Cause Of Duchenne Muscular Dystrophy Dmd Biology Essay


The primary cause of Duchenne muscular dystrophy is a mutation in the dystrophin gene leading to the absence of the corresponding mRNA transcript and protein. Absence of dystrophin leads to disruption of the dystrophin-associated protein complex and pathological changes in skeletal muscle. Clinical examinations can be done to identify the presence of DMD.

Blood test could be done to check the level of serum creatine kinase (CK). CK levels are highly elevated in diseased muscle (2595-45495 U/L) compared to normal (25-200U/l).

CK is an enzyme that is present normally in high concentrations in the muscle cells. As muscle degeneration or breakdown occurs, contents from the muscle are released into the bloodstream. Therefore elevated levels of serum CK can be detected from a blood test and it is a measure of muscle damage. Elevated levels can be the result of multiple reasons hence it is not specific to skeletal muscle.

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Genetic testing involves looking at the genetic instructions and makeup of an individual. This done to identify genes that is defective by PCR, sequencing, multiplex ligation-dependent probe amplification and single-condition amplification. In DMD, the dystrophin which is located at Xp21 gene is defective. This can establish the diagnosis of DMD without performing a muscle biopsy though none of these techniques is universally available.

A Muscle biopsy can be done if the differential diagnosis includes DMD among other muscular dystrophy. This is a procedure in which a small sample of muscle tissue is removed from the body with a biopsy needle, which can then be analysed by histological means. A muscle biopsy for dystrophin studies can be done to look for abnormal levels of dystrophin in the muscle using immunoblotting. The dystrophin protein can also be visualized by immnunostaining the dystrophin protein (fig 1B). Histological features in DMD include the infiltration of inflammatory cells due to overexpressed immune response signals, increased endomysial connective tissue fibrosis seen more with late pathology due to extracellular matrix genes in DMD muscle. Myonuclei for normal muscle are located at the periphery of the muscle fibre while that of a DMD patient are found at the centre of the myofibre (fig 1A). A muscle which has average amounts of dystrophin will appear with the staining technique as though there is caulking around the individual myofibres and it is holding them together like window panes. A boy with Duchenne, on the other hand, will have an absence of dystrophin and appear to have an absence of the caulking around the muscle cells. There will be variable fibre size with the small fibres rounded; muscle fibre degeneration & regeneration especially in the early stage. As the disease progresses, the space between individual myofibres are filled with adipose tissue. Almost no dystrophin protein is expressed (fig 1C) as well as other membrane proteins such as sarcoglycans. A combination of clinical findings, family history, blood CK concentration and muscle biopsy with dystrophin studies confirms the diagnosis.

Fig 1. Muscle biopsy of DMD patient. A. immnunostainig in normal and diseased muscle. B. Immnuostainig of dystrophin in wildtype (WT) and mouse models shows that dystrophin is bot expressed after being knocked out. C. lane 1: Becker dystrophy; Dystrophin has reduced abundance but normal size.lane 2: Becker dystrophy; Dystrophin has reduced size and abundance. lane 3: Normal; Dystrophin has normal size and amount. lane 4: DMD; Almost no protein is present.


In DMD, an exon, or exons are deleted which interfere with the rest of the gene being assebled leading to the absence of the corresponding RNA transcript and protein. In this case, exon 50 cannot join up with exon 54 due to incompatible codon boundaries, which prevents the rest of the exons from assembling by disrupting the open reading frame (ORF) of the transcript and aborting the synthesis of the dystrophin protein, prematurely (fig 3). For the dystrophin protein to function properly, it must have both ends of the protein (fig 2). Therefore, this mutation results in a completely non-functional dystrophin protein and the severe symptoms of DMD.

Fig 2. Schematic representation of the exons in dystrophin gene, its splicing to mature mRNA and translation to the dystrophin protein.

Fig 3. Schematic representation of the deletion of exon 51 and 53. A.inducated the gene of interest in a normal exon. B. the deletion of exon 52. C splicing of exon 51 to 53 in dystrophin gene leading to an out-of-frame mRNA transcript hene a non fuctional dystrophin.


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Although muscular dystrophies still lacks an effective therapy, I would suggest exon skipping therapy to restore the missing dystrophin. Exon skipping of dystrophin gene containing a mutation is a promising potential therapy for DMD and other recessive muscular dystrophies. As the name suggests, the principle of exon skipping is to encourage the cellular machinery to skip over an exon. This can be achieved by using antisense oligonucleotides (AONs) which are small pieces of modified synthetic DNA or RNA (15-30 bp), also called molecular patches which are complementary to their target mRNA. They target one or more of the donors splice site, acceptor splice site or exonic sequences essential for exon definition during pre-mRNA splicing of specific exons (Cossu and Sampaolesi, 2007 [1]). They are used to mask the exon that is to be spliced, so as to prevent the incorporation of the targeted exon in the mature mRNA and protein production. In the case of this boy, if an AON designed to mask exon 52 is used, exon 51 can now join up to exon 53 and continue to make the rest of the protein, with exon 52 missing in the middle. Hence skipping specific exons would be expected to restore the ORF and result in the production of internally deleted gene, but essentially functional dystrophin (fig 4) which then converts a severe DMD into a typically milder Becker muscular dystrophy (BMD) phenotype thus providing significant functional improvement of DMD [1].

Since the discovery of dystrophin as the defective gene in DMD, many potential therapies have been developed and are either undergoing clinical trials or have proceeded to clinical trials with varying degree of success. The development of therapeutic AONs that correct mRNA ORF is not only promising but a feasible therapy for various reasons. Firstly, AONs have been used to induce strong dystrophin expression in skeletal muscle of mdx mice by administering morpholinos as the AON, in vivo. Also, morpholinos have been reported to have very low toxicity. More importantly, exon skipping therapy can be applied to a majority of DMD patients; 90% of DMD patients with deletions are potentially treatable by targeting selected multiple exons compared to read-through therapy such as gentamicin which is applicable for only nonsense mutation hence it is feasible for Ë‚20% of DMD patients (Yokota et al., 2007[2]). However, this therapy has its demerits. It is a mutation-specific therapy since each individual patient mutation will require specific AONs. The lifetime of AONs in tissues is limited; hence repeated administration is therefore required.

Fig. 4. Antisense oligonucleotide-mediated exon skipping. Binding of an exon-specific AON against exon 52 hides the exon from the splicing machinery. The exon will be 'skipped' and not incorporated in the mRNA. Thereby the reading frame is restored and translation of a shorter, but still largely functional dystrophin protein can occur


The condition is Marfan syndrome. Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by a structural defect in fibrillin-1 gene at 15q21 encoding for fibrillin (Ramirez et al 2006[3]). Fibrillin is a cysteine rich, large modular extracellular matrix glycoprotein which is a major component of 10nm microfibrils. Microfibrils are thin filamentous assemblies of fibril polymers that are present in both elastic and non-elastic connective tissues. The incidence of MFS is estimated to be 1 in 5,000-10,000 individuals.

Features displayed by individuals with MFS include scoliosis, chest deformities, arachnodactyly, and tall stature caused by the overgrowth of long bones; with relative abundance of fibrillin microfibrils in the affected tissues. The various manifestations of MFS are now considered to be the result of an overall abnormality in the homeostasis of the ECM, in which defective fibrillin results in reduced extracellular fibrillin-rich microfibrils levels, which normally act as a TGFβ reservoir; decrease matrix sequestration of latent TGF thus rendering it more prone to or accessible for activation; and increased TGFβ signalling [(Jordan et al 2006[4]).

Previously the role of fibrillin has been known as the architectural or mechanical framework which properly shapes and supports the body but recent investigations have indicated an additional role of fibrillin microfibrils as a mediator of growth factor signalling by showing that Latent TGF Binding Proteins (LTBPs) are associated with fibrillin microfibrils and that LTBP-1 and LTBP-4 interact directly with fibrillin (fig 5). TGF-β/BMP signals through serine/threonine kinase receptors that activate intracellular Smad proteins which regulate gene activity by binding to specific DNA and by interacting with nuclear co-factors [3]. The TGF β cytokines are secreted as large latent complexes (LLC), consisting of TGFβ, latency-associated peptide, and one of three latent TGFβ-binding proteins. TGFβ signalling requires release of the mature LLC, interaction with cell-surface receptors, and initiation of a downstream signalling cascade (Canadas et al 2010[5]). Through the interaction of the LTBPs with fibrillin microfibrils, latent TGF complexes are properly targeted to the ECM and sequestered or presented [4]). The homology Fibrillin-1 with the LTBPs, led to the hypothesis that extracellular microfibrils might participate in the regulation of TGFβ activation [4]. Neptune et al (2003) then showed that TGF signalling is dysregulated in Fbn1 mutant mice.

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Fig 5. Fibrillin-1 is translated from an mRNA encoded by the FBN1 gene on chromosome 15. The protein is processed and polymerise to form microfibrils in the matrix in association with other extracellular molecules. Copied from Kaartinen, V., and Warburton, D. (2003). Fibrillin controls TGF-β activation. Nat. Genet. 33:331-332.


The most likely diagnosis for this condition is Ehlers-Danlos syndrome (EDS). From the picture, the individual's skin shows hyperextensibility, thinness and fragility which is consistent with some forms of EDS. EDS is an inherited heterogeneous group of connective tissue disorders, characterized by abnormal collagen synthesis which affects skin, ligaments, joints, blood vessels and other organs. The molecular bases of the clinical manifestations of the major forms of EDS are based primarily on mutations in the genes encoding collagen polypeptide subunits (type I, IV, V, III collagens Tenascin X) or enzymes that modify the primary collagen translation products (ADAMTS-2, PLOD) Uitto, 2004 [6].

EDS can be misdiagnosed with other connective tissue disorder but can be differentiated byy some clinical features which include hyperextensibility of the skin, joints hypermobility, tissue fragility demonstrated by easy bruising and delayed wound healing with atrophic scarring. The Skin hyperextensibility seen in EDS patients mean that the skin is easily extended and snaps back after release as opposed to cutis laxa where skin, after being extended hangs redundant to return to its former position. Joint hypermobility is often seen in EDS, affecting both large and small joints. It frequently leads to propensity to dislocation and chronic musculoskeletal pain. In EDS, the bleeding diathesis is explained by an abnormal capillary structure with deficiency of normal perivascular collagen, resulting in poor support of cutaneous blood vessels which rupture when subjected to pressure. Osteogenesis Imperfecta, caused by type I collagen defect causes bone defect which causes brittle bone as opposed to EDS where bones are not unusually fragile and fractures are not increased. Stickler Syndrome is caused by defective type II Collagen in (cartilage, eye) whereas type II collagen is not affected in EDS. While EDS is caused by defective collagen and its synthesis, MFS is caused by defective fibrillin-1 which is also a connective tissue. Careful evaluation of the medical and family history; and rigorous clinical examination with special attention to skin features that are characteristic for EDS, are mandatory to distinguish between a connective tissue disorder Malfait et al 2009[7].


There are six recognized genetic subtypes of EDS as classified by Beighton et al (1998) which differ in clinical symptoms, inheritance pattern and the nature of the underlying biochemical and molecular defect(s). They include the vascular, classical, hypermobility, kyphoscoliosis, arthrochalasia and dermatosparaxis.

The classical type can be identified by the clinical features they present which include skin laxity, easy bruising, scars, joint hypermobility, muscle hypotonia, hernias. The vascular type can be identified by the clinical features they present which include arterial/intestinal/uterine fragility or rupture; extensive bruising and characteristic facial appearance, hypermobility of small joints, varicose veins. Unlike other types of EDS, the skin in vascular EDS is not hyperelastic, but rather thin and translucent, showing a visible pattern over the chest, abdomen and extremities. The hypermobility type is marked by joint hypermobility, minor skin findings. The kyphoscoliosis type can be identified by joint hypermobility and kyphoscoliosis recalcitrant to surgical intervention, risk for arterial rupture. The arthrochalasia type can be identified by marked joint hypermobility and bilateral congenital hip dislocation. The dermatosparaxis is can be identified by soft, very fragile skin with late onset skin redundancy, blue sclerae, and joint hypermobility (Beighton et al, 1998[8]). In the EDS subtypes, biochemical and molecular analyses can be very helpful to confirm the diagnosis using cultured skin fibroblasts following physical clinical presentations. Biochemical study of the collagen types I, III and V includes SDS-polyacrylamide gel electrophoresis of radio-labelled collagens, extracted from the cultured fibroblasts. Molecular screening of the gene of interest can identify the mutations [7].

Progress in the management of EDS has been slow as there is no specific treatment but EDS is managed according to their clinical presentations. Risk factors of EDS can be controlled by living a healthy life style; avoidance of contact sports and heavy exercise [9], refraining from drugs which interfere with platelet function and clotting including aspirin, is also advised. Beta blockers may reduce aortic dilatation; and tranexamic acid has been used to reduce episodes of bleeding postoperatively. There are reports of improvements in the bleeding time in patients treated with Desmopressin acetate tablets. For the vascular type of EDS, prophylactic measures are also useful (Parapia et al 2008[9]). Supplementation of ascorbic acid, a cofactor for cross-linking of collagen fibrils, can make bruising tendency more tolerable in some patients [9]).