Duchenne Muscular Dystrophy
Disease Details
Family Health Simplified
- Description
- Duchenne muscular dystrophy is a severe genetic disorder characterized by rapid progression of muscle degeneration and weakness, primarily affecting males.
- Type
- Duchenne muscular dystrophy is a type of genetic disorder characterized by progressive muscle degeneration and weakness. It is X-linked recessive.
- Signs And Symptoms
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DMD 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 from the moment 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. His ability to walk usually disintegrates completely before age 13. Most men affected with DMD 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 (irregular heartbeat) 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 DMD is trouble getting up from lying or sitting position, 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: 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. 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).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), which are believed to be the result of inadequate dystrophin in the brain. - 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, but this varies. People born with DMD after 1990 have a median life expectancy of approximately 28–30. With excellent medical care, affected men often live into their 30s. David Hatch of Paris, Maine, may have been the oldest person in the world with the disease; he lived to the age of 56.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. Early planning of the required supports for later-life care has shown greater longevity for people 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 (ILMs) are protected and do not undergo myonecrosis. 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. In addition, patients with Duchenne muscular dystrophy also have elevated plasma lipoprotein levels, implying a primary state of dyslipidemia in patients.
- Onset
- Duchenne muscular dystrophy (DMD) typically has an onset in early childhood, around ages 2 to 3 years.
- Prevalence
- Duchenne muscular dystrophy (DMD) is one of the most common types of muscular dystrophy. It affects approximately 1 in 3,500 to 5,000 male births worldwide.
- Epidemiology
- DMD is the most common type of muscular dystrophy; it affects about one in 5,000 males at birth. DMD has an incidence of one in 3,600 male infants.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.
- Intractability
- Yes, Duchenne Muscular Dystrophy (DMD) is currently considered intractable. Although advancements in medical care and treatments have improved the quality of life and extended life expectancy for individuals with DMD, there is no cure. The disease is characterized by progressive muscle weakness and degeneration due to mutations in the dystrophin gene, which is essential for muscle function. Efforts in gene therapy and other therapeutic approaches are ongoing, but managing DMD primarily involves supportive care and interventions to slow disease progression and address complications.
- Disease Severity
- Duchenne Muscular Dystrophy (DMD) is a severe, progressive muscle-wasting disease. It primarily affects boys and typically presents in early childhood. Individuals with DMD usually lose the ability to walk by their early teens and may experience life-threatening heart and respiratory complications by their twenties or thirties.
- Healthcare Professionals
- Disease Ontology ID - DOID:11723
- Pathophysiology
- Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the DMD gene, which encodes the protein dystrophin. Dystrophin is crucial for maintaining the structural integrity of muscle fibers. The absence or deficiency of functional dystrophin leads to muscle fiber damage and progressive muscle degeneration. This results in inflammation, fibrosis, and a gradual replacement of muscle tissue with fat and connective tissue, leading to the characteristic muscle weakness and wasting seen in DMD.
- Carrier Status
- Carrier status for Duchenne Muscular Dystrophy (DMD) primarily involves females, as DMD is an X-linked recessive disorder. A female carrier has one altered copy of the DMD gene on one of her X chromosomes. While carriers typically do not show severe symptoms, they can sometimes exhibit mild muscle weakness or cardiac issues. Carriers have a 50% chance of passing the mutated gene to their sons (who will be affected) and a 50% chance of passing it to their daughters (who will also be carriers).
- Mechanism
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Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration due to mutations in the DMD gene.
**Mechanism:**
DMD primarily affects the dystrophin protein, which is critical for maintaining muscle cell integrity. The absence or dysfunction of dystrophin leads to muscle fiber damage and loss over time.
**Molecular Mechanisms:**
1. **Genetic Mutation:** Mutations in the DMD gene, often deletions, duplications, or point mutations, result in the production of a nonfunctional or absent dystrophin protein.
2. **Lack of Dystrophin:** Dystrophin is part of the dystrophin-glycoprotein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix. Without functional dystrophin, this structure is compromised.
3. **Muscle Fiber Damage:** The absence of dystrophin makes muscle fibers more susceptible to damage during contraction. This leads to repeated cycles of muscle fiber degeneration and regeneration.
4. **Inflammation and Fibrosis:** Continuous muscle damage triggers inflammatory responses, contributing to fibrosis (scarring) and further reducing muscle function.
5. **Progressive Muscle Weakness:** Over time, muscle tissue is replaced by fat and connective tissue, culminating in severe muscle weakness and loss of motor function.
These molecular deficiencies ultimately account for the severe and progressive nature of the disease. - Treatment
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No cure for DMD 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 (Agamree) 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 is helpful to maintain muscle strength, flexibility, and function. It aims 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 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 (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.
Cardiac problems may require a pacemaker.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 as eteplirsen failed to establish a clinical benefit; it has been refused approval by the European Medicines Agency.The medication Ataluren (Translarna) is approved for use in the European Union.The antisense oligonucleotide Golodirsen (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.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. 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 (Amondys 45) 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 DMD gene that is amenable to exon 45 skipping.Comprehensive multidisciplinary care guidelines for DMD 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 (Elevidys) is a gene therapy that in June 2023 received United States FDA accelerated approval for treatment of four and five-year-old children.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. - Compassionate Use Treatment
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Duchenne Muscular Dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration. For compassionate use, off-label, or experimental treatments, the following are notable:
1. **Exon Skipping Therapies**: Drugs like eteplirsen (Exondys 51) or golodirsen (Vyondys 53) are designed to skip certain exons in the dystrophin gene, potentially producing a functional protein. These are specific to certain genetic mutations.
2. **Gene Therapy**: Experimental treatments, such as micro-dystrophin gene therapy, aim to deliver a shortened but functional version of the dystrophin gene to muscle cells.
3. **Corticosteroids**: Prednisone and deflazacort are commonly used off-label to slow disease progression by reducing inflammation.
4. **Utrophin Modulators**: Utrophin is a protein similar to dystrophin. Drugs like ezutromid (previously under investigation) aim to upregulate utrophin as a substitute for dystrophin.
5. **Anti-Inflammatory Agents**: Edasalonexent (formerly in trials) was intended to reduce muscle inflammation and degeneration through NF-kB inhibition.
6. **Myostatin Inhibitors**: These aim to increase muscle mass and strength by inhibiting myostatin, a protein that restricts muscle growth.
7. **Vitamins and Supplements**: Various supplements like Coenzyme Q10, creatine, and omega-3 fatty acids are sometimes used off-label to support muscle function and overall health.
Access to these treatments often depends on clinical trial availability, regulatory approvals, and regional medical policies. - Lifestyle Recommendations
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For Duchenne muscular dystrophy (DMD), the following lifestyle recommendations might be beneficial:
1. **Physical Therapy**: Regular sessions to maintain muscle function, flexibility, and prevent contractures.
2. **Exercise**: Low-impact exercises, like swimming or cycling, to maintain cardiovascular health and muscle strength without overexertion.
3. **Assistive Devices**: Use braces, wheelchairs, or other mobility aids as needed to maintain independence and mobility.
4. **Respiratory Care**: Regular monitoring and exercises to maintain lung function; use of ventilatory support if necessary.
5. **Nutrition**: A balanced diet to maintain optimal weight and overall health. Monitor for potential swallowing difficulties.
6. **Cardiac Care**: Regular cardiac evaluations to monitor and manage heart health, as DMD can affect the heart muscle.
7. **Bone Health**: Measures to prevent osteoporosis, such as calcium and vitamin D supplements, and weight-bearing activities as tolerated.
8. **Medication Adherence**: Consistent use of prescribed medications, such as corticosteroids, to slow disease progression.
9. **Psychological Support**: Counseling and support groups to help manage emotional and mental health challenges associated with DMD. - Medication
- For Duchenne muscular dystrophy, corticosteroids such as prednisone and deflazacort are commonly prescribed to slow muscle degeneration and improve motor function. There is ongoing research into additional treatments, including gene therapy and exon-skipping drugs like eteplirsen.
- Repurposable Drugs
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Repurposable drugs for Duchenne Muscular Dystrophy (DMD) include:
1. **Ataluren (Translarna)**: Originally developed to treat nonsense mutations in DMD.
2. **Prednisone**: A corticosteroid that can help slow muscle degeneration.
3. **Deflazacort**: Another corticosteroid, often used as an alternative to prednisone with different side effect profiles.
4. **Lisinopril**: An ACE inhibitor, typically used for heart conditions, which can help manage associated cardiac issues in DMD.
5. **Metformin**: Traditionally used for diabetes, under investigation for its potential to improve muscle metabolism.
These drugs, developed for other conditions, show potential in altering the progression or symptoms of DMD and are subjects of ongoing research. - Metabolites
- Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration due to mutations in the dystrophin gene. Metabolites associated with DMD can provide insights into the disease's progression and potential therapeutic targets. Changes in metabolites such as creatine, creatinine, and various amino acids have been observed. Elevated levels of serum creatine kinase (CK) are a hallmark of the disease and indicate muscle damage. Variations in metabolites involved in energy production, oxidative stress, and muscle metabolism are frequently studied to understand and monitor DMD.
- Nutraceuticals
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For Duchenne Muscular Dystrophy (DMD), there is ongoing research into various nutraceuticals as potential supportive therapies. Nutraceuticals are food-derived compounds that may offer health benefits beyond basic nutrition. Some of these include:
1. **Coenzyme Q10 (CoQ10)**: This antioxidant is believed to improve mitochondrial function and may help with muscle energy metabolism.
2. **Omega-3 Fatty Acids**: Found in fish oil, these may have anti-inflammatory properties that could benefit muscle health.
3. **Vitamin D**: Important for bone health, which is particularly critical in DMD patients who are prone to fractures and osteoporosis.
4. **Creatine**: Often used by athletes to improve muscle mass and strength; its use in DMD is being investigated.
5. **Green Tea Extract**: Contains epigallocatechin gallate (EGCG), which has antioxidant properties that might provide protective effects on muscle cells.
However, none of these are established treatments for DMD, and their effectiveness is still under study.
"Nan" appears to be truncated or incorrect in this context and does not relate directly to Duchenne Muscular Dystrophy or nutraceuticals associated with it. If "nan" was meant to refer to a specific topic, please provide further clarification. - Peptides
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Duchenne muscular dystrophy (DMD) is primarily associated with the absence of dystrophin, a protein that helps strengthen muscle fibers. Peptide-based therapeutic approaches in DMD aim to restore some function to the muscles. One prominent strategy involves exon skipping using antisense oligonucleotides, which are short DNA or RNA molecules designed to modify splicing of the dystrophin gene transcript, enabling the production of a truncated yet partially functional dystrophin protein. Specific peptides might also be used to enhance delivery and efficacy of such oligonucleotides.
Nanotechnology in DMD treatment could involve nanoparticles designed to deliver drugs or genetic therapies specifically to muscle tissue, improving the efficiency and reducing side effects of the treatment. These nanoparticles can encapsulate therapeutic agents, protect them from degradation, and provide controlled release, potentially optimizing the management of DMD.