Its most common form in children, Duchenne muscular dystrophy, affects approximately 1 in every 3, to 6, male births each year in the United States. Many muscular dystrophies are familial, meaning there is some family history of the disease. Duchenne cases often have no prior family history. This is likely due to the large size of the dystrophin gene that is implicated in the disorder, making it a target for spontaneous mutations.
Muscles are made up of thousands of muscle fibers. Each fiber is actually a number of individual cells that have joined together during development and are encased by an outer membrane. Muscle fibers that make up individual muscles are bound together by connective tissue. Muscles are activated when an impulse, or signal, is sent from the brain through the spinal cord and peripheral nerves nerves that connect the central nervous system to sensory organs and muscles to the neuromuscular junction the space between the nerve fiber and the muscle it activates.
There, a release of the chemical acetylcholine triggers a series of events that cause the muscle to contract. Affected muscle fibers eventually die from this damage, leading to progressive muscle degeneration. Although MD can affect several body tissues and organs, it most prominently affects the integrity of muscle fibers. The disease causes muscle degeneration, progressive weakness, fiber death, fiber branching and splitting, phagocytosis in which muscle fiber material is broken down and destroyed by scavenger cells , and, in some cases, chronic or permanent shortening of tendons and muscles.
Also, overall muscle strength and tendon reflexes are usually lessened or lost due to replacement of muscle by connective tissue and fat.
Are there other MD-like conditions? There are many other heritable diseases that affect the muscles, the nerves, or the neuromuscular junction. The differential diagnosis for people with similar symptoms includes congenital myopathy, spinal muscular atrophy, and congenital myasthenic syndromes.
The sharing of symptoms among multiple neuromuscular diseases, and the prevalence of sporadic cases in families not previously affected by MD, often makes it difficult for people with MD to obtain a quick diagnosis. Gene testing can provide a definitive diagnosis for many types of MD, but not all genes have been discovered that are responsible for some types of MD.
Some individuals may have signs of MD, but carry none of the currently recognized genetic mutations. Studies of other related muscle diseases may, however, contribute to what we know about MD. How do the muscular dystrophies differ? There are nine major groups of the muscular dystrophies.
The disorders are classified by the extent and distribution of muscle weakness, age of onset, rate of progression, severity of symptoms, and family history including any pattern of inheritance. Although some forms of MD become apparent in infancy or childhood, others may not appear until middle age or later.
Overall, incidence rates and severity vary, but each of the dystrophies causes progressive skeletal muscle deterioration, and some types affect cardiac muscle. Because inheritance is X-linked recessive caused by a mutation on the X, or sex, chromosome , Duchenne MD primarily affects boys, although girls and women who carry the defective gene may show some symptoms.
About one-third of the cases reflect new mutations and the rest run in families. Sisters of boys with Duchenne MD have a 50 percent chance of carrying the defective gene. Duchenne MD usually becomes apparent during the toddler years, sometimes soon after an affected child begins to walk. Other symptoms include loss of some reflexes, a waddling gait, frequent falls and clumsiness especially when running , difficulty when rising from a sitting or lying position or when climbing stairs, changes to overall posture, impaired breathing, lung weakness, and cardiomyopathy.
Many children are unable to run or jump. As the disease progresses, the muscles in the diaphragm that assist in breathing and coughing may weaken. Affected individuals may experience breathing difficulties, respiratory infections, and swallowing problems. Some affected children have varying degrees of cognitive and behavioral impairments.
Between ages 3 and 6, children may show brief periods of physical improvement followed later on by progressive muscle degeneration. Children with Duchenne MD typically lose the ability to walk by early adolescence. Without aggressive care, they usually die in their late teens or early twenties from progressive weakness of the heart muscle, respiratory complications, or infection. However, improvements in multidisciplinary care have extended the life expectancy and improved the quality of life significantly for these children; numerous individuals with Duchenne muscular dystrophy now survive into their 30s, and some even into their 40s.
Duchenne MD results from an absence of the muscle protein dystrophin. Dystrophin is a protein found in muscle that helps muscles stay healthy and strong. Blood tests of children with Duchenne MD show an abnormally high level of creatine kinase; this finding is apparent from birth. People with Becker MD have partial but insufficient function of the protein dystrophin. The disorder usually appears around age 11 but may occur as late as age 25, and affected individuals generally live into middle age or later.
Many individuals are able to walk until they are in their mid-thirties or later, while others are unable to walk past their teens.
Some affected individuals never need to use a wheelchair. As in Duchenne MD, muscle weakness in Becker MD is typically noticed first in the upper arms and shoulders, upper legs, and pelvis. Early symptoms of Becker MD include walking on one's toes, frequent falls, and difficulty rising from the floor.
Calf muscles may appear large and healthy as deteriorating muscle fibers are replaced by fat, and muscle activity may cause cramps in some people. Cardiac complications are not as consistently present in Becker MD compared to Duchenne MD, but may be as severe in some cases.
Cognitive and behavioral impairments are not as common or severe as in Duchenne MD, but they do occur. They affect both boys and girls. The degree and progression of muscle weakness and degeneration vary with the type of disorder.
Weakness may be first noted when children fail to meet landmarks in motor function and muscle control. Muscle degeneration may be mild or severe and is restricted primarily to skeletal muscle.
The majority of individuals are unable to sit or stand without support, and some affected children may never learn to walk. Defects in the protein merosin cause nearly half of all cases of congenital MD. Some individuals have normal intellectual development while others become severely impaired. Weakness in diaphragm muscles may lead to respiratory failure. Congenital MD may also affect the central nervous system, causing vision and speech problems, seizures, and structural changes in the brain.
Some children with the disorders die in infancy while others may live into adulthood with only minimal disability. Distal MD, also called distal myopathy, describes a group of at least six specific muscle diseases that primarily affect distal muscles those farthest away from the shoulders and hips in the forearms, hands, lower legs, and feet.
Distal dystrophies are typically less severe, progress more slowly, and involve fewer muscles than other forms of MD, although they can spread to other muscles, including the proximal ones later in the course of the disease. Distal MD can affect the heart and respiratory muscles, and idividuals may eventually require the use of a ventilator. Affected individuals may not be able to perform fine hand movement and have difficulty extending the fingers. As leg muscles become affected, walking and climbing stairs become difficult and some people may be unable to hop or stand on their heels.
Onset of distal MD, which affects both men and women, is typically between the ages of 40 and 60 years. In one form of distal MD, a muscle membrane protein complex called dysferlin is known to be lacking. Although distal MD is primarily an autosomal dominant disorder, autosomal recessive forms have been reported in young adults. Table 1: Characteristics of muscular dystrophy publications Click here to view The number of authors also increased from to The average number of authors per paper ranged from a minimum of 3.
The average number of authors per paper was 4. The research impact in terms of the citation count has been taken as the number of citations scored by each article published in that year, as was the status in October The average citation per paper was The highest number of citations per paper Figure 1: Publication growth and citation trends of muscular dystrophy research Click here to view The self-citation trend was found to be occurring in an increasing order.
Self-citation is a common and fundamental attribute of scientific articles. About Country of publication The authors' countries relating to muscular dystrophy publications were analyzed based on the affiliation of at least one author. Okinaka was correct; the patient was probably suffering from polymyositis rather than muscular dystrophy. However, the incident led to one of the monumental achievements in the history of muscular dystrophy research due to the outstanding professional intuition of Dr.
Setsuro Ebashi. When Dr. Momoi, a close friend of Dr. Ebashi since middle school, told him about the serum aldolase activity in muscular dystrophy, he pointedly asked Dr. You should look at the level creatine phosphokinase, which is more specific to skeletal muscle than aldolase. At his suggestion, we set up a team, headed by Dr. Ebashi and including Drs. In Duchenne muscular dystrophy, dystrophin is almost totally absent; the less dystrophin that is produced, the worse the symptoms and etiology of the disease.
In Becker muscular dystrophy, there is a reduction in the amount or size of the dystrophin protein. The gene coding for dystrophin is the largest known gene in humans. More than 1, mutations in this gene have been identified in Duchenne and Becker muscular dystrophy. Diagnosis There are a variety of techniques used to definitively diagnose muscular dystrophy: The genetic mutations involved in muscular dystrophy are well known and can be used to make a diagnosis.
Enzyme assay: Damaged muscles produce creatine kinase CK. Elevated levels of CK in the absence of other types of muscle damage could suggest muscular dystrophy.
Genetic testing: As genetic mutations are known to occur in muscular dystrophy, these changes can be screened for. Heart monitoring: Electrocardiography and echocardiograms can detect changes in the musculature of the heart. This is especially useful for the diagnosis of myotonic muscular dystrophy. Lung monitoring: Checking lung function can give additional evidence.
Electromyography: A needle is placed into the muscle to measure the electrical activity. The results can show signs of muscle disease. In fact, scientists have observed that the extent of fibrosis in DMD muscle tracks with diminished function.
In addition, scientists hope that reducing fibrosis also may help increase the efficacy of other potential therapies. HT is a delayed-release formulation of halofuginone, a compound that has been studied for years for its effects on autoimmune and fibrotic diseases.
Halofuginone exerts its effects by inhibiting the formation of collagen 1, a major component of fibrotic tissue. A second approach to reducing fibrosis is to introduce a peptide called angiotensin In a mouse model of DMD, angiotensin has been shown to reduce the formation of fibrotic tissue in muscle and also suppress some of the signals that have been implicated in the growth of fibrotic tissue.
This therapy will undergo phase 2 clinical testing in This work showed that CTGF reduces the ability of damaged muscle cells to repair themselves and promotes muscle fibrosis, and that inhibiting CTGF reduces muscle fibrosis and improves muscle function. In addition, FG also has been tested in phase 2 clinical studies for idiopathic pulmonary fibrosis, where it was shown to reverse fibrosis in a significant number of patients.
Maximizing blood flow to muscle Phosphodiesterase Inhibitors People with DMD experience inadequate blood flow to their muscles while exercising, which may contribute to fatigue and reduced performance. Thus, scientists hope that drugs that restore proper blood flow to muscles may benefit muscle strength and function.
On the basis of these and other findings, researchers have started investigating the possibility that phosphodiesterase inhibitors can improve muscle function in people with DMD or BMD.
This study demonstrated that tadalafil could restore normal blood flow regulation after a single dose. Further study is ongoing to determine whether this effect will lead to improved muscle function in BMD. A later study conducted in DMD found that treatment with either sildenafil or tadalafil restores blood flow to muscles during exercise or rest in DMD patients.
Additional clinical studies are planned to determine whether this increased blood flow will translate to increased muscle function in DMD. Unfortunately, a trial with sildenafil showed that it was unlikely to help heart function in these patient groups. A second study with sildenafil, which had enrolled a small number of participants, was in fact terminated due to concerns about the potential for negative impact on cardiac function in adults with Duchenne and Becker muscular dystrophy.
Due to the small study size, questions remain about whether sildenafil is in fact unsafe for the BMD heart. Nitric oxide is the product of an enzyme called nNOS which is absent in DMD and BMD muscle and works in a similar manner to the phosphodiesterase inhibitors described above. Naproxinod is a potential therapy in preclinical development by a French pharmaceutical company called NicOx. Naproxinod is a version of naproxen Aleve that has been modified to release nitric oxide into the body.
This therapy has been tested clinically for arthritis and other indications, and has demonstrated promising effects in a mouse model of DMD. The hope is that this therapy could increase blood flow to muscles and reduce inflammation, both of which may help to improve the function of DMD muscle.
Scientists in Italy are developing a combination therapy for DMD, using ibuprofen a nonsteroidal anti-inflammatory drug and isosorbide dinitrate a nitric oxide donor. This combination therapy has undergone two clinical trials named Isofen 1 and 2 to determine its safety and to establish the most effective dose of each drug.
Additional clinical trials are planned to determine whether this combination has a beneficial effect in people with DMD. Finally, researchers from Cedars-Sinai Medical Center currently are studying the effects of sodium nitrate, a nitric oxide donor, in people with BMD in two separate clinical trials. The first trial is a phase study to determine whether sodium nitrate improves blood flow to muscle, as the phosphodiesterase inhibitors have been shown to do.
The second is a phase 1 clinical study to determine whether there is a functional benefit to muscle that results from treatment with sodium nitrate. Protecting the dystrophin-deficient heart DMD heart muscle, like skeletal muscle, is more susceptible to damage because it is missing dystrophin, an important structural component of the cell membrane.
More information about cardiomyopathy in DMD can be found here and here.
Researchers at a company called Nobelpharma have developed another stop codon read-through therapy called NPC
This compound is currently in preclinical development, but Akashi plans to bring it into clinical testing in the near future. This therapy will undergo phase 2 clinical testing in They are particularly useful in studying families with members in different generations who are affected. The prognosis varies according to the type of MD and the speed of progression. Affected individuals may have double vision and problems with upper gaze, and others may have retinitis pigmentosa progressive degeneration of the retina that affects night vision and peripheral vision and cardiac irregularities.