Introduction
Muscular dystrophy (MD) is an aberrant health condition where the muscular system gets affected. Considered to have a genetic etiology, this condition leads to a defect or absence of vital genes that make up the proteins essential for hygienic muscles. As such, it is widely believed that MD is an inherited disorder and not to be transmitted through contact from one individual to another indicating that it is not infectious or contagious.
Examining the types of muscular dystrophies
Duchenne muscular dystrophy (DMD): This is the very important and frequent type of muscular dystrophy commonly encountered in children. It is clinically identified during the childhood age of 3 to 6 years. It occurs due to an aberration in the gene coding for a protein known as dystrophin which is responsible for muscles to retain their vigor and power.
The absence of dystrophin would lead to the total collapse of muscles and the affected individual turns weak. Boys are the favorable targets for DMD and in severe consequences would need to depend on a wheelchair. The symptoms noted are walking defects, repeated falling, trouble while lying down or sitting. The gradual beak down of muscles never ceases until the age of 12 when children with DMD fail to walk
DMD is also common in teenagers in their 20’s as it leads to respiratory or heart problems, or both. As such, individuals with DMD would tend to die during early teenage or adulthood. The other conditions reported to occur are rigidness in the joints of the spine and scoliosis.
Becker muscular dystrophy (BMD), is another type that is analogous to DMD in its incidence. It manifests slowly and is less problematic. Therefore, muscle collapse and loss of vigor tend to develop late at the age of 10 or during adolescence. Like DMD, the affected individuals develop respiratory, Musculoskeletal disorders. These individuals do not rely on a wheelchair and could survive for a prolonged period. However, this could depend on the magnitude of problems encountered during the disease condition.
The other type of Muscular dystrophy is that of Emery-Dreifuss muscular dystrophy (EDMD). It usually occurs late in childhood and continues till the age of 25. This disorder also affects boys and the affected organs include that of a musculoskeletal system comprising of shins, arms in the upper region, shoulders, and joints. The heart muscle may also be affected.
Limb-girdle muscular dystrophy (LGMD) is another type where boys and girls become evenly affected. This disorder affects regions like upper arms, hips and shoulders thereby causing muscles to become weak. This type of dystrophy affects children and /or even adults at their middle age and develops gradually.
Facioscapulohumeral muscular dystrophy (FSHD) is another type of muscular dystrophy that also equally affects boys and girls and originates during adolescence. The regions where the weakness affects are legs facial muscles and shoulders. Individuals having FSHD face difficulties in moving arms and closure of eyes. The degree of severity changes from one individual to the other.
Another type of Muscular Dystrophy is that of Myotonic dystrophy (MMD). This condition affects muscles that struggle to relax. It induces weakness and shrinkage of muscles, and heart ailments.
The last type of muscular dystrophy is that of Congenital muscular dystrophy (CMD). This condition is known to occur in infants and children at a very early age. This type leads to a weak muscular tone in boys and girls. The degree of severity often fluctuates in occurrence in individuals. This disorder could also lead to mental decline and learning difficulties.
Therefore, the above-mentioned types of muscular dystrophies have become a health concern and need to be investigated further for precise treatment and management. This could be because the survival period for the types of muscular dystrophies varies greatly corresponding to the severity of weakness in muscular and cardiorespiratory systems.
Genetics
Next, it is essential to know the genetics of Muscular Dystrophies. Earlier there were few reports with regard to the genetics of Muscular dystrophies. However, with the identification of the gene for DMD and BMD, the mystery was resolved. The gene responsible for Duchenne/Becker Muscular Dystrophy (DBMD) was reported to be present on the X-chromosome. This gene is responsible for the hygienic muscular workout.
The gene that causes DMD when present on the X-chromosome becomes X-linked. Males with a single gene copy of DBMD are considered to possess mutation Since females carry two X-chromosomes, they carry a functional gene and a mutated gene. The normal copy (x-chromosome without mutation) generally masks the DBMD mutation such that females possess symptoms of moderate degree.
But females could pass on the mutation to the offspring to become a ‘carrier.’ Thus, a male child born to a mother carrying dystrophin mutation on a single X-chromosome has a 50% probability of acquiring the gene by inheritance and developing DBMD. Although males run the risk of the mutated gene being inherited from the mother, there is one-third of the chance that mothers will not carry the gene.
Hence, males more often get affected by disorders of X-linked recessive origin when compared to females. However, fathers have no role to pass on the traits of X-linkage to the male offspring, which is a noteworthy feature X-linked mode of inheritance. Females with a DMD mutation on their X-chromosome suffer from muscular cramps and weakness which are milder than that of males. These females are also more likely to develop heart ailments like dilated cardiomyopathy. These examples indicate that Muscular Dystrophies are inherited.
Hence, it can be inferred that the offspring gets the inherited copy of the gene when a mother carries an x-linked recessive gene on one of the copies of the X- chromosome. She could pass the defective gene to the male child and would not manifest the symptoms characteristic of muscular dystrophy. Therefore, the transmitting agent is the DMD gene present on the X-chromosome in a recessive manner.
The vulnerable individuals are males at an age range of 3 to 12 years. The muscles that are greatly affected are that of skeletal and coronary muscles. Therefore, it is reasonable to highlight that mutation in genes coding for the DMD gene plays a causative role in the occurrence of Duchenne and Becker muscular dystrophy.
As far as Emery-Dreifuss muscular dystrophy is concerned, the mutations in the lamin A/C gene cause muscular dystrophy both in an autosomal dominant and recessive manner (Hayashi, 2005). This gene is considered an important compound of the nuclear lamina (Hayashi, 2005).
Mutations in the lamin A/C gene lead to progeria syndrome, neuropathy, lipodystrophy, and cardiomyopathy in addition to muscular dystrophy (Hayashi, 2005). The X-linked recessive nature of EDMD is due to mutation in EMD (or STA) gene that is responsible for producing the inner nuclear membrane’s integral protein (Hayashi, 2005).
Similarly, Facioscapulohumeral muscular dystrophy (FSHD) was reported to be an autosomal dominant condition (Fisher and Upadhyaya, 1997). The gene coding FSHD was found on chromosome 4q35 (FSHD1A) through mapping. It is related to D4F1O4S1 that identifies two polymorphic regions (located at 4q35 and 10q26), through EcoRI restriction digestion analysis (Fisher and Upadhyaya, 1997).
However, the disease loci do not bear a linkage to 4q35 (locus designated FSHD1B) in nearly 5-10% of the families and this was not even mapped to chromosomes. Therefore, the candidate gene is FRG1 (FSHD region gene 1) on 4q35 (Fisher and Upadhyaya, 1997). This would facilitate the precise diagnosis of FSHD provided some uncertainties are addressed with regard to the 4q35 FSHD region (Fisher and Upadhyaya, 1997).
Myotonic dystrophy (DM) also gets inherited in a dominant mode (Ranum and Day, 2002). Here, the phenotype of DM is linked to two loci DM1 and DM2 which are present on chromosome 19 and chromosome 3, respectively (Ranum and Day, 2002). Earlier the mutation responsible for DM1 was detected as the growth of the CTG region (Ranum and Day, 2002). This was reported to be present on the dystrophic myotonica-protein kinase gene at the untranslated portion of 3′-region (Ranum and Day, 2002).
But a debate has also been initiated with regard to the CTG growth that is vital for DM.1. Later discoveries have shed light on the significant role of the untranslated CCTG region in causing DM1(Ranum and Day, 2002). This has furnished insights on the RNA function where CUG and CCUG regions disturb cell function gene splicing (Ranum and Day, 2002).
Congenital muscular dystrophies (CMDs) are inherited in an autosomal recessive fashion (Reed, 2009). This occurs most probably due to Walker-Warburg syndrome, CMD1C, CMD1D, Muscle-eye-brain disease, merosin deficiency and integrin deficiency (Reed, 2009). Therefore, the above-mentioned genetic conditions contribute to the development of Muscular dystrophies in various forms.
Diagnostics
It is central to get awareness regarding the diagnostic methods employed for the detection of muscular dystrophies. The old methods of diagnosing muscular dystrophies include physical activity, mediations that retard or remove the process of muscle wasting, and steroids. Physical therapy is important as the disorder causes muscles to lose tone, and occurrence of contractures in joints. The main objective of physical therapy is to enable free movement through exercises in order to maintain flexibility, retard the development of contractures, spine curvatures.
Hydrotherapy is another approach to enable the movement of joints. Assisted tools like braces are employed to assist weak muscles of hands and legs, and flexibility of tendons and muscles, and delay contractures. Specially designed Walkers and wheelchairs have also been employed to enable patients to move independently. The drugs used for muscular dystrophy include mexiletine (Mexitil), phenytoin (Dilantin, Phenytek), carbamazepine, etc for Myotonic Dystrophy.
Anti-inflammatory drugs like prednisone have the potential to enhance muscle rigidity and retard the development of disease. Tendon release surgery is another option to provide relief to painful joints. This is focused on the Achilles tendon on the back portion of the foot and the tendons of the knee and hip. Further, research-based methods have played a vital role in the precise diagnosis of Muscular Dystrophies.
Hence, there is a need to know about the kinds of diagnostic methods in detail. Earlier DMD has been diagnosed by using molecular probes that are connected to and flank the DMD locus (Hejtmancik et al., 1986). These probes have been largely employed to identify mutations especially in female carriers (Hejtmancik et al., 1986). This strategy has led to the precise diagnosis of nearly 75 females who were at risk in 24 families where a male individual was reported to be affected (Hejtmancik et al., 1986). Hence, it was described that carrier detection is feasible through the Recombinant diagnostic approach to detect DMD in males at risk in families (Hejtmancik et al., 1986).
It was described recently that magnetic resonance imaging scans have the potential to detect variations in muscular movements (Mercuri et al., 2010). This has worked out for certain disorders like limb-girdle muscular dystrophy, spinal abnormalities, congenital muscular dystrophy and myopathy, and mutations in the Col6 A1-A3 regions, LMNA defects specific to Emery-Dreifuss muscular dystrophy (Mercuri et al., 2010).
In another study, researchers have employed multiplex quantitative real-time PCR technology (Traverso et al., 2006). To detect dystrophin exon 5, 45, and 51 that are specific to two deletion and duplication hotspots. (Traverso et al., 2006). Here, they have also amplified the exon by employing the target fragment’s copy number and an X-linked gene. This was evaluated by a technique of comparative threshold cycle (delta deltaC(t)) (Traverso et al., 2006).
To assess the reliability of this method, end-point PCR fluorescent analysis (EPFA) was also used (Traverso et al., 2006). This has yielded fruitful results in the detection of mutations already familiar in the carriers who are at risk (Traverso et al., 2006). This has indicated that Q-PCR sensitive and precise tool for the diagnosis of DMD/BMD provided the duplications and deletions are detected (Traverso et al., 2006).
Immunohistochemistry has also become an important tool in the diagnosis of Duchenne and Becker muscular dystrophy (Freund et al., 2007). This was revealed when 106 patients were investigated by assays of immunohistochemical method in the muscle tissue obtained through a biopsy for the presence of dystrophin (Freund et al., 2007).
In addition, an analysis of exons specific to the gene coding for dystrophin in whole blood. Through this biopsy, investigation diagnosis was made specific to unclassified limb-girdle muscular dystrophy, congenital myopathy, sarcoglycan deficiency and spinal muscular atrophy (Freund et al., 2007). Therefore, it was described that immunohistochemistry was proven to be the reliable strategy for Dystrophin analysis that would aid in DMD/BMD diagnosis provided the dystrophin gene is without deletions in the exon region (Freund et al., 2007).
The next method of diagnosis is the utility of RNA fluorescence in situ hybridization. This strategy was considered to be the most reliable one for myotonic dystrophy type I with regard to the prenatal approach (Bonifazi et al., 2006). In this method, cultured cells obtained chorionic villus samples (CVS) having mutation specific to DM1 were mostly employed for analysis (Bonifazi et al., 2006). This strategy identifies the specific phenotype of DM1 which is unique for the nuclei that harbor ribonuclear inclusions (foci) with the transcripts of extended DMPK regions (Bonifazi et al., 2006).
The researchers were able to identify a good number of cellular ribonuclear inclusions associated with CTG expansion (Bonifazi et al., 2006). Hence, the diagnosis of DM1 mutation is well connected to the RNA-FISH enabled identification of trophoblast cells belonging to the interphase nuclei where there are nearly more than 200 copies of expanded CTG regions are present (Bonifazi et al., 2006).
Sewry et al. (1996) have described a method of immunocytochemical analysis to diagnose congenital muscular dystrophy. Here, muscle biopsies obtained were analyzed for the presence of alpha2 chain of laminin-2 (merosin) present on chromosome 6 (Sewry et al., 1996). This gene when becomes defective contributes to the development of congenital muscular dystrophy (Sewry et al., 1996). In this method of diagnosis, skin biopsies would be obtained and checked for the expression of laminin alpha2 (Sewry et al., 1996). The intersection of the dermis and epidermis region would be examined for this purpose (Sewry et al., 1996).
A comparison between normal and suspected (for congenital muscular dystrophy) skin biopsies would reveal the deficiency of laminin alpha2 (Sewry et al., 1996). Hence, the immuocytogentic analysis method of employing skin biopsy specimens were considered to be an efficient tool for the prediction and diagnosis of laminin-2 (merosin) in patients with congenital muscular dystrophy (Sewry et al., 1996).
Recently, it was described that Gene therapy has a significant role to play in the diagnosis of DMD. In this strategy which is better known as a non-viral delivery system, a vector constructed using human ribosomal DNA (hrDNA) would be targeted to minidystrophin-GFP fusion gene (Yang et al., 2009). This is done in HT 1080 cells particularly in the region of hrDNA locus where the novel gene construct would show continuous expression (Yang et al., 2009).
The physiological role of minidystrophin-GFP fusion protein was revealed when it was detected on the cell plasma membrane (Yang et al., 2009). Hence, it was made clear that MD gene therapy of utilisining hrDNA-targeting vector would yield significant results and might be helpful for the management of DMD (Yang et al., 2009).
In another method, a novel therapeutic target was designed keeping in view of the beta-adrenergic signaling pathway which is vital for the control of protein synthesis and breakdown in the skeletal muscle (Koopman et al, 2009). The beta-adrenoceptor agonists also known as beta-agonists have been reported to weaken the process of muscle wasting that is associated with muscular dystrophies (Koopman et al, 2009).
The administration of beta-agonists activates the signaling pathway which in turn leads to an anabolic response in skeletal muscle (Koopman et al, 2009). But the drawbacks of using beta-agonists are that they would induce side effects related to cardiovascular problems (Koopman et al, 2009).
Therefore, the diagnosis of muscular dystrophies has been a serious task for health care professionals. Earlier a new muscle disease named macrophagic myofasciitis, was reported in Europe. This induces destruction of connective tissue between strands of muscle and inflammation (New muscle disease spreading, 1998). However, there are certain mutations that could lead to new types of muscular dystrophies that need to be investigated.
Summary
In view of the above information, it can be summarized that muscular dystrophies have been considered as one of the major health problems that affect children of 3- 12 years with some dystrophies continuing till middle age. The organ systems that have become susceptible to muscular dystrophies include skeletal, muscular, and cardiovascular. The muscle movement is chiefly affected and this prevents physical activity. Hence, the confinement of muscular dystrophy patients to wheelchairs has become inevitable.
The pathophysiology of muscular dystrophy was emphasized on the genetics part as this disorder gets inherited in autosomal dominant or recessive forms. The sex chromosome ‘X’ was reported to carry the mutation in the gene coding for dystrophin. The lack of this gene is essential for the development of disease where muscle breakdown is primarily involved.
Females possess the affected chromosome, serve as carriers and pass on the disease to the male offspring. Hence, it is the boys who become subjects for muscular dystrophy. There are various types of muscular dystrophies each having a unique genetic background.
However, diagnostic methods have been devised to meet the challenges presented by the Muscular dystrophies. These include immunohistochemistry, immcytogenetics, multiplex PCR technology, RNA-FISH and Gene therapy. Treatment strategies have also been modulated that range from physical activity to medication.
From the description, it can be concluded that muscular dystrophy is characterized by severe physical inactivity associated with perturbations in the skeletal and cardiac muscular systems. The inheritance pattern of this disorder is due to the X- chromosome carrying the mutation. The management of this disorder could be possible through genetic counseling at the earliest stage.
References
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