Muscle dystrophies

Question 1

What are muscular dystrophies?

Answer 1

• 1 in 3,500 live male births
• It can occur at any age
• It is a group of inherited diseases where the voluntary muscles weaken progressively
• Dystrophy means the abnormal growth
• It can affect the heart and other organs

Question 2

What is the difference between muscular diseases and neuromuscular diseases?

Answer 2

• It is a primary myopathy
• It has a genetic basis
• It has a progressive course
• Degeneration and the death of muscle fibers occur at a particular stage in the disease

Question 3

What are the criteria for differentiating between different muscular dystrophies?

Answer 3

1) The severity of the disease

2) The muscles affected

3) Rate of progression

Question 4

What are the different classifications of muscular dystrophies?

Answer 4

• Notice how the diseases are characterized by the mode of inheritance & the name of the disease can tell us which group of muscles are being affected

1) Sex-linked:

• Duchene muscular dystrophy (upper part of the UL till the elbow including the neck & upper part of the LL, including the lateral part of the foot)
• Becker muscular dystrophy (upper part of the UL till the elbow including the neck & upper part of the LL, including the lateral part of the foot)
• Emery-dreifuss muscular dystrophy (UL till the elbow, lateral part of the leg)

2) Autosomal-recessive:

• Limb-girdle muscular dystrophy (upper part of the UL till the elbow without the neck & upper part of the LL)
• Facio-scapulo humeral muscular dystrophy (UL till the elbow, mouth, and nose region, lateral part of the leg)

3) Autosomal dominant:
- Oculopharyngeal muscular dystrophy (upper part of the UL till the elbow including the neck & upper portion of the LL)

Question 5

Describe DMD

Answer 5

1) It Is the most common hereditary muscular dystrophy affecting all races and ethnic groups

2) Its characteristic clinical features are:

• Progressive weakness
• Intellectual impairment
• Hypertrophy of the calves
• Proliferation of connective tissue in the muscle
• Patients can present with cardiomyopathies, and even the respiratory muscles are affected

3) More severe than BMD

Question 6

Describe BMD

Answer 6

1) Similar to DMD

2) It has the same genetic defect as DMD

3) Clinically it is milder than DMD

Question 7

Describe the genetic etiology and pathogenesis of DMD & BMD

Answer 7

• Duchenne protein is present in the sarcolemma of the membrane (at the periphery) and it stabilizes the membrane to avoid any lesions
  (Lesions in the membrane covering muscles will affect the calcium homeostasis)
• X-linked mutations
• There is a cytoskeletal protein known as dystrophin, which is encoded by the gene at Xp21
• The mutation of the dystrophin gene occurs at the short arm (petit arm) in the X-chromosome at the exact position of 21.2
• The mutations occur in the dystrophin gene at the Xp21 locus
• It disrupts the function of a large structural protein, which is dystrophin that links muscle cells to the extracellular matrix stabilizing the membrane and protecting the sarcolemma from the stress that developed during the muscle contraction
• The mechanical damage through eccentric contractions puts high stress on fragile membranes, provoking micro lesions that will eventually lead to the loss of calcium homeostasis and cell death

Question 8

What are the clinical features of DMD in infants (the early stage)?

Answer 8

• Rarely symptomatic at birth or in early infancy, although some are mildly hypotonic
• Other gross motor skills (sitting, standing, etc) might be slightly delayed
• Poor head control is usually the first sign
• You can discover that the baby suffers from DMD very early on from amniocentesis and sonar but it’s too late to do anything by then

Question 9

What are the clinical features of DMD in the toddler age “end of 2yrs” (transitional phase)?

Answer 9

1) Hip girdle weakness

2) Delayed walking, falling, toe weakness, and trouble running or waking up the stairs

3) Developmental delay

4) Lordotic posture when standing, compensating for the gluteal weakness

Question 10

What are the clinical features of DMD between ages 3-9 (transitional phase)?

Answer 10

1) Early Gowers sign (pushing on the leg to stand)

2) Pseudohypertrophy of calf muscles (fat deposition)

3) Contractures mainly in the ankles, knees, hip, and elbow

Question 11

What are the clinical features of DMD between the ages 10-14 years?

Answer 11

1) The child uses a wheelchair

2) Scoliosis due to sitting and back weakness

3) UL weakness and difficulty in retaining the use of fingers making daily activities difficult

• In BMD, children remain ambulatory until early adult life

Question 12

What are the clinical features of DMD in individuals more than 15 years old?

Answer 12

1) Cardiomyopathies, persistent tachycardia, dyspnea, and LL edema

2) Respiratory problems, ineffective cough, frequent pulmonary infections, and decreasing respiratory reserve (The most common cause of death in DMD patients is due to respiratory infections (such as pneumonia))

3) CNS; learning disability

Question 13

How to diagnose DMD?

Answer 13

1) History taking

2) Physical examination

3) Investigations

4) Karyotyping

Question 14

What are the different investigations done for DMD patients?

Answer 14

1) Serum CK levels

2) PCR

3) Muscle biopsy

Question 15

Describe the serum CK test

Answer 15

• It is usually greatly elevated in DMD patients >1000 U/L, (15,000-35000IU/L),norm(<160IU/L)
• CK levels at the beginning will be elevated but at the end of the CK will be low since all the muscles have been destructed

Question 16

Describe the PCR test

Answer 16

• PCR test is done for the dystrophin gene mutation
• It is the largest known human gene
• It is located in the short arm of X chromosome 21.2
• Found primarily in the skeletal and cardiac muscles

Question 17

Describe the muscle biopsy done for DMD patients

Answer 17

• It shows the myopathic changes like; connective tissue proliferation, scattered degenerating, and regenerating myofibers
• The common muscles sampled for the biopsy are the vastus lateralis (quadriceps femoris) and the gastrocnemius
• In biopsy, we use: H&E stain: Hematoxylin & Eosin, and Immunohistochemical stain

Question 18

Describe the microscopic photo of a muscle biopsy of a DMD patient

Answer 18

1) Increased number of nuclei

2) Different muscle fiber sizes

3) Internalization of nuclei (some nuclei are inside the cells instead of staying at the periphery “it denotes muscle fiber regeneration”)

4) At late stages the spaces between the muscle fibers will increase

Question 19

GENERAL REFER TO SLIDE 25 THE DR WILL GET FROM THOSE PICS

Answer 19

YOU CAN SEE NUCLE INTERNALIZATION IN PIC3 BY H&E STAIN INDICATING DMD

Question 20

Describe the immunohistochemistry done for muscle biopsies

Answer 20

• A technique done on muscle tissue where it is placed on the slide, then the physician orders for Duchenne protein

1) Add Duchenne antibody to check for problems in the Duchenne protein (antigen)

2) Add a counter stain (hematoxylin “purple in color”) for better view

• If there was a brown pigmentation in the periphery it is +ve for the dystrophin protein
• If the brown pigmentation is not present then it is -ve for the dystrophin protein

1) Complete absence of the brown color = DMD

2) Partial absence of brown discoloration = BMD

• Physicians report the color, intensity of color, and the localization of brown pigmentation (normal in the periphery, as Duchenne protein is present in the sarcolemma of the membrane, abnormal if the brown color was not at the periphery)

Question 21

What is the standard care for DMD patients?

Answer 21

• There is no medical cure nor a method for slowing it
• We can treat the complications and improve the life quality of the patient by:

1) Neurologist or pediatric neurologist

2) Rehabilitation Specialist

3) Pediatricians

4) Primary care physician

Question 22

Describe the prognosis of DMD

Answer 22

• Poor prognosis, mostly
• Death usually occurs at 18-20 years due to:

1) Respiratory failure

2) Heart failure

3) Pneumonia

4) Aspiration

5) Airway obstruction

Question 23

What are the complications of DMD?

Answer 23

1) Mental impairment

2) Cardiomyopathy

3) Lung failure (most common and fatal)

4) Contractures (shortening and hardening of muscles, tendons or other tissues)

5) Decreased mobility