lecture 33 Flashcards
1
Q
What causes DMD?
A
- loss of dystrophin
2
Q
What is the mouse model for DMD?
A
mdx
3
Q
What are dystrophinopathies?
A
- DMD
- BMD
- familial cramps and myalgia syndrome
- other
→ x-linked dilated cariomyopathy
→ isolated elevated CK
→ manifesting carrier females
→ isolated quadriceps myopathy
4
Q
What is the onset/incidence/diagnosis of DMD/BMD?
A
DMD: onset 5 years
- incidence 1/35,000 male birhts
- clinical onset variable
→ wheelchair dependency > 16 years
5
Q
What are the clinical presentations of DMD?
A
- 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
6
Q
What do you see in physical examination of a patient with DMD?
A
- 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
7
Q
What is muscle hypertrophy?
A
- 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’
8
Q
What is gowers’ sign?
A
- 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
9
Q
What is muscle atrophy?
A
- thinned muscles
10
Q
How is DMD diagnosed?
A
- 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
11
Q
What is seen regarding serum CK levels?
A
normal (100 U/L)
- congenital muscular dystrophies
- FSH MD
- Duchenned and Becker MD
- limb girdle MD
very broad differential diagnosis
12
Q
What is the natural history of DMD?
A
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
13
Q
What is the course of DMD?
A
- 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
14
Q
What is the natural history of Becker MD?
A
- 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
15
Q
What is the respiratory deficit in DMD?
A
- 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
16
Q
What is sleep-disordered breathing?
A
- 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
17
Q
What is obstructive lung disease?
A
- 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)
18
Q
What is restrictive lung disesase?
A
- 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
19
Q
What do you see in advanced DMD re: respiratory deficit?
A
- 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
20
Q
What is cardiac involvement in DMD and BMD?
A
- 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
21
Q
What is the orthopaedic involvement in DMD?
A
- 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
22
Q
Does scoliosis repair improve respiratory function?
A
- no
- only stabilises
23
Q
What is the CNS involvement in DMD?
A
- 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
24
Q
What are cognitive issues in DMD?
A
- 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
25
Q
What are possible multifactorial contributes to cognitive problems in DMD?
A
- 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
26
Q
Summary of clinical findings?
A
- 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
