Lecture 11: Duchenne Muscular Dystrophy (an X-linked disease) Flashcards
1
Q
Summarise what is muscular dystrophy
A
- Genetic disease affecting skeletal muscles
- Characterized by progressive muscle weakness and wasting, and loss of motor skills
- X-linked recessive most common: Duchenne and Becker (Becker is less severe)
- More than 1 in 3500 males born
- Onset age from infancy to adulthood
- Most end up wheelchair-bound
2
Q
Define DMD
A
- The most common of several childhood muscular dystrophies
- An inherited disorder X-linked recessive with progressive degeneration of muscle
- Onset is generally before age 6 years
- Muscle loss usually not noticed until observation of unusual walking and/or talking around the age of 3
- > parents spot issue first by comparing to siblings= allows early detection
3
Q
State the incidence rates of DMD for men and women
A
- About 1 in every 3,500 to 5,000 males is born with DMD
- rarer for women
4
Q
Describe the phenotype of female carriers of DMD
A
- Much rarer in females
- > experience some symptoms: weaker muscles in the back, legs and arms that fatigue easily
- > Carriers may have heart problems, shortness of breath or failure to do moderate exercise
- heart problem picked later on in life or undetected
- they try to avoid exercise-> because symptoms
- > Untreated heart problems, can be serious, even life-threatening
5
Q
State the cause of DMD
A
- DMD caused by a mutation in the gene that produces an important muscle protein called dystrophin
6
Q
Describe what dystrophin is
A
- Muscles are made up bundles of muscle fibres
- Interdependent proteins along the membrane surrounding each fiber- keep muscle cells working properly
->dystrophin is an interdependent protein - Dystrophin acts as a spring
- When dystrophin missing = DMD
Constant muscle contraction/ relaxation → weaken & destroys muscles
7
Q
Explain the different types of muscular dystrophy
A
- Becker muscular dystrophy - inability to produce functional dystrophin
- Dystrophin: not 100% non-functional
- Limited function = less severe
- Duchenne muscular dystrophy – inability to produce dystrophin
- No dystrophin production or production of only non-functional dystrophin
- No function = more severe disease
8
Q
When do you suspect DMD and what are the ways of diagnosis
A
When:
- if no family history of MD -> when not walking by >16-18 months
- > Gowers’ signs
- if pos. family history of MD-> any abnormal muscle function
- patient has unexplained increase in transaminases
Screening:
- creatine kinase
- > conc. high= more testing
- > conc. low= another diagnosis
Confim diagnosis:
- testing for mutation found
- muscle biopsy to see if dystrophin protein absent
- gene sequencing if both test before doesn’t give results
Pos. result- confirmed
dystrophinopathy diagnosis
9
Q
Explain what happens after post-diagnosis
A
- Muscle biopsy is optional -may distinguish DMD from milder phenotypes
- Referral to specialist multidisplinary follow-up is required
- Genetic counselling needs to be offered to any ‘at risk’ female family members
- Patient and family support and contact with patient/family support organisations should be offered
10
Q
Give the clinical features of DMD
A
- Early onset: signs appear before 6 years of age
- Delayed development of motor skills
- Difficulty in keeping balance
- Progressive muscle weakness/fatigue
- Respiratory muscles eventually involved in muscle weakness and fatigue
- Pseudohypertrophy- enlargement of muscle tissue because it’s abnormal
- Contractures- when elastic tissue of muscle is replaced by non-elastic tissue, making them remain too tight for too long and become shorter
- Wheelchair dependent by early teens
- Death usually in late teens, early twenties
11
Q
Give the symptoms of DMD
A
Early - Delayed Onset Walking - Difficulty in performing a standing jump - Waddling when walking (like penguin) - Difficulty standing up - Enlarged Calves-> pseudohypertrophy ( swollen due to muscle damage) Later - Difficulty getting up from a chair - Loss of ability to climb stairs - Wide gaited walk with balance problems
More symptoms
- Fatigue
- Mental retardation
- Muscle weakness: begins in legs and pelvis, less severe in arms, neck
- Poor motor skills (running, hopping, jumping)
- Frequent falls
- Rapidly worsening weakness
- Progressive difficulty walking by age 10 may need braces soon after most confined to wheelchair
12
Q
Describe and explain what the Gower Manoeuvre is
A
- Used to detect DMD
- Uses more of upper body muscle than lower to stand-> sign of DMD
- Immediate response-> roll over to use hands
- Wide gait present throughout manoeuvre
- Affected boys stand up by bracing their arms against their legs because of the weakness in the proximal muscles
13
Q
Give the potential Complications of DMD
A
- Scoliosis – Curvature due to contractures and muscle weakness
- Cardiac
– Dilated cardiomyopathy
– Arrhythmia, shortness of breath and fatigue - Respiratory
– Progressive weakening of the diaphragm
– Pneumonia or other respiratory infections leads to:
– Respiratory failure - Cognitive impairment (non-progressive)
- Permanent, progressive disability
- Decreased mobility
- Decreased ability to care for self
- Individuals affected by DMD killed by failure of the heart muscles usually by age 25
14
Q
Explain how muscle histology is used to diagnose DMD
A
- Histology of normal (A) and DMD (B) muscle biopsies
- Stained by H&E
A: - Myofibers uniform size
- evenly space
- polygonal (uniform shape)
B: - increased size variation - due to atropy and hypertropy
- necrosis
- fibrosis
- fatty replacements
- Muscle biopsies (brown stain)
- Stained with antibody against dystrophin
Normal: - Regular cellular architecture
- dystrophin on all outer membranes
DMD: - Irregular architecture
- dystrophin absent from surface of muscle fibers
Carrier: - Biopsy from a female carrier of DMD
- patchy staining around outer cell membranes
15
Q
How can DMD be inherited
A
- female carriers
-> because they have offspring who are affected or carriers
-> obligate carriers of the disease gene
x-linked recessive
