A REVIEW ON RECENT DEVELOPMENT IN DUCHENE MUSCULAR DYSTROPHY MANAGEMENT
INTRODUCTION
Muscular dystrophy is a term that covers a diverse group of inherited disorders in which primary defect is seen to be in skeletal muscle.In past ten years ,there is an increase in forms of muscular dystrophy caused by number of genes. One such muscular disoreder is Duchenne Muscular Dystrophy(DMD).And the gene which is responsible for it is Dystrophin gene. It is an X-linked recessive disease , thus mainly affects the male in a ratio of 1:3500 male live births.
Dystrophin, 427 kDa protein product of the dystrophin gene,is one of the largest component of the dystrophin glycoproteincomplex (DGC). It is located at locus Xp21.2. Its is the only known human metagene ,codes for 14 kb mRNA,and contains 79 exons. Thus any small mutation leads to the most rare, fatal disease, that is DMD.It mainly occurs as a result of deleteion mutation or frame shift mutation.Due to this , progressive muscle degeneration takes place leading to loss of independent ambulation by the age of 13.
The molecular basis of DMD is known for over 2-3 decades.And many promising therapeutic stategies have been developed in animal models.Human trials of these strategies have also been started , opening a way to treat this currently uncurable disease. Corticsteroid, respiratory, cardiac, orthopaedic, and rehabilitative interventions have led toimprovement in function, life, health, and longevity with children who are diagnosed today having the possibility of a life expectancy into their fourth decade.
The developent and implementation of standardised care recommendations were initially emphasised by stake holders in the DMD community, which includes government agencies, clinicians,scientists, health agencies, firm organisations such as Parent Project Muscular Dystrophy(PPMD) and Muscular Dystrophy Association. The development in these care recommendations provides anew hope tomanage the DMD across the whole world. The purpose of this review is to provide a framework for recognising the primary manifestions and planning optimum treatment with a coordinated multidisciplinary team.
INTERDISCIPLINARY MANAGEMENT
Coordination of clinical care is a crucial component of the management of DMD. And it is best proided by the multidosciplinary care setting in the patient and his family can have an access to the experts of the multisystem management of DMD in a small effort. It can be provided by a wide range of health-care professionals depending on the services available nearby . It is crucial that the health-care professionals are well aware of the avaiable tools, interventions,assessments to proactively act and manageall issues involving DMD.
Practically, management of patient with DMD in clinic requires an easy access to the physicians, all the equipments required for the screening and testing and most importantly skilled personnel who will be available to help the non-ambulatory patients. Such patients must be provided with comfy wheelchairs for their locomotion.
Tools to test the creatine kinase level , muscle biopsy and genetic testing should be readily available at an affordable rate. Once these tests are done to check whether the patient is suffering from DMD genetic counselling and family support must be provided as a primary intervention.
DIAGNOSIS OF DMD
The aim of providing health-care recommendations is to provide an accurate and prompt diagnosis ,so that appropriate interventioons can be provided to the patient alongwith his family.Thus , diagnosis should be done by a well trained nueromuscular specialist who can asses the child clinically and accurately at much faster rate of interpretation.
After the diagnosis the family will be supported by geneticists and genetic counsellor.Diagnosis should be generally started at an early stage of around 5 years of age irrespective of his family history when they find that there is some difference in the way he walks when compared to his healthy peers. Generally, one could observe that the child has hard time lifting his head or has a week neck. Though the child would be more than one year, still he wont be able to walk , there will be difficulty in running, climbing up the stairs. He will be requiring help to get up from the floor or walk his hands up his legs in order to stand , a gower maneuver.
As soon as we discover that the child has muscle disfunction as mentioned above he should clinically be checked. The detection of an increase in serum creatine kinase tested for unrealted indication or after the discovery of increased amount in transaminases ( aspartate and amino transferase are the chemicals which leaks out of the degenerated muscle), the confirmaton of the DMD takes place.
CONFIRMATION
The confirmation of the diagnosis completely depends of the relible testing and screeing done by the technicians. Initially, testing for a DMD mutation in a blood sample is always necessary even though it is confirmed that there is absence of dystrophin protein expression in muscle biopsy. The mutations in DMD can be due to the genetic basis for the DMD. Therefore , the results of genetic tst can be used to assist the individual and support his family. The most common genetic testing for dystrophin mutation is mutiplex PCR.It detects deletion and does not cover the whole gene,so that adeletion might not always be fully characterized. In a collaboration ,the technique of Multiple ligation-dependent probe Amplification (MLPA) can be aplied to discern deletions and duplications.
When the phenotype and genotype of the patients are correlated ,it transparently demonstartes that genetic studies of lymphocyte DNA may not always reflect the situation in the tissue i.e. muscle incolved in dystrophin.The disease phenotype needs further confirmation.
A muscle biopsy could be done , depending on the clinical situation , availability of genetic testing, and the facilities in the centre where the patient is seen. Muscle biopsy is necessary if the differntial diagnosis includes DMD among other diagnostic posibilities such as other types of muscular dystrophy ,so that adequate amounts of tissue will be available for further analysis.
PRENATAL DIAGNOSIS
UNTIL recently carrier detection in Duchenne muscular dystrophy (DMD) families depended on a serum creatine phosphokinase (CK) test that was not very reliable. But by the use of a series of closely linked DNA probes detecting restriction fragment length polymorphisms (RFLPs) distributed over the short arm of the X chromosome, a double crossover was detected in a Duchenne muscular dystrophy carrier and an affected male fetus was diagnosed at 12 weeks of gestation, with a probable accuracy of more than 99.0%. Prenatal diagnosis of Duchenne muscular dystrophy using a single fetal nucleated erythrocyte in maternal blood is safer than amniocentesis or cordocentesis and can be applied to other X-linked diseases. In pregnant women who carry X-linked diseases, 75% of the fetuses has the poten- tial to develop into healthy children (all females, 50%, and unaffected males, 25%). It is therefore nec- essary to obtain informed consent when using prena- tal diagnosis to determine sex and perform genetic analyses of X-linked disease at the same time.
CONCLUSION
The key to perish any kind of disease is to prevent it from occurring rather finding ways to cure it. In the absence of a complete cure, DMD imposes an immense burden on affected individuals and their families. Prenatal diagnosis (PND) appears to be the best method to reduce the burden on individuals, their families and society. The pre-natal genetic diagnosis provides with an accuracy rate of 95% and serves as a tool for terminating the onset of the Duchenne to the next generation.
Although Duchenne is a rare disorder, the health care centres should involve in encouraging the peoples to go for a prenatal diagnosing.
The implementation of this methodology in the primary health care centres across the rural india may serve as a vital step toward the management of Duchenne muscular dystrophy.
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