ABSTRACT
Muscular dystrophy disorders are hereditary neuromuscular disorders in which the skeletal muscles deteriorate progressively due to loss of the functional protein dystrophin encoded by the DMD gene. There are many types of muscular dystrophy and they are classified based on the genetic mechanisms involved. Muscular dystrophy symptoms are usually caused by mutations in the link between cytoskeletal and basal lamina proteins since dystrophin is a sarcolemmal membrane protein (Meregalli M, 2013). Loss of ambulation is also an important clinical milestone in the clinical diagnosis of muscular dystrophy. Respiratory muscles, particularly the intercostal and diaphragm muscles are also affected by muscular dystrophy making breathing very difficult. In addition, cardiomyopathy symptoms are almost always a universal symptom of all muscular dystrophy disorders. Thus, there is tremendous heterogeneity in the molecular mechanisms behind each type of muscular dystrophy and it is responsible for the variety of clinical symptoms (Flanigan KM, 2012).
Currently the most effective medicinal treatment for Duchene’s Muscular Dystrophy (DMD) is corticosteroid treatment. However, long-term corticosteroids such as prednisone have associated side-effects of weight gain, behavior changes, ostopenia, fractures and other side-effects. The emerging therapies for muscular dystrophy such as gene therapy, bio-active compounds and stem cell therapy although promising have still not yet been able to deliver sufficient relief from the symptoms of muscular dystrophy. Multidisciplinary teams consisting of physical therapists, occupational therapists, speech therapists, psychiatrists, neurologists and other trained medical professionals in addition to the primary care physician help care for muscular dystrophy patients. It is vital for the medical team to keep updated with new therapies.
MUSCULAR DYSTROPY CAUSES AND TYPES
Muscular Dystrophy is characterized by progressive skeletal muscular weakness. Muscular dystrophy disorders are hereditary neuromuscular disorders in which the muscles deteriorate with fibrosis and fatty replacement. Muscular dystrophy symptoms are usually caused by mutations in the link between cytoskeletal and basal lamina proteins since dystrophin is a sarcolemmal membrane protein (Meregalli M, 2013). Symptoms of muscular dystrophy occur due to mutations in the DMD gene which encodes the dystrophin protein (Hoffman E, 1987). Duchene’s Muscular Dystrophy (DMD) is a type of muscular dystrophy that was named after the French neurologist Duchene du Bologne. DMD is caused by the loss of functional protein dystrophin and the symptoms of DMD occur early between the ages of 3 and 5. There is tremendous heterogeneity in the molecular mechanisms behind each type of dystrophy and it is responsible for the variety of clinical symptoms (Flanigan KM, 2012).
The X-linked types of muscular dystrophy are Dunchene’s Muscular Dystrophy (DMD), Becker’s Muscular Dystrophy (BMD), X-linked Dilated Cardiomyopathy (XLDCM) and Emery-Dreifuss Muscular Dystrophy (EDMD). The Autosomal recessive types of muscular dystrophy are Limb-Girdle Muscular Dystrophy (LGMD), Congenital Muscular Dystrophy (CMD) and Fukuyuma-type Congenital Muscular Dystrophy (FCMD). An example of the Autosomal dominant type of muscular dystrophy is Facioscapulohumeral Muscular Dystrophy (FSHD) (Campbell KP, 1985). CMD sub-types are classified based on the involvement of the Central Nervous System (CNS). Thus, these are some of the types of Muscular Dystrophy classified based on the genetic mechanisms and Central Nervous System (CNS) involvement in the disease symptoms. Patient care needs to be individualized to meet the patient’s needs.
SIGNS AND SYMPTOMS
Duchene’s Muscular Dystrophy (DMD) patients show the most severe symptoms of all the Muscular Dystrophies. The early symptoms occurring between ages 3 and 5 are associated with gait and include symptoms such as toe walking and waddling. The loss of ambulation in muscular dystrophy patients is associated with loss of strength in hip extension and ankle dorsiflexion. The calf muscle hypertrophy usually occurs at 4-5 years and continues to progressively deteriorate while other muscles start to atrophy. Thus, loss of ambulation is also an important clinical milestone in the clinical diagnosis of muscular dystrophy (Morrison LA, 2011).
Other muscles besides those directly involved with walking are also affected in muscular dystrophy patients. Respiratory muscles, particularly the intercostal and diaphragm muscles are affected by muscular dystrophy and this makes breathing very difficult. In addition, cardiomyopathy symptoms are almost always a universal symptom of all muscular dystrophy disorders. Thus overall, this progressive loss of muscle function often results in tremendous fatigue and a loss of balance and coordination.
Gastrointestinal symptoms are rare in muscular dystrophy patients but gastroparesis can occur with fatal consequences for the patient. Brain function is also compromised in DMD and BMD patients and they have an average IQ of 80-90. Brain dystrophin is found in the hippocampus and cerebellum and they are affected by loss of neurons that normally express dystrophin (Morrison LA, 2011).
PREVELANCE AND INCIDENCE RATES
DMD is more likely to occur in males since the DMD gene is X-chromosome linked and females are more likely to be carriers of the mutated gene. Male offspring of female carriers have a 50% risk of inheriting the DMD/BMD mutation for muscular dystrophy. New mutations also account for approximately one-third of the cases globally (Morrison LA, 2011). In some cases carriers of the mutated genes with one good copy also show symptoms (Hoogerwaard, EM, 1999). It is estimated that 1 in 5600 to 7400 males between the ages of 5 to 24 years in the United States has Duchene or Becker Muscular Dystrophy (CDC Website). The average age of diagnosis in the United States is 4.9 years on average.
DIAGNOSTIC PROCEDURES
Diagnosis of muscular dystrophy is usually performed by detecting abnormalities in the dystrophin protein. Detection of the dystrophin gene mutations only results in the detection of 65% of the cases while detection of the dystrophin protein results in 100% detection of muscular dystrophy cases (Wessell H, 1989). The severity of dystrophin deficiency can be determined by using special markers of dystrophin on muscle biopsy specimens from the affected individual.
Testing for Creatine Kinase (CK) levels in the serum helps in the diagnosis of muscular dystrophy. CK testing along with genetic testing is used currently in the diagnosis of DMD. Direct sequencing along with dosage analysis and a combination of genetic testing methods helps in the diagnosis of 93-96 % muscular dystrophy patients (Morrison LA, 2011). Electromyogram (EMG) is a test for muscle electrical activity and it helps detect true muscle weakness instead of weakness from reduced use or lack of motivation to use the muscle. Thus, EMG tests can be very useful in muscular dystrophy diagnosis.
TREATMENT
Currently the most effective medicinal treatment for Duchene’s Muscular Dystrophy (DMD) is corticosteroid treatment. Daily doses of prednisone at 0.75 mg per day delay the loss of ambulation by 1-3 years (Flanigan KM, 2012). However corticosteroids are not very effective in other types of muscular dystrophies besides DMD. Furthermore, DMD patients on corticosteroids do not develop scoliosis which is a curving of the spine that is usually associated with muscular dystrophy (Talan J, 2011). Unfortunately, long-term corticosteroids such as prednisone have associated side-effects of weight gain, behavior changes, ostopenia, fractures and other side-effects. These many side-effects of long-term corticosteroid therapy cause several patients to give up these steroid medicines. For cardiac symptoms, treatment with Angiotensin Converting Enzyme Inhibitors (ACEIs) improves left ventricular function irrespective of age of onset.
There are several other experimental treatments for muscular dystrophy but these treatments have yet to reach their potential and be validated by large scale clinical trials in many patients. Gene therapy is a newer treatment option for muscular dystrophy patients and it aims to deliver healthy genes to specific muscles by means of non-infectious viruses. In small scale test studies of gene therapy with limb-girdle muscular dystrophy patients, an increase in dystrophin protein was seen in tests as compared to placebos (Talan J, 2011). Larger scale clinical trials are needed to validate these experimental studies. Biologic agents such as ACE-031 manufactured by Acceleron Pharmaceuticals function to limit myostatin and thereby try to increase muscle mass and strength are being developed to treat muscular dystrophy patients (Talan J, 2011).
In studies from the UK, experiments in DMD patients aimed at correctly localizing dystrophin protein at the sarcolemma by means of a splice switching oligomer AVI-4658 showed promise (Cirak S, 2011). These studies show that AVI-4658 has the potential to become a disease modifying drug for DMD. Stem cell therapy is also an attractive method of treating muscular dystrophy. Unfortunately, muscle homing mechanisms of stem cells are not studied enough to develop effective therapy from systemic delivery of stem cells (Meregalli M, 2013). Thus overall, these emerging therapies such as gene therapy, bio-active compounds and stem cell therapy although promising have still not yet been able to deliver sufficient relief from the symptoms of muscular dystrophy.
PATIENT CARE
Multidisciplinary teams consisting of physical therapists, occupational therapists, speech therapists, psychiatrists, neurologists and other trained medical professionals in addition to the primary care physician help care for muscular dystrophy patients. The main treatments of dystrophinopathies used to be rehabilitation and surgical interventions until clinical trials for corticosteroid treatments started in the late 1980s. With the help of modern technologies life expectancy of muscular dystrophy patients has been increasing from an average of 16 years in the past to approximately 25 years during current times. In rare cases patients have been known to survive in their early to mid- 30s (Morrison LA, 2011).
There are several aspects of patient care and because different organs and systems in the body are affected by muscular dystrophy many associated conditions need to be screened for and treated as the disease progresses and the patient grows. Patient care needs to be individualized with the emotional and cultural needs of the family members of the muscular dystrophy patient taken into consideration.
CARDIAC CARE
Cardiac symptoms are not necessarily treated well by preventive treatments in cardiomyopathy caused by muscular dystrinopathies. Screening recommendations for cardiac care in muscular dystrophy patients and carriers are unclear with some groups recommending screening every 2 years till age 10 in DMD and other clinicians recommending less frequent screening. Cardiac transplantation is also an option for BMD patients doing well from a neuromuscular perspective (Morrison LA, 2011).
PULMONARY CARE
Lung function testing and sleep studies were recommended for DMD patients in the US. The Centers for Disease Control (CDC) recommends an annual pulmonary function testing while sitting for ambulatory muscular dystrophy patients six years and older. For all non-ambulatory patients, additional lung function testing such as peak cough flow, maximum expiratory and inspiratory pressure should also be checked every six months (Morrison LA, 2011).
In patients with DMD and associated sleep-related breathing disorder (SRBD), nocturnal ventilation is considered to be effective. The surgical options for treating sleep-related disorders are tonsillectomy and adenoidectomy (Morrison LA, 2011).
GASTROENTEROLOGY AND NUTRITION
The nutritional requirement of muscular dystrophy patients is important to consider since under nutrition would decrease the ability of the muscles to undergo repair while the muscular atrophy advances. On the other hand excessive weight gain exacerbated by corticosteroid therapy would further compromise the neuromuscular system. Ideal nutrition for muscular dystrophy patients would include high-quality protein, complex carbohydrates and hydration while avoiding foods that would lead to weight gain and diabetes. During the later stages of muscular dystrophy, decubitus ulcers are a concern especially in poorly nourished sitting patients (Morrison LA, 2011).
ORTHOPEDIC CARE
Scoliosis screening should begin once ambulation is lost. Scoliosis surgery is recommended once it is detected in order to improve the ability of the patient to sit comfortably. Stretching activities may be effective for some patients early on but certain types of exercise may result in more rapid muscle function deterioration. Sporting activities are encouraged in children with muscular dystrophy symptoms and are to be modified as physical abilities decline (Morrison LA, 2011).
ADAPTATIONS AND ACCOMODATIONS
As expected, muscular dystrophy patients require several adaptations and accommodations to live their lives as the disease progresses and muscle function is progressively lost. The home environment needs to be equipped with several devices which aid the patient in daily activities. Children have learning disabilities in school and have difficulty with reading and writing. Computer skills should be acquired as soon as possible after the diagnosis of muscular dystrophy (Morrison LA, 2011).
ASSISTING DEVICES
There are several medical devices available presently to help assist patients with Muscular Dystrophy and improve their Quality of Life. Lightweight customized orthopedic devices have now replaced the older heavy metal leg braces. Feeding devices and mobile arm supports also help to assist the patient. In addition, power wheelchairs and power scooters help muscular dystrophy move around unassisted. Power wheelchairs should have reclining options to relieve pressure points and should be able to tilt in space. Due to the difficulty associated with muscular dystrophy patient’s ability to walk up or down stairs, lifts are required.
Special beds and mattresses which can assist in the transfer of the patient from the wheelchair to the bed help make the patient’s life a little easier. Bathroom aids and communication aids also help make it easier for the patient to handle more activities of daily living on their own. These devices designed to improve the lives of muscular dystrophy patients are very useful but they are costly as well (Morrison LA, 2011).
CONCLUSION
Genes responsible for muscular dystrophy symptoms have been at the forefront of genetic mapping efforts. Several clinical trials are underway to advance emerging therapies such as gene therapy, stem cell therapy and bio-active compounds for the treatment of muscular dystrophy. It is vital that the medical team keeps updated with the latest therapies to assist in patient treatment. These novel gene-corrective therapies are a major hope for some relief from symptoms and increasing the life-span of affected individuals.
References
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http://www.cdc.gov/ncbddd/musculardystrophy/data.html
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