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Duchenne Muscular Dystrophy(DMD)

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Duchenne muscular dystrophy (DMD) is a progressive form of muscular dystrophy that occurs primarily in males, though in rare cases may affect females. DMD causes progressive weakness and loss (atrophy) of skeletal and heart muscles. [1] It is a recessive X-/a

Duchenne muscular dystrophy (DMD) is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or respiratory complications. Treatment modalities such as corticosteroid therapy and use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life, and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. [2]

Cause :

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene. The DMD gene provides instructions for making a protein called dystrophin. Dystophin is primarily made in the muscle cells of the heart and skeletal muscle. The main job of dystrophin in muscle cells is to help stabilize and protect muscle fibers. [1]

When dystrophin is missing, the muscle cells become damaged more easily. In response to the damage, inflammation occurs, which only worsens the process. Over time, the muscle cells without dystrophin weaken and die, leading to the muscle weakness and heart problems seen in DMD. The non-progressive memory and learning problems, as well as social behavioral problems, in some boys with DMD are most likely linked to loss of dystrophin in the neurons of the hippocampus and other parts of the brain where dystrophin is normally produced in small amounts, but at this point it is not known why this occurs and why only some people with DMD have these problems. [1]

Different genetic changes in the DMD gene can cause a spectrum of disorders known as dystrophinopathies. The dystrophinopathies can range from very mild symptoms to the more severe symptoms seen in people with DMD. Other dystrophinopathies include Becker muscular dystrophy (BMD) and DMD-associated dilated cardiomyopathy (DCM). [1]

Dystrophin in muscle fibers


Inheritance :

This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In many cases, an affected male inherits the mutation from his mother, who carries one altered copy of the DMD gene. The remainder of cases probably result from new mutations in the gene in affected males and are not inherited.

In X-linked recessive inheritance, a female with one mutated copy of the gene in each cell is called a carrier. She can pass on the altered gene but usually does not experience signs and symptoms of the disorder. Occasionally, however, females who carry a DMD gene mutation may have muscle weakness and cramping. These symptoms are typically milder than the severe muscle weakness and atrophy seen in affected males. Females who carry a DMD gene mutation also have an increased risk of developing heart abnormalities including cardiomyopathy. [3]

Symptoms :

Symptoms of Duchenne muscular dystrophy (DMD) are usually noticed in boys between 1 to 6 years of age. There is a steady decline in muscle strength between the ages of 6 and 11 years. By age 10, braces may be needed for walking. By age 13, most boys with DMD are using a wheelchair full-time. The signs and symptoms include:

⦁ Taking longer to learn to sit, stand, or walk on own, which is known as delayed motor development. The average age for walking in boys with DMD is 18 months.
⦁ Having a waddling walk and difficulty climbing stairs or running.
⦁ Difficulty getting up from the floor. Children may walk their hands up their legs to stand which is known as the Gower maneuver.
⦁ Enlarged calf muscles due to the calf muscle cells being replaced by fat and connective tissue(pseudohypertrophy). This may also cause calf pain.
⦁ Muscle weakness first affecting the muscles of the hips, pelvic area, thighs and shoulders, and later the skeletal (voluntary) muscles in the arms, legs and trunk.
⦁ Tight or rigid joints (also known as contractures) may develop as muscle loss progresses. If not treated, these will become severe, causing discomfort and restricting mobility and flexibility. Contractures can affect the knees, hips, feet, elbows, wrists and fingers.
⦁ Scoliosis may develop within several years of full-time wheelchair use.
⦁ By the early teens, the respiratory and heart muscles are also affected.
⦁ Breathing problems due to weakness of the diaphragm and the other muscles around the lungs. Skeletal changes, such as scoliosis, may also increase breathing problems. Breathing problems may become life-threatening.
⦁ Progressive enlargement of the heart (cardiomyopathy) that stops the heart from pumping blood efficiently and becomes life-threatening in many cases.
⦁ Learning and memory issues (cognitive impairment) may occur in some cases, but do not worsen as DMD progresses.
⦁ Communication may be more difficult for some.
⦁ Social behavior may be affected, as well as the ability to read facial cues. [1]

Diagnosis :

A child’s doctor may suspect Duchenne muscular dystrophy (DMD) in young boys who have the signs and symptoms of DMD, including progressive muscle weakness. Family history is also important. Blood tests can be used to check for increased levels of certain special proteins called muscle enzymes in the blood which can leak from damaged muscles. Most commonly, the blood level of the enzyme creatine phosphokinase (CPK or CK) is checked, but a doctor may also check the blood levels of transaminases such as aspartate transaminase and alanine transaminase. Finding a change in the DMD gene that can cause DMD through genetic testing confirms the diagnosis of DMD.

Testing for DMD may include :  

  • Blood test which measures the levels of serum creatine phosphokinase (CK or CPK). Very high CK levels indicate muscle damage is causing the muscle weakness, rather than nerve damage.
  • Molecular genetic testing (usually blood cells are used) to see whether there is a change or mutation in the DMD gene that can cause DMD or one of the related dystrophinopathies.
  • Electromyography can be used to distinguish conditions that only impact the muscles (myotonic) from those that involve that brain and muscles (neurogenic). [1]

Treatment :

There is no known cure for Duchenne muscular dystrophy (DMD) but research is ongoing. The goal of treatment is to control the symptoms of DMD and related complications caused by severe progressive muscle weakness and loss in order to maximize the quality of life. An enlarged, weakened heart (dilated cardiomyopathy) may be treated with medications, but in severe cases a heart transplant may be necessary. Assistive devices for breathing difficulties may be needed, especially at night and as the disease progresses.

Gentle exercise is encouraged for people with DMD. Physical inactivity (such as bed rest) can worsen the muscle disease, but so can overexertion. Physical therapy may be helpful to maintain muscle strength and function. Orthopedic devices (such as braces and wheelchairs) may improve the ability to move and take care of oneself.

Steroids (corticosteroids) may improve the strength and function of muscles in people with DMD, including lung function. Steroid options include:
⦁ Prednisone is a steroid that has been shown to extend the ability to walk by 2 to 5 years. However, the possible side effects of prednisone include weight gain, high blood pressure, behavior changes, and delayed growth.
Deflazacort (another form of prednisone), is used in Europe and believed to have fewer side effects and was recently approved in the United States by the FDA.

Oxandrolone, a medication used in a research study, also has similar benefits to prednisone, but with fewer side effects. [3]

Rehabilitation: Physical therapy, occupational therapy, speech therapy and other recreational therapies play a very important role in helping the patient to go about his daily activities and increasing their own independency. The main aim of these therapies is to maintain the muscle extensibility and prevent joint contractures that lead to deformities.

Rehabilitative improve quality of life of the patients and prevent secondary complications like contractures and deformity. [4]

Gene Therapy: The aim of the Gene Therapy is precisely to introduce these genes into the patients to normalize the gene expression and protein production. Although it might seem like an easy task, in reality it is quiet daunting due to the complexity of human genes and gene expression.

Several novel strategies for replacing or repairing the defective gene are in development, with early encouraging results from animal models. In most of the gene therapies a normal gene is inserted into the genome to replace the abnormal gene causing the disease. This can be done using viral vectors, Antisense- Induced Exon Skipping or Read through Stop Codon Strategies. However, the high cost and lack of human clinical trials, makes gene therapy an apprehensive approach.

All the treatment options that are available so far provide only symptomatic treatment but fail to act at a cellular level. They fail to regenerate the wasted muscles or reverse the pathology of the disease.

Also, Muscular Dystrophy is a genetic disorder and hence no treatment can repair the core changes in the defective genetic structure. [4]

Case Study 1:

Credit: NeurogenGen Brain & Spine Institute by Dr. Nandini Gokulchandran and Dr. Alok Sharma

The patient who is 5 years old child residing in Kanchrapara, Kolkata. The patient is a known case of Duchenne’s Muscular Dystrophy (DMD). Since birth, there were small movements on a bed which patient could not perform but not really noticed by his parents. His parents first noticed an abnormality in their child when he was 3 years old. It all started with difficulty in climbing stairs and not being able to pull himself upright from a sitting or sleeping position, running slowly etc. When he was around 4 years old he was diagnosed with Duchene Muscular Dystrophy on the basis of clinical investigations.

At NeuroGen on examination following problems were noted in Patient:
⦁ Partially dependent in all ADLs (All Day Living Activities)
⦁ Difficulty in climbing stairs
⦁ Difficulty in running and walking
⦁ Couldn’t comfortably pull himself upright from seating or sleeping position.
⦁ Abnormal thickness and tightening in calf muscles
⦁ Gait was abnormal, he used to bend is stomach front and used to walk by bending on each side.
⦁ Lower limb – strongest muscles of our body the hip muscles and inner thigh muscles were affected.
⦁ Poor breathing capacity
⦁ Walking balance was fair
⦁ Poor stability and mobility of trunk muscles like abdominals and back extensors.
⦁ Performing hand functions was difficult.
⦁ Difficulty in bed mobility
⦁ standing balance was poor
⦁ Speech was affected, he stammers a lot.
⦁ Can’t do cycling or one leg standing
⦁ Stamina to do exercise is less, gets tired early.
⦁ He used to fall for once or twice every day.
⦁ Occurrence of bed wetting occasionally
He underwent Stem Cell Transplantation and advised to continue a certain diet chart along with medications. He is doing 4-5 hours of therapy in a day. Within two months after discharge, He has shown tremendous improvements and has reached a near around 70% improvement stage. On following up with a patient condition on the telephone, we have found below improvements:
⦁ Patient has now started cycling with his friends which he was unable to do earlier.
⦁ Standing and walking balance has improved – now he attempts to do one leg standing which was not possible before at all.
⦁ He can run properly now and play with his friends.
⦁ Qualitative improvements are noted in terms of shifting himself on his own. He has to put lesser efforts now for doing bed mobility activities like rolling and getting up from sleeping position.
⦁ His speech has improved, he stammers less now and hence speech has become almost normal.
⦁ Upper limb activity like wearing his own clothes and brushing teeth etc has become better than before.
⦁ Gait and posture has improved, he sits with more erect posture now and walks with better foot clearance.
⦁ Calf muscle hypertrophy has reduced; calves are softer now.
⦁ Stamina has improved – earlier he used to so only 1-2hrous or therapy but now he can do 4-5hours of therapy sessions every day and can now perform any activity for longer duration.
⦁ Falls have reduced greatly, after stem cell therapy since December 2015, he has fallen only twice. It has almost stopped.
⦁ Bed wetting has completely stopped.

Case Study 2:
Credit: Rupam Sinha, Soumyabrata Sarkar, Tanya Khaitan and  Soumyajit Dutta
Department of Oral Medicine and Radiology, Haldia Institute of Dental Sciences and Research, Haldia, West Bengal, India
J Family Med Prim Care. 2017 Jul-Sep; 6(3): 654–656.

A 12-year-old male patient with a chief complaint of the painful decayed tooth in the lower right jaw region.

The medical history of repeated falls, fatigue, muscle weakness, and inability to climb stairs. There was no history of muscular pain and cranial nerve involvement. His intelligence quotient was claimed to be in the normal range. Patient’s family history revealed that one of his maternal uncles died of the same illness at a young age.

On general physical examination, the child had an obese appearance and presented with difficulty in standing, walking, getting up from sitting position and climbing stairs, proximal weakness, calf hypertrophy, hamstring muscle contracture, and positive Gower’s sign.

Figure: Proximal muscle weakness of upper and lower limbs and calf hypertrophy

There was no thinning and twitching of muscles, muscle tone, and cranial nerve examination was also found to be normal. Intraoral examination revealed anterior open bite, left posterior cross bite, enlarged tongue, crowding in lower anteriors, decayed 46, and poor oral hygiene status.

The patient was subjected to radiological and laboratory investigations. Panoramic radiography revealed no abnormality except for grossly carious 46 indicative of chronic periapical abscess. Serological analysis showed creatine kinase (CK) level to be elevated to 7342 U/L, lactate dehydrogenase to 595 μg/dl, and alanine transaminase level to 124 U/L. On electromyographic examination, interference pattern analysis revealed myopathic pattern in the right vastus lateralis suggestive of primary muscle disease. Deltoid muscle biopsy revealed positivity for alpha, beta, gamma, delta-sarcoglycan and negativity for DYS1, DY2, and DYS3. Based on the history, clinical examination and investigations, a diagnosis of DMD were established.

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