Muscular dystrophies

Muscular dystrophies

1. Muscular Dystrophies Dr.Manoj Prabhakar.M , Resident (Dept of Pediatrics)

2. Case Scenario Age: 5 ½ years with rare Xp21 mutation with Point mutation of exon 7 of the dystrophin gene resulting in complete absence of dystrophin . Presentation: (Early ambulatory stage ) - Ambulant, weight – 50th %, hypertrophy of the calves, + ve Gowers sign, mild lordosis . Problem List: Poor attention, Speech delay, hyperactivity(reported by mother), proximal weakness of lower and upper limbs and neck flexors, epistaxis , poor balance, gait- waddle/flat footed, muscle spasm of calves. Initially presented with developmental delays before he was diagnosed.

3. Muscular dystrophy is distinguished from all other neuromuscular diseases by 4 obligatory criteria: It is a Primary myopathy It has a genetic basis, The course is progressive, and Degeneration and death of muscle fibers occur at some stage in the disease. DEF : The term dystrophy means abnormal growth.

4. Duchenne and Becker Muscular dystrophies. Emery- Dreifuss Muscular Dystrophy. Myotonic Muscular Dystrophy. Limb-Girdle Muscular Dystrophies. Facioscapulohumeral Muscular Dystrophy. Congenital Muscular Dystrophies. TYPES:

5. Duchenne muscular dystrophy (DMD ) It is the most common hereditary neuromuscular disease affecting all races and ethnic groups. Its characteristic clinical features are progressive weakness, intellectual impairment , hypertrophy of the calves, and proliferation of connective tissue in muscle. This disease is inherited as an X-linked recessive trait. The abnormal gene is at the Xp21 locus. The incidence is 1 in 3,600 live born infant boys .

6. The disorder is caused by a mutation in the dystrophin gen e, the largest gene located on the human X chromosome which codes for the protein dystrophin . Without dystrophin , muscles are susceptible to mechanical injury and undergo repeated cycles of necrosis and regeneration . Ultimately , regenerative capabilities are exhausted or inactivated.

7. Clinical Features • Clinical onset of muscular weakness usually occurs between 2 and 3 years of age. • Histologic and laboratory evidence of a myopathy may be observed from birth.

8. Posture changes during progression of DMD

9. Stage 1 – Presymptomatic Creatine kinase usually elevated Positive family history CLNICAL FEATURES

10. Stage 2- Early ambulatory C lumsy & Waddling gait, manifesting in children aged 2-6 years Progressive weakness in the proximal musculature, initially in the lower extremities, but later involving the neck flexors, shoulders, and arms. Possible toe-walking Can climb stairs

11.   Gower's sign -'climbing up legs' using the hands when rising from the floor

12. Stage 3- Late ambulatory More difficulty walking Around age 8 years, most patients notice difficulty with ascending stairs and respiratory muscle strength begins a slow but steady decline Cannot arise from the floor The forced vital capacity begins to gradually wane, leading to symptoms of nocturnal hypoxemia such as lethargy and early morning headaches

13. Stage 4 – Early nonambulatory Can self-propel for some time Able to maintain posture Possible development of scoliosis

14. Stage 5 – Late nonambulatory Scoliosis may progress, especially when more wheelchair dependent If wheelchair bound and profoundly weak, patients develop terminal respiratory or cardiac failure, usually by the early 30s poor nutritional intake Contractures may develop

15. Complications Cardiomyopathy Decreased self-independence and mobility Lung failure (cause of death) Muscle tightness around joints Mental impairment

16. PHYSICAL EXAMINATION Generally, neck flexors, wrist extensors, quadriceps, tibialis anterior, biceps, and triceps muscles are affected more . Deep tendon reflexes, slowly diminish and ultimately disappear Calf muscle enlargement (pseudo hypertrophy) contractures of the iliotibial bands, hip flexors, and heel cords Equinovarus deformity of ankle is universal Asymmetric weakening of the paraspinal muscles leads to kyphoscoliosis , which in turn further compromises pulmonary and gastrointestinal function.

17. WORK UP Serum Creatine Phosphokinase (Elevated) Electromyography Nerve Conduction Velocity Study Molecular diagnosis Muscle biopsy Imaging Studies Electrocardiogram E chocardiogram

18. DIFFERENTIAL DIAGNOSIS

19. Differences between DMD & BMD

20. Carrier detection Carrier detection is an important aspect of the care and evaluation of patients with DMD and their family members For many years, CPK testing was the best method for carrier detection; however, it is elevated in only two thirds of female carriers If affected male in family has a known deletion or duplication of the dystrophin gene, testing for carrier status is performed accurately by testing possible carriers for the same deletion or duplication

21. TREATMENT There is no medical cure for this disease. Much can be done to treat complications and to improve the quality of life of affected children . Cardiac decompensation often responds initially well to digoxin . Preservation of a good nutritional state is important.

22. GENETIC CONSELLING Genetic counseling can offer many benefits for families living with Duchenne or Becker muscular dystrophy, including: - Education about the disorder - Coordination and explanation of genetic testing - Emotional counseling

23. EXON SKIPPING In DMD, exon skipping is a potential treatment approach that is under investigation to correct for specific genetic mutations and restore production of dystrophin protein.

24. As the name suggests, the principle of exon skipping is to encourage the cellular machinery to ‘skip over’ an exon . Small pieces of DNA called  antisense oligonucleotides  (AOs) or ‘ molecular patches ‘ are used to mask the exon that you want to skip, so that it is ignored during protein production

25. Drisapersen and eteplirsen are exon 51 skipping antisense oligonucleotides that bind RNA and skip (bridge) over the defective exon , thus producing a shorter but potentially functional dystrophin protein.