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Flashcards in 2 - Muscular Dystrophy Deck (34):
1

7

Difference between congenital myopathy and muscular dystrophy?

  • Congenital myopathy - affects contractile apparatus, static changes
  • Muscular dystrophy - affects supporting structures, progressive changes

2

7 What is the Z disc?

I band?

A band?

  • Z disc - actin attached
  • I band - only actin
  • A band - overlapping actin and myosin
  • H zone - only myosin

3

8 Features of the dystrophin gene?

  • X-linked
  • Second largest gene - 79 exons, 2.4Mbp
  • Mutations cause DMD and BMD

4

8

Features of the dystrophin protein?

  • Several isoforms due to large DMD gene (predominant is in skeletal and cardiac 427kDA)
  • 4 domains - N-terminal binds actin, middle rod w/spectrin, cysteine-rich, C-terminal assembles DAPC

5

8

What are the different genetic causes of DMD?

  • Nonsense mutations - 15% of DMD, MLPA does not pick
  • Frameshift mutations - 65% of DMD, MPLA picks
  • In-frame deletion - BMD
  • Duplications - 5% of DMD, MPLA picks

6

8 What is the function of dystrophin?

Dystrophin loss?

  • Links actin cytoskeleton to ECM via DAPC
  • Sarcolemma fragility, Ca2+ homeostasis lost --> inflammation

7

8 How is DMD genetically detected?

  • Multiplex PCR - selected exons
  • MLPA - all exons within gene, detects 2/3

8

8 What are the pathological changes of muscle in DMD?

  • Immunohistochemistry - reduced sarcoglycans and aquaporin 4
  • Early changes - phagocytosis and necrosis
  • Late changes - increased connective tissue, variable fibre size

9

9 What are the clinical presentations of DMD?

  • Multiple systems
  • Delayed motor milestones
  • Gait difficulties
  • Gowers' sign - proximal weakness, climbing up legs
  • Fatigability and falls
  • Muscle enlargement
  • Speech delay and learning problems

10

9 How is DMD diagnosed?

  • Serum CK level - DMD>10000 IU/L
  • Thyroid function tests
  • Genetic testing - MLPA and sequencing
  • Muscle biopsy - necessary in 1/3 if no sequencing

11

9 What is the natural history of DMD?

BMD?

  • 3-6 yrs - honeymoon
  • 8 yrs - difficulty climbing stairs, walking
  • 10-13 yrs - wheelchair
  • Late teens-early 20s - respiratory or cardiac failure
  • About 25 yrs - death usually caused by respiratory issues
  •  
  • Onset >5yrs, progressive limb-girdle weakness
  • Can walk until 15 yrs
  • After 4th decade - respiratory failure

12

9

Describe the DMD respiratory deficit.

  • Weakness of intercostal muscles then diaphragm
  • Vital capacity increases (childhood) then plateaus (teens), finally respiratory failure (early 20s)
  • Restrictive lung disease (reduced expansion, lower TLC) - worst in sleep due to lower respiratory muscle tone
  • Pump failure - atelectasis, pneumonitis

13

9

Describe cardiac involvement in DMD.

  • Dilated cardiomyopathy --> conduction defects
  • Decreased left ventricular contractility, occasional cardiac failure

14

9

Describe orthopaedic involvement in DMD.

  • Toe-walking
  • Contractures in achilles tendon and ITB
  • Scoliosis

15

9

Describe CNS involvement in DMD.

  • Static cognitive impairment
  • 1SD shift in IQ
  • Multifactorial - dystrophin in brain, psychosocial issues

16

10

How are muscular dystrophies classified?

  • Age of onset
  • Pattern of weakness
  • Pattern of inheritance
  • Involvement of other systems
  • Specific abnormalities on muscle biopsy
  • Causative gene

17

10

What is myotonic dystrophy?

  • Autosomal dominant
  • Proximal and distal weakness
  • Myotonia
  • Cognitive deficits
  • Smooth and cardiac effects

18

10

What are the different phenotypes of myotonic dystrophy?

  • Congenital - severe, respiratory failure
  • Classic - most common, muscle weakness
  • Mild - cataract and mild weakness

19

10

What is the molecular pathogenesis of myotonic dystrophy?

  • Expanded CTG trinucleotide repeat in DMPK gene
  • Normal 5-35
  • Pre-mutation 35-49
  • Fully penetrant >50 - DM1

20

10

RNA in myotonic dystrophy?

  • Mutant RNA induces symptoms - RNA CUG expansions, bind MBNL1 and CUGBP1
  • MBNL1 sequestered
  • CUGBP1 upregulated
  • Embryonic isoforms

21

10

What are limb-girdle muscular dystrophies?

  • Progressive muscle weakness and hypertrophy, proximal first
  • Respiratory and cardiac involvement

22

10

How are LGMDs classified?

How is it diagnosed?

  • Pattern of weakness
  • Inheritance
    • Recessive - 2
    • Dominant - 1
    • X-linked - EGMD
  • Similar to DMD

23

10

What is facioscapulohumeral muscular dystrophy?

  • 3rd most common
  • Dominant
  • Facial weakness, scapular winging, proximal arm weakness

24

10

What is the genetic basis of FSHD?

Likely inappropriate expression of DUX4 gene

FSHD1 - 95% 1-10 D4Z4 - D4Z4 repeat sequence - epigenetic repression of DUX4

FSHD2 - 5% mutation in SMCHD1

25

11

How can DMD patients maintain ambulation?

  • Prevention and treatment of contractures (cause toe-walking, progressive) - physiotherapy stretching, splints, surgery
  • Exercise - aerobic, avoid high-intensity strength training

26

11

What medical therapy is available for DMD patients?

  • Corticosteroids - mechanism unknown
    • improves strength and survival
    • cushingoid features
    • osteoporosis
    • psychosis
    • adrenal suppression
  • Nutrition - calcium and vitamin D for osteoporosis
  • Endocrine

27

11

How is anticipatory monitoring conducted for DMD patients?

  • Management of learning disability
  • Spinal monitoring
  • Respiratory function
  • Cardiac involvement - ACE inhibitors and beta blockers
  • Bone health
  • Adult issues

28

11

Steroidal effect on spine?

How is spinal monitoring conducted for DMD patients?

  • No steroids - more likely scoliosis
  • Steroids - more likely vertebral fractures
  • Not walking - X rays, spinal curve over 25d, VC over 30% predicted
  • Spinal fusion - straightens spine, eliminates pain of vertebral fractures, slows decline of deformity and respiratory

29

11

How is respiratory function managed for DMD patients?

  • Nocturnal assisted ventilation - positive pressure
  • Pulmonary function tests less 60 - SDB less 40 - nocturnal

30

12

What 3 treatment options are available for MD?

  • Gene repair or replacement
  • Upregulation of compensatory proteins
  • Blocking downstream effects

31

12

How can gene repair or replacement be carried out?

  • Cell replacement - myoblast transfer therapy (no objective benefit) or stem cell therapy (trials, little benefit)
  • Gene replacement - microdystrophins using vectors
  • Nonsense mutation suppression - Ataluren induces dose-dependent read through of stop codons, not statistically significant
  • Targeted exon skipping - antisense oligonucleotides (eterplisen approved)

32

12

How can upregulation of compensatory proteins be carried out?

  • Utrophin is an autosomal homologue of dystrophin
  • DMD - upregulated and expressed in sarcolemma
  • Ezutromid - oral, clinical trials

33

12 What downstream effects can be targeted?

  • Ca influx
  • Fibrosis
  • Inflammation

34

12

What is CRISPR-Cas9 mediated genome editing?

  • AAV vector
  • Single guide RNA targets DNA sequence
  • Cas9 nuclease cleaves to restore reading frame
  • Mice studies