Becker muscular dystrophy

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Becker muscular dystrophy
Other namesBenign pseudohypertrophic muscular dystrophy [1]
X-linked recessive.svg
X-linked recessive is the manner in which this condition is inherited
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Severe upper extremity muscle weakness, [2] Toe-walking [3]
CausesMutations in DMD gene [4]
Diagnostic method Neurological exam, muscle exam [3]
TreatmentNo current cure, Physical therapy [3]

Becker muscular dystrophy (BMD) is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. [5] [3] The cause is mutations and deletions in any of the 79 exons encoding the large dystrophin protein, essential for maintaining the muscle fiber's cell membrane integrity. [6] Becker muscular dystrophy is related to Duchenne muscular dystrophy in that both result from a mutation in the dystrophin gene, however the hallmark of Becker is milder in-frame deletions. [4] and hence has a milder course, with patients maintaining ambulation till 50–60 years if detected early. [7] [8]

Contents

While there is no known cure, management strategies such as physical therapy, braces, and corrective surgery may alleviate symptoms. [9] Assisted ventilation may be required in those with weakness of breathing muscles. [6] Several drugs designed to address the root cause are currently available including gene therapy (Elevidys). [6]

Other medications used include glucocorticoids (Deflazacort, Vamorolone); calcium channel blockers (Diltiazem); to slow skeletal and cardiac muscle degeneration, anticonvulsants to control seizures and some muscle activity, and Histone deacetylase inhibitors (Givinostat) to delay damage to dying muscle cells. [9] [6] These patients do not require antisense drugs (Ataluren, Eteplirsen etc.) as certain percentage of dystrophin is already expressed. [6]

Signs and symptoms

Some symptoms consistent with Becker muscular dystrophy are:

Individuals with this disorder typically experience progressive muscle weakness of the leg and pelvis muscles, which is associated with a loss of muscle mass (wasting). Muscle weakness also occurs in the arms, neck, and other areas, but not as noticeably severe as in the lower half of the body. Calf muscles initially enlarge during the ages of 5–15 (an attempt by the body to compensate for loss of muscle strength), but the enlarged muscle tissue is eventually replaced by fat and connective tissue (pseudohypertrophy) as the legs become less used (with use of wheelchair).[ medical citation needed ]

Complications

Possible complications associated with muscular dystrophies (MD) are cardiac arrhythmias. [11] Becker muscular dystrophy (BMD) also demonstrates the following:

Genetics

The gene affected is the DMD gene, is located on the X chromosome and is inherited in an X-linked recessive pattern. [13] Since women have two X chromosomes, if one X chromosome has the non-working gene, the second X chromosome will have a working copy of the gene to compensate, because of this ability to compensate, women rarely develop symptoms. All dystrophinopathies are inherited in an X-linked recessive manner. The risk to the siblings of an affected individual depends upon the carrier status of the mother. Carrier females have a 50% chance of passing the DMD mutation in each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation will be carriers. Men who have Becker muscular dystrophy can have children, and all their daughters are carriers, but none of the sons will inherit their father's mutation. [12] [14] [15]

The DMD gene can be broken down into four different regions: the N terminal, rod, cysteine-rich, and carboxy terminal. [13] This is the largest gene/protein in the human body, and due to its size, can have many different mutations affecting it and therefore differing clinical presentations.[ citation needed ]For example some patients with Becker's can be asymptomatic aside from blood work abnormalities, and some can present with progressive muscle weakness, heart defects, and difficulty with activities of daily living.[ citation needed ]Some literature even describes unique cases where muscle pain, cramping, and elevated creatine kinase levels are the only presenting symptoms instead of the classic presentation of muscle weakness. [16]

Becker muscular dystrophy occurs in approximately 1.5 to 6 in 100,000 male births, making it much less common than Duchenne muscular dystrophy. Symptoms usually appear in men at about ages 8–25, but may sometimes begin later. [17] Genetic counseling may be advisable when potential carriers or patients want to have children. Sons of a man with Becker muscular dystrophy do not develop the disorder, but daughters will be carriers (and some carriers can experience some symptoms of muscular dystrophy), so the daughters' sons may develop the disorder. [18]

Diagnosis

Creatine kinase 3b6r.png
Creatine kinase

In terms of the diagnosis of Becker muscular dystrophy symptom development resembles that of Duchenne muscular dystrophy. A physical exam indicates lack of pectoral and upper arm muscles, especially when the disease is unnoticed through the early teen years. Muscle wasting begins in the legs and pelvis, then progresses to the muscles of the shoulders and neck. Calf muscle enlargement (pseudohypertrophy) is quite obvious. Among the exams/tests performed are: [19] [20]

Treatment

There is no known cure for Becker muscular dystrophy yet. Treatment is aimed at control of symptoms to maximize the quality of life which can be measured by specific questionnaires. [21] Activity is encouraged and can be considered vital for long term survivability for these patients. [22] Inactivity (such as bed rest) or sitting down for too long can worsen the muscle disease. Physical therapy may be helpful to maintain muscle strength. Orthopedic appliances such as braces and wheelchairs may improve mobility and self-care. [14]

Immunosuppressant steroids have been known to help slow the progression of Becker muscular dystrophy. [23] The drug prednisone contributes to an increased production of the protein utrophin which closely resembles dystrophin, the protein that is defective in BMD. [24]

The cardiac problems that occur with EDMD and myotonic muscular dystrophy may require a pacemaker. [25] Other cardiomyopathy seen in Beckers can also be treated with ACE-inhibitors, cardiac transplant, and other personalized treatment. [22]

The investigational drug Debio-025 is a known inhibitor of the protein cyclophilin D, which regulates the swelling of mitochondria in response to cellular injury. Researchers decided to test the drug in mice engineered to carry MD after earlier laboratory tests showed deleting a gene that encodes cyclophilin D reduced swelling and reversed or prevented the disease's muscle-damaging characteristics. [26] According to a review by Bushby, et al. if a primary protein is not functioning properly then maybe another protein could take its place by augmenting it. Upregulation of compensatory proteins has been done in models of transgenic mice. [27]

Prognosis

The progression of Becker muscular dystrophy is highly variable—much more so than Duchenne muscular dystrophy. There is also a form that may be considered as an intermediate between Duchenne and Becker MD (mild DMD or severe BMD). Severity of the disease may be indicated by age of the patient at the onset of the disease. One study showed that there may be two distinct patterns of progression in Becker muscular dystrophy. Onset at around age 7 to 8 years of age shows more cardiac involvement and trouble climbing stairs by age 20, if onset is around age 12, there is less cardiac involvement. [19] [28]

The quality of life for patients with Becker muscular dystrophy can be impacted by the symptoms of the disorder. But with assistive devices, independence can be maintained. People affected by Becker muscular dystrophy can still maintain active lifestyles. [29]

Research

There is no cure for any type of muscular dystrophy group. [30] Several drugs designed to address the root cause are under development, including gene therapy (Microdystrophin), and antisense drugs (Ataluren, Eteplirsen etc.). [31] Other medications used include corticosteroids (Deflazacort), calcium channel blockers (Diltiazem) to slow skeletal and cardiac muscle degeneration, anticonvulsants to control seizures and some muscle activity, and immunosuppressants (Vamorolone) to delay damage to dying muscle cells. [9] Physical therapy, braces, and corrective surgery may help with some symptoms [9] while assisted ventilation may be required in those with weakness of breathing muscles. [6] Outcomes depend on the specific type of disorder. [9] [31]

History

Becker muscular dystrophy is named after the German doctor Peter Emil Becker who published an article about it in 1955. [32] [33]

Related Research Articles

<span class="mw-page-title-main">Muscular dystrophy</span> Genetic disorder

Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Some types are also associated with problems in other organs.

<span class="mw-page-title-main">Glycogen storage disease</span> Medical condition

A glycogen storage disease is a metabolic disorder caused by a deficiency of an enzyme or transport protein affecting glycogen synthesis, glycogen breakdown, or glucose breakdown, typically in muscles and/or liver cells.

<span class="mw-page-title-main">Limb–girdle muscular dystrophy</span> Medical condition

Limb–girdle muscular dystrophy (LGMD) is a genetically heterogeneous group of rare muscular dystrophies that share a set of clinical characteristics. It is characterised by progressive muscle wasting which affects predominantly hip and shoulder muscles. LGMD usually has an autosomal pattern of inheritance. It currently has no known cure or treatment.

<span class="mw-page-title-main">Dystrophin</span> Rod-shaped cytoplasmic protein

Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costamere or the dystrophin-associated protein complex (DAPC). Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere. It has a molecular weight of 427 kDa

<span class="mw-page-title-main">Duchenne muscular dystrophy</span> Type of muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy predominantly affecting boys. The onset of muscle weakness typically begins around age four, with rapid progression. Initially, muscle loss occurs in the thighs and pelvis, extending to the arms, which can lead to difficulties in standing up. By the age of 12, most individuals with Duchenne muscular dystrophy are unable to walk. Affected muscles may appear larger due to an increase in fat content, and scoliosis is common. Some individuals may experience intellectual disability, and females carrying a single copy of the mutated gene may show mild symptoms.

<span class="mw-page-title-main">Fukuyama congenital muscular dystrophy</span> Medical condition

Fukuyama congenital muscular dystrophy (FCMD) is a rare, autosomal recessive form of muscular dystrophy (weakness and breakdown of muscular tissue) mainly described in Japan but also identified in Turkish and Ashkenazi Jewish patients; fifteen cases were first described on 1960 by Dr. Yukio Fukuyama.

Sarepta Therapeutics, Inc. is a medical research and drug development company with corporate offices and research facilities in Cambridge, Massachusetts, United States. Incorporated in 1980 as AntiVirals, shortly before going public the company changed its name from AntiVirals to AVI BioPharma soon with stock symbol AVII and in July 2012 changed name from AVI BioPharma to Sarepta Therapeutics and SRPT respectively. As of 2023, the company has four approved drugs.

<span class="mw-page-title-main">Mitochondrial myopathy</span> Medical condition

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. Adenosine triphosphate (ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative phosphorylation when the mitochondrion is either damaged or missing necessary enzymes or transport proteins. With ATP production deficient in mitochondria, there is an over-reliance on anaerobic glycolysis which leads to lactic acidosis either at rest or exercise-induced.

<span class="mw-page-title-main">Congenital muscular dystrophy</span> Medical condition

Congenital muscular dystrophies are autosomal recessively-inherited muscle diseases. They are a group of heterogeneous disorders characterized by muscle weakness which is present at birth and the different changes on muscle biopsy that ranges from myopathic to overtly dystrophic due to the age at which the biopsy takes place.

The dystrophin-associated protein complex, also known as the dystrophin-associated glycoprotein complex is a multiprotein complex that includes dystrophin and the dystrophin-associated proteins. It is one of the two protein complexes that make up the costamere in striated muscle cells. The other complex is the integrin-vinculin-talin complex.

<span class="mw-page-title-main">Sarcospan</span>

Sarcospan is a protein that in humans is encoded by the SSPN gene.

In molecular biology, exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty or misaligned sections (exons) of genetic code, leading to a truncated but still functional protein despite the genetic mutation.

Drisapersen is an experimental drug that was under development by BioMarin, after acquisition of Prosensa, for the treatment of Duchenne muscular dystrophy. The drug is a 2'-O-methyl phosphorothioate oligonucleotide that alters the splicing of the dystrophin RNA transcript, eliminating exon 51 from the mature dystrophin mRNA.

<span class="mw-page-title-main">Eteplirsen</span> Medication

Eteplirsen is a medication to treat, but not cure, some types of Duchenne muscular dystrophy (DMD), caused by a specific mutation. Eteplirsen only targets specific mutations and can be used to treat about 14% of DMD cases. Eteplirsen is a form of antisense therapy.

The mdx mouse is a popular model for studying Duchenne muscular dystrophy (DMD). The mdx mouse has a point mutation in its DMD gene, changing the amino acid coding for a glutamine to STOP codon. This causes the muscle cells to produce a small, nonfunctional dystrophin protein. As a result, the mouse has a mild form of DMD where there is increased muscle damage and weakness.

<span class="mw-page-title-main">Ezutromid</span> Chemical compound

Ezutromid is an orally administered small molecule utrophin modulator involved in a Phase 2 clinical trial produced by Summit Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). DMD is a fatal x-linked recessive disease affecting approximately 1 in 5000 males and is a designated orphan disease by the FDA and European Medicines Agency. Approximately 1/3 of the children obtain DMD as a result of spontaneous mutation in the dystrophin gene and have no family history of the disease. Dystrophin is a vital component of mature muscle function, and therefore DMD patients have multifarious forms of defunct or deficient dystrophin proteins that all manifest symptomatically as muscle necrosis and eventually organ failure. Ezutromid is theorized to maintain utrophin, a protein functionally and structurally similar to dystrophin that precedes and is replaced by dystrophin during development. Utrophin and dystrophin are reciprocally expressed, and are found in different locations in a mature muscle cell. However, in dystrophin-deficient patients, utrophin was found to be upregulated and is theorized to replace dystrophin in order to maintain muscle fibers. Ezutromid is projected to have the potential to treat all patients suffering with DMD as it maintains the production of utrophin to counteract the lack of dystrophin to retard muscle degeneration. Both the FDA and European Medicines Agency has given ezutromid an orphan drug designation. The FDA Office of Orphan Products and Development offers an Orphan Drug Designation program (ODD) that allows drugs aimed to treat diseases that affect less than 200,000 people in the U.S. monetary incentives such as a period of market exclusivity, tax incentives, and expedited approval processes.

<span class="mw-page-title-main">Calpainopathy</span> Medical condition

Calpainopathy is the most common type of autosomal recessive limb-girdle muscular dystrophy (LGMD). It preferentially affects the muscles of the hip girdle and shoulder girdle.

Dystrophinopathy refers to a spectrum of diseases due to mutations in the DMD gene, which encodes for the dystrophin protein found in muscle. The severe end of the spectrum includes Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and DMD-associated dilated cardiomyopathy. The mild end of the spectrum includes asymptomatic increases in serum creatine kinase and muscle cramps with myoglobinuria. Because dystrophin is located on the X chromosome, dystrophinopathy mainly affects males, whereas females range from being carriers, to having delayed-onset and mild disease, to having severe DMD.

Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.

Casimersen, sold under the brand name Amondys 45, is an antisense oligonucleotide medication used for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping. It is an antisense oligonucleotide of phosphorodiamidate morpholino oligomer (PMO). Duchenne muscular dystrophy is a rare disease that primarily affects boys. It is caused by low levels of a muscle protein called dystrophin. The lack of dystrophin causes progressive muscle weakness and premature death.

References

PD-icon.svg This article incorporates public domain material from websites or documents of the Centers for Disease Control and Prevention .

  1. ↑ "Becker muscular dystrophy: MedlinePlus Medical Encyclopedia". medlineplus.gov. Archived from the original on 15 March 2017. Retrieved 30 July 2019.
  2. 1 2 3 4 5 6 7 "Becker's Muscular Dystrophy information. Patient". 12 June 2023. Archived from the original on 25 October 2015. Retrieved 28 October 2015.
  3. 1 2 3 4 5 6 7 8 9 "Becker muscular dystrophy". NIH. Archived from the original on 7 April 2016. Retrieved 17 April 2016.
  4. 1 2 "Becker muscular dystrophy | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". Archived from the original on 2016-04-28. Retrieved 2016-04-19.
  5. ↑ "Duchenne and Becker muscular dystrophy". NIH.gov. NIH. Archived from the original on 24 March 2017. Retrieved 17 April 2016.
  6. 1 2 3 4 5 6 "Muscular Dystrophy: Hope Through Research". NINDS. March 4, 2016. Archived from the original on 30 September 2016. Retrieved 12 September 2016.
  7. ↑ Aslesh, Tejal; Maruyama, Rika; Yokota, Toshifumi (2018-01-02). "Skipping Multiple Exons to Treat DMD—Promises and Challenges". Biomedicines. 6 (1): 1. doi: 10.3390/biomedicines6010001 . ISSN   2227-9059. PMC   5874658 . PMID   29301272.
  8. ↑ "Muscular Dystrophy, Becker". NORD (National Organization for Rare Disorders). Archived from the original on 2021-10-31. Retrieved 2021-04-17.
  9. 1 2 3 4 5 "NINDS Muscular Dystrophy Information Page". NINDS. March 4, 2016. Archived from the original on 30 July 2016. Retrieved 12 September 2016.
  10. ↑ Greco, Giovanni N. (2008). Tissue Engineering Research Trends. Nova Publishers. p. 89. ISBN   9781604562644. Archived from the original on 28 April 2024. Retrieved 19 April 2016.
  11. ↑ "Cardiovascular Complications Associated with Muscular Dystrophy". Archived from the original on 2016-09-02. Retrieved 2016-04-19.
  12. 1 2 "Error 403". Archived from the original on 2015-12-25. Retrieved 2016-04-19.
  13. 1 2 Forrest, S.M.; Cross, G.S.; Flint, T.; Speer, A.; Robson, K.J.H.; Davies, K.E. (February 1988). "Further studies of gene deletions that cause Duchenne and Becker muscular dystrophies". Genomics. 2 (2): 109–114. doi:10.1016/0888-7543(88)90091-2. PMID   3410474.
  14. 1 2 Becker Muscular Dystrophy~clinical at eMedicine
  15. ↑ Darras, Basil T.; Urion, David K.; Ghosh, Partha S. (1993). "Dystrophinopathies". GeneReviews®. University of Washington, Seattle. PMID   20301298. Archived from the original on 2017-01-18. Retrieved 2017-08-30.
  16. ↑ Tavallaee, Zachary; Hamby, Tyler; Marks, Warren (December 2022). "Myalgic Becker Muscular Dystrophy Due to an Exon 15 Point Mutation: Case Series and Literature Review". Journal of Clinical Neuromuscular Disease. 24 (2): 106–110. doi:10.1097/CND.0000000000000413. PMID   36409343. S2CID   253733072.
  17. ↑ Mah, Jean K.; Korngut, Lawrence; Dykeman, Jonathan; Day, Lundy; Pringsheim, Tamara; Jette, Nathalie (June 2014). "A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy". Neuromuscular Disorders. 24 (6): 482–491. doi:10.1016/j.nmd.2014.03.008. PMID   24780148. S2CID   20687867.
  18. ↑ Grimm, Tiemo; Kress, Wolfram; Meng, Gerhard; Müller, Clemens R (December 2012). "Risk assessment and genetic counseling in families with Duchenne muscular dystrophy". Acta Myologica. 31 (3): 179–83. PMC   3631803 . PMID   23620649.
  19. 1 2 "Becker muscular dystrophy | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". Archived from the original on 2016-04-28. Retrieved 2016-04-19.
  20. ↑ RESERVED, INSERM US14 – ALL RIGHTS. "Orphanet: Becker muscular dystrophy". www.orpha.net. Archived from the original on 2016-04-13. Retrieved 2016-04-19.{{cite web}}: CS1 maint: numeric names: authors list (link)
  21. ↑ Dany, Antoine; Barbe, Coralie; Rapin, Amandine; Réveillère, Christian; Hardouin, Jean-Benoit; Morrone, Isabella; Wolak-Thierry, Aurore; Dramé, Moustapha; Calmus, Arnaud; Sacconi, Sabrina; Bassez, Guillaume; Tiffreau, Vincent; Richard, Isabelle; Gallais, Benjamin; Prigent, Hélène; Taiar, Redha; Jolly, Damien; Novella, Jean-Luc; Boyer, François Constant (4 July 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. PMID   26141500. S2CID   25834947.
  22. 1 2 Angelini, C; Marozzo, R; Pegoraro, V (September 2019). "Current and emerging therapies in Becker muscular dystrophy (BMD)". Acta Myologica: Myopathies and Cardiomyopathies. 38 (3): 172–179. PMC   6859412 . PMID   31788661.
  23. ↑ "Duchenne/Becker Treatment and Care | Muscular Dystrophy | NCBDDD | CDC". www.cdc.gov. Archived from the original on 2016-04-19. Retrieved 2016-04-19.
  24. ↑ "Dystrophinopathies Treatment & Management: Medical Care, Consultations, Activity". 2017-01-07. Archived from the original on 2016-10-27. Retrieved 2016-04-19.{{cite journal}}: Cite journal requires |journal= (help)
  25. ↑ Verhaert, David; Richards, Kathryn; Rafael-Fortney, Jill A.; Raman, Subha V. (January 2011). "Cardiac Involvement in Patients With Muscular Dystrophies". Circulation: Cardiovascular Imaging. 4 (1): 67–76. doi:10.1161/CIRCIMAGING.110.960740. PMC   3057042 . PMID   21245364.
  26. ↑ Reutenauer, J; Dorchies, O M; Patthey-Vuadens, O; Vuagniaux, G; Ruegg, U T (29 January 2009). "Investigation of Debio 025, a cyclophilin inhibitor, in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy". British Journal of Pharmacology. 155 (4): 574–584. doi:10.1038/bjp.2008.285. PMC   2579666 . PMID   18641676.
  27. ↑ Bushby, Kate; Lochmüller, Hanns; Lynn, Stephen; Straub, Volker (November 2009). "Interventions for muscular dystrophy: molecular medicines entering the clinic". The Lancet. 374 (9704): 1849–1856. doi:10.1016/S0140-6736(09)61834-1. PMID   19944865. S2CID   41929569.
  28. ↑ Delisa, Joel A; Gans, Bruce M; Walsh, Nicholas E (2005). Physical medicine and rehabilitation: Principles and practice. Lippincott Williams & Wilkins. pp. 915–16. ISBN   978-0-7817-4130-9. Archived from the original on 2024-04-28. Retrieved 2016-09-30.
  29. ↑ "Facts | Muscular Dystrophy | NCBDDD | CDC". 2018-04-10. Archived from the original on 2019-08-16. Retrieved 2017-09-08.
  30. ↑ "Muscular Dystrophy Information Page: National Institute of Neurological Disorders and Stroke (NINDS)". July 30, 2016. Archived from the original on 30 July 2016.
  31. 1 2 "Muscular Dystrophy: Hope Through Research". September 30, 2016. Archived from the original on 30 September 2016.
  32. ↑ Becker, P. E.; Kiener, F. (1955). "Eine neue x-chromosomale Muskeldystrophie" [A new x-linked muscular dystrophy]. Archiv für Psychiatrie und Nervenkrankheiten (in German). 193 (4): 427–448. doi:10.1007/BF00343141. PMID   13249581. S2CID   22284081.
  33. ↑ Becker, P.E. (1957). "Neue Ergebnisse der Genetik der Muskeldystrophien" [New results of genetics of muscular dystrophy]. Human Heredity (in German). 7 (2): 303–310. doi:10.1159/000150994. PMID   13469170.

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