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Dickens Muscular dystrophy

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Dickens Muscular dystrophy

Overview of Duchenne Muscular Dystrophy (DMD)

  • What is DMD?: Duchenne muscular dystrophy is a severe type of muscular dystrophy, characterized by progressive muscle degeneration and weakness.

History

  • Initial Discovery:

    • First reported in the 1860s by Dr. Duchenne de Boulogne, noting muscle degeneration and cognitive difficulties.

  • Gene Identification:

    • In 1987, Dr. Eric Kaufman and Dr. Louis Lewis Huckle identified the dystrophin gene as the genetic basis for DMD, marking significant progress in genetic research.

  • Advancements in Care:

    • Late 1980s saw the introduction of respiratory support to prolong life expectancy, such as the use of ventilators and tracheostomy, which became more common worldwide in the early 2000s.

    • Steroid treatments (e.g., prednisone) began in the early 2000s to reduce inflammation in muscle tissue.

    • ACE inhibitors became part of standard care in 2007 to manage heart stress due to muscle weakening.

Symptoms

  • Early Mobility Issues:

    • Mobility challenges can present as early as infancy; parents might notice delayed walking.

    • Characteristic gait includes walking with shoulders back and knees together.

  • Pseudohypertrophy:

    • "Large calves" is a common symptom; however, this is due to muscle loss replaced by fat/connective tissue instead of true hypertrophy.

  • Prolonged Implications:

    • Mobility issues can lead to scoliosis, potentially requiring surgical correction.

    • Most patients are wheelchair-bound by age 12.

  • Cognitive Effects:

    • Many patients experience learning difficulties; early interventions can mitigate these issues.

Genetics

  • Inheritance Pattern:

    • DMD follows an X-linked recessive inheritance pattern due to mutations in the dystrophin gene located at Xp21, the largest gene in the human genome with 89 exons.

  • Dystrophin Protein Characteristics:

    • Dystrophin weighs 427 kDa and consists of about 2.5 million base pairs.

    • Primarily expressed in cardiac muscles, brain, and retina.

  • Female Carriers:

    • Female carriers can exhibit mild symptoms due to reduced expression or functional dystrophin, occurring in 20% of cases.

Mutations

  • Common Types of Mutations:

    • 70-80% of mutations in DMD involve deletions or duplications that shift the open reading frame.

    • 50-60% primarily consist of entire exon deletions.

    • 30% of mutations are de novo—new mutations not inherited from parents, possibly influenced by maternal age.

  • Becker Muscular Dystrophy (BMD):

    • In-frame mutations lead to Becker muscular dystrophy, characterized by later onset and less severity compared to DMD.

Diagnosis

  • Initial Testing:

    • Elevated creatine kinase levels in blood tests typically indicate muscle damage. Genetic testing follows for confirmation.

  • Muscle Biopsies:

    • Histological examination reveals damage and weakness in muscle cells, aiding in diagnosis.

  • Electrocardiograms (EKGs):

    • Monitor cardiovascular health, crucial due to eventual heart muscle weakening.

  • Genetic Counseling:

    • Recommended for families with a history of DMD who plan to have children, assessing genetic risks due to the fatal nature of the disease.

Treatment and Management

  • Monitoring and Early Intervention:

    • Cardiac monitoring and intervention typically start at age 10; beginning attention to cardiovascular health is critical at diagnosis.

  • Medications:

    • ACE inhibitors and angiotensin receptor blockers help reduce blood pressure and heart stress.

    • Steroid treatments like prednisone also slow muscle degeneration and can mitigate the need for surgeries.

  • Respiratory Support:

    • As the disease progresses, patients may require a ventilator or tracheostomy due to diaphragm muscle weakness.

  • Exon Skipping Therapy:

    • A promising approach being researched to restore dystrophin function in muscle.

  • Physical Therapy:

    • Vital for maintaining ambulation and prolonging patients' walking abilities as long as possible.

Long-term Outlook

  • Life Expectancy:

    • Average life expectancy for DMD patients is approximately 23.7 years; early diagnosis and intervention can improve this outlook significantly.

  • Care for Female Carriers:

    • Monitoring them is important, though their symptoms are typically less severe due to having a single affected allele.

Research Outlook

  • Becker Muscular Dystrophy:

    • Less severe and later-onset, offers more effective longitudinal research due to longer survival, providing insights into disease progression and treatment options.