White- Cyto Protein Defects Flashcards
Hemolytic Anemia
- Fragile cytoskeleton of RBC
- Leads to anemia (possibly lethal)
Muscular Dystrophy
- Duchenne - complete absence of cytoskeletal protein dystrophin
- Becker - dystrophin protein made but is unnatural
Life Cycle of RBC
Birth: Bone Marrow (2.4 million RBCs/sec)
Existence: In Circulation for 120 days
Death/Removal: Reticulo-Endothelial System (Spleen/Liver)
___ ___ result from abnormally shortened RBC lifespan. When the cells lyse what 3 products are released?
Hemolytic anemias
Hemoglobin, heme, Fe 2+
Hereditary Spherocytosis is a hemolytic anemia characterized by ___ and ___ RBCs that lyse and release ___.
Clinically it presents as ___, ___, or ___.
The clinical presentations can range from mild to severe anemia and can be fatal. It is caused by mutations in the genes for the ___ ___ ___ of RBCs.
spherical, fragile
hemoglobin
hemolysis, anemia, splenomegaly
erythrocyte membrane skeleton
Describe the osmotic fragility test and how it indicates a patient has HS.
Place a few drops of blood into slightly hypotonic saline. Water rushes into the cells by osmosis. Normal cells will swell but not break. Hereditary spherocytosis cells will swell and break releasing hemoglobin.
HS is the most common hemolytic anemia in people of ___ ___ descent. (1/2000)
At a local hospital, 120 HS patients are seen for yearly evaluation.
Northern European
What are the most common EMS mutations involved in HS?
**finding these genetic defects in mice lead to the discovery of them in humans
Spectrin/Ankyrin defect 63% Band 3 Defect 22% Protein 4.2 defect 3% Other defects 2% No Know Defect 10%
This is added when iron is not available fast enough to make good hemoglobin.
An Protporphyrin
Nan is a mutation in __ ___ protein called Kruppel-like factor 1 or Klf1. The targets of these proteins are…
Nan encodes 3 zinc finger domains (dna binding protein). The mutation is __ to __ or __ to __.
DNA binding protein
All the EMS genes
GAA-GAT
Glu-Asp
Treatments for HS
- Blood transfusions
- Splenectomy
- Increase RBC # and Hb
Duchenne Muscular dystrophy
Most common fatal neuoromuscular disorder.
Sever, progressive muscle degeneration.
Loss of ability to walk by age 12. Scoliosis.
Loss of lung and cardiac function.
Premature death (20-30)
No cure
X linked recessive caused by dystrophin gene mutations
The genetic defect is present at birth but is asymptomatic until about age 3.
Treatment for DMD
No treatment can significantly alter course of disease.
Maintenance of good mental health and QOL is important.
Glucocorticoids slow the decline in muscle strength. Effect is short (18-36 mos) and do not alter the overall course of disease.
Duchenne Muscular dystrophy
Most common fatal neuoromuscular disorder.
Sever, progressive muscle degeneration.
Loss of ability to walk by age 12. Scoliosis.
Loss of lung and cardiac function.
Premature death (20-30)
No cure
X linked recessive caused by dystrophin gene mutations
The genetic defect is present at birth but is asymptomatic until about age 3.
increased levels of creatine kinase.
Dystrophin
Provides structural stability to the muscle cell membrane during cycles of contraction and relaxation. (Muscle Integrity)
The 4 Functional Domains of Dystrophin
- N-Terminus
- Long spectrin-like repeat domain (cytoskeleton rich portion)
- Cysteine rich
- C-terminus Domain
Last two bind to dystroglycans and syntophins
The 4 Functional Domains of Dystrophin
- N-Terminus
- Long spectrin-like repeat domain (cytoskeleton rich portion)
- Cysteine rich
- C-terminus Domain
Last two bind to dystroglycans and syntophins
Dystrophin is localized to the ___ surface of the muscle ___. The loss of dystrophin results in destabilization of ____.
inner, membrane
the entire dystrophin-glycoprotein complex.
Pseudohypertropy
replacement of muscle with adipose and fibrous connective tissue characteristic of duchennes. enlarged calves are one distinct area of interest.
What changes in stature/movement are common with Duchennes
-waddling walk/run
-difficulty in climbing stairs
-use of handrail to pull up
-walk on tip toes
-lordosis, kyphosis, scolosis
-frequent falls
pseudohypertrophy
What changes in stature/movement are common with Duchennes
-waddling walk/run
-difficulty in climbing stairs
-use of handrail to pull up
-walk on tip toes
-lordosis, kyphosis, scoliosis
-frequent falls
pseudohypertrophy
Becker Muscular Dystrophy
- Milder than Duchenne. Some dystrophin present, but abnormal quantity and size.
- Incidence 1/18,000
- Similar but milder symptoms
- Loss of walking AFTER 16 years
- Muscle pain, dilated cardiomyopathy
- Most common COD is from heart failure
List the 5 treatment strategies for DMD
- Use of growth factors (make more muscle)
- Use of gene therapy (full length dystrophin, utrophin)
- Use of gene therapy (microdystrophins)
- Exon Skipping
- Nonsense (stop) codon read-through
