Microscopic image of cross-sectional calf muscle from a person with Duchenne muscular dystrophy, showing extensive replacement of
muscle fibers by
fat cells.
In males, 1 in 3,500-6,000[3] In females, 1 in 50,000,000[4]
Duchenne muscular dystrophy (DMD) is a severe type of
muscular dystrophy that primarily affects boys.[3]Muscle weakness usually begins around the age of four, and worsens quickly.[2]Muscle loss typically occurs first in the thighs and
pelvis followed by the arms.[3] This can result in trouble standing up.[3] Most are unable to walk by the age of 12.[2] Affected muscles may look larger due to increased
fat content.[3]Scoliosis is also common.[3] Some may have
intellectual disability.[3] Females with a single copy of the defective gene may show mild symptoms.[3]
Although there is no known cure,
physical therapy,
braces, and corrective surgery may help with some symptoms.[2]Assisted ventilation may be required in those with weakness of
breathing muscles.[3] Medications used include
steroids to slow muscle degeneration,
anticonvulsants to control
seizures and some muscle activity, and
immunosuppressants to delay damage to dying
muscle cells.[2]Gene therapy, as a treatment, is in the early stages of study in humans.[3] A small initial study using gene therapy has given some children improved muscle strength, but long term effects are unknown as of 2020.[5]
Various figures of the occurrence of DMD are reported. One source reports that it affects about one in 3,500 to 6,000 males at birth.[3] Another source reports DMD being a rare disease and having an occurrence of 7.1 per 100,000 male births.[6] A number of sources referenced in this article indicate an occurrence of 6 per 100,000.[7]
It is the most common type of muscular dystrophy.[3] The median
life expectancy is 28–30;[8][9] however, with excellent care, some may live up to their 30s or 40s.[3] The disease is much more rare in girls, occurring approximately once in 50,000,000 live female births.[4]
Signs usually appear before age five, and may even be observed from the moment a boy takes his first steps.[13] There is general difficulty with
motor skills, which can result in an awkward manner of walking, stepping, or running.[14] They tend to
walk on their toes,[14] in part due to shortening of the Achilles tendon,[15] and because it compensates for knee extensor weakness.[11] Falls can be frequent.[16] It becomes increasingly difficult for the boy to walk. His ability to walk usually disintegrates completely before age 13.[14] Most men affected with DMD become essentially "paralyzed from the neck down" by the age of 21.[13]Cardiomyopathy, particularly
dilated cardiomyopathy, is common, seen in half of 18-year-olds.[14] The development of
congestive heart failure or
arrhythmia (irregular heartbeat) is only occasional.[11] In late stages of the disease, respiratory impairment and swallowing impairment can occur, which can result in
pneumonia.[17]
A classic sign of DMD is trouble getting up from lying or sitting position,[16] as manifested by a positive
Gowers's sign. When a child tries to arise from lying on his stomach, he compensates for pelvic muscle weakness through use of the upper extremities:[14] first by rising to stand on his arms and knees, and then "walking" his hands up his legs to stand upright. Another characteristic sign of DMD is
pseudohypertrophy (enlarging) of the muscles of the tongue, calves, buttocks, and shoulders (around age 4 or 5). The muscle tissue is eventually replaced by fat and connective tissue, hence the term pseudohypertrophy. Muscle fiber deformities and
muscle contractures of Achilles tendon and hamstrings can occur, which impair functionality because the muscle fibers shorten and
fibrose in
connective tissue.[11] Skeletal deformities can occur, such as
lumbar hyperlordosis,
scoliosis, anterior
pelvic tilt, and chest deformities. Lumbar hyperlordosis is thought to be compensatory mechanism in response to gluteal and quadriceps muscle weakness, all of which cause altered posture and gait (e.g.: restricted hip extension).[18][19]
Non musculoskeletal manifestations of DMD occur. There is a 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),[14] which are believed to be the result of inadequate dystrophin in the brain.[20]
Cause
DMD is caused by a mutation of the dystrophin gene, located on the short arm of the
X chromosome (
locus Xp21)[21] that codes for dystrophin protein. Mutations can either be inherited or occur spontaneously during germline transmission,[citation needed] causing a large reduction or absence of dystrophin, a protein that provides structural integrity in muscle cells.[22]Dystrophin is responsible for connecting the
actincytoskeleton 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 (the cell membrane).[23]
DMD is extremely rare in females (about 1 in 50,000,000 female births).[4] It can occur in females with an affected father and a carrier mother, in those who are missing an X chromosome, or those who have an inactivated X chromosome (the most common of the rare reasons).[24] The daughter of a carrier mother and an affected father will be affected or a carrier with equal probability, as she will always inherit the affected X-chromosome from her father and has a 50% chance of also inheriting the affected X-chromosome from her mother.[25]
Disruption of the
blood–brain barrier has been seen to be a noted feature in the development of DMD.[26]
Diagnosis
DMD can be detected with about 95% accuracy by genetic studies performed during pregnancy.[17]
DNA test
The muscle-specific isoform of the dystrophin gene is composed of 79
exons, and DNA testing (
blood test) 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.[27]
Muscle biopsy
If DNA testing fails to find the mutation, a muscle biopsy test may be performed.[28] A small sample of muscle tissue is extracted using a biopsy needle. The key tests performed on the biopsy sample for DMD are
immunohistochemistry,
immunocytochemistry, and
immunoblotting for dystrophin, and should be interpreted by an experienced neuromuscular pathologist.[29] These tests provide information on the presence or absence of the protein. Absence of the protein is a positive test for DMD. Where dystrophin is present, the tests indicate the amount and molecular size of dystrophin, helping to distinguish DMD from milder
dystrophinopathy phenotypes.[30] 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 DMD.[31]
Prenatal tests
A prenatal test can be considered when the mother is a known or suspected carrier.[32]
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 (cffDNA) 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.
Non invasive prenatal testing can be done around 10–12 weeks.[33] Another option in the case of unclear genetic test results is fetal muscle biopsy.[citation needed]
Treatment is generally aimed at controlling symptoms to maximize the quality of life which can be measured using specific questionnaires,[35] and include:
Corticosteroids such as
Prednisolone,
Deflazacort and
Vamorolone (Agamree) lead to short-term improvements in muscle strength and function up to 2 years.[36] Corticosteroids have also been reported to help prolong walking, though the evidence for this is not robust.[37]
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 by recommending bracing and durable medical equipment[39]
Monitor respiratory function and advise on techniques to assist with breathing exercises and methods of clearing secretions[38]
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.
The medication
Eteplirsen, a
Morpholino antisense oligo, has been approved in the United States for the treatment of mutations amenable to dystrophin exon 51 skipping. The US approval has been controversial[41] as eteplirsen failed to establish a clinical benefit;[42] it has been refused approval by the European Medicines Agency.[43][44]
The medication
Ataluren (Translarna) is approved for use in the European Union.[45][46]
The
antisense oligonucleotideGolodirsen (Vyondys 53) was approved for medical use in the United States in 2019, for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript.[47][48]
The
Morpholino antisense oligonucleotide
Viltolarsen (Viltepso) was approved for medical use in the United States in August 2020, for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.[49] It is the second approved targeted treatment for people with this type of mutation in the United States.[49] Approximately 8% of people with DMD have a mutation that is amenable to exon 53 skipping.[49]
Casimersen (Amondys 45) was approved for medical use in the United States in February 2021,[50] and it is the first FDA-approved targeted treatment for people who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping.[50]
Delandistrogene moxeparvovec (Elevidys) is a gene therapy that in June 2023 received United States
FDA accelerated approval for treatment of four and five-year-old children.[53][54]
In March 2024, the US
Food and Drug Administration (FDA) granted approval for
Givinostat (Duvyzat), an oral medication, to be used in the treatment of Duchenne muscular dystrophy in people aged six years and older. Givinostat is the first
nonsteroidal drug to receive FDA approval for the treatment of all genetic variants of Duchenne muscular dystrophy. Functioning as a histone deacetylase (
Histone deacetylase (HDAC) inhibitor, givinostat operates by targeting pathogenic processes within the body, ultimately leading to a reduction in inflammation and muscle loss associated with the disease.[55]
Prognosis
Duchenne muscular dystrophy is a rare progressive disease which eventually affects all voluntary muscles and involves the heart and breathing muscles in later stages. Life expectancy is estimated to be around 25–26,[17][56] but this varies. People born with DMD after 1990 have a median life expectancy of approximately 28–30.[9][8] With excellent medical care, affected men often live into their 30s.[57] David Hatch of
Paris, Maine, may have been the oldest person in the world with the disease; he lived to the age of 56.[58][59]
The most common direct cause of death in people with DMD is
respiratory failure. Complications from treatment, such as mechanical ventilation and
tracheotomy procedures, are also a concern. The next leading cause of death is cardiac-related conditions such as heart failure brought on by
dilated cardiomyopathy. With respiratory assistance, the
median survival age can reach up to 40. In rare cases, people with DMD have been seen to survive into their forties or early fifties, with proper positioning in wheelchairs and beds, and the use of ventilator support (via
tracheostomy or mouthpiece), airway clearance, and heart medications.[60] Early planning of the required supports for later-life care has shown greater longevity for people with DMD.[61]
Curiously, in the
mdx mouse model of Duchenne muscular dystrophy, the lack of dystrophin is associated with increased calcium levels and skeletal muscle myonecrosis. The
intrinsic laryngeal muscles (ILMs) are protected and do not undergo myonecrosis.[62] ILMs have a calcium regulation system profile suggestive of a better ability to handle calcium changes in comparison to other muscles, and this may provide a mechanistic insight for their unique pathophysiological properties.[63] In addition, patients with Duchenne muscular dystrophy also have elevated plasma lipoprotein levels, implying a primary state of dyslipidemia in patients.[64]
Epidemiology
DMD is the most common type of muscular dystrophy; it affects about one in 5,000 males at birth.[3] DMD has an incidence of one in 3,600 male infants.[17]
In the US, a 2010 study showed a higher amount of those with DMD age ranging from 5 to 54 who are Hispanic compared to non-Hispanic Whites, and non-Hispanic Blacks.[65]
History
The disease was first described by the Neapolitan physician Giovanni Semmola in 1834 and Gaetano Conte in 1836.[66][67][68] However, DMD is named after the French neurologist
Guillaume-Benjamin-Amand Duchenne (1806–1875), who in the 1861 edition of his book Paraplégie hypertrophique de l'enfance de cause cérébrale, 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 to do a biopsy to obtain tissue from a living patient for microscopic examination.[69][70]
Society and culture
Notable cases
Alfredo Ferrari was an Italian automotive engineer, the eldest son of automaker
Enzo Ferrari, and the planned heir to his father's sports car company,
Ferrari. Alfredo died of DMD on 30 June 1956 at the age of 24.[71][72]
Rapper and disability rights advocate Darius Weems had the disease and used his notoriety to raise awareness and funds for treatment, as seen in the documentary Darius Goes West (2007).[73] He died at the age of 27 in 2016.[74]
This section needs to be updated. Please help update this article to reflect recent events or newly available information.(August 2019)
Efforts are ongoing to find medications that either return the ability to make dystrophin or utrophin.[76] Other efforts include trying to block the entry of calcium ions into muscle cells.[77]
Exon-skipping
Antisenseoligonucleotides (oligos), structural analogs of DNA, are the basis of a potential treatment for 10% of people with DMD.[78] 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.[79] It is also known as nonsense suppression therapy.[80]
Two kinds of antisense oligos, 2'-O-methyl phosphorothioate oligos (like
Drisapersen) and
Morpholino oligos (like
Eteplirsen), have tentative evidence of benefit and are being studied.[81] Eteplirsen is targeted to skip exon 51.[81] "As an example, skipping exon 51 restores the reading frame of ~ 15% of all the boys with deletions. It has been suggested that by having 10 AONs to skip 10 different exons it would be possible to deal with more than 70% of all DMD boys with deletions."[78] This represents about 1.5% of cases.[78]
People 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.[82] In 1990 England et al. noticed that a patient with mild Becker muscular dystrophy was lacking 46% of his coding region for dystrophin.[82] 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).[83] Kole demonstrated success using splice-targeted AONs to correct missplicing in cells removed from beta-thalassemia patients[84][85] Wilton's group tested exon skipping for muscular dystrophy.[86][87]
Gene therapy
Researchers are working on a gene editing method to correct a mutation that leads to Duchenne muscular dystrophy (DMD).[88] Researchers used a technique called
CRISPR/Cas9-mediated genome editing, which can precisely remove a mutation in the
dystrophin gene in DNA, allowing the body's
DNA repair mechanisms to replace it with a normal copy of the gene.[89][90]
Genome editing through the CRISPR/Cas9 system is not currently feasible in humans. However, it may be possible, through advancements in technology, to use this technique to develop therapies for DMD in the future.[91][92] In 2007, researchers did the world's first clinical (viral-mediated) gene therapy trial for Duchenne MD.[93]
^Sutherland DH, Olshen R, Cooper L, Wyatt M, Leach J, Mubarak S, et al. (February 1981). "The pathomechanics of gait in Duchenne muscular dystrophy". Developmental Medicine and Child Neurology. 23 (1): 3–22.
doi:
10.1111/j.1469-8749.1981.tb08442.x.
PMID7202868.
S2CID895379.
^Nico B, Ribatti D (January 2012). "Morphofunctional aspects of the blood–brain barrier". Current Drug Metabolism. 13 (1): 50–60.
doi:
10.2174/138920012798356970.
PMID22292807.
^
abBushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, et al. (January 2010). "Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management". The Lancet. Neurology. 9 (1): 77–93.
CiteSeerX10.1.1.176.4466.
doi:
10.1016/s1474-4422(09)70271-6.
PMID19945913.
S2CID328499.
^Dany A, Barbe C, Rapin A, Réveillère C, Hardouin JB, Morrone I, et al. (November 2015). "Construction of a Quality of Life Questionnaire for slowly progressive neuromuscular disease". Quality of Life Research. 24 (11): 2615–2623.
doi:
10.1007/s11136-015-1013-8.
PMID26141500.
S2CID25834947.
^De Rosa G (October 2005).
"Da Conte a Duchenne" [By Conte in Duchenne]. DM (in Italian). Unione Italiana Lotta alla Distrofia Muscolare. Archived from
the original on 4 March 2016. Retrieved 24 August 2015.
^Allen DG, Gervasio OL, Yeung EW, Whitehead NP (February 2010). "Calcium and the damage pathways in muscular dystrophy". Canadian Journal of Physiology and Pharmacology. 88 (2): 83–91.
doi:
10.1139/Y09-058.
PMID20237582.