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.