cytoskeletal dieases Flashcards
What are two dieases related to cytoskeleton?
- Hemolytic anemia
- fragile cytoskeleton of RBC
- Leads to Anemia (can be lethal)
- Muscular DYstrophy
- Duchenne (comple absence of cytoskeletal protein dystrophin)
- Becker dystrophin is abnormally made
What is a hemolytic anemia?
- Premature death of RBCs
- Result from abnormally shortened RBC lifeSpan
- systemic hemolysis
- Release of RBC products
- Hemoglobin
- heme
- FE
What is hereditary spherocytosis?
spherical and fragile RBC that lyse and release hemoglobin
Clinical presentation: hemolysis, anemia, splenomegaly
mutations in genes for the erythocyte membrane skeleton of RBC
most common in people of northern european descent (1/2000)
What is the osmotic fragility test?
- Test that determines if your RBC show signs of HSnfew drops of blood are place into a hypotonic solution
- water rushes in to RBC
- Normal cells swell not break
- HS cells will swell and bevause they are fragile will break releasing hemoglobin (solution turns pinkish red)
- mostly a defect in spectrin and ankyrin causes mutation in EMS
What is nan Mutation ?
Not a mutation in cytoskeletal protein
Nan is a mutation in a DNA binding protein called Kruppel-like factor 1 of klf1
This DNA binding protein targets are all the Erthyocyte Membrane Skeleton genes
what is Klf1?
- KRUppel like factor 1
- 3 exons that encode 3 zinc finger domains
- MOUSE MUT
- Nan mutation of GAA to GAT or (GlU to ASP)
- ARG-GLU-ARG (R-E-R) to ARG-ASP-ARG (R-D-R)
- GLUTAMIC ACID (E) TO ASPARTIC ACID (D)
- THiS R-E-R DNA binding motif is highly conserved in KLF1
- ARG-GLU-ARG (R-E-R) to ARG-ASP-ARG (R-D-R)
- Nan mutation of GAA to GAT or (GlU to ASP)
- In MAN, you see ACT to ATT (different mutation than mice thats more upstream)
KLF1 mutation most likely causative of HS
What are treatements for HS ?
Blood transfusions
Splenectomy (removes spherpcytes from circulation)
Increase RBC # and Hb
What are two types of musclar dystrophies?
Duchene Muscular dystrophy
Becker musclular Dystrophy
What is Duchenne Muscular Dystrophy?
- DMD most common fatal neruro musclar fatal disorder
- loss of ability walk - wheel chair bound by 12
- Loss of lung and cardiac finction (respitiory failure and cardiomyopathy =death)
- chronic hypoxia - respiratory
- Scoliosis
- No cure
- no treatment
improvement of quality of life
glucocortidcoid (prednisone) slow decline in muscle strength
physio therapy
physical aids (wheel therapy)
Respitory assistance
Patients live into their 20s
What is DMD from a genetics perspective?
X linked recessive
gene mutation causing a mutation in dystrophin
present at birth but not appartent until 3yrs
assocated with Frame shift mutations
WHat is Dystrophin Protein?
- N terminus binds to ACTIN
- Long spectrin like repate domain: binds to cytoskeleta; portion of Dystrophin proteins
- Cysteine Rich and C terminus domain
- Bind to syntrophin proteins ( linking)
- Bind to dystro/sarco glycans
- MAIN function to provide structural stabiltiy to sarcolemma
- Its gene is at Xp21.2
- 1.5% of X chromsome
What the clinical signs of DMD
Dystrophic myopathy = progressive muscle degeneration with loss of functional muscle = weakeness
Elevated creatine kinase (CK) in bloood
Necrosis of muscle fiber and replacement with connective (adipose and fibrous) tissue = pseudohypertrophy
- Waddling run/walk
- Difficulty in climbing steps
- Use of handrail to pull
- Walk on tiptoes
- Lordosis: excessive inward curvature
- Kyphosis: upward back curvature outward
- Scoliosis
- Frequent falls
- Gower maneuver “walking up legs”
EMG (eletromyography (EMG) test used to recod the eletrical activity of muscles
CRDs = complex repetitive discharges - abnormal spontaneously firing action potentials assocaiated with membrane instability
What is beaker muscular Dystrophy?
- BMD milder former than Duchenne
- Incidence is 1/18000
- milder form of DMD
- loss of walking after 16 years
- muscle pain, dilated cardio myopathy
- BMD: increased workload on left ventricle leads to left ventricular enlargement -> heart failure and death
What are genetic characteristics of BMD?
associated with in frame mutations , Ex: deletion of G
X linked recessive
DMD sever while BMD milder
BMD abnormal size and quanitity of dystrophin made
How do DMF and DMD vary phenotypically?
Mail walking at 16 years and average life span 45 - BMD
Wheel chair bound by 12 and average life span is 25 - DMD
