lecture 33

Question 1

What causes DMD?

Answer 1

• loss of dystrophin

Question 2

What is the mouse model for DMD?

Answer 2

mdx

Question 3

What are dystrophinopathies?

Answer 3

• DMD
• BMD
• familial cramps and myalgia syndrome
• other
  → x-linked dilated cariomyopathy
  → isolated elevated CK
  → manifesting carrier females
  → isolated quadriceps myopathy

Question 4

What is the onset/incidence/diagnosis of DMD/BMD?

Answer 4

DMD: onset 5 years
- incidence 1/35,000 male birhts
- clinical onset variable
→ wheelchair dependency > 16 years

Question 5

What are the clinical presentations of DMD?

Answer 5

• delayed motor milestones
  → mean age walking 18m (normal s manoeuvre
  → persistent toe-walking, (less commonly) flat feet
• fatigability, frequent falls
  → inability to run or to keep up with peers
• calf/thigh cramps, muscle hypertrophy
• speech delay, learning problems

Question 6

What do you see in physical examination of a patient with DMD?

Answer 6

• waddling gait
• proximal weakness
• enlarged, rubbery muscles
  → calves +/– quads, gluteal, deltoid, even tonuge
  → early hypertrophy, late pseudohypertrophy
• facial muscles spared
• extra-ocular muscles always spared
• weak neck flexors
• lumbar lordosis
• usually never had the ability to jump

Question 7

What is muscle hypertrophy?

Answer 7

• muscles look larger but infact this apparent enlargement is due to increased fat and fibrosis rather than an increase in true muscle tissue i.e. ‘pseudohypertrophy’

Question 8

What is gowers’ sign?

Answer 8

• has to roll over
• pushes up
• walks up knees with hands
• important neurologic sign
• climbing up legs on arising from ground
• indicative of proximal weakness in older children (>4 years)
• normal in younger children <3 years
• non-specific i.e. seen in any muscle disorder causing proximal weakness
  → DMD, BMD
  → myotonic dystrophy
  → congenital myopathies
  → muscle disorders of adulthood including steroid myopathy

Question 9

What is muscle atrophy?

Answer 9

• thinned muscles

Question 10

How is DMD diagnosed?

Answer 10

• serum creatine kinase level
  → enzyme released by damaged muscle cells intp blood
  → normal 10,000
• thyroid functiont ests (blood)
  → hypothyroidism can look very much like DMD
• genetic testing by MLPA for DMD
  → positive in 65-70% of cases
  → deletions 65%, duplications 5%, point mutations 10-15%
• muscle biopsy
  → high suspicion of DMD, genetic tests are negative
  → necessary in about 1/3 of cases

Question 11

What is seen regarding serum CK levels?

Answer 11

normal (100 U/L)

• congenital muscular dystrophies
• FSH MD
• Duchenned and Becker MD
• limb girdle MD

very broad differential diagnosis

Question 12

What is the natural history of DMD?

Answer 12

3 - 6 years: ‘honeymoon’ phase

• mild weakness but overall strength and function may increase
• increasing disparity between affected child and his peers

8 years: difficulty climbing stairs, walking

• increasing fatigability, inability to run and jump
• increasingly prominent lumbar lordosis
• progressive contractures Achilles, ITBs, hips

~10-13 years: transition to wheelchair use

respiratory or cardiac failure late teens - early 20s

Question 13

What is the course of DMD?

Answer 13

• some variability in course
• ambulation lost anywhere between 8-14 years
• gradual decline in upper limb function: difficult bringing hands to mout by 16-18 years
• death average approx 25 years
• death is usually from respiratory failure
• cardiac death in about 10%: cardiomyopathy or arrhythmias

Question 14

What is the natural history of Becker MD?

Answer 14

• onset after age 5 years
  → commonly 5 - 15 years
  → occasionally as late as 3rd or 4th decade
• progressive limb-girdle weakness
• calf pain and myalgias common
• able to walk after 15 years
• respiratory failure after 4th decade
• cardiomyopathy is MORE common than in DMD
  → greater strain caused by greater exercise and activity

Question 15

What is the respiratory deficit in DMD?

Answer 15

• weakness of intercostal muscles > diaphragm
• in the early years, vital capacity increases with age and growth
• in the early teens, vital capacity plateaus ajnd then declines steadily (5-10%/year)
• resipiratory failure typically occurs in the late teens or early 20s

Question 16

What is sleep-disordered breathing?

Answer 16

• muscle weakness causes restrictive lung disease
• in all neuromuscular disorders, respiratory muscle function is worst sleep
  → decreased respiratory muscle tone and central drive
• sleep disordered breathing (SDB) is worst in
  → REM sleep and disorders affecting diaphragmactic function
• may manifest with sleepiness, headache etc
  → fatigability, poor exercise tolerance, poor school performance
  → symptoms relate to CO2 retention, not to hypoxia
  → does not cause shortness of breath or cough
• progresses to nocturnal/daytime hypoventiliation
• early recognition enables appropriate treatment

Question 17

What is obstructive lung disease?

Answer 17

• increased resistance to airflow due to parital or complete obstruction at any level (trachea, bronchi, terminal or respiratory bronhcioles)
• lung function tests show decreased maximal airflow rates during forced expiration, usually measured by forced expiratory volume in 1 sec (FEV1)

Question 18

What is restrictive lung disesase?

Answer 18

• reduced expansion of lung parenchyma and decreased total lung capacity (TLC), an an expiratory flow rate that is normal or reduced proportionally to TLC
• restrictive defects occur int wo general conditions
  1) chest wall disorders e.g. neuromuscular diseases, severe obesity, kyposcoliosis
  2) chronic interstitial and infiltrative diseases e.g. pneumoconioses and interstitial fibrosis

seen in DMD

Question 19

What do you see in advanced DMD re: respiratory deficit?

Answer 19

• progresses to nocturnal/daytime hypoventilation
• nocturnal hypoventiliation and hypoxia: severe SDB
• development of atelectasis, pneumonitis
  → pump failure - poor inflation and emptying of lungs
• loss of respiratory reserve correlates with severity of kyphoscoliosis
  → scoliosis is caused by weakness of paraspinal muscles
• diaphragm relatively spared till late in disease

Question 20

What is cardiac involvement in DMD and BMD?

Answer 20

• dilated cardiomyopathy > hypertrophic > conduction defects
• cardiomyopathy
  → decreased left ventricular contractility, occassional cardiac failure
  → commonly asymptomatic/subclinical
  → 1/3 teenage years, 1/2 by 18 years, all > 18 years
  → symptoms often minimal until late owing to musculoskeletal limitations
• myocardial fibrosis, sinus tachycardia, ectopic rhythms
  → 90% abnormal ECG
• cardiac death in 10% of cases
• cardiomyopathy more common in becker MD

Question 21

What is the orthopaedic involvement in DMD?

Answer 21

• early toe-walking common
• achilles tendon and iliotibial band (ITB) contractures
• progressive contractures: hips, knees, elbows, wrists
  → more problematic after wheelchair-bound, immobile
• scoliosis
  → increases rapidly after non-ambulant

Question 22

Does scoliosis repair improve respiratory function?

Answer 22

• no

- only stabilises

Question 23

What is the CNS involvement in DMD?

Answer 23

• non-progressive (static) cognitive impairment
  → affects verbal > performance IQ
  → mean IQ shifted 1SD, approx 80 (normal 100)
  → no good correlation with location of deletions
• two major types
  → reduced verbal IQ
  → reduced total IQ < 80
• occasional autism
• increased ADHD

Question 24

What are cognitive issues in DMD?

Answer 24

• degree of cognitive involvement is variable:
  → 1/3 significant learning difficulties
• selective impairment of verbal working memory skills leads to increased risk or learning difficulty
• greater difficulty remembering stories, difficult manipulating verbal information that requires immediate memory storage, difficulty with comprehension
• profile similar in subjects with DMD regardless of whether high or low intelligence

Question 25

What are possible multifactorial contributes to cognitive problems in DMD?

Answer 25

- altered dystrophin expression in brain → static intellectual deficits - effect of chronic illness → school absences - psychosocial effects → anxiety → depression → behavioural problems (increased by steroids) - effect upon family → parental expectations → parental mood problems

Question 26

Summary of clinical findings?

Answer 26

- boys appear relatively normal for first few years of life - then: rapid loss of muscle strength and function - multiple systems involved → musculoskeletal → respiratory → cardiac → cns → orthopaedic - management must address all affected systems