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McAdam, Laura C., Amanda L. Mayo, Benjamin A. Alman, and W. Douglas Biggar. “The Canadian experience with long term deflazacort treatment in Duchenne muscular dystrophy.” Acta Myologica 31, no. 1 (2012): 16.


The Duchenne Timeline

A talk with Karanveer Singh on World Rare Disease Day 2018 at DART

What is Muscular Dystrophy?

Muscular dystrophy (MD) is a group of more than 30 inherited disorders which causes all the muscles in the body to weaken. This leads to progressive disability and the child/adult may not be able to walk or engage in everyday life activities. In some forms of muscular dystrophy, the heart and respiratory system are also affected and the child/adult may require breathing support. Muscular dystrophy is caused by mutations in the gene responsible for producing the protein which is essential for healthy muscle formation and maintenance.

Currently, there is no cure for MD and treatment involves management of the condition with physiotherapy and medications like steroids. Research for gene therapy is in progress and has been giving positive results in clinical trials. Since MD is an x-linked autosomal recessive disorder, it affects mostly males.

There are nine major forms of MD each of which varies in severity and in its impact on life expectancy:
  • Duchenne MD (DMD) – is the most common and severest form of MD. It affects 1 in every 3500 boys. Females carry the symptoms but do not present with the disease. This form of dystrophy is linked to the absence or mutated form of the protein dystrophin. Lack of this protein leads to a gradual weakening of muscles. Boys with DMD present with symptoms in early childhood as early as 1-5 years of age. As the child is learning to sit up, stand or walk; parents may notice slow, dragging movements. Gradually the child may require the aid of a wheelchair or crutches. DMD also affects the heart and respiratory system.
  • Becker MD (BMD) – is less severe and progresses slowly. BMD develops in late childhood.
  • Myotonic MD – is also known as Steinert’s disease. It is an adult form of MD and usually appears under the age of 20. Major symptoms include muscle weakness, myotonia (low muscle tone and flexibility) and muscle wasting. Some children with myotonic MD also present with heart ailments.
  • Limb-girdle MD – affects both boys and girls. Symptoms begin anytime between the ages 8-15. LGMD affects the pelvic, shoulder and back muscles. Severity varies and it can be mild or even affect overall mobility requiring the aid of a wheelchair.
  • Facioscapulohumeral muscular dystrophy – again affects both boys and girls with symptoms appearing in the teens. Muscle weakness appears in the face with the child finding it difficult to close the eyes. Gradually the limbs and pelvic muscles lose muscle strength.
  • Oculopharyngeal MD – is the adult form of MD appearing usually during the 50s. This MD does not affect life expectancy.
  • Emery-Dreifuss MD – develops in early adulthood.
DMD, the most common form of MD is inherited in an x-linked recessive pattern. If the X chromosome from the mother has the DMD gene mutation, the son will have DMD. Since females have two copies of the X chromosome, if she inherits one DMD gene mutation, the other copy of the gene acts as backup to produce the protein dystrophin. A female with a DMD mutation is only a carrier and does not express the disease. There is a 50% chance of passing on the mutated gene to the son and 50% chance that the daughter will also inherit the mutated gene and be a carrier.
Infants born with MD seem normal until they reach early childhood. Gradually they develop problems with movement. Parents may notice one or more of the following signs and symptoms:
  • slow movement and difficulty sitting up and standing/li>
  • stumbling while walking/li>
  • difficulty with climbing stairs/li>
  • walking on the tip of his toes/li>
  • enlarged calf muscles
If the pediatrician or orthopedician suspects MD, he/she will usually take a family history and history of the child’s symptoms. Some of the tests that are used to diagnose MD include:
  • biochemical tests – like serum creatine kinase (an enzyme released into the blood when muscle fibers break down), muscle biopsy where a small sample of the muscle is surgically removed and examined.
  • molecular test – DNA tests like Next Generation Sequencing (NGS) to locate the exact mutation causing the form of MD.

Currently, no permanent cure is available for MD. Treatment is aimed at preventing deterioration of muscles and preserving mobility. An interdisciplinary team of doctors including pediatricians, neurologists, orthopedicians, pulmonologist, cardiologist and physiotherapist will be required to take care of the clinical needs of the child/adult. In the early stages when just diagnosed, it is important to keep up with physical therapy, braces and medications.

Physical therapy enables the child to protect and preserve muscle tone. Physiotherapists usually use braces to prevent joint contractions that lead to painful joint locking. With bracing, the child can walk independently as it provides the right support.

In recent years, prescriptions for steroids have moved away from prednisone to deflazacort especially for DMD. Deflazacort has preserved mobility, improved cardiac and respiratory function, delayed the onset of scoliosis and improved survival rates. Deflazacort has fewer side effects like weight gain and does not rapidly lead to bone mass weakness and also has less glucose intolerance. Children/adults on deflazacort have to be monitored regularly.

Many children with DMD/BMD develop scoliosis of the spine due to muscle weakness. Children with severe scoliosis need to undergo a surgery known as spinal fusion to minimize the curvature and the pain. This surgery enables children to sit comfortably without pain and it also prevents the spinal curvature from impacting breathing.

Children/adults with MD must be encouraged to participate in non-impact sports like swimming which strengthens core muscles. Safe exercises like light yoga, Tai-chi, pilates or water exercises are permitted. Diet and nutrition are important for preserving muscle and bone strength and a diet rich in calcium is recommended. Calcium and D3 supplements are also given to children and adults.

Many children and adults with MD may use supportive measures like crutches, braces and wheelchair and if required breathing support.

Gene therapy has the potential for a permanent cure for MD. In DMD, gene therapy works using a viral vector to deliver the correct form of the dystrophin gene to allow for normal production of the protein. The challenge however is the size of the DMD gene which is the largest in the human genome and hence finding a vector to carry is difficult.

In recent years, scientists are experimenting with a shortened version of the DMD gene which can produce a protein called micro-dystrophin. Micro-dystrophin has key elements to allow for functionality. Phase 1/2 human trials are now in progress (NCT03375164) at Nationwide Children’s Hospital in Columbus, Ohio. According to a press release from the Parent Project Muscular Dystrophy (PPMD), the first DMD patient has received the microdystrophin gene therapy.

Closer home, Bengaluru-based Dystrophy Annihilation Research Trust (DART) and Hanugen therapeutics are working towards a therapy known as exon skipping. The idea of exon skipping is to skip an exon using a mask or molecular patch (antisense oligonucleotides (AONs) in the dystrophin pre-mRNA to allow the production of a small quantity of microdystrophin. This breakthrough therapy will be the first form of any treatment to reach children with muscular dystrophy.

Children and adults with MD can participate in all life activities and must be encouraged to go to regular schools, colleges and participate in social activities. Genetic counselling and psychosocial counselling must be made available whenever required with other supportive measures.

If there is a known case of MD in the family, it is absolutely essential for closest female relatives like siblings, uncles, aunts and cousins to test for carrier status.

If a woman with a carrier status is pregnant, prenatal test is essential to determine if the fetus has the disease mutation.