Duchenne muscular dystrophy

1. History The disease was first described by the Neapolitan physician Giovanni Semmola in 1834 and Gaetano Conte in 1836 DMD is named after the French neurologist  Guillaume Benjamin Amand Duchenne  In an 1868 publication, Duchenne established the diagnostic criteria that are still used Gowers was the first to deduce the genetic basis for the disease In 1986, Kunkel provided molecular genetic confirmation of the X-linked inheritance pattern

2. Introduction The muscular dystrophies are a group of genetically determined, progressive diseases of skeletal muscle They are non-inflammatory and have no neurological cause Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy affecting 1 in 3500 boys born worldwide. Seen in males only (expect in females with TURNER’S SYNDROME)

3. Genetics DMD is inherited in an  X-linked recessive pattern (defect at Xp21 locus) Females will typically be carriers for the disease while males will be affected The son of a carrier mother has a 50% chance of inheriting the defective gene from his mother. The daughter of a carrier mother has a 50% chance of being a carrier or having two normal copies of the gene.

4. Pathology The disorder is caused by a mutation in the  dystrophin gene , 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

5.  Dystrophin is responsible for connecting the cytoskeleton  of each muscle fiber to the underlying basal lamina The absence of dystrophin permits excess calcium  to penetrate the sarcolemma leading to mitochondrial dysfunction mitochondrial dysfunction gives rise to an amplification of stress-induced cytosolic calcium signals and an amplification of stress-induced  reactive-oxygen species (ROS) production.

6. Increased oxidative stress within the cell damages the sarcolemma   and eventually results in the death of the cell. Muscle fibers undergo  necrosis  and are ultimately replaced with  adipose and connective tissue

7. Clinical features age of onset is between 2-6 years of age Stage 1 – Presymptomatic Creatine kinase usually elevated Positive family history

8. Stage 2- Early ambulatory clumsy & Waddling gait , manifesting in children aged 2-6 years; secondary to hip girdle muscle weakness Inexorable progressive weakness in the proximal musculature , initially in the lower extremities, but later involving the neck flexors, shoulders, and arms Meryon’s sign child slips through examiner’s grasp when lifted under arms Possible toe-walking Can climb stairs

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

10. 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

11. Stage 4 – Early nonambulatory Can self-propel for some time Able to maintain posture Possible development of scoliosis 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 can also be a serious complication in individuals with severe end-stage DMD Contractures may develop

12. PHYSICAL EXAMINATION Generally , neck flexors, wrist extensors, quadriceps, tibialis anterior, biceps, and triceps muscles are affected more. Deep tendon reflexes , which tend to parallel muscle fiber loss, 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.

13. Prognosis most are unable to ambulate independently by age 10 most are wheelchair dependent by age 15 most die of cardio respiratory problems by age 25-30

14. Differential diagnosis Similar traits to Duchenne's Distinguishing traits from Duchenne's Becker's Calf pseudo hypertrophy • markedly elevated CPK • x-linked transmission   Becker's has slower progression of weakness with diagnosis made later (~8 yrs) • cardiac involvement is frequent Spinal muscular atrophy  proximal weakness onset of weakness is earlier in childhood • absent deep tendon reflexes and fasciculations  •  CPK levels are normal • pseudo hypertrophy is absent Emery- Dreifuss dystrophy  similar clinical picture • no calf pseudo hypertrophy • CPK levels near normal  • elbow and ankle contractures develop early Limb girdle dystrophy • progressive motor weakness no calf pseudohypertrophy • CPK levels are only mildly elevated

15. Work up Serum Creatine phosphokinase Electromyography Nerve Conduction Velocity Study Molecular diagnosis Muscle biopsy Imaging Studies Electrocardiogram and echocardiogram

16. Serum Creatine phosphokinase It is elevated in patients with muscle disease and is not specific to the muscular dystrophies As the muscle cell degenerates, CK is released and levels can be elevated 20 to 200 times above normal It is elevated in the Presymptomatic phase, falls as the disease worsens, and approaches near-normal levels in end-stage disease  useful for carrier screening Muscle provocation test- After strenuous exercise,cpk levels rise more in carrier females than non carriers.

17. Electromyography not diagnostic but excludes primarily neurogenic processes. Myopathic pattern decreased amplitude, short duration, polyphasic motor

18. Nerve Conduction Velocity Study In a neuropathy , nerve conduction velocities usually are slowed In a myopathy , nerve conduction velocities usually are normal

19. Molecular diagnosis PCR amplification to examine deletion "hotspots Absence of a DNA abnormality does not exclude them as carriers

20. Muscle biopsy used for quantifying the amount of muscle dystrophin as well as for detecting asymptomatic female carriers  the ideal muscle to biopsy is one that is easily accessible and exhibits moderate weakness (i.e., has 80% strength) Gastrocnemius are involved early and are a poor site to obtain material for a biopsy Quadriceps (esp. vastus lateralis at midthigh) & rectus abdominis usually are the most reliable. General anesthesia carries the known risk of anesthetic complications, such as malignant hyperthermia . Regional anesthesia may be used

21. Open muscle biopsy -precautions The typical muscle biopsy sample consists of 2 specimens: fresh and fixed . A second sample of muscle tissue should be taken at the time of biopsy and sent for dystrophin analysis Electrocautery should not be used while obtaining a specimen for muscle biopsy A fresh specimen is used for histochemical studies in all patients and for immunofluorescence in selected patients

22. It should measure approximately 0.5 X 0.5 cm in cross-section, or 0.5 cm in diameter, and 1 cm in length along the longitudinal axis of the muscle fibers. The sample can be sent to the laboratory on saline-moistened gauze in a sealed container on ice . This technique keeps the specimen cold but does not cause it to freeze A fixed specimen is used for routine microscopy and possible electron microscopy  The preferred fixative is liquid nitrogen for light microscopy and for electron microscopy 3% glutaraldehyde be used.

23. Muscle biopsy increased fibrosis in and between muscle spindles with necrosis of the fibers deposition of fat within the fibers accompanied by hyaline and granular degeneration of the fibers Special histochemical stains that can show muscle fiber type show a preponderance of type I fibers will show  absent dystrophin  with immunostaining 

24. Imaging Studies Radiographs of the spine are important for screening and evaluating the degree of scoliotic deformity As the disease progresses and dyspnea becomes a complaint, chest radiography is also likely to become a part of the evaluation Dual energy x-ray absorptiometry  - Individuals with dystrophinopathies can have accelerated osteopenia/osteoporosis/fracture risk

25. Electrocardiogram & echocardiogram sinus arrhythmias and also may demonstrate deep Q waves and elevated right precordial R waves. Transthoracic echocardiography often reveals small ventricles with prolonged diastolic relaxation.

26. 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

27. Carrier detection Absence of a DNA abnormality does not exclude them as carriers In families in which the affected male has no detectable deletion or duplication, muscle immunofluorescence for dystrophin used - Carrier females should exhibit a mosaic pattern, with some myofibers being normal and some being abnormal

28. Medical treatment corticosteroid   therapy (prednisone 0.75 mg/kg/day) acutely improves strength, slows progressive weakening, prevents scoliosis formation, and prolongs ambulation delays deterioration of pulmonary function side effects osteonecrosis weight gain cushingoid appearance GI symptoms short stature pulmonary care with   nightly ventilation

29. Rehabilitation physiotherapy for range of motion exercises adaptive equipment power wheelchairs KAFO bracing The purpose of this is to keep the foot from pointing downward and sustain the stretch of the Achilles tendon also used for walking or for standing and can be used to prolong ambulation or help delay the onset of lower limb contractures

30. Orthopaedic treatment The goal of orthopaedic treatment is to maintain functional ambulation as long as possible

31. For surgical correction of lower extremity contractures , three approaches have been used, as follows Ambulatory approach: goal - to correct any contractures in the lower extremity while the patient is still ambulatory . Rideau indications: first appearance of contractures in lower extremities a plateau in muscle strength difficulty in maintaining upright posture with the feet together. surgery be performed before deterioration of the Gower maneuver time

32. Rehabilitative approach: Surgery is performed after the patient has lost the ability to walk but with the intention that walking will resume. Surgery during this stage usually allows for only minimal ambulation with braces . Palliative approach: Treats only contractures that interfere with shoe wear( equinovarus ) and comfortable positioning in a wheelchair.

33. Percutaneous release of Hip flexion and abduction contractures and Achilles tendon contracture Rideau technique a similar technique, but with an open procedure to release the hip flexor contractures and lateral thigh contractures. They also excised the iliotibial band and the lateral inter muscular septum

34. TRANSFER OF THE POSTERIOR TIBIAL TENDON TO THE DORSUM OF THE FOOT

35. TRANSFER OF THE POSTERIOR TIBIAL TENDON TO THE DORSUM OF THE BASE OF THE SECOND METATARSAL

36. Luque –Galveston technique

37. THANK YOU