the membrane cytoskeletal protein dystrophin in contractile fibers [9]. As outlined in Figure 1, the tissue-specific expression of different dystrophins, which range in molecular mass from approximately 71 kDa to 427 kDa, is driven by 7 different promoters. The full-length dystrophin isoform Dp427-M belongs to the class of giant muscle proteins and contains an amino-terminal actin binding site, a spectrin-like rod domain that is interspersed by proline-rich hinge regions and a unique carboxy-terminal region with a binding site for the integral glycoprotein beta-dystroglycan [19]. In normal muscle, the sub-sarcolemmal dystrophin scaffold forms a supramolecular complex with cortical actin, dystroglycans, sarcoglycans, sarcospan, dystrobrevins, syntrophins and laminin, and this membrane assembly is involved in cellular signaling, lateral force transduction and the stabilization of the muscle surface via linking the membrane cytoskeleton to the extracellular matrix [20–22].
Gene expression changes in human iPSC-derived cardiomyocytes after X-ray irradiation
Published in International Journal of Radiation Biology, 2018
Benjamin V. Becker, Matthäus Majewski, Michael Abend, Andreas Palnek, Kai Nestler, Matthias Port, Reinhard Ullmann
Apart from genes associated with cell cycle, the list of genes significantly down-regulated upon irradiation contained several candidates possibly involved in the irradiation associated reduction of the beat rate in hiPSC-CMs, which we and others have observed in previous studies (Frieß et al. 2015; Frieß 2016; Becker et al. 2018). Some of those genes have already been implicated in the etiology of cardiovascular disease. Sarcoglycan-delta (SGCD) encodes a protein highly expressed in skeletal and cardiac muscle, but which was found only moderately transcribed in hiPSC-CMs. Autosomal recessive mutations in this gene can lead to sarcoglycanopathy (limb-girdle muscular dystrophy (LGMD2F (Politano et al. 2001); OMIM: #601287), which recurrently includes cardiomyopathy.
Assessing diagnosis and managing respiratory and cardiac complications of sarcoglycanopathy
Published in Expert Opinion on Orphan Drugs, 2020
Corrado Angelini, Valentina Pegoraro
The diagnosis is done by muscle biopsy, which identifies in the cryostat sections the lack of immunohistochemical staining with one of the proteins of sarcoglycan complex (figure 1), subsequent western blotting using sarcoglycan muscle proteins, followed by identification of pathogenetic mutations [11–13]. Next-generation sequencing (NGS) is a powerful technique to be performed in unsolved myopathy or hyperCkemia cases [14,15].