Exam 2: Lecture 29 Flashcards
(36 cards)
1
Q
Describe Mendelian Inheritance
A
2
Q
Autosomal dominance
A
- pathogenic variant on ONE copy of the autosomal gene causes disorders
- can be loss of function or gain of function
- often incomplete penetrance (not very one who has a pathogenic variant gene will express the disorder) –> may look like generations are skipped in a pedigree
3
Q
Autosomal Recessive
A
- pathogenic variants on BOTH copies of the autosomal gene
- typically, enzyme deficiencies (almost all inborn errors of metabolism
- complete penetrance… but variable effects bases on percentage of enzyme that works (10% vs 50%… 10% would be more severe)
- heterozygotes or carriers, typically unaffected and usually do not know they are carriers
4
Q
X linked
A
- mostly recessive
- males are hemizygous (only have one x chromosome)
- females may show features of the disorder based on X- inactivation patterns, often milder
- if more wildtype is inactivated, the mutation will show up more
5
Q
What are connective tissue disorders?
A
- involves CT, collagen fibers, elastic fibers, reticular fibers, etc.
- may affect bone, cartilage, tendons, ligaments, skin, cornea, blood vessels, and gut
- can be due to defects in different types of genes–> those affecting collagen is more common
- 40+ genes
6
Q
Marfan Syndrome
A
- affects the skeleton, eyes, and CVS
- defect in gene FBN1; encodes fibrillin-1
- CT disorder
- autosomal dominant
- high penetrance (people with the gene mutation will mostly express the phenotype)
- variable expressivity (symptom manifestation is variable with each person)
7
Q
What are the cardiovascular effects of Marfan Syndrome?
A
- dilation of the ascending aorta leading to aortic dissection (tear in the inner layer of the aorta)
- mitral valve prolapses (leaflets of the mitral valve bulge back into the left atrium)
8
Q
What are the skeletal effects of Marfan syndrome?
A
- joint ligaments are lax–> hypermobility in some joints
- Tall stature, long wingspan ( longer that height)
- Arachnodactyly (fingers/ thumbs and toes are abnormally long and slender in comparsion to portion of palm and arch of foot)–> SPIDER-LIKE FINGERS
- Kyphosis pr scoliosis
- pectus excavatum (sternum and some ribs grow inward, creating a depression in the chest) or carinatum (breastbone sticks out more than normal)–> PIGEON CHEST
- able to wrap pinky and thumb around their wrist with overlap
9
Q
What are the ocular effects of Marfan Syndrome?
A
- ectopia lentis: dislocation of the lens–> classically up and out; often bilateral (zona fibers usually pulls lens…attached to it)
- myopia, often sever (nearsighted–> can see near, but difficult to see at a distance)
10
Q
What happens with fibrillin-1 in normalcy and with a deficiency?
A
1) Fibrillin- 1 is the major component of microfibrils in the extracellular matrix
2) provides scaffold on which tropoelastin is deposited to form elastic fibers
3) fibrils are abundant in AORTA, LIGAMENTS, and ciliary zones of the LENS
4) Loss of structural support in microfibril-rich CT
5) excessive activation of transforming growth factor- beta (TGF-B)
11
Q
Describe the relationship between Marfan and TGF B
A
- excessive activation of TGF B
- Fibrillin- 1 controls bioavailability of TGFB
- microfibrils sequester (divide and separate) TGF-B
- Excessive TGF-B lead to overgrowth of skeletal system and myxoid changes in mitral valves
- TGF B promotes cellular proliferation, differentiation, migration, and survival (growth factor)
12
Q
What is a syndrome similar to Marfan?
A
- Loeys-Dietz
- problems in the gene TGF-B2 and others in the same pathway causes the Loeys- Dietz
- arterial aneurysms, pectus abnormalities, joint laxity, velvety/translucent skin
13
Q
Ehler’s Danlos Syndrome
A
- 13 different types
- result from problems in collagen genes –> sometiems it enzymes that modify collagen or proteins in teh ECM
14
Q
Describe collagen
A
- collagen genes have repetative sequence ..like glycine with others AA and it is repeated; needed in order to fold correctly so different strand can for the triple helix structure
- If you have a small change, it will not be able to fold correctly or bind o itself correctly
- Different types of collagen are more abundant i different parts of teh body
15
Q
Ehlers-Danlos Syndrome
A
- skin, ligament, and joints are affected (hypermobility and joint issues)
- skin is often affected –> fragile, stretchy, and has abnormal scarring
- eyes, arteries, and other organs are affected like colonic ruptures and arterial aneurysm
16
Q
Classic Ehlers-Danlos Syndrome
A
- autosomal dominant
- due to defects in genes COL1A1, COL5A1, or COL5A2
- joint problems like joint dislocation, joint pain, and hypermobility
17
Q
How do you diagnose joint hypermobility
A
- does the fifth finger bends more than 90 degrees
- can you touch teh floor with legs straight
- can teh thumb touch teh forearm
- 9 point scale… 5 points is considered hypermobile but is adh=justed by age because we are less flexible
18
Q
EDS and skin
A
- test on forearm to test if there is extra stretchiness
- skin breaks –> gets cuts easily and scars don’t heal easily ( looks like cigarette burns)
- Skin findings: hyperextensible, fragile, and atrophic scarring
- kysogenic vacuoles?- outpouching of skin when someone puts weight on their foot
19
Q
How do you treat classic EDS?
A
- mostly supportive
-joint instability and pain: PT, OT, braces and specialized equipment, pain management
Specialist: ortho, physical medicine and rehab, neurology, and pain clinic - skin: caution with closure…stiches may need to be left in longer to let it heal
20
Q
Vascular EDS
A
- problems with COL3A1 gene
- type 3 collagen is abundant in blood vessels and in the intestines
- Autosomal dominant
- prone to rupture of the vascular system and internal organs
- high risk of uterine rupture–> especially during pregnancy
- spontaneous GI perforations
- vascular dissection (tears in the inner layer) /rupture
21
Q
A
- skin is translucent–> looking like an older person’s skin
- small joint hypermobility (like hands)
- characteristic of facial appearance and aged appearance to hands
22
Q
How do you manage vascular EDS?
A
- periodic arterial screenings (US, MRA, CTA)
- screen to look for dilations before dissections occur
- counsel them to stay away from contact sports to avoid trauma
- avoid colonoscopy (weighing family history of colon cancer)
- pregnancy considerations: women have 5% mortality risk with each pregnancy
23
Q
Hypermobile EDS
A
- use a checklist to diagnose; don’t know what gene is effected
- may be multiple genes or multifactorial
- clinically diagnosed only
24
Q
Cystic fibrosis
A
- defective CFTR channel
- channel is supposed to transport chloride and bicarbonate in exocrine gland, sweat glands/ducts, lungs, and the pancreas
- end up with thick mucus secretions
25
What are the clinical features of cystic fibrosis?
- recurrent sinusitis and bronchitis
- progressive obstructive pulmonary disease with bronchiectasis
- exocrine pancreatic deficiency
- GI abnormalities including meconium ileus (sticky poop) leading to rectal prolapse (rectum slips out of the anus causing pain or fecal incontinence)
- hypoplasia of the vas deferens causing fertility issues
26
How do you diagnose Cystic fibrosis?
- sweat chloride testing: elevated (electrodes connected to arm delivers mild electrical current and device collects sweat from the arm)
- molecular testing: two pathogenic variants on the gene CFTR
- newborn screen: elevated immunoreactive trypsinogen
27
Ingeritence
- autosomal recessive
- common mutations is different populations (caucasians)
- increase prevalence in pops due to founder mutations
28
How do you manage cystic fibrosis?
- airway clearance and pulmonary treatment
- antibiotics
- nutrition management
- pancreatic enzyme replacement
medications for specific variants
- lung transplant
29
Alpha 1- antitrypsin (A1AT) Disorder
- defect in serum A1AT
- A1AT inactivates neutrophil elastase
- pathogenic variant causes you to not be able to inactivate neutrophil elastase, leading to destruction of elastin in the walls of the lungs--> can lead to emphysema
- build-up of abnormal protein in the liver since liver produces the protein--> build up in the liver and causes damage
- elevated aminotransferases
- cholestasis (slowing or stoppage of bile flow from the liver--> symptoms are itching, jaundice, dark urine, and pale stool) with hyperbilirubinemia
-LUNG and LIVER issues
30
Describe the inheritance of Alpha 1 Anti-trypsin disorder
- autosomal co- dominant
- Gene SERPINA1
- PI typing (differentiated by protease inhibitor) --> PI-M (Most common normal allele); PI-Z (common pathogenic allele)
- PI*MZ--> at risk for emphysema if they smoke
- PI*ZZ--> at risk for COPD even without smoking, can have liver disease (varying severities); if have a history of alcohol abuse or hep, would cause their liver to get bad where they may need a liver transplant
31
Describe cholesterol metabolism
- we get cholesterol in 2 ways, diet (chyromicrons in intestinal mucosa--> blood--> remnants are delivered to the liver) and endogenous synthesis (begins and ends in the liver)
- 70% of plasma LDL is cleared by the liver...LDL must bind to the receptor via APOB
- receptor bound to LDL internalized to form vesicles which fuse with lysosome
- LDL degraded...Apoproteins hydrolyzed to AA...cholesterols broken down to free cholesterol; free cholesterol enters cytoplasm and used for membrane synthesis; also regulates cholesterol homeostasis
-LDL dissociates from the receptor, which is recycled (recycling regulated by PCSK9)
32
What happens once intracellular cholesterol is released? (4)
- cholesterol metabolism
1) suppresses cholesterol synthesis within cell by inhibiting HMG CoA reductase enzyme [ statins inhibit HMG CoA reductase leading to increase LDL receptor synthesis]
2) activates acyl CoA: cholesterol acyltransferase, favoring storage of excess cholesterol
3) suppresses synthesis of LDL receptors to prevent excessive accumulation
4) upregulates expression of PCSK9 to prevent excessive accumulation (PCSK9 regulates recycling of LDL-R) --> monoclonal antibody drugs that inhibit PCSK9 reduces degradation of LDL receptors thus increasing cholesterol clearance
33
What causes familial hypercholesteremia?
- defects in the LDL receptor (80-85% of all cases)
- Apolipoprotein B-100 defect--> ligand for LDL-R on the LDL particle; reduces binding
- PCSK9 issue--> reduces number of LDL-R on cell surface due to increased degradation
- all lead to inadequate removal of plasma LDL by the liver--> hypercholesteremia--> atherosclerosis
34
What are the clinical features of familial hypercholesteremia?
- elevated cholesterol
- Xanthomas--> yellowish lumps that are accumulations of cholesterol on the skin; can be around the eyes or achilles tendon (tendons)
- premature atherosclerosis and early myocardial infarctions (like MI in their 40s)
35
Describe the Inheritance patterns of familial hypercholesteremia
- autosomal dominant
- heterozygotes: 2-3x normal cholesterol; 1/200 individuals
- Homozygotes (almost no LDL receptors): 5-6x normal cholesterol; earlier skin findings; MI may occur before age 20
36
How do you manage familial hypercholesteremia?
- follow up with a lipid specialist
- pharmacotherapy to reduce lipid levels
- reduce risk factors for coronary artery disease
- cessation of smoking
- healthy diet/weight control
- regular physical activity
- treatment of hypertension, diabetes, etc
- children must be monitored starting early and treated similarly
