On December 18, 2001 the [[MD CARE Act]] was signed into law and amends the [[Public Health Service Act]] to provide research for the various muscular dystrophies. This law also established the [[Muscular Dystrophy Coordinating Committee]] to help focus research efforts through a coherent research strategy.<ref name="govtrack">[http://www.govtrack.us/congress/bill.xpd?bill=h107-717 H.R. 717--107th Congress (2001)]: MD-CARE Act, GovTrack.us (database of federal legislation), (accessed Jul 29, 2007)</ref><ref name="PL107-84">[http://history.nih.gov/01Docs/historical/documents/PL107-84.pdf Public Law 107-84], PDF as retrieved from [[NIH]] website</ref>
On December 18, 2001 the [[MD CARE Act]] was signed into law and amends the [[Public Health Service Act]] to provide research for the various muscular dystrophies. This law also established the [[Muscular Dystrophy Coordinating Committee]] to help focus research efforts through a coherent research strategy.<ref name="govtrack">[http://www.govtrack.us/congress/bill.xpd?bill=h107-717 H.R. 717--107th Congress (2001)]: MD-CARE Act, GovTrack.us (database of federal legislation), (accessed Jul 29, 2007)</ref><ref name="PL107-84">[http://history.nih.gov/01Docs/historical/documents/PL107-84.pdf Public Law 107-84], PDF as retrieved from [[NIH]] website</ref>
==Types of Muscular Dystrophy==
===Becker's muscular dystrophy (BMD) ===
{{Main|Becker's muscular dystrophy}}
Becker muscular dystrophy (BMD) is a less severe variant of [[Duchenne muscular dystrophy]] and is caused by the production of a truncated, but partially functional form of dystrophin.<ref name="2006 report to Congress"/>
Survival is usually into middle age. <ref name="MD USA WEBSITE">[http://www.mdausa.org/disease/40list.html]: MD USA Website (accessed 03SEP2007)</ref>
===Congenital muscular dystrophy===
{{Main|Congenital muscular dystrophy}}
Age at onset: birth; symptoms include general muscle weakness and possible joint deformities; disease progresses slowly; shortened life span.
Congenital muscular dystrophy includes several disorders with a range of symptoms. Muscle degeneration may be mild or severe. Problems may be restricted to skeletal muscle, or muscle degeneration may be pair with effects on the brain and other organ systems. A number of the forms of the congenital muscular dystrophies are caused by defects in proteins that are thought to have some relationship to the dystrophin-glycoprotein complex and to the connections between muscle cells and their surrounding cellular structure. Some forms of congenital muscular dystrophy show severe brain malformations, such as [[lissencephaly]] and [[hydrocephalus]].<ref name="2006 report to Congress"/>
===Duchenne muscular dystrophy (DMD)===
{{Main|Duchenne muscular dystrophy}}
Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy. DMD usually becomes clinically evident when a child begins walking. Patients typically require a wheelchair by age 10 to 12 and die in their late teens or early 20s. In the early 1990s, researchers identified the gene for the protein dystrophin which, when absent, causes DMD. The dystrophin gene is the largest known gene in humans. Since the gene is on the X-chromosome, this disorder affects primarily males. Females who are carriers have milder symptoms. Sporadic mutations in this gene occur frequently, accounting for a third of cases. The remianing two-thirds of cases are inherited in a recessive pattern.
age at onset: two to six years; symptoms include general muscle weakness and wasting; affects pelvis, upper arms, and upper legs; eventually involves all voluntary muscles; survival beyond 20 years is rare.<ref name="2006 report to Congress"/>
Dystrophin is part of a complex structure involving several other protein components. The "dystrophin-glycoprotein complex" helps anchor the structural skeleton within the muscle cells, through the outer membrane of each cell, to the tissue framework that surrounds each cell. Due to defects in this assembly, contraction of the muscle leads to disruption of the outer membrane of the muscle cells and eventual weakening and wasting of the muscle.<ref name="2006 report to Congress"/>
===Distal muscular dystrophy===
{{Main|Distal muscular dystrophy}}
Distal muscular dystrophies' age at onset: 40 to 60 years; symptoms include weakness and wasting of muscles of the hands, forearms, and lower legs; progress is slow and not life-threatening.<ref name="MD USA WEBSITE">
Miyoshi myopathy, one of the distal muscular dystrophies, causes initial weakness in the calf muscles, and is caused by defects in the same gene responsible for one form of [[LGMD]].<ref name="2006 report to Congress"/>
===Emery-Dreifuss muscular dystrophy===
{{Main|Emery-Dreifuss muscular dystrophy}}
Age at onset, childhood to early teens. Symptoms include weakness and wasting of shoulder, upper arm, and shin muscles; joint deformities are common; progress is slow; sudden death may occur from cardiac problems.<ref>[http://www.emedicine.com/neuro/topic513.htm Emedicine re EDMD] Retrieved 30 July 2007.</ref>
FSHD initially affects muscles of the face, shoulders, and upper arms with progressive weakness. Symptoms usually develop in the teenage years. Some affected individuals become severely disabled. The pattern of inheritance is autosomal dominant, but the underlying genetic defect is poorly understood. Most cases are associated with a deletion near the end of chromosome 4.<ref name="2006 report to Congress"/>
===Limb-girdle muscular dystrophy (LGMD)===
{{Main|Limb-girdle muscular dystrophy}}
LGMD's all show a similar distribution of muscle weakness, affecting both upper arms and legs. Many forms of LGMD have been identified, showing different patterns of inheritance (autosomal recessive vs. autosomal dominant). In an autosomal recessive pattern of inheritance, an individual receives two copies of the defective gene, one from each parent. The recessive LGMDs are more frequent than the dominant forms, and usually have childhood or teenage onset. The dominant LGMDs usually show adult onset. Some of the recessive forms have been associated with defects in proteins that make up the dystrophin-glycoprotein complex.<ref name="2006 report to Congress"/>
Death from LGMD is usually due to cardiopulmonary complications.
===Myotonic muscular dystrophy===
{{Main|Myotonic muscular dystrophy}}
Myotonic MD's age at onset: 20 to 40 years
Myotonic muscular dystrophy is the most common adult form of muscular dystrophy. It is marked by [[myotonia]] as well as muscle wasting and weakness. Myotonic dystrophy varies in severity and manifestations and affects many body systems in addition to skeletal muscles, including the heart, endocrine organs, eyes, and gastrointestinal tract. Myotonic dystrophy follows an autosomal dominant pattern of inheritance. Myotonic dystrophy results from the expansion of a short repeat in the DNA sequence (CTG in one gene or CCTG in another gene). In other words, the gene defect is an abnormally long repetition of a three- or four-letter "word" in the genetic code. While the exact mechanism of action is not known, this molecular change may interfere with the production of important muscle proteins.<ref name="2006 report to Congress"/>
===Oculopharyngeal muscular dystrophy===
{{Main|Oculopharyngeal muscular dystrophy}}
Oculopharyngeal MD's age at onset: 40 to 70 years; symptoms affect muscles of eyelids, face, and throat followed by pelvic and shoulder muscle weakness, has been attributed to a short repeat expansion in a gene which regulates the translation of the genetic code into functional proteins.<ref name="2006 report to Congress"/>
Muscular dystrophy refers to a group of genetic, hereditarymuscle diseases that cause progressive muscle weakness.[1][2] Muscular dystrophies are characterized by progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue.[3] Nine diseases including Duchenne, Becker, limb girdle,
congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss are always classified as muscular dystrophy[4] but there are more than 100 diseases in total with similarities to muscular dystrophy. Most types of MD are multi-system disorders with manifestations in body systems including the heart, gastrointestinal and nervous systems, endocrine glands, skin, eyes and other organs.[4]
Historical Perspective
In the 1860s, descriptions of boys who grew progressively weaker, lost the ability to walk, and died at an early age became more prominent in medical journals. In the following decade, French neurologist Guillaume Duchenne gave a comprehensive account of thirteen boys with the most common and severe form of the disease, which now carries his name—Duchenne muscular dystrophy.
It soon became evident that the disease had more than one form.[4]
Age at onset: birth; symptoms include general muscle weakness and possible joint deformities; disease progresses slowly; shortened life span.[6]
Congenital muscular dystrophy includes several disorders with a range of symptoms.
Muscle degeneration may be mild or severe. Problems may be restricted to skeletal muscle, or muscle degeneration may be paired with effects on the brain and other organ systems.
A number of the forms of the congenital muscular dystrophies are caused by defects in proteins that are thought to have some relationship to the dystrophin-glycoprotein complex and to the connections between muscle cells and their surrounding cellular structure.
Some forms of congenital muscular dystrophy show severe brain malformations, such as lissencephaly and hydrocephalus.[4]
Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy, it generally affects only boys (with extremely rare exceptions), becoming clinically evident when a child begins walking.
By age 10, the child may need braces for walking and by age 12, most patients are confined to a wheelchair.[7]
Patients usually die around age 25, but this depends from person to person.[7]
In the early 1990s, researchers identified the gene for the protein dystrophin which, when absent, causes DMD. The amount of dystrophin correlates with the severity of the disease (i.e. the less dystrophin present, the more severe the phenotype). Since the gene is on the X chromosome, this disorder affects primarily males, and females who are carriers have milder symptoms. Sporadic mutations in this gene occur frequently, accounting for a third of cases. The remaining two-thirds of cases are inherited in a recessive pattern.
Dystrophin is part of a complex structure involving several other protein components. The "dystrophin-glycoprotein complex" helps anchor the structural skeleton (cytoskeleton) within the muscle cells, through the outer membrane (sarcolemma) of each cell, to the tissue framework (extracellular matrix) that surrounds each cell.
Due to defects in this assembly, contraction of the muscle leads to disruption of the outer membrane of the muscle cells and eventual weakening and wasting of the muscle.[4]
Distal muscular dystrophies' age at onset: 20 to 60 years; symptoms include weakness and wasting of muscles of the hands, forearms, and lower legs; progress is slow and not life-threatening.[5]
Miyoshi myopathy, one of the distal muscular dystrophies, causes initial weakness in the calf muscles, and is caused by defects in the same gene responsible for one form of LGMD (Limb Girdle Muscular Dystrophy).[4]
Emery-Dreifuss Muscular Dystrophy patients normally present in childhood and the early teenage years with contractures.
Clinical signs include muscle weakness and wasting, starting in the distal limb muscles and progressing to involve the limb-girdle muscles. Most patients also suffer from cardiac conduction defects and arrhythmias which, if left untreated, increase the risk of stroke and sudden death.
There are three subtypes of Emery-Dreifuss Muscular Dystrophy, distinguishable by their pattern of inheritance: X-Linked, autosomal dominant and autosomal recessive. The X-linked form is the most common. Each type varies in prevalence and symptoms.
The disease is caused by mutations in the LMNA gene, or more commonly, the EMD gene. Both genes encode for protein componenets of the nuclear envelope. However, how the pathogenesis of these mutations is not well understood.[8]
Facioscapulohumeral muscular dystrophy (FSHD) initially affects the muscles of the face, shoulders, and upper arms with progressive weakness. Symptoms usually develop in the teenage years. Some affected individuals become severely disabled.
The pattern of inheritance is autosomal dominant, but there are a significant number of spontaneous mutations.
Seminal research published in August 2010 documents that two defects are needed for FSHD, which for the first time provides a unifying theory for the underlying genetics of FSHD. The first is the deletion of D4Z4 repeats and the second is a "toxic gain of function" of the DUX4 gene.[4][9]
Limb-girdle muscular dystrophy is also called LGMD. Affects both boys and girls. LGMDs all show a similar distribution of muscle weakness, affecting both upper arms and legs.
Many forms of LGMD have been identified, showing different patterns of inheritance (autosomal recessive vs. autosomal dominant).
In an autosomal recessive pattern of inheritance, an individual receives two copies of the defective gene, one from each parent. The recessive LGMDs are more frequent than the dominant forms, and usually have childhood or teenage onset. The dominant LGMDs usually show adult onset. Some of the recessive forms have been associated with defects in proteins that make up the dystrophin-glycoprotein complex.[4]
Though a person normally leads a normal life with some assistance, in some extreme cases, death from LGMD occurs due to cardiopulmonary complications.[11]
Myotonic muscular dystrophy is an autosomal dominant condition that presents with myotonia (delayed relaxation of muscles) as well as muscle wasting and weakness.[12] * Myotonic dystrophy varies in severity and manifestations and affects many body systems in addition to skeletal muscles, including the heart, endocrine organs, eyes, and gastrointestinal tract.
Myotonic muscular dystrophy type 1 (DM1), also known as Steinert disease, is the most common adult form of muscular dystrophy. It results from the expansion of a short (CTG) repeat in the DNA sequence of the DMPK (myotonic dystrophy protein kinase) gene.
Myotonic muscular dystrophy type 2 (DM2) is much rarer and is a result of the expansion of the CCTG repeat in the ZNF9 (zinc finger protein 9) gene. While the exact mechanisms of action are not known, these molecular changes may interfere with the production of important muscle proteins.[4]
Oculopharyngeal MD's age at onset: 40 to 70 years.
Symptoms affect muscles of eyelids, face, and throat followed by pelvic and shoulder muscle weakness, has been attributed to a short repeat expansion in the genome which regulates the translation of some genes into functional proteins.[4]
Pathophysiology
Genetic
These conditions are inherited, and the different muscular dystrophies follow various inheritance patterns
The best-known type, Duchenne muscular dystrophy (DMD), is inherited in an X-linked recessive pattern, meaning that the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes, and is thus considered sex-linked. 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 must generally be present in both copies of the gene to cause the disorder (relatively rare exceptions, manifesting carriers, do occur due to dosage compensation/X-inactivation). Males are therefore affected by X-linked recessive disorders much more often than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
In about two thirds of DMD cases, an affected male inherits the mutation from a mother who carries one altered copy of the DMD gene. The other one third of cases probably result from new mutations in the gene. Females who carry one copy of a DMDmutation may have some signs and symptoms related to the condition (such as muscle weakness and cramping), but these are typically milder than the signs and symptoms seen in affected males.
Duchenne muscular dystrophy and Becker's muscular dystrophy are caused by mutations of the gene for the dystrophinprotein and lead to an overabundance of the enzymecreatine kinase.[13][14] The dystrophin gene is the second largest gene in mammals.[15]
Natural History, Complications and Prognosis
Prognosis
The severity of disability depends on the type of muscular dystrophy. All types of muscular dystrophy slowly get worse, but how fast this happens varies widely.
Some types of muscular dystrophy, such as Duchenne muscular dystrophy, are deadly. Other types cause little disability and people with them have a normal lifespan.
Early in the disease process, creatine phosphokinase (CPK) levels are 50-300 times greater than normal levels, but the levels tend to decrease as the muscle mass decreases.
Electromyography
Myopathic disease has these defining EMG characteristics:
There is no known cure for muscular dystrophy. Inactivity (such as bed-rest and even sitting for long periods) can worsen the disease. Physical therapy and orthopedic instruments (e.g.,wheelchairs, standing frames) may be helpful.
There is no specific treatment for any of the forms of muscular dystrophy. Physical therapy to prevent contractures (a condition when an individual with a muscular dystrophy grows and the muscles don't move with the bones and can easily be slowed down and/or make the individual's body straighter by daily physical therapy), orthoses (orthopedic appliances used for support) and corrective orthopedic surgery may be needed to improve the quality of life in some cases. The cardiac problems that occur with Emery-Dreifuss muscular dystrophy and myotonic muscular dystrophy may require a pacemaker. The myotonia (delayed relaxation of a muscle after a strong contraction) occurring in myotonic muscular dystrophy may be treated with medications such as quinine, phenytoin, or mexiletine.
MYO-029 is an experimental myostatin inhibiting drug developed by Wyeth Pharmaceuticals for the treatment of muscular dystrophy. Myostatin is a protein that inhibits the growth of muscle tissue, MYO-029 is a recombinant human antibody designed to bind and inhibit the activity of myostatin. A 2005/2006 trial was completed by Wyeth in Collegeville, PA. As of April 2007, the results of the study have not yet been made public, but it is one of the few known drugs in development for the treatment for muscular dystrophy.
National research and support in the United States