Duchenne muscular dystrophy

Duchenne muscular dystrophy

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.
Classification and external resources
Specialty Medical genetics, pediatrics
ICD-10 G71.0
ICD-9-CM 359.1
OMIM 310200
DiseasesDB 3985
MedlinePlus 000705
Patient UK Duchenne muscular dystrophy
MeSH D020388

Duchenne muscular dystrophy (DMD) is a rare recessive X-linked form of muscular dystrophy, affecting around 1 in 3,600 boys, which results in muscle degeneration and premature death.[1] The disorder is caused by a mutation in the gene dystrophin, located on the human X chromosome, which codes for the protein dystrophin. Dystrophin is an important 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 are rarely affected.

Symptoms usually appear in boys between the ages of 2 and 3 and may be visible in early infancy.[2] Even though symptoms do not appear until early infancy, laboratory testing can identify children who carry the active mutation at birth.[3] Progressive proximal muscle weakness of the legs and pelvis associated with 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 without help or an inability to walk up stairs. 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 individuals afflicted with DMD is around 25.[1]

Signs and symptoms

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 those of the hips, pelvic area, thighs, shoulders, and calves. Muscle weakness also occurs later, in the arms, neck, and other areas. Calves are often enlarged. Symptoms usually appear before age 6 and may appear in early infancy. Other physical symptoms are:

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.[4] 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 particularly (dilated cardiomyopathy) is common, but the development of congestive heart failure or arrhythmia (irregular heartbeat) is only occasional.

Cause

DMD is inherited in a X-linked recessive manner

Duchenne muscular dystrophy (DMD) is caused by a mutation of the dystrophin gene at locus Xp21, located on the short arm of the X chromosome.[5] 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 (the cell membrane).[6] Alterations in calcium and 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 and a 50% chance of having two normal copies of the gene. In all cases, an unaffected 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 has an incidence of 1 in 3,600 male infants.[1] Mutations within the dystrophin gene can either be inherited or occur spontaneously during germline transmission.

Diagnosis

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.[1]

DNA test

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.[7]

Muscle biopsy

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.

Prenatal tests

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.[8]

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.

Treatment

There is no cure for DMD, and an ongoing medical need has been recognized by regulatory authorities.[9] 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:

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.[11]

Physical therapy

Physical therapists are concerned with enabling patients to reach their maximum physical potential. Their aim is to:

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).

A cough assist device can help with excess mucus in lungs by hyperinflation of the lungs with positive air pressure, then negative pressure to get the mucus up.

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.

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. As of 2013, the life expectancy is estimated to be around 25,[1] 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".[12]

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.

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 (ILM) are protected and do not undergo myonecrosis.[13] ILM have a calcium regulation system profile suggestive of a better ability to handle calcium changes in comparison to outher muscles, and this may provide a mechanistic insight for their unique pathophysiological properties.[14] The ILM may facilitate the development of novel strategies for the prevention and treatment of muscle wasting in a variety of clinical scenarios.[15]

History

The disease was first described by the Neapolitan physician Giovanni Semmola in 1834 and Gaetano Conte in 1836.[16][17][18] 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.[19][20]

Notable cases

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.

Ongoing research

Current research includes exon-skipping, stem cell replacement therapy, analog up-regulation, gene replacement and supportive care to slow disease progression.

Exon-skipping

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.[21]

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. Clinical trials are ongoing.[22][23]

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.[24][25] 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.[26] In 1990 England et al. noticed that a patient with mild Becker muscular dystrophy was lacking 46% of his coding region for dystrophin.[26] 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).[27] Kole demonstrated success using splice-targeted AONs to correct missplicing in cells removed from beta-thalassemia patients[28][29] Wilton's group tested exon skipping for muscular dystrophy.[30][31] 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.[32] 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.[33]

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.[34] 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.[35] 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.

Gene therapy

In 2014 and 2015, researchers used a new gene editing method to correct a mutation that leads to Duchenne muscular dystrophy (DMD) in a mouse model of the condition. 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. The benefit of this over other gene therapy techniques is that it can permanently correct the “defect” in a gene rather than just transiently adding a “functional” one. 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.[36][37]

In 2007, researchers did the world's first clinical (viral-mediated) gene therapy trial for Duchenne MD.[38]

Biostrophin is a delivery vector for gene therapy in the treatment of Duchenne muscular dystrophy and Becker muscular dystrophy.[39]

Clinical trials

While PTC124 showed promising results in mice,[40][41] the Phase II trial was suspended when participants did not show significant increases in the six-minute walk distance.[42]

The Phase II trial of ACE-031 was suspended due to safety issues.[43][44]

Safety and efficacy studies of antisense oligonucleotides for exon skipping in Duchenne muscular dystrophy with Morpholino oligos[45] and with 2'-O-methyl phosphorothioate oligos[46] are in progress.

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).[47]

A small study published in May 2014 in the journal Neurology showed that the erectile dysfunction drug sildenafil could improve blood flow in boys affected with Duchenne MD. A larger and longer trial of the related drug tadalafil is underway to determine if improved blood flow will translate into improved muscle function.[48]

Preclinical trials

Rimeporide, a sodium–hydrogen antiporter 1 inhibitor, is in preclinical trials as of May 2015.[49]

References

  1. 1 2 3 4 5 6 MedlinePlus Encyclopedia Duchenne muscular dystrophy
  2. 1 2 http://www.mayoclinic.org/diseases-conditions/muscular-dystrophy/basics/symptoms/con-20021240
  3. ↑ Woodhead, Avril (1985). Molecular Biology of Aging. Plenum Press. pp. 327–8.
  4. ↑ Rowland, L. P. (1985). Clinical Perspective: Phenotypic Expression In Muscular Dhystrophy. In R. C. Strohman & S. Wolf (Eds.), Gene Expression in Muscle (pp. 3-5). New York, NY: Plenum Press.
  5. ↑ "OMIM Entry - # 310200 - MUSCULAR DYSTROPHY, DUCHENNE TYPE; DMD". Omim.org. Retrieved 2014-06-29.
  6. ↑ "Duchenne Muscular Dystrophy: Pathophysiological Implications of Mitochondrial Calcium Signaling and ROS Production". Web.archive.org. 2012-05-02. Retrieved 2014-06-29.
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  9. ↑ "Duchenne Muscular Dystrophy Statement". Drug Safety and Availability. US FDA. 2014-10-31.
  10. ↑ Mendell JR, Moxley RT, Griggs RC, Brooke MH, Fenichel GM, Miller JP, King W, Signore L, Pandya S, Florence J (1989). "Randomized, Double-Blind Six-Month Trial of Prednisone in Duchenne's Muscular Dystrophy". New England Journal of Medicine 320 (24): 1592–1597. doi:10.1056/NEJM198906153202405. PMID 2657428.
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  13. ↑ Marques, Maria Julia; Ferretti, Renato; Vomero, Viviane Urbini; Minatel, Elaine; Neto, Humberto Santo (2007). "Intrinsic laryngeal muscles are spared from myonecrosis in themdx mouse model of Duchenne muscular dystrophy". Muscle & Nerve 35 (3): 349–53. doi:10.1002/mus.20697. PMID 17143878.
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  25. ↑ Study Shows Patients With Duchenne's Muscular Dystrophy Are Walking Better With PRO051 Treatment. By Daniel J. DeNoon WebMD Health News. March 23, 2011
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  32. ↑ "Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients - Full Text View". ClinicalTrials.gov. Retrieved 2013-02-16.
  33. ↑ Goyenvalle A, Vulin A, Fougerousse F, Leturcq F, Kaplan JC, Garcia L, Danos O (2004). "Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping". Science 306 (5702): 1796–9. Bibcode:2004Sci...306.1796G. doi:10.1126/science.1104297. PMID 15528407.
  34. ↑ Morgan JE, Pagel CN, Sherratt T, Partridge TA (1993). "Long-term persistence and migration of myogenic cells injected into pre-irradiated muscles of mdx mice". J. Neurol. Sci. 115 (2): 191–200. doi:10.1016/0022-510X(93)90224-M. PMID 7683332.
  35. ↑ Dellavalle A, Sampaolesi M, Tonlorenzi R, Tagliafico E, Sacchetti B, Perani L, Innocenzi A, Galvez BG, Messina G, Morosetti R, Li S, Belicchi M, Peretti G, Chamberlain JS, Wright WE, Torrente Y, Ferrari S, Bianco P, Cossu G (2007). "Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells". Nat. Cell Biol. 9 (3): 255–67. doi:10.1038/ncb1542. PMID 17293855.
  36. ↑ Long, C.; McAnally, J. R.; Shelton, J. M.; Mireault, A. A.; Bassel-Duby, R.; Olson, E. N. (2014). "Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA". Science 345 (6201): 1184–8. Bibcode:2014Sci...345.1184L. doi:10.1126/science.1254445. PMC 4398027. PMID 25123483.
  37. ↑ Wade, Nicholas (31 December 2015). "Gene Editing Offers Hope for Treating Duchenne Muscular Dystrophy, Studies Find". The New York Times. Retrieved 1 January 2016.
  38. ↑ Rodino-Klapac, Louise R.; Chicoine, Louis G.; Kaspar, Brian K.; Mendell, Jerry R. (2007). "Gene Therapy for Duchenne Muscular Dystrophy". Archives of Neurology 64 (9): 1236–41. doi:10.1001/archneur.64.9.1236. PMID 17846262.
  39. ↑ Khurdayan, V.K.; Bozzo, J.; Prous, J.R. (2005). "Chronicles in drug discovery". Drug News & Perspectives 18 (8): 517–22. doi:10.1358/dnp.2005.18.8.953409. PMID 16391721.
  40. ↑ "Preliminary Results of DMD Clinical Trial Encouraging" (Press release). Muscular Dystrophy Association. October 21, 2006. Retrieved August 24, 2015.
  41. ↑ "First Demonstration of Muscle Restoration in an Animal Model of Duchenne Muscular Dystrophy" (PDF) (Press release). Parent Project Muscular Dystrophy. April 23, 2007. Retrieved August 24, 2015.
  42. ↑ "PTC Therapeutics and Genzyme Corporation Announce Preliminary Results from the Phase 2b Clinical Trial of Ataluren for Nonsense Mutation Duchenne/Becker Muscular Dystrophy" (Press release). PTC Therapeutics. March 3, 2010. Retrieved August 24, 2015.
  43. ↑ Clinical trial number NCT01099761 for "Study of ACE-031 in Subjects With Duchenne Muscular Dystrophy" at ClinicalTrials.gov
  44. ↑ "ACE-031 Clinical Trials in Duchenne MD Stopped for Now | Quest Magazine Online". Quest.mda.org. Retrieved 2013-02-16.
  45. ↑ Clinical trial number NCT00159250 for "Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy" at ClinicalTrials.gov
  46. ↑ "Clinical trial information for 2'-O-methyl phosphorothioate (PRO051) trial". Nederlands trial register. Retrieved 2013-02-16.
  47. ↑ Cirak, Sebahattin; Arechavala-Gomeza, Virginia; Guglieri, Michela; Feng, Lucy; Torelli, Silvia; Anthony, Karen; Abbs, Stephen; Garralda, Maria Elena; Bourke, John; Wells, Dominic J; Dickson, George; Wood, Matthew JA; Wilton, Steve D; Straub, Volker; Kole, Ryszard; Shrewsbury, Stephen B; Sewry, Caroline; Morgan, Jennifer E; Bushby, Kate; Muntoni, Francesco (2011). "Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study". The Lancet 378 (9791): 595–605. doi:10.1016/S0140-6736(11)60756-3. PMC 3156980. PMID 21784508. Lay summary – NHS Choices (July 25, 2011).
  48. ↑ Nelson, Michael D.; Rader, Florian; Tang, Xiu; Tavyev, Jane; Nelson, Stanley F.; Miceli, M. Carrie; Elashoff, Robert M.; Sweeney, H. Lee; Victor, Ronald G. (2014). "PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy". Neurology 82 (23): 2085–91. doi:10.1212/WNL.0000000000000498. PMC 4118495. PMID 24808022. Lay summary – Medscape Medical News (May 20, 2014).
  49. ↑ Spreitzer, Helmut (26 May 2015). "Rimeporide". Österreichische Apothekerzeitung (in German) 69 (11): 12.

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