Lecture 27: Muscular Dystrophy

Question 1

Define muscular dystrophies.

Answer 1

• Group of genetic disorders of muscle characterised by progressive weakness and degeneration of the skeletal or voluntary muscles which control movement
• Number of different types: Duchenne muscular dystrophy (DMD) => most severe and most common

Question 2

Recall the symptoms of DMD.

Answer 2

Question 3

Recall the causes of MD symptoms.

Answer 3

• Increasing proximal limb muscle weakness due to progressive muscle degeneration
• Caused by pathogenic variant in a gene encoding a muscle protein called dystrophin
• Dystrophinfound in all muscle (located at sub sarcolemma) and brain
• Forms link between actin (cytoskeletal) and extracellular matrix

Question 4

Describe DAPC and mention its function.

Answer 4

Question 5

Recall the effects of dystrophin deficiency/dysfunction.

Answer 5

Question 6

Recall the consequences in DMD.

Answer 6

Question 7

Compare Duchenne and Becker MD.

Answer 7

Question 8

Recall the inheritance of MD.

Answer 8

Question 9

Recall dystrophin gene and protein.

Answer 9

Question 10

Duchenne mutations disrupt the reading frame and cause ______________________ –mRNA usually degraded. Becker mutations cause the reading frame to be intact resulting ___________________.

Answer 10

Duchenne mutations disrupt the reading frame and cause premature termination of protein and non-functioning protein –mRNA usually degraded. Becker mutations cause the reading frame to be intact resulting in a shorter but partially functional protein.

Question 11

How are DMD and BMD diagnosed?

Answer 11

• Creatine kinase(blood) –a screening test
  
  • Skeletal muscle isoform of creatine kinase levels are elevated in serum (20 to 50x)
  • Normal range: 40-240 U/L
• Pathology of a muscle biopsy (‘gold’ standard –but now only done if DNA testing does not provide a result)
• DNA tests – Tests look primarily for deletions (PCR, MLPA, chromosomal microarrays); sequencing (NGS) for other mutations

Question 12

Recall histology and immunocytochemistry of DMD muscle.

Answer 12

Question 13

Recall immunocytochemistry of BMD muscle.

Answer 13

Question 14

Recall previous methods of DNA diagnosis of DMD/BMD.

Answer 14

Question 15

Describe the role and limitations of MLPA in DMD/BMD diagnosis.

Answer 15

Question 16

Describe the features of MLPA probes.

Answer 16

Question 17

Recall about DMD gene sequencing.

Answer 17

Question 18

Recall future therapies for MD.

Answer 18

r