Disease Overview: Duchenne muscular dystrophy

Duchenne Muscular Dystrophy (DMD) is the most common form of muscular dystrophy characterised by progressive skeletal muscle degeneration and weakness. DMD causes motor delays, loss of ambulation (the ability to walk without assistance), respiratory impairment and cardiomyopathy that may eventually lead to death. DMD is a rare genetic disorder affecting males primarily, with an incidence rate of 1 in 5,000 live male births. Symptoms occur in early childhood and continue throughout the patient’s life. However, due to the advances in respiratory and cardiac care, the life expectancy of DMD patients is increasing, and many young adults with DMD attend college, have careers, get married and have children.^1,2,3

Causes

DMD is caused by the lack of a protein called dystrophin protein, which is primarily caused by a mutation in the dystrophin gene (the largest gene of the human genome) responsible for its production. Dystrophin protein is a cytoskeletal protein located at the cytoplasmic side of the sarcolemma (the cell membrane that surrounds the skeletal fibre or cardiomyocyte). It links the internal cytoskeleton to the extracellular matrix and therefore maintains the structural integrity of the skeletal muscles and the heart. Therefore, dystrophin deficiency causes the muscles to become weak and fragile.^1,2,3

The mutation in the dystrophin gene can be of any type: deletion, duplication, point mutation, or any other rearrangement. These mutations result in no production of dystrophin at all or the production of non-functional dystrophin. DMD is an X-linked recessive neuromuscular disorder that is typically inherited from the mother. The dystrophin gene is located on the X-chromosome, which means DMD affects boys more often than girls, whereas girls are carriers. Nevertheless, in about 25% of cases of DMD, the disease occurs spontaneously in people with no previous family history of DMD.^1,2

Diagnosis

It is estimated that 20,000 children around the globe are diagnosed with DMD each year.¹

Diagnosis usually takes place in early childhood after the first appearance of signs and symptoms related to DMD, such as weakness, clumsiness, and walking or stair climbing difficulty. Doctors usually begin by taking the patient’s family history as well as performing a physical examination. Thereafter, doctors often order a CK blood test to determine the level of the enzyme Creatine Kinase (CK), which usually leaks out of damaged muscles. High levels of CK do not confirm the diagnosis of DMD, but it indicates that muscles are being disintegrated by some abnormal process, such as muscular dystrophy or inflammation. By age 2, the CK levels peak at 10 to 20 times the upper limit value, then fall progressively returning to normal levels eventually when a considerable amount of muscle tissue has been replaced by fat and fibrotic tissue.

For those with clinical findings of dystrophinopathy and elevated serum CK levels, genetic testing is recommended, where either the presence or absence of a mutation in the DMD gene will be confirmed. Moreover, doctors might also refer you to a cardiologist as well as ask for an electrocardiogram, echocardiography, or cardiac MRI, to help them detect any structural changes in the heart or conduction abnormalities indicating cardiomyopathy. Furthermore, a muscle biopsy might be indicated in patients without a detectable mutation.^2,3,5

Signs and Symptoms

DMD is a multi-systemic disorder that affects many parts of the body with a greater influence on the skeletal, pulmonary, and cardiac muscles:

– Skeleton and Muscle: Fatigue, muscle weakness, difficulty walking, difficulty in climbing stairs, muscle cramps, contractures, gait abnormalities, pseudohypertrophy (enlarged calves), lordosis (exaggerated inward curve of the spine), scoliosis (when the spine twists and curves to the side).

– Lungs: Breathing difficulties, respiratory infections, sleep apnea (breathing repeatedly stops and starts during sleep).

– Heart: Cardiomyopathy

– Nervous System: Developmental delay, motor delay.

– Cognition: Learning disability.

– Gastrointestinal: Dysphagia (difficult swallowing), constipation, reflux, gastroparesis (delayed gastric emptying).^1,4,5

The general outline of the disease and expectations

The onset of symptoms occurs between the ages of 3 and 5. The early signs include delayed ability to sit, stand or walk and difficulties in learning to speak. Usually, muscle weakness begins in the hips, pelvic area, upper legs, and shoulders, where it worsens with age, progressing to the arms, legs, and trunk. It is typical of children with DMD to develop an unusual walk and difficulty in running and climbing stairs. Some children will have problems getting up from the floor and are therefore forced to use a special method called Gower’s manoeuvre, or Gower’s sign, where they will need to walk their hands up their thighs in order to stand up. Disease progression varies from one person to another; however, boys usually lose their ability to walk and transition to full-time use of a wheelchair at age 12.¹

DMD also affects memory, learning, communication, and certain emotional skills. A small percentage of boys develop some degree of learning disability. This usually includes three general areas:

– Attention-focusing problems

– Verbal learning and memory problems

– Emotional interaction problems.

Respiratory and heart muscle problems begin in the teen years and can lead to serious complications. At about age 10, the diaphragm and other muscles operating the lungs begin to weaken, making the lungs less effective at moving air in and out. Some of the signs of poor respiratory function include headaches, difficulty concentrating or staying awake, and nightmares. Moreover, with weak respiratory muscles, it becomes difficult to cough, which increases the risk of developing serious respiratory infections. For instance, a simple cold can quickly progress to pneumonia. Nevertheless, advances in the treatment and management of DMD make survival into the early 30s more common. Furthermore, there is proof of cases of men with DMD living into their 40s and 50s.¹

Management and Treatment

Different therapeutic strategies have been explored and considered for the treatment and management of DMD.

Treatment strategies

Steroids

The golden standard of treatment of DMD is corticosteroids. They can:

– slow down the decline in function and muscle strength

– prolong independent ambulation

– improve lung function

– delay the onset of cardiomyopathy

– reduce the incidence of scoliosis.²

Corticosteroid therapy is associated with a lower mortality rate and a lower incidence of cardiomyopathy. It is thought that steroids work partly by reducing inflammation. Corticosteroids should not be started in patients under the age of 2 years or those whose motor skills are still developing. The most frequent adverse effects of corticosteroids are weight gain and a reduction in the patient’s height. Other side effects include cataracts, vertebral fractures, acne, hirsutism, arterial hypertension, immunosuppression, delayed puberty, behaviour disorders, cushingoid facies and gastrointestinal problems, loss of bone mass, and increased appetite.

The most common example of steroids is Prednisone, which, when given at 0.75mg/kg/day, improved muscle strength in 6 months and quality of life in 12 months.2 Deflazacort (brand name Emflaza) is a synthetic steroid with anti-inflammatory and immunosuppressive properties. 0.9 mg/kg/day of Deflazacort is equivalent to 0.75 mg/kg/day of Prednisone. Deflazacort has fewer side effects but causes more cataracts than Prednisone.

Emflaza is the only corticosteroid approved by the FDA for the treatment of DMD in individuals 5 years of age or older.^2,3

2) Genetic Engineering

Since the discovery of gene expression manipulation using antisense oligonucleotides, exon skipping has become a potential therapy. Antisense oligonucleotides are designed to produce a transcription messenger of ribonucleic acid (mRNA) that produces several levels of truncated but functional dystrophin. Antisense oligonucleotides are short nucleic acid sequences designed to selectively bind to the mRNA sequences or specific pre-mRNA to inflict a small double-helical region on the target mRNA. Through binding with this region and forming double helices at the target location, the mutated exon will be skipped. ²

Most deletions occur at exons 44 and 55. Exon 51 is chosen as the target because, in contrast to other exons, skipping at this exon can correct the reading frames in several patients. The skipping process of dystrophin exon 51 in patients with relevant deletions repairs the open reading frames and induces the expression of dystrophin proteins. ²

Eteplirsen (brand name Exondys 51) is an FDA-approved, “exon skipping” drug that targets the exon 51 section of DNA. Exondys is not a cure for DMD, but it potentially could lessen the severe muscle weakness and atrophy helping up to 13% of individuals with DMD. Studies in patients receiving 30 mg/kg and 50 mg/kg intravenous eteplirsen weekly showed an improvement in walking ability as well as increased production of dystrophin by 40-50% (as shown on biopsy).^2,3

3) Stem Cells

It is the latest and most controversial form of treatment, with the main challenges being transportation, immunological rejection, and high cost. In the skeletal muscle, progenitor cell populations that hold myogenic potential include:

Mesangioblasts, MDSCs (muscle-derived stem cells), muscle-derived CD133+ progenitors, and mesenchymal stem cells. 2 Ideal stem cells used to treat DMD, should fulfil several criteria:

– be expandable in vitro without losing stem cell properties.

– Be immune- privileged,

– Differentiate into muscle fibres either to repair damaged fibres or replace fibres that have already been lost.

– Re-constitute the satellite cell pool with functional stem cells, leading to improvement in muscle strength. ²

Management strategies

Physiotherapy and exercise help to restore and maintain muscle strength and function. Stretching helps to maintain the range of motion.
Braces or orthoses support the ankle and foot or may extend up over the knee.
Occupational therapy helps improve daily living and work skills.
Assisted ventilation can help with respiratory muscle weakness.
Educational and psychological interventions can help with learning disabilities.

Corrective orthopaedic surgery, including spine-straightening surgery, may help make sitting, sleeping, and breathing more comfortable.¹

Conclusion

Timely diagnosis of DMD plays a crucial part in the course of the disease and the patient’s life expectancy. Moreover, prompt referral to a neuromuscular specialist and a geneticist would avoid diagnostic delay. Although there is no cure for DMD, the advances in medications and therapy help to manage some of the symptoms and slow down the course of the disease. More research in the genetic engineering and stem cell therapeutic approach is required, with more large-scale randomised controlled trials to be completed.

References:

Muscular Dystrophy association, what is Duchenne Muscular Dystrophy, American Medical Association, 2019, Available from:

https://www.mda.org/sites/default/files/2019/03/Duchenne_Muscular_Dystrophy_Fact_Sheet.pdf

Machfoed MH, Besin V, Basuki M, Lasmono SF. Duchenne muscular dystrophy: overview and future challenges. Aktualności Neurologiczne 2017 Nov 30,;17(3):144-149.
Birnkrant D. et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. The Lancet Neurology 2018 23rd January.
Muscular Dystrophy Association [Internet]. 2017 [cited 2023 Aug 16]. Research – duchenne muscular dystrophy (Dmd) – diseases. Available from:

https://www.mda.org/disease/duchenne-muscular-dystrophy/research