Duchenne muscular dystrophy
|Duchenne muscular dystrophy|
|Classification and external resources|
Histopathology of gastrocnemius muscle from patient who died of pseudohypertrophic muscular dystrophy, Duchenne type. Cross section of muscle shows extensive replacement of muscle fibers by adipose cells.
Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy, affecting around 1 in 3,600 boys, which results in muscle degeneration and eventual death. The disorder is caused by a mutation in the dystrophin gene, the largest gene located on the human X chromosome, which codes for the protein dystrophin, an important structural component within muscle tissue that provides structural stability to the dystroglycan complex (DGC) of the cell membrane. While both sexes can carry the mutation, females rarely exhibit signs of the disease.
Symptoms usually appear in male children before age 6 and may be visible in early infancy. Even though symptoms do not appear until early infancy, laboratory testing can identify children who carry the active mutation at birth. Progressive proximal muscle weakness of the legs and pelvis associated with a loss of muscle mass is observed first. Eventually this weakness spreads to the arms, neck, and other areas. Early signs may include pseudohypertrophy (enlargement of calf and deltoid muscles), low endurance, and difficulties in standing unaided or inability to ascend staircases. As the condition progresses, muscle tissue experiences wasting and is eventually replaced by fat and fibrotic tissue (fibrosis). By age 10, braces may be required to aid in walking but most patients are wheelchair dependent by age 12. Later symptoms may include abnormal bone development that lead to skeletal deformities, including curvature of the spine. Due to progressive deterioration of muscle, loss of movement occurs, eventually leading to paralysis. Intellectual impairment may or may not be present but if present, does not progressively worsen as the child ages. The average life expectancy for patients afflicted with DMD is around 25.
- 1 History
- 2 Pathogenesis
- 3 Symptoms
- 4 Signs and tests
- 5 Diagnosis
- 6 Treatment
- 7 Occupational and physical therapy
- 8 Ongoing research
- 9 Counseling
- 10 Famous persons with muscular dystrophy
- 11 References
- 12 External links
The disease was first described by the Neapolitan physician Giovanni Semmola in 1834 and Gaetano Conte in 1836. However, DMD is named after the French neurologist Guillaume Benjamin Amand Duchenne (1806–1875), who, in the 1861 edition of his book "Paraplegie hypertrophique de l'enfance de cause cerebrale", described and detailed the case of a boy who had this condition. A year later, he presented photos of his patient in his "Album de photographies pathologiques." In 1868 he gave an account of 13 other affected children. Duchenne was the first who did a biopsy to obtain tissue from a living patient for microscopic examination.
Duchenne muscular dystrophy (DMD) is caused by a mutation of the dystrophin gene at locus Xp21. Dystrophin is responsible for connecting the cytoskeleton of each muscle fiber to the underlying basal lamina (extracellular matrix) through a protein complex containing many subunits. The absence of dystrophin permits excess calcium to penetrate the sarcolemma (cell membrane). Alterations in these signalling pathways cause water to enter into the mitochondria which then burst. In skeletal muscle dystrophy, mitochondrial dysfunction gives rise to an amplification of stress-induced cytosolic calcium signals and an amplification of stress-induced reactive-oxygen species (ROS) production. In a complex cascading process that involves several pathways and is not clearly understood, increased oxidative stress within the cell damages the sarcolemma and eventually results in the death of the cell. Muscle fibers undergo necrosis and are ultimately replaced with adipose and connective tissue.
DMD is inherited in an X-linked recessive pattern. Females will typically be carriers for the disease while males will be affected. Typically, a female carrier will be unaware they carry a mutation until they have an affected son. The son of a carrier mother has a 50% chance of inheriting the defective gene from his mother. The daughter of a carrier mother has a 50% chance of being a carrier or having two normal copies of the gene. In all cases, the father will either pass a normal Y to his son or a normal X to his daughter. Female carriers of an X-linked recessive condition, such as DMD, can show symptoms depending on their pattern of X-inactivation.
Duchenne muscular dystrophy is caused by mutations in DMD gene which codes for protein dystrophin. DMD gene is located on the short arm of the X chromosome (Xp21.2-p21.1). Duchenne muscular dystrophy has an incidence of 1 in 3,600 male infants. Mutations within the dystrophin gene can either be inherited or occur spontaneously during germline transmission.
The main symptom of Duchenne muscular dystrophy, a progressive neuromuscular disorder, is muscle weakness associated with muscle wasting with the voluntary muscles being first affected, especially affecting the muscles of the hips, pelvic area, thighs, shoulders, and calf muscles. Muscle weakness also occurs in the arms, neck, and other areas, but not as early as in the lower half of the body. Calves are often enlarged. Symptoms usually appear before age 6 and may appear as early as infancy. The other physical symptoms are:
- Awkward manner of walking, stepping, or running. (patients tend to walk on their forefeet, because of an increased calf tonus. Also, toe walking is a compensatory adaptation to knee extensor weakness.)
- Frequent falls
- Difficulty with motor skills (running, hopping, jumping)
- Increased Lumbar lordosis, leading to shortening of the hip-flexor muscles. This has an effect on overall posture and a manner of walking, stepping, or running.
- Muscle contractures of achilles tendon and hamstrings impair functionality because the muscle fibers shorten and fibrosis occurs in connective tissue
- Progressive difficulty walking
- Muscle fiber deformities
- Pseudohypertrophy (enlarging) of tongue and calf muscles. The muscle tissue is eventually replaced by fat and connective tissue, hence the term pseudohypertrophy.
- Higher risk of neurobehavioral disorders (e.g., ADHD), learning disorders (dyslexia), and non-progressive weaknesses in specific cognitive skills (in particular short-term verbal memory), which are believed to be the result of absent or dysfunctional dystrophin in the brain.
- Eventual loss of ability to walk (usually by the age of 12)
- Skeletal deformities (including scoliosis in some cases)
Signs and tests
According to Lewis P. Rowland, in the anthology Gene Expression In Muscle, if a boy is affected with Duchenne muscular dystrophy (DMD), the condition can be observed clinically from the moment he takes his first steps. It becomes harder and harder for the boy to walk; his ability to walk usually completely disintegrates between the time the boy is 9 to 12 years of age. Most men affected with DMD become essentially “paralyzed from the neck down” by the age of 21. Muscle wasting begins in the legs and pelvis, then progresses to the muscles of the shoulders and neck, followed by loss of arm muscles and respiratory muscles. Calf muscle enlargement (pseudohypertrophy) is quite obvious. Cardiomyopathy (DCM) is common, but the development of congestive heart failure or arrhythmias (irregular heartbeats) is only occasional.
- A positive Gowers' sign reflects the more severe impairment of the lower extremities muscles. The child helps himself to get up with upper extremities: first by rising to stand on his arms and knees, and then "walking" his hands up his legs to stand upright.
- Affected children usually tire more easily and have less overall strength than their peers.
- Creatine kinase (CPK-MM) levels in the bloodstream are extremely high.
- An electromyography (EMG) shows that weakness is caused by destruction of muscle tissue rather than by damage to nerves.
- Genetic testing can reveal genetic errors in the Xp21 gene.
- A muscle biopsy (immunohistochemistry or immunoblotting) or genetic test (blood test) confirms the absence of dystrophin, although improvements in genetic testing often make this unnecessary.
The muscle-specific isoform of the dystrophin gene is composed of 79 exons, and DNA testing and analysis can usually identify the specific type of mutation of the exon or exons that are affected. DNA testing confirms the diagnosis in most cases.
If DNA testing fails to find the mutation, a muscle biopsy test may be performed. A small sample of muscle tissue is extracted (usually with a scalpel instead of a needle) and a dye is applied that reveals the presence of dystrophin. Complete absence of the protein indicates the condition.
Over the past several years DNA tests have been developed that detect more of the many mutations that cause the condition, and muscle biopsy is not required as often to confirm the presence of Duchenne's.
DMD is carried by an X-linked recessive gene. Males have only one X chromosome, so one copy of the mutated gene will cause DMD. Fathers cannot pass X-linked traits on to their sons, so the mutation is transmitted by the mother.
If the mother is a carrier, and therefore one of her two X chromosomes has a DMD mutation, there is a 50% chance that a female child will inherit that mutation as one of her two X chromosomes, and be a carrier. There is a 50% chance that a male child will inherit that mutation as his one X chromosome, and therefore have DMD.
Prenatal tests can tell whether their unborn child has the most common mutations. There are many mutations responsible for DMD, and some have not been identified, so genetic testing only works when family members with DMD have a mutation that has been identified.
Prior to invasive testing, determination of the fetal sex is important; while males are sometimes affected by this X-linked disease, female DMD is extremely rare. This can be achieved by ultrasound scan at 16 weeks or more recently by free fetal DNA testing. Chorion villus sampling (CVS) can be done at 11–14 weeks, and has a 1% risk of miscarriage. Amniocentesis can be done after 15 weeks, and has a 0.5% risk of miscarriage. Fetal blood sampling can be done at about 18 weeks. Another option in the case of unclear genetic test results is fetal muscle biopsy.
There is no current cure for DMD, although phase 1-2a trials with exon-skipping treatment for certain mutations have halted decline and produced small clinical improvements in walking.
Treatment is generally aimed at controlling the onset of symptoms to maximize the quality of life, and include the following:
- Corticosteroids such as prednisolone and deflazacort increase energy and strength and defer severity of some symptoms.
- Randomised control trials have shown that beta2-agonists increase muscle strength but do not modify disease progression. Follow-up time for most RCTs on beta2-agonists is only around 12 months and hence results cannot be extrapolated beyond that time frame.
- Mild, non-jarring physical activity such as swimming is encouraged. Inactivity (such as bed rest) can worsen the muscle disease.
- Physical therapy is helpful to maintain muscle strength, flexibility, and function.
- Orthopedic appliances (such as braces and wheelchairs) may improve mobility and the ability for self-care. Form-fitting removable leg braces that hold the ankle in place during sleep can defer the onset of contractures.
- Appropriate respiratory support as the disease progresses is important.
Comprehensive multi-disciplinary care standards/guidelines for DMD have been developed by the Centers for Disease Control and Prevention (CDC), and were published in two parts in The Lancet Neurology in 2010. To download the two articles in PDF format, go to the TREAT-NMD website.
Duchenne muscular dystrophy is a progressive disease which eventually affects all voluntary muscles and involves the heart and breathing muscles in later stages. The life expectancy is currently estimated to be around 25, but this varies from patient to patient. Recent advancements in medicine are extending the lives of those afflicted. The Muscular Dystrophy Campaign, which is a leading UK charity focusing on all muscle disease, states that "with high standards of medical care young men with Duchenne muscular dystrophy are often living well into their 30s".
In rare cases, persons with DMD have been seen to survive into the forties or early fifties, with the use of proper positioning in wheelchairs and beds, ventilator support (via tracheostomy or mouthpiece), airway clearance, and heart medications, if required. Early planning of the required supports for later-life care has shown greater longevity in people living with DMD.
Physical therapists are concerned with enabling children to reach their maximum physical potential. Their aim is to:
- minimize the development of contractures and deformity by developing a programme of stretches and exercises where appropriate
- anticipate and minimize other secondary complications of a physical nature
- monitor respiratory function and advise on techniques to assist with breathing exercises and methods of clearing secretions
- Schedule weekly to monthly sessions at a massage therapist to alleviate pain present.
Mechanical ventilatory/respiration assistance
Modern "volume ventilators/respirators," which deliver an adjustable volume (amount) of air to the person with each breath, are valuable in the treatment of people with muscular dystrophy related respiratory problems. The ventilator may require an invasive endotracheal or tracheotomy tube through which air is directly delivered, but, for some people non-invasive delivery through a face mask or mouthpiece is sufficient. Positive airway pressure machines, particularly bi-level ones, are sometimes used in this latter way. The respiratory equipment may easily fit on a ventilator tray on the bottom or back of a power wheelchair with an external battery for portability.
Ventilator treatment may start in the mid to late teens when the respiratory muscles can begin to collapse. If the vital capacity has dropped below 40 percent of normal, a volume ventilator/respirator may be used during sleeping hours, a time when the person is most likely to be under ventilating ("hypoventilating"). Hypoventilation during sleep is determined by a thorough history of sleep disorder with an oximetry study and a capillary blood gas (See Pulmonary Function Testing).
If the vital capacity continues to decline to less than 30 percent of normal, a volume ventilator/respirator may also be needed during the day for more assistance. The person gradually will increase the amount of time using the ventilator/respirator during the day as needed.
However, there are also people with the disease in their 20's who have no need for a ventilator.
Occupational and physical therapy
The goal of occupational therapy is to obtain a clear understanding of the individual, of their social circumstances and of their environment in order to develop a treatment plan that will improve their quality of life. Individuals with DMD often experience difficulties in areas of self-care, productivity and leisure. This is related to the effects of the disorder, such as decreased mobility; decreased strength and postural stability; progressive deterioration of upper-limb function; and contractures. Occupational and physical therapists address an individual's limitations using meaningful occupations and by grading the activity, by using different assessments and resources such as splinting, bracing, manual muscle testing (MMT), ROM, postural intervention and equipment prescription.
Splints, also referred to as orthoses, are designed to maintain or improve ROM, prevent deformity, and improve function. Splints help to support and keep limbs stretched, which delays or prevents the onset of contractures that commonly affect the knees, hips, feet, elbows, wrists and fingers. Ankle foot orthoses (AFOs) can be used during sleep or during the day. The purpose of this is to keep the foot from pointing downward and sustain the stretch of the achilles tendon. Maintaining the length of the tendo-achilles, also referred to as the gastrocnemius-soleus complex, is extremely important for walking. Knee ankle foot orthoses (KAFOs) are also used for walking or for standing and can be used to prolong ambulation or help delay the onset of lower limb contractures.
Manual muscle testing (MMT) and range of motion (ROM)
MMT is used to evaluate muscular strength, whereas goniometry or ROM tests measure movement around a joint. These tests indicate need for intervention such as passive and active ROM, strengthening and splinting. Passive ROM combined with the use of night splints can significantly improve tendo-achilles contractures.
Seating and positioning
Proper seating is essential to prevent spinal curvatures. Severe scoliosis is common in DMD and can interfere with sitting, sleeping, and breathing. A wheelchair that is fitted appropriately accounts for frame size, type of seat, lumbar support and cushioning to avoid pressure ulcers. It should be equipped with other mechanical devices, such as tilt ability, in order to provide comfort and to protect the skin. Power wheelchairs are indicated for most clients who can no longer ambulate, as they do not have enough upper extremity strength to propel a manual wheelchair independently. DMD affects many people in their adolescence, so it is crucial for occupational therapists to be conscious that significant development may occur during this time. Without proper seating and postural support throughout development, deformation may occur. This could then result in dysfunctional positioning. It is important for occupational therapists to re-evaluate the fit of an individual’s wheelchair as often as every year during adolescence.
Adaptive equipment and devices
There are many alternate mobility options, positioning aids and other equipment that occupational therapists may prescribe. These include walkers or quad-canes, which can be used for individuals who are able ambulate to reduce the risk of falling. In addition, transfer boards, mechanical lifts and specific transferring education are important because fractures have been seen to occur during transfers as a result of osteoporosis. Handheld shower heads and bath benches are indicated to enable individuals to manage their own self-care needs as much as possible. Individuals who are able to bear weight and take a few steps may utilize commode chairs, thus giving them the ability to visit the toilet independently. To complement an individualized wheelchair, an occupational therapist may also consider prescribing a hospital bed, pressure-relieving mattresses and foam wedges for proper positioning to prevent pressure skin ulcers, contractures and deformities. Specialized trays, input devices and software may also be prescribed to facilitate computer use.
Social skills development
Along with physical difficulties, individuals with DMD may have social issues that an occupational therapist can assist them in overcoming. Group sessions or individualized programs that focus on coping mechanisms for depression are examples of what an occupational therapist can facilitate. Self-esteem building for individuals of all ages is an essential part of ensuring that a high quality of life is achieved. Occupational therapy intervention can play an essential role in supporting the development of social skills through group interactions and other life experiences. An occupational therapist can use a variety of psychosocial frameworks for developing strategies and techniques for individuals to utilize, which will help them work through various psychosocial issues they may be experiencing.
Sexuality is a topic that many people feel uncomfortable discussing and thus may be overlooked by health care professionals. An occupational therapist will educate individuals with DMD on safe and effective ways to experience their sexual life. Such education can include various forms of sex as well as numerous positions that they would be able to perform.
Gaining and maintaining employment can be difficult for individuals with DMD. An occupational therapist may collaborate with an individual, employer and case manager to ensure that the individual’s work environment is as enabling and accessible as possible. By adapting the physical work environment, the social environment and the work requirements and guidelines, an individual can maintain meaningful employment as well as be as an asset to his or her employer. This may not only impact the individual’s perceived self-efficacy but also his or her financial well-being.
If it is a priority of the client, maintaining independence is often a main focus of occupational therapy interventions. Within the home, there are numerous obstacles that may prevent a client from being as independent as possible. Home modifications and adaptations are something that an occupational therapist can assist with. Such modifications may include: railings for safe mobility and transfers, lifts, adapted kitchens that are accessible for wheelchairs and bathroom modifications such as raised toilet seats or modified baths. Other examples are adaptive equipment for playing computer and video games, supports for biking and adaptations for fishing rods.
An occupational therapist can support individuals with DMD to find leisure activities in which it is meaningful for them to take part. Accommodations and adaptations can be made to enhance participation.
In order to create a successful therapeutic relationship, it is important to coordinate with family members, friends and other social resources to ensure that a person with DMD has both physical and emotional support. An occupational therapist can act as an advocate for his or her client and can educate those around him or her regarding information about the illness, supports, resources and other concerns. An occupational therapist can also provide his or her client with the tools to learn how to provide his or her own advocacy.
Current research includes exon-skipping, stem cell replacement therapy, analog up-regulation, gene replacement and supportive care to slow disease progression.
Antisense oligonucleotides (oligos), structural analogs of DNA, are the basis of a potential therapy for patients afflicted with DMD. The compounds allow faulty parts of the dystrophin gene to be skipped when it is transcribed to RNA for protein production, permitting a still-truncated but more functional version of the protein to be produced.
Two kinds of antisense oligos, 2'-O-methyl phosphorothioate oligos (like drisapersen) and Morpholino oligos (like eteplirsen), have been tested in early-phase clinical trials for DMD and have restored some dystrophin expression in muscles of DMD patients with a particular class of DMD-causing mutations. Further clinical trials are proceeding with these compounds.
Oligo-mediated exon skipping has resulted in clinical improvement in 12 patients in a Phase 1-2a study. On a standard test, the 6-minute walk test, patients whose performance had been declining instead improved, from 385 meters to 420 meters. DMD may result from mRNA that contains out-of-frame mutations (e.g. deletions, insertions or splice site mutations), resulting in frameshift or early termination so that in most muscle fibers no functional dystrophin is produced (though some revertant muscle fibers produce some dystrophin). In many cases an antisense oligonucleotide can be used to trigger skipping of an adjacent exon to restore the reading frame and production of partially functional dystrophin.
Patients with Becker's muscular dystrophy, which is milder than DMD, have a form of dystrophin which is functional even though it is shorter than normal dystrophin. In 1990 England et al. noticed that a patient with mild Becker muscular dystrophy was lacking 46% of his coding region for dystrophin. This functional, yet truncated, form of dystrophin gave rise to the notion that shorter dystrophin can still be therapeutically beneficial. Concurrently, Kole et al. had modified splicing by targeting pre-mRNA with antisense oligonucleotides (AONs). Kole demonstrated success using splice-targeted AONs to correct missplicing in cells removed from beta-thalassemia patients Wilton's group tested exon skipping for muscular dystrophy. Successful preclinical research led to the current efforts to use splice-modifying oligos to change DMD dystrophin to a more functional form of dystrophin, in effect converting Duchenne MD into Becker MD.
Though AONs hold promise, one of their major pitfalls is the need for periodic redelivery into muscles. Systemic delivery on a recurring basis is being tested in humans. To circumvent the requirement for periodic oligo delivery, a long-term exon-skip therapy is being explored. This therapy consists of modifying the U7 small nuclear RNA at the 5' end of the non-translated RNA to target regions within pre-mRNA. This has been shown to work in the DMD equivalent mouse, mdx.
Stem cell replacement
Though stem cells isolated from the muscle (satellite cells) have the ability to differentiate into myotubes when injected directly into the muscle of animals, they lack the ability to spread systemically throughout. To effectively deliver a therapeutic dose to an isolated muscle it would require direct injections to that muscle every 2mm. This problem was circumvented by using another multipotent stem cell, termed pericytes, that are located within the blood vessels of skeletal muscle. These cells have the ability to be delivered systemically and uptaken by crossing the vascular barrier. Once past the vasculature, pericytes have the ability to fuse and form myotubes. This means that they can be injected arterially, crossing through arterial walls into muscle, where they can differentiate into potentially functional muscle. These findings show potential for stem cell therapy of DMD. The pericyte-derived cells would be extracted, grown in culture, and then these cells would be injected into the blood stream where the possibility exists that they might find their way into injured regions of skeletal muscle.
Scientific research published on 15 April 2010 from the Université Laval's Faculty of Medicine and the CHUQ Research Center indicates it is possible to repair the gene associated with causing DMD through the use of meganuclease enzymes though significant work remains until it can be tested in human patients.
In 2011, in a study by the UK Medical Research Council and Sarepta Therapeutics (formerly known as AVI BioPharma), researchers trialled a new drug, known as Eteplirsen(AVI-4658), designed to make the body bypass genetic mutations when producing dystrophin. When given to 19 children with Duchenne muscular dystrophy, researchers found that higher doses of the drug led to an increase in dystrophin. Researchers believe that drugs which are designed to make the body “skip over” mutations in this way could be used to treat approximately 83% of Duchenne muscular dystrophy cases. However, the drug used in this trial only targeted mutations in a region implicated in 13% of cases. This study was conducted well and demonstrated the potential of this approach for increasing the levels of dystrophin in the short term. The trial’s principal aim was to work out the appropriate dosages of the drug, therefore the drug’s safety profile and effects will need to be confirmed in larger, longer-term studies, particularly as patients would need to take it for the rest of their lives (or until a better treatment is available).
Genetic counseling is advised for people with a family history of the disorder. Duchenne muscular dystrophy can be detected with about 95% accuracy by genetic studies performed during pregnancy.
Famous persons with muscular dystrophy
Alfredo Ferrari (born January, 1932 in Modena), nicknamed Alfredino or Dino, was the son of Enzo Ferrari. He designed the 1.5 L DOHC V6 engine for F2 at the end of 1955. Dino would never see the engine; he died 30 June 1956 in Modena at the age of 24, before his namesake automobiles Fiat Dino and Dino (automobile) were produced.
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- Researchers prove the gene responsible for Duchenne muscular dystrophy can be repaired, Published: Thursday, April 15, 2010 - 11:32 in Biology & Nature
- Khurdayan VK, Bozzo J, Prous JR (Oct 2005). "Chronicles in drug discovery". Drug news & perspectives 18 (8): 517–522. doi:10.1358/dnp.2005.18.8.953409. ISSN 0214-0934. PMID 16391721.
- "MDA Research | Preliminary Results of DMD Clinical Trial Encouraging". Mda.org. 2006-10-21. Retrieved 2013-02-16.
- "PTC THERAPEUTICS AND GENZYME CORPORATION ANNOUNCE PRELIMINARY RESULTS FROM THE PHASE 2B CLINICAL TRIAL OF ATALUREN FOR NONSENSE MUTATION DUCHENNE/BECKER MUSCULAR DYSTROPHY (NASDAQ:PTCT)". Ptct.client.shareholder.com. Retrieved 2013-02-16.
- ClinicalTrials.gov NCT01099761
- "ACE-031 Clinical Trials in Duchenne MD Stopped for Now | Quest Magazine Online". Quest.mda.org. Retrieved 2013-02-16.
- ClinicalTrials.gov NCT00159250 Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy
- "Clinical trial information for 2'-O-methyl phosphorothioate (PRO051) trial". Trialregister.nl. Retrieved 2013-02-16.
- "New muscular dystrophy drug trialled - Health News - NHS Choices". Nhs.uk. 2011-07-25. Retrieved 2013-02-16.
|Wikimedia Commons has media related to Duchenne muscular dystrophy.|
- GeneReviews/NCBI/NIH/UW entry on Dystrophinopathies
- CDC’s National Center on Birth Defects and Developmental Disabilities (previously listed below as "Duchenne/Becker Muscular Dystrophy, NCBDDD") at CDC
- Online 'Mendelian Inheritance in Man' (OMIM) MUSCULAR DYSTROPHY -310200 on NCBI
- Genes and Disease Page at NCBI
- Muscular Dystrophies on the Open Directory Project