Progressive muscular dystrophies

Question 1

Types

Answer 1

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive diseases,
== only male individuals affected in DMD and BMD

limb-girdle muscular dystrophy (LGMD) may be either autosomal dominant or recessive,

facioscapulohumeral dystrophy (FSHD) is usually autosomal dominant.

Question 2

DMD vs BMD

Answer 2

DMD is the most severe form of muscular dystrophy, with disease onset typically occurring at two to three years of age - dystrophin is absent. BMD usually does not become evident before the age of 15 - reduced dystrophin. DMD progresses rapidly and typically leads to ambulatory inability by age 12.

Age of onset
DMD: 2–5 years
BMD: adolescence or early adulthood, usually > 15 years
Incidence
DMD: 1/3500
BMD: 1/30,000

Question 3

Gene

Answer 3

dystrophin gene on the short arm of the X chromosome (Xp21)
DMD: frameshift deletion or nonsense mutation → shortened or absent dystrophin protein
BMD: in-frame deletion → partially functional dystrophin protein

anchors the cytoskeleton of skeletal and cardiac muscle cells to the extracellular matrix
disturbance of numerous cellular signaling pathways → necrosis of affected muscle cells → replacement with connective tissue and fatty tissue → affected muscles are weak even though they appear larger (“pseudohypertrophy”)

Question 4

symptoms DMD

Answer 4

Progressive muscle paresis and atrophy
Starts in the proximal lower limbs (pelvic girdle)
Extends to the upper body and distal limb

Weak reflexes
Waddling gait (i.e., Duchenne limp) with bilateral Trendelenburg sign

Gower maneuver:
The individual arrives at a standing position by supporting themselves on their thighs and then using the hands to “walk up” the body until they are upright.
Classic sign of DMD,
Calf pseudohypertrophy
Dilated cardiomyopathy: common cause of death
Cardiac arrhythmias
Respiratory insufficiency

Question 5

BMD symptoms

Answer 5

Less severe, slower progression

Question 6

Dx

Answer 6

Increased CK,
Genetic
Muscle biopsy

Question 7

Facioscapulohumeral muscular dystrophy (FSHD)

Answer 7

progressive muscle weakness of the face, scapula, upper arm
AD~70%
Deletion of D4Z4 repeat unit
Progressive muscle weakness
Onset usually in childhood and adolescence
Asymmetrical involvement
Affects the face, scapula, and upper arms
Less commonly, the girdle and/or lower leg can be involved
Extramuscular manifestations: retinal vasculopathy, hearing loss

Question 8

Limb-girdle muscular dystrophy (LGMD)

Answer 8

progressive muscle weakness that primarily affects the pelvic and shoulder girdle
autosomal dominant (LGMD1) or autosomal recessive (LGMD2)
Fourth most common muscular dystrophy (after dystrophinopaties, myotonic dystrophy, and FSHD)
Onset in childhood or adolescence

Paresis and subsequent atrophy of the pelvic and shoulder girdle muscles
Normal intellect and absent distal muscle weakness

Question 9

Diff dx

Answer 9

Polymyositis
Spinal muscular atrophy
Myotonic syndromes

Question 10

Tx

Answer 10

Supportive
DMD:
Glucocorticoids (e.g., prednisone, deflazacort)
Eteplirsen - in individuals with mutations within exon 51 of the dystrophin gene (An antisense oligonucleotide)