Muscular Dystrophy Flashcards
The M line anchors ________ and the Z disc anchors _________.
M line: myosin
Z disc: actin
What is the fundamental thing that Becker and Duchenne muscular dystrophies share?
They both arise from dystrophin mutations.
They are both dystrophinopathies
How would you very quickly describe Duchenne MD?
Inherited, progressive neuromuscular disease.
X-linked recessive.
What is the most common form of MD?
Duchenne
What is the frequency of DMD in the male population?
1/3500 males
What is the prognosis for DMD?
Variable progression but typically palliative by age 20-25.
DMD appears at about age _____, but ________
2-3 years onset,
4-5 years for diagnosis (more time for muscles to develop and healthy milestones to be missed).
The gene for dystrophin is located at _____
Xp21.2
What’s the first thing noticed on onset with DMD?
Weakness in the calves
How big is the dystrophin gene?
Massive - 2.5Mbp, 79 axons.
What’s F-actin?
Just the filamentous form of actin. Not complicated.
Without proper anchoring of dystrophin to DAPC, what’s the problem?
The contractions create acute (transient) sarcolemma ruptures, which allow for Ca2+ influx.
What MD pathophysiological problem is related to signalling?
DAPC has a signalling role; when it’s disrupted, muscle fibres fail to regenerate. This is an important to the progressive aspect of the disease.
What is a biochemical blood marker for DMD and where does it come from?
Creatine Kinase - leaks out of the cell like calcium leaks in.
What is creatine kinase for?
Catalyses the formation of phosphocreatine - an energy store for muscles.
Why is it called calf PSEUDOhypertrophy?
Because the muscle tissue isn’t getting bigger - the size comes from infiltrations of fat and fibrotic tissue into the muscle.
What’s something apart from calcium fuckery that leads to necrosis?
Inflammatory response to the cell rupture.
What external physical symptom is the CLASSIC sign of DMD?
GOWER’S MANEUVER
As a short answer prompt: break down for me the three aspects of DMD diagnosis.
- Physical Examination
- Lab Diagnostic Techniques
- Family history
As a short answer prompt, break down the lab diagnostic techniques:
- Blood screening
- Gene testing
- Muscle biopsy
List the three major physical signs.
- GOWER’S MANEUVER
- Trendelenberg gait
- Missing physical/intellectual milestones (inc. late walking, toe walking, frequent falls, speech/difficulty hearing).
Which is the term for inability to stabilise the pelvis, resulting in a dropping away from the load-bearing leg and a leaning toward the load-bearing side to correct balance?
Trendelenburg Gait
Which is the term for a rolling into the prone position, widening of the base and “climbing up” the body to rise from a supine position?
Gower’s sign.
List four physical milestones and another buzzword for physical examinations that can tie them all together.
Pull-to-sit (not head lag)
Unsupported sitting/self-sitting
Gait
Running
Refer to the MOTOR DELAY ALGORITHM for advancement to lab testing (CK blood test).
What needs to test positive before genetic testing or a muscle biopsy?
Creatine kinase positive in the blood test.
Why might you check creatine kinase if there’s no family history?
Because he’s not walking or there’s Gower’s sign.
Gower’s sign is such a hallmark that they’ll go to a CK test even if…..
…. even if there’s no family history.
If there’s a family history they’ll check CK if …..
…… if there’s pretty much any suspicion of abnormal muscle development.
If we don’t know family history we might check CK if …
…. there’s abnormal blood transaminases (AST, ALT), which are part of routine blood tests.
Quickly, list three types of genetic DMD testing.
- multiplex PCR
- quantitative assay
- next-gen sequencing.
If you see someone’s 3yo kid doing the Gower sign and falls over a lot, what would I tell them in my capacity as an omniscient med sci undergrad?
Don’t say their kid’s got DMD. You’ll sound like an idiot to the doctor they go to.
Tell them not to fret until they have DNA testing results because DMD is a common thing to diagnose based on phys exam alone.
What does a healthy dystrophin-stained biopsy look like?
Nice, tiled, thin layers of connective tissue, relatively even size
What does a Becker’s MD slide look like compared to a DMD slide?
Beckers: relatively fucked
DMD: basically absent dystrophin.
What is gonadal mosaicism and why is it significant to screening algorithms?
Gonadal mosaicism refers to mutations in germline cells (not somatic cells), which are the cause of around 20% of all diagnosed cases.
So just because the mother and father tested double-negative doesn’t mean the offspring can’t inherit muscular dystrophy.
What is a manifest carrier?
There’s this thing called LYONISATION which is where X chromosomes are non-ramdomly inactivated (presumably to stop overdosing on X genes).
If this happens to a carrier, she can manifest symptoms of DMD.
How common are manifest carriers?
About 5% of female carriers;
About 2/3 of carriers have elevated CK.
What’s the only pharmacological treatment of DMD and what’s it’s down side?
What are they also often given?
Corticosteroids (e.g. prednisone) but the side effects are pretty significant and require constant monitoring.
They’ll often get NSAIDs too.
List 3 non-drug treatments for DMD.
Surgery
Physiotherapy & excercise
Diet & nutrition
What do we hope to achieve with current available treatments?
We basically can only hope to control the symptoms and the progression of muscle degeneration.
Short answer prompt: What’s the relevance of genetic counselling? (three headings)
- X-linked recessive
- Gonadal mosaicism
- Manifest carriers (lyonisation)
In what circumstances can DMD usually be diagnosed in the presymptomatic stage?
Family history or increased CK (NB the kid can’t walk yet)
A negative result for CK is a negative result for DMD. True or false?
True.
The NH2 terminus of dystrophin attaches to ________ and the COOH terminus attaches to DAPC.
Amino: F-actin.
Carboxy: DAPC.
65% of DMD mutations are……
5-15% are…
large intragenic deletions
large intragenic duplications
There are 8 experimental approaches. What are they?
Antisense oligonucleotides Aminoglycoside antibiotics (exon skipping) Stem cell therapy Myoblast transfusion Gene correction Gene addition Proteosome inhibition Upregulation therapy (utrophin)
What’s the idea of antisense oligonucleotides?
An antisense mRNA strand binds to the mutated region of an affected dystrophin immature mRNA, which modifies the exon phasing of the pre-mRNA and thus the exon content of the final gene. The result is still a defective dystrophin gene but MUCH MORE function retained than whatever fuckery was being caused by the original mutation, with an improved prognosis.
