Duchenne muscular dystrophy
Duchenne muscular dystrophy 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.
Duchenne muscular dystrophy is caused by mutations or deletions in any of the 79 exons encoding the large dystrophin protein, which is essential for maintaining the muscle fibers' cell membrane integrity. The disorder follows an X-linked recessive inheritance pattern, with approximately two-thirds of cases inherited from the mother and one-third resulting from a new mutation. Diagnosis can frequently be made at birth through genetic testing, and elevated creatine kinase levels in the blood are indicative of the condition.
While there is no known cure, management strategies such as physical therapy, braces, and corrective surgery may alleviate symptoms. Assisted ventilation may be required in those with weakness of breathing muscles. Several drugs designed to address the root cause are currently available including gene therapy, and antisense drugs. Other medications used include glucocorticoids ; calcium channel blockers ; to slow skeletal and cardiac muscle degeneration, anticonvulsants to control seizures and some muscle activity, and Histone deacetylase inhibitors to delay damage to dying muscle cells.
Various figures of the occurrence of Duchenne muscular dystrophy are reported. One source reports that it affects about one in 3,500 to 6,000 males at birth in the U.S.,. Another source reports Duchenne muscular dystrophy being a rare disease and having an occurrence of 7.1 per 100,000 male births globally. A number of sources referenced in this article indicate an occurrence of 6 per 100,000.
Duchenne muscular dystrophy is the most common type of muscular dystrophy, with a median life expectancy of 27–31 years. However, with comprehensive care, some individuals may live into their 30s or 40s. Duchenne muscular dystrophy is considerably rarer in females, occurring in approximately one in 50,000,000 live female births.
Signs and symptoms
Duchenne muscular dystrophy causes progressive muscle weakness due to muscle fiber disarray, death, and replacement with connective tissue or fat. The voluntary muscles are affected first, especially those of the hips, pelvic area, thighs, calves. It eventually progresses to the shoulders and neck, followed by arms, respiratory muscles, and other areas. Fatigue is common.Signs usually appear before age five, and may even be observed when a boy takes his first steps. There is general difficulty with motor skills, which can result in an awkward manner of walking, stepping, or running. They tend to walk on their toes, in part due to shortening of the Achilles tendon, and because it compensates for knee extensor weakness. Falls can be frequent. It becomes increasingly difficult for the boy to walk. The ability to walk usually disintegrates completely before age 13. Most men affected with Duchenne muscular dystrophy become essentially "paralyzed from the neck down" by the age of 21. Cardiomyopathy, particularly dilated cardiomyopathy, is common, seen in half of 18-year-olds. The development of congestive heart failure or arrhythmia is only occasional. In late stages of the disease, respiratory impairment and swallowing impairment can occur, which can result in pneumonia.
A classic sign of Duchenne muscular dystrophy is trouble getting up from a lying or sitting position, as manifested by a positive Gowers's sign. When a child tries to rise from lying on his stomach, he compensates for pelvic muscle weakness through the use of the upper extremities: 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 Duchenne muscular dystrophy is pseudohypertrophy of the muscles of the tongue, calves, buttocks, and shoulders. Fat and connective tissue eventually replace the muscle 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. Skeletal deformities can occur, such as lumbar hyperlordosis, scoliosis, anterior pelvic tilt, and chest deformities. Lumbar hyperlordosis is thought to be a compensatory mechanism in response to gluteal and quadriceps muscle weakness, all of which cause altered posture and gait.
Non-musculoskeletal manifestations of Duchenne muscular dystrophy occur. There is a higher risk of neurobehavioral disorders, learning disorders, and non-progressive weaknesses in specific cognitive skills, which are believed to be the result of inadequate dystrophin in the brain.
Cause
Duchenne muscular dystrophy is caused by a mutation of the dystrophin gene, located on the short arm of the X chromosome that codes for dystrophin protein. Mutations can either be inherited or occur spontaneously during germline transmission, causing a large reduction or absence of dystrophin, a protein that provides structural integrity in muscle cells. Dystrophin is responsible for connecting the actin cytoskeleton of each muscle fiber to the underlying basal lamina, through a protein complex containing many subunits. The absence of dystrophin permits excess calcium to penetrate the sarcolemma.Duchenne muscular dystrophy is extremely rare in females. It can occur in females with an affected father and a carrier mother, in those who are missing an X chromosome, or in those who have an inactivated X chromosome. It must be noted that the vast majority of clinical trials excluded female patients from enrollment, thus reducing the generalizability of the findings and limiting our understanding of potential sex-specific differences in disease manifestation and treatment response. 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.
Disruption of the blood–brain barrier has been seen to be a noted feature in the development of Duchenne muscular dystrophy.
Diagnosis
Duchenne muscular dystrophy can be detected with about 95% accuracy by genetic studies performed during pregnancy.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.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 using a biopsy needle. The key tests performed on the biopsy sample for Duchenne muscular dystrophy are immunohistochemistry, immunocytochemistry, and immunoblotting for dystrophin, and should be interpreted by an experienced neuromuscular pathologist. These tests provide information on the presence or absence of the protein. Absence of the protein is a positive test for Duchenne muscular dystrophy. Where dystrophin is present, the tests indicate the amount and molecular size of dystrophin, helping to distinguish Duchenne muscular dystrophy from milder dystrophinopathy phenotypes. 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 muscular dystrophy.Prenatal tests
A prenatal test can be considered when the mother is a known or suspected carrier.Before invasive testing, determination of the fetal sex is important; while males are sometimes affected by this X-linked disease, female Duchenne muscular dystrophy is extremely rare. This can be achieved by ultrasound scan at 16 weeks or more recently by free fetal DNA testing. Chorion villus sampling 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. Another option in the case of unclear genetic test results is fetal muscle biopsy.
Treatment
No cure for Duchenne muscular dystrophy is known.Treatment is generally aimed at controlling symptoms to maximize the quality of life which can be measured using specific questionnaires, and include:
- Corticosteroids such as prednisolone, deflazacort, and Vamorolone lead to short-term improvements in muscle strength and function up to 2 years. Corticosteroids have also been reported to help prolong walking, though the evidence for this is not robust.
- Disease-specific physical therapy helps maintain muscle strength, flexibility, and function. It aims to:
- * Minimize the development of contractures and deformity by developing a program of stretches and exercises where appropriate
- * Anticipate and minimize other secondary complications of physical nature by recommending bracing and durable medical equipment
- * Monitor respiratory function and advise on techniques to assist with breathing exercises and methods of clearing secretions
- Orthopedic appliances 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.
- Cardiac problems may require a pacemaker.
The medication ataluren is approved for use in the European Union.
The antisense oligonucleotide golodirsen 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.
The Morpholino antisense oligonucleotide viltolarsen was approved for medical use in the United States in August 2020, for the treatment of Duchenne muscular dystrophy in people who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. Developed by Nippon Shinyaku and the National Center of Neurology and Psychiatry, viltolarsen's pre-clinical development was supported by pioneering work from Toshifumi Yokota and colleagues. It is the second approved targeted treatment for people with this type of mutation in the United States. Approximately 8% of people with DMD have a mutation that is amenable to exon 53 skipping.
Casimersen was approved for medical use in the United States in February 2021, and it is the first FDA-approved targeted treatment for people who have a confirmed mutation of the Duchenne muscular dystrophy gene that is amenable to exon 45 skipping.
Comprehensive multidisciplinary care guidelines for Duchenne muscular dystrophy have been developed by the US Centers for Disease Control and Prevention and were published in 2010. An update was published in 2018.
Delandistrogene moxeparvovec is a gene therapy that in June 2023 received United States FDA accelerated approval for the treatment of four and five-year-old children.
In October 2023, the US Food and Drug Administration approved Vamorolone as a Treatment for Duchenne muscular dystrophy. Catalyst Pharmaceuticals holds the exclusive North American license and commercial rights.
In March 2024, the US Food and Drug Administration approved givinostat, 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 inhibitor, givinostat operates by targeting pathogenic processes within the body, ultimately leading to a reduction in inflammation and muscle loss associated with the disease.