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��ࡱ�>��	�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������[�	���%bjbj����	8Pΐΐ5+O������� 	 	cc����������8#����(0�����TTTI(K(K(K(K(K(K($�)��,>o(�T@TTTo(cc���(���TcR���I(�TI(��V5%@�"�%������6�"��r�u%5(�(0�(�%x�,��,�%�%p�,�i&�TT�TTTTTo(o(�TTT�(TTTT���������������������������������������������������������������������,TTTTTTTTT 		):	Eteplirsen: Unattainable Attained 
Mukta Sharma, Ashwin K. Jainanarayan1
CSIR-Institute of Genomics and Integrative Biology, New Delhi, Inida
                                      *Correspondence to [sharmamukta.924@gmail.com] 

Rare diseases are highly diverse and it is critical to know the signs that predict the development, progression and manifestation of disease. Though a very small number of people get affected by the rare diseases but its impact is outrageous, Duchenne Muscular Dystrophy1 (DMD) being one such rare genetic disorder is characterized by progressive muscle deterioration and wasting. An overall estimate of prevalence of DMD reflects 30 per 100,000 population (1 in 3000 or ~ 0.029%). However, there are ~7000 other rare hereditary diseases as well suggesting that about 400 million people worldwide are affected with some form of rare disease. The major challenge in the area of rare diseases is the need to determine the signs that mark the development of most important disease manifestations. There are many ways to diagnose DMD; a clinical diagnosis can be made by checking whether the child has experienced gradual muscle weakness. The symptoms are noticeable at a very tender age of 5 or may be before that accompanied by an increase in the blood creatine kinase levels. Normally, creatine kinase is present in high concentrations in the muscle cells of our body but muscle degeneration and/or breakdown results in breakage of muscle cells which lead to an elevated level of creatine kinase. Elevated creatine kinase levels in the body thus can prove to be a substantial evidence for the diagnosis of DMD. Some of the other important methods to diagnose DMD are presented below:
Muscle Biopsy can be done for determining the abnormal levels of dystrophin in muscles.
Genetic analysis can help in diagnosing DMD by examining the alterations (gene deletion/gene duplication) occurring in DMD gene.
Evaluating the family history, blood creatine kinase concentration and muscle biopsy with dystrophin studies substantiates the diagnosis. 
Non-invasive prenatal diagnosis testing can also be carried out to identify X-linked disorders. As DMD is X-linked, prenatal diagnosis can help in its early identification.
Although there are adequate diagnostic measures but still there is an unmet medical need for DMD. In DMD, the defective �dystrophin� gene2 which is also known to be the largest gene identified in humans is �X-linked� which states that the gene is positioned on the X chromosome. It stretches more than 2.5 million base pairs of genomic sequence, relatively about 0.1% of the total human genome and literature reveals that 99 percent of dystrophin gene is build up of introns. However, the coding sequence also constitutes 86 exons which further include seven promoters linked to unique first exons.  The dystrophin gene is predominantly expressed in skeletal and cardiac muscle and is expressed in the brain as well but in a very small amount. As formerly stated, this disorder affects male children whereas women become the carriers. Impediment in walking in the early childhood is one of the symptoms when the disease often becomes perceptible. The child experiences general muscle weakness and fatigue at a later stage and eventually all voluntary muscles gets affected. Sadly, it is believed that by 10-12 years, the child with DMD dread being immobile as they become totally dependent on others and die by 18-20 years. Though life is not easy for those who have a child with any form of rare disease but providentially, the society is now more open to people with DMD and also, various support groups are available these days. Moreover the law capacitates the young ones to comprehensive education and employment opportunities as well as participation in every public event which has led to a lesser discrimination towards the physically challenged children. 
Mutations in the dystrophin gene triggers DMD which as previously explained is a severe form of inherited and progressive muscle wasting. Dystrophin protein binds the �actin� to connective tissue thereby acting as a cushion when the muscle fibre contracts. In DMD, mutations block the functioning of dystrophin either by producing a premature stop codon or by hampering the reading frame which results in the detachment of actin from connective tissue thereby damaging muscle fibres during contraction.
The production of �Dystrophin� can be obstructed by diminutive mutations and various mutations affecting "Dystrophin� are summarized below:
A small deletion and/or insertion can interrupt the reading frame resulting in a non-functional dystrophin. 
Splice-site mutations results in the deletion of a single-exon at the mRNA level leading to a moderately functional or a non-functional dystrophin.
Missense mutations have also been reported in the patients with DMD, which hampers the link between actin and extracellular matrix. 
Conspicuously, a translocation mutation which involves the dystrophin gene will result in DMD in females. Although it is an X-linked disorder, but carrier females have 50% of dystrophin only. However, translocation mutations results in inactivation of translocated dystrophin gene thereby hampering the production of dystrophin.
In DMD an exon(s) is deleted which interferes with the other genes. Evidently, �Exon 51� cannot unite with �Exon 53� and does not let other exons join as well (Fig 1). Since, �dystrophin� can function only if it has both ends of the protein hence, this mutation results in a non-functional �dystrophin� which raises an alarm for the presence of DMD.


Figure  SEQ Figure \* ARABIC 1: Deletion of Exon 51 in Dystrophin protein interferes with the functioning of the other genes being pieced together.
A massive research has been carried out across the world and researchers have made great advancements in their knowledge of DMD. One of the approaches intends to leave out the defected segment of the gene so that �dystrophin� can be produced, even if in a condensed form. Food and Drug3 Administration�s (FDA) endeavor to safeguard the life-threatening rare diseases has led to an accelerated approval of one such ground-breaking medical product �Exondys51� (Generic Name: Eteplirsen). �Exondys51� has been manufactured by �Sarepta Therapeutics of Cambridge, Massachusetts� which is believed to develop a molecular patch over the mutant DNA in patients who are susceptible to Exon 51 skipping which nearly affects approximately 13% of the population. Exon skipping allocates an internally truncated �dystrophin� to be produced. Fortunately, phase II clinical trial studies revealed that patients enrolled for the trials of Exondys51 are doing well. It is assumed that this new drug is not a complete cure for DMD but it is hoped that it can certainly facilitate improvement in symptoms, ambulation and life expectancy. It is believed that �Exondys51� will prove that how a small percent of enhancement of �dystrophin� production can result in a drastically improved quality of life.
References:
Yiu, E. M and Kornberg, A. J., Duchenne muscular dystrophy, Neurol India., 2008, 56, 236-247.
Ahn AH and Kunkel LM., The structural and functional diversity of dystrophin., Nat Genet., 1993,3, 283-91.
Lim K R., Eteplirsen in the Treatment of Duchenne Muscular Dystrophy., Drug Des Devel Ther., 11, 533-545.
Acknowledgment:
I deeply thank Prof. Samir K Brahmachari for his valuable suggestions and guidance.









 PAGE   \* MERGEFORMAT 1



Deletion of Exon 51 results in disassembled Dystrophin protein causing DMD






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