MUSCULAR DYSTROPHY

OVERVIEW OF MUSCULAR DYSTROPHY Dystrophinopathies

Is a Neurological disorder:
● Headaches & migraine Disease of the upper motor neuron ● Spinal Muscular Atrophy (SMA) DUCHENN MD (DMD) BECKER MD (BMD)
● Seizures (Paroxysmal disorders) ● Peripheral Neuropathy 1. Loss of Dystrophin 01. Misshapen of Dystrophin
● Weakness & Hypotonia Disease of the spinal cord ● Myasthenia Gravis 2. Severe 02. Milder
● Ataxia & movement dis. ● Infant Botulism
● Altered mental status 3. Symptoms at age of 5 03. Symptoms at age of 10-20
● Neurodegenerative dis. Disease of the lower motor neuron MUSCULAR DYSTROPHY
● Neurocutaneous dis. (muscle) (bad) (nourishment)
● Congenital malformations of CNS *without nerve / neuromuscular junction damage DUCHENNE MUSCULAR DYSTROPHY
DEFINITION: INTRODUCTION
A group of genetic muscle diseases, characterized by: ● the most common type of MD one of the most common genetic disorders of childhood.
● Progressive myofiber degeneration ● 1 in 3500 affecting male infants worldwide
● Gradual replacement of muscle by fibrotic tissue AETIOLOGY
TYPES AND CLASSIFICATION
9 major forms of MD, including congenital MD & myotonic dystrophy (not shown in this picture):

Autosomal Dominant Sex-Linked (X-linked recessive) Autosomal recessive

● Fascioscapulohumeral MD ● Duchenne MD (DMD) ● Limb-girdle MD 2*
● Myotonic dystrophy (DM) ● Becker MD (BMD) ● Emery-Dreiffus MD*
● Oculopharyngeal MD ● Emery-Dreiffus MD*
● Distal MD*
● Limb-girdle MD 1*
● Emery-Dreiffus MD*
AETIOLOGY X-linked recessive disorder (Xp21) / Spontaneous gene mutations (in ⅓ cases)
results in:
*Key note: different types of MD may be due to different protein defect(s).(*defect as a result of gene mutation)
Deletion on the short arm of X chromosome (at Xp21 site)
-> codes for a protein called dystrophin (functions to stabilize the sarcolemma)
 PATHOGENESIS CLINICAL MANIFESTATIONS

● Infant boys are only rarely symptomatic in early infancy

○ Poor head control
○ Mild slowness in attaining motor milestones

● Clinical onset: usually occurs between 2-3 years of age

○ Delayed motor development (taking longer to learn to sit, stand or walk)
○ Usually does not begin to walk until about age 18 months or later
○ Cognitive & intellectual impairment
○ Tend to be slower & clumsier than their peers
○ Muscle weakness that worsens over time
○ Delayed speech & language department

1. Gene mutation that leads to defective Dystophin 1. WADDLING GAIT

Dystrophin connects actin cytoskeleton to the surrounding ECM ● Wide-based gait
2. Leads to myofibril membrane instability ● A “duck-like” walk
3. Muscles contract ➔ small rips/tears of the membrane ● Caused by:
- Weakness in the gluteus maximus and gluteus medius
muscles & the patient’s inability to support a single-leg
stance
● The child leans the body toward the other side to balance the center of gravity, and the motion is repeated with each step

2. LUMBAR LORDOSIS
● Hip extensor weakness
● Resulting in: forward tilt of the pelvis to hyperlordosis of the spine, in
order tomaintain posture

3. TOE WALKING
● Easier to stay vertical with an equinus foot position

4. Influx of extracellular calcium into muscle fibers PROGRESSION

5. Calcium activates the protease in the muscle fibers (hence, more intracellular calcium ➔ more activated protease) ● Gradually, child is observed to have increasingly noticeable difficulty
*Note: Efflux of creatinine kinase through these rips can also occur with steptaking
● Frequent falls without tripping or stumbling often occur
● Begins having problems getting up from sitting or supine position

4. GOWER’S SIGN
● Patient use their hands and arms
to"walk" up their own body from
a squatting position (to stand)
● Caused by:
- Weakness in the child’s proximal hip muscles

5.OTHERS
6. More activated protease => increased muscle proteolysis ● Pain in the calves with activity (<30%)
7. Progressive muscle degeneration ● Progressive enlargement of the heart (dilated cardiomyopathy)
8. Gradual replacement of muscle by fibrotic tissue ○ Dystrophin also expressed in heart muscle
● Enlarged calf muscles (pseudohypertrophy)
○ Replacement of muscle fibers by fat and fibrous tissue (60%)
● Macroglossia (large tongue) (30%)

● Upper-extremity involvement manifests in later stages

● Most children need to use wheelchair by age of 12, and
die of respiratory complications in their 20s or early 30s
 DIFFERENTIAL DIAGNOSIS
● Becker muscle dystrophy (BMD)
● Limb-girdle muscular dystrophy
● Emery-Dreiffus muscular dystrophy
● Dilated cardiomyopathy
● Spinal muscular atrophy (SMA)
DIAGNOSIS & INVESTIGATIONS
● WHEN TO SUSPECT?
○ If positive family Hx of DMD: when any evidence of delayed
motor milestones in a young child appear
○ If no Hx of DMD: when a child is not walking by 16 to 18
months,or the presence of Gower’s sign, toe walking or calf
hypertrophy

● TO CONFIRM THE DIAGNOSIS:

○ Elevated Creatinine Kinase (CK) levels (100-200x)
○ Genetic testing for Dystrophin gene mutation
○ Muscle biopsy

COMPLICATIONS

● Cardiopulmonary failure
● Contractures and early wheelchair dependence
● Osteoporosis and fracture

PROGNOSIS

● May improve between 3-6 years of age.

● This is then followed by gradual but relentless deterioration.
● Before the age of 12 years, most patients lose ambulation and require noninvasive ventilation (NIV) by late teenage years
● Survival into adulthood is now common, but survival beyond the third decade is uncommon

MANAGEMENT
● No known cure for Duchenne MD
● Aim: to manage symptoms & complications

STEROID THERAPY:
to slow down pace of the disease & delay motor disability

SUPPORTIVE CARE:
includes physical therapy, bracing, proper wheelchairs & treatment of cardiac dysfunction or pulmonary infections
*Genetic therapy - under research
*Management for complications of DMD