Duchenne Muscular Dystrophy

1. Duchenne Muscular Dystrophy Presented by: Sujitha B Subramaniam 11408044 IV yr Genetic Engineering SRM University

2. DUCHENNE MUSCULAR DYSTROPHY (DMD) is a recessive X-linked form of muscular dystrophy, which results in muscle degeneration, difficulty in walking, breathing, and death. Muscular dystrophy - Group of hereditary muscle diseases. Duchenne Muscular Dystrophy

3. MUSCLE STRUCTURE Duchenne Muscular Dystrophy

4. EPONYM: DMD is named after the French neurologist Benjamin Amand Duchenne  (1806–1875), who first described the disease in 1861. • The Era of Modern Neurology – His findings: • Neural pathways, • The effect of lesions on these structures, • Deep tissue biopsy • Nerve conduction tests (NCS) • Clinical photography. Duchenne Muscular Dystrophy

5. DMD Research: Duchenne Muscular Dystrophy

6. SYMPTOMS: • The main symptom of Duchenne muscular dystrophy, • A progressive neuromuscular disorder, is muscle weakness associated with muscle wasting. • The Other Physical Symptoms Are: • Awkward manner of walking, stepping, or running. • Frequent falls • Fatigue • Difficulty with motor skills (running, hopping, jumping) • Pseudohypertrophy – Enlarging of calve Duchenne Muscular Dystrophy

7. PREVALENCE: • DMD has an incidence of 1 in 4,000 newborn males across the world. • Diagnosis in boys usually occurs between 16 months and 8 years. INHERITANCE PATTERN: Mother carries the recessive gene and passes it to her child. Traitis usually expressed in males only. Duchenne Muscular Dystrophy

8. Disease Development with age Duchenne Muscular Dystrophy

9. THE GENE: Duchennemuscular dystrophy is caused by a mutation of the dystrophin gene at locus Xp21. Duchenne Muscular Dystrophy

10. MOLECULAR MAKEUP • Genomic DNA: 2.2 million base pairs. • There are 79 exons: which makeup 0.6% of the entire gene. • There are 8 promoters. • N-terminal or actin binding sight: binds dystrophin to membranes surrounding striated muscle fiber. • Rod Domain: contains 24 proteins that repeat and maintain molecular structure. • The cysteine-rich domain • The C-terminal: contains the syntrophin binding sight. Duchenne Muscular Dystrophy

11. Dystrophin - protein Duchenne Muscular Dystrophy

12. GENOTYPE OF DMD • Mutations which affect the DMD gene. • 96% are frame-shift mutations. • 2-3% are mutations involving changes in nucleotide. • 10-20% of mutations occur in the gametocyte. • The most common mutation are repeats of the CAG nucleotides. • Mutations within the dystrophin gene can either be inherited or occur spontaneously during germline transmission. Duchenne Muscular Dystrophy

13. DIAGNOSIS: • DNA test: • The presence of isoforms of the gene. • The size of transcript should be 14kb, any change in this can be detected. • The common mutation prone regions Exon 45-53 and 2 to 20 can be sequenced and mutation can be done. • Muscle biopsy: • Complete absence of the protein indicates the condition. Duchenne Muscular Dystrophy

14. Prenatal tests: • The prenatal tests are done to check if the child has inherited the mutated X chromosome from mother, who has a family history of the disease. • The samples for the test are got by: • Chorionic villus sampling (CVS) 11–14 weeks. • Amniocentesis can be done after 15 weeks. • Fetal blood sampling can be done at about 18 weeks. • Manual muscle testing (MMT). • An electromyography (EMG) shows that weakness is caused by destruction of muscle tissue rather than by damage to nerves. Duchenne Muscular Dystrophy

15. TREATMENT: • There is no current cure for DMD. • Treatment is generally aimed at controlling the onset of symptoms to maximize the quality of life, and include the following: • Corticosteroids -  increase energy and strength . • Mild, physical activity such as swimming is encouraged. • Physical Therapies. • Orthopedic appliances. • Splinting and Orthoses. Splinting and Orthoses. Duchenne Muscular Dystrophy

16. POSSIBLE COMPLICATIONS: • A complete neurological, heart, lung, and muscle exam may show: • a. c. d. b. e. • Cardiomyopathy – Detoriation of heart muscle • Muscular atrophy • Scoliosis – Curved spine • Muscle contractures • Muscle deformities • Respiratory disorders Duchenne Muscular Dystrophy

17. ONGOING RESEARCH: • Exon-skipping. • Stem cell replacement therapy. • Analog up-regulation. • Supportive care. • Gene therapy. COUNSELING: Genetic counselling is advised for people with a family history of the disorder. Duchenne muscular dystrophy can be detected with about 95% accuracy by genetic studies performed during pregnancy. Duchenne Muscular Dystrophy

18. PATIENT ORGANIZATIONS: AktionBenni & Co e.v. - Conny and Claus, Germany CureDuchenne - Debra and Paul Miller, Newport Beach, USA. United Parent Projects Muscular Dystrophy Duchenne Parent Project, Netherlands. The shakthi foundations, Chennai – India. Duchenne Muscular Dystrophy

19. CHILDREN WITH DMD Stan Groten - 5  Thomas Tonino - 2 Maarten Rooseleers - 17months Bram - 2 Duchenne Muscular Dystrophy Jayden Hendricks - 3.5

20. Jonathan – Spine fusion, 3 heart surgery, Lung infection  Howard Thomas – San Pedro Sampler 20 Duchenne Muscular Dystrophy

21. ‘LIFE IS SHORT, SO WORK/PLAY HARD’. References: http://www.mja.com.au/ www.geneticseducation.nhs.uk www.nature.com www.mda.org www.genomebiology.com www.ncbi.nlm.nih.gov www.wikipedia.com Duchenne Muscular Dystrophy