DMD 1 and 2 Flashcards
What does DMD stand for
Duchenne muscular dystrophy
What is the lesser intense version of DMD
Becker’s disease (BMD)
What is DMD?
Progressive muscle wasting and weakness
What causes DMD?
Genetic mutation in the gene encoding protein dystrophin
Who does it affect?
Almost only boys, women carry mutated gene and may manifest mild symptoms
Purpose of dystrophin complex and associated proteins?
Maintain structure of sarcolema and myofibrils during contraction (dystrophin is the most important part of complex)
What is dystrophin?
One of the largest proteins and the largest gene.
What causes dmd and Beckers disease?
Mutation in dystrophin
What is the difference of DMD and Becker’s disease?
Nature of mutation and resultant affect on protein (but pretty same, just severity)
What kind of genetic disorder is DMD?
x-LINKED rd (the most common) and most common NMD of childhood
What gene is the mutation affect?
Xp21 (largest human gene)
How many cases are spontaneous?
1/3 cases
If the mother is a carrier of DMD what is the probability of kids affected?
50% chance (son affected, daughter carrier)
Onset and severity differences of DMD and BMD?
DMD is more sever and onset later
How do we diagnose DMD?
Family history, delayed motor and language milestones, clinical presentation of patient (progressive, symmetric, proximal predominant weakness and Gowers’ maneuver
What is Gowers’ maneuver?
A test to diagnose DMD, have child lay in supine position and ask to stand up
What else do you use to diagnose DMD?
Serum creatine kinase assay, genetic testing muscle biopsy and examination of dystrophin levels by immunflourensce and Western blotting
What is serum creatin kinase?
Serum to identify creatine kinase which is found in the muscle and blood, its an indication that the muscle is damaged and the enzymes are leaking in the blood
What are levels of Creatine kinase like in kids with DMD?
High
DMD disease at ages 5 o 7
motor delay, can walk, toe walking (enlagered calves)
DMD ages 8 to 11
increase loss of walking ability, part time wheel chair use
DMD early teens
Loss of ambulation, full time wheel chair, increasing loss of upper limb function
DMD Teens
Increasing respiratory impairments, ventilation support often required, unable to preform activities of daily life
DMD teens to twenties
cardiac dysfunction, heart failure, death
What does DMD affetct physiologically?
Skeletal, diaphragm and cardiac muscle
Is there a cure for DMD?
No
What is spectrin? And do you see it in DMD patients?
Protein found in sarcolemma, yes but very little
Do you see dystrophin in patients with BMB with immuoflorescence?
Not very much
Do you see dystrophin in patients with DMD?
No
What does western blotting of Dystrophin in DMD and BMB show?
Truncated dystrophin (smaller) in BMB
What anti-body can be used in immuoflorescence of DMD?
Dys 3 (recognizes the end terminal region of protein)
Using dys 3, dys 1 and dys 2 do you see dystrophin in DMD?
NO
Dys 1, 2 and 3 in BMB?
dYS 3 (end terminal) dytrophin looks the same as control (healthy), dys 1: 0
What areas do dys 1, 2 and 3 correlate to?
Dys 3 - n terminal, dys 2 - c terminal and dys 1: central rod
What does dystrophin in the n terminal and c-terminal in BMD patients mean?
Terminals are intact and dytrophin being expressed in sacrolemma
Where is utrophin localized?
in the NMJ of healthy muscle
How does utophin react to deficiency of dystrophin?
up regulation in the extrasynaptic regions along the sacrolemma (where dytrophin should be expressed)
Is the compensation of utrophin enough to prevent dystrophin?
No
What causes the muscle decline, in wasting and weakness of DMD?
Progressive deterioration of muscle quantity and quality (degeneration and regeneration cycle) regeneration fails
When regeneration fails, what is the muscle replaced by?
Adipose tissue and fibrous tissue
Explain the degeneration regeneration process
with injury, immune infiltration and inflammation digest damaged myofiber components, muscle stem (satellite) cells become more activated, proliferate and migrate to the injury site. Satellite cells fuse into the mytubes to form new myofibrils or fuse to and repair existing fiber. Hallmark of regenerating fibers are centrally located myonuclie (move to periphery when repaired)
What is RGC in the DAPC?
protein in cytosol that buffers calcium
Calcium hypothesis of DMD:
DAPC dissolution weakens sarcolemma & t-tubules, muscle surface susceptible to rupturing
• Pathophysiological Ca2+ influx and increased proteolytic destruction of myofiber components
• Impaired Ca2+ handling via voltage sensors (DHPR), Ca2+ release channels (RyR), Ca2+ pumps
(SERCA), and Ca2+ binding proteins (CSQ) occurs in dystrophic muscle
• Chronically elevated Ca2+ triggers destructive cycle of proteolysis and muscle degeneration
Other than muscles and tears where else does Calcium leak through?
Dysfunctional proteins such as TRPC and RGC has lower expression
What is the most common treatment for DMD?
Glucocorticoids (steroids)
What do Glucocorticoids do?
Target inflammatory pathways, reduce inflammation and suppress immune response
Main affects of Glucocorticoids?
Prolong early stages of DMD (early to late ambulatory)
How old and how often is Glucocorticoids given?
Around age 5 and every day
Symptoms of taking Glucocorticoids
disregulated glucose metabolism, weight gain, osteoporosis, hypertension, cataracts and changes in behaviours
Types of Glucocorticoids?
Deflazacort and prednisone
In a study with boys ages 5-15 over 52 weeks with DMD and is the similarities difference between deflazacort vs prednisone?
GC’s increased muscle strength vs. placebo, muscle strength was same between GC’s and DFZ associated with less weight gain than PRED.
When was deflazacort approved by FDA in the usa?
2017
How much dystrophin levels is required to increase survival and function?
Very modest levels
What percentage of dystrophin levels are sufficient to avoid muscular dystrophy in humans?
As low as 30%
What does the mdx mice mdx mice engineered to express
variable levels of dystrophin
demonstrate
15-30% normal levels result in prolonged survival and mild phenotype • ≥4% restoration of dystrophin significantly improved lifespan and pathology in mdx mice
in humans with DMD what does low dystrophin levels do?
They associate with milder dystrophinopathy, Dystrophin quantities of <5%, as low as <0.5%, associated with milder phenotype for most of
the clinical outcomes, including age at loss of ambulation, respiratory function, and survival (alive at 30 years old)
In these low levels is it full length or truncated dystrophin?
Truncated (with n and c terminals)
What did they see in Ringo and Suflair: dogs without dystrophin
• 2 GRMD dogs without dystrophin have markedly increased serum CK, histological markers of
degeneration/regeneration, but undetectable clinical signs of weakness & mild phenotype
• Ringo died of cardiac arrest at 11 years old, displayed normal lifespan of healthy GR dog
• Surprisingly, muscle utrophin content was not different versus typical GRMD dogs
Two brazillian brothers with DMD
• Two dystrophin-null patients with unexpectedly mild phenotypes • In exceptional cases, human muscle without dystrophin is functional Similar utrophin upregulation in discordant DMD brothers suggests milder course not due to increased utrophin
A novel dystrophin-independent therapeutic target for DMD: what is the gene they identified for the muscular dystrophy?
Jagged 1
What is Jagged 1 and where was it expressed more?
differentially expressed b/w affected and escaped (dmd not symptoms) dogs. Jagged 1 expressed more in escaper dogs
What animal did they use to test jagged 1 and why? What was the result?
Zebrafish because it is easy to manipulate their genome an they are see through, over-expressed jagged 1 - rescued fish
