10: Single Gene Genetic Disorders Flashcards
Most common lethal genetic disease in Caucasians
CF
What happens in heterozygote carriers of CF?
Higher incidence of respiratory and pancreatic disease
Some bacteria that are typical CF pathogens
- Staphylococcus aureus
- Haemophilus influenzae
- Pseudomonas aeruginosa
- Burkholderia cepacia
Chest radiograph of CF pt
Can show bronchiectasis, atelectasis, infiltrates, hyperinflation
How to Dx CF
- Characteristic phenotype OR Hx CF in sibling OR positive newborn screen
PLUS - Increased sweat chloride OR 2+ CF mutations OR abnl epithelial nasal ion transport
Galactosemia defect and result
Defective galactose-1-phosphate uridyltransferase -> increased galactose -> tissue damage
Lesch-Nyhan
Increased intermediate produce and their toxic breakdown products
Single most important preventive measure for pts with a1-antitrypsin deficiency
Avoiding cigarette smoking bc it markedly accelerates emphysema
Thalassemias vs sickle cell disease
Thalassemia: Mutation in globin gene -> affects amount of globin
Sickle cell disease: mutation in structure of globin molecule
Fibrillin-2 mutation in Marfan’s
Rare, causes congenital contractural arachnodactyly
Where are microfibrils involved in Marfan’s found?
Aorta, ligaments, ciliary Zonula that support lens
What does increased TGF-B signaling lead to in Marfan’s?
Inflammation -> deleterious effects on vascular SM development, increases activity of metalloproteases -> loss of ECM
Serious risks of the three types of Ehler’s Danlos that were studying
Classic: diaphragmatic hernia
Vascular: colon and large artery rupture
Kyphoscoliosis: ocular fragility, rupture of cornea, retinal detachment
LDL receptor mutation is the most common cause of FH, but what other two proteins can be mutated to cause it?
ApoB, PCSK9
Carrier state for Gaucher + having Neimann-Pick type C increases risk for which two diseases?
Carrier of Gaucher: Parkinson’s
Niemann-Pick type C: Alzheimers
How lysosomal enzymes are made and transported
- Made in ER
- Transported to Golgi
- Tagged with M6P
- Transport out and fuse with lysosomes
Link between lysosomal storage diseases and what?
Neurodegenerative disorders
Primary accumulation vs secondary accumulation in lysosomal storage diseases
Primary accumulation: catabolism of substrate is incomplete -> accum in lysosome
Secondary accumulation: impaired autophagy
Gm2 gangliosidoses
Group fo three lysosomal storage diseases caused by an inability to catabolize Gm2 gangliosides
Most common Gm2 gangliosidosis
Tay-Sachs
Which chromosome (mat or pat) typically expresses Niemann-Pick dz
Maternal, paternal usually silenced
Cells in Neimann-Pick disease
Cells enlarge due to sphingomyelin and cholesterol accum -> foamy cytoplasm + Zebra bodies (lysosomes with concentric lamellations)
Cells in Gaucher disease
Gaucher cells: distended phagocytes in BM, liver, spleen, LNs, tonsils, thymus, etc. - in bone marrow, causes bone erosion which leads to pathological issues
Cytoplasm in Gaucher disease
Is fibrillary type cytoplasm -> looks like crumpled tissue paper
Mucopolysaccharidoses
Deficiencies in enzymes that degrade glycosaminoglycans -> abundant Mucopolysaccharidoses in ground substance of CT
Histo of MPS
- Balloon cells: clear cytoplasm, many vacuoles, swollen lysosomes, PAS+
- Lamellated zebra bodies (similar to Niemann-Pick)
Sx common to all mucopolysaccharidoses
Hepatosplenomegaly, arterial deposits (esp coronary A’s), brain lesions, skeletal deformities, valvular lesions
Three major types of glycogen storage disorders and explain them
- Hepatic: increased storage of glycogen in liver, hypoglycemia
- Myopathic: increased glycogen storage in muscles -> muscle cramping, no increase in blood lactate after exercise
- Misc: assoc with glycogen storage in many organs and death early in life
