Genetics of Cardiovascular and Hematologic Disease Flashcards
What are the two pathways associated with the coagulation cascade?
- intrinsic pathway
- extrinsic pathway
The activation of what factor initiates the first step of the common pathway of the coagulation cascade?
factor X
What allows you to stop bleeding by forming clots?
fibrin
What is a bleeding disorder that has a combined incidence of 1 in 5000 males?
hemophilia
Hemophilia is caused by a mutation of what?
on the F8 or F9 genes on the X chromosome
Hemophilia A and B are what type of disorders?
X-linked recessive disorders
1/3 of hemophilia patients do not have a family history of this disease, so they are what type of mutations?
do novo mutations
Who is usually affected in hemophilia?
males
Will affected fathers with hemophilia ever pass the disease to their sons?
No
Hemophilia A is a disorder due to mutations on which gene?
F8 (factor 8)
Hemophilia A has a deficiency with which clotting factor?
Factor VIII
What type of hemophilia is considered the “classic” hemophilia and is the most common?
Hemophilia A
Which Hemophilia is also named the “Christmas disease”?
Hemophilia B
Hemophilia B is associated with mutations on which gene?
F9 gene (factor 9)
Hemophilia B has a deficiency with which clotting factor?
factor IX
Which hemophilia is considered the “Christmas disease” and is less common than the other?
Hemophilia B
Hemophilia A and B are clinically indistinguishable, what does this mean?
both will present the same way
Who can manifest mild symptoms of Hemophilia or may have more classic symptoms?
female carriers
What are some possible explanations as to why female carriers of hemophilia may manifest mild symptoms or have more classic symptoms?
- X-chromosome inactivation during embryogenesis
- mating between an affected male and carrier female
- an abnormal karyotype resulting in loss of all or part of one chromosome (turner syndrome)
Most children with hemophilia become symptomatic by age (1) and are typically diagnosed by age (2)?
- 2
- 6
If there is so trauma or witnessed bleeding at birth, what can be missed with newborns?
hemophilia diagnosis
Newborns with what disease can present with:
- intracranial hemorrhage
- seizures
- increased bleeding with circumcision
Hemophilia
What are these manifestations associated with:
- excessive bleeding as result of injury or surgical procedure
- excessive bruising
- skin hematomas
- joint hemarthrosis
- knees, ankles, and elbows commonly affected
hemophilia
What are these ENT manifestations associated with:
- nose epistaxis (bloody nose)
- bleeding from posterior pharynx after coughing
- hematochezia
- hematuria
- menorrhagia
Hemophilia
What is the term for blood in stool?
hematochezia
What is the term for blood in urine?
hematuria
What is the term for a heavier menstrual cycle?
menorrhagia
What can be used to diagnose hemophilia A and B?
specific coagulation factor assays and genetic testing
What is a bleeding disorder associated with hemophilia?
hemophilia C
Hemophilia C is a disease with a deficiency with what clotting factor?
factor XI
What is the inheritance pattern for hemophilia C?
autosomal recessive
What is a large glycoprotein with several functions and is involved in platelet adhesion to the sub-endothelium?
Von Willebrand factor
What acts as a “bridge” between platelets and the injured sub-endothelium (brings them together)?
Von Willebrand factor
What binds to the Von Willebrand factor?
receptors in platelets
Von Willebrand factor acts as a carrier for which factor in circulation?
factor VIII
Von Willebrand factor increases factor 8’s half-life by?
five-fold
Factor VIII levels are low in Von Willebrand factor which results in what?
reduced clotting potential
What is the most common inherited bleeding disorder?
Von Willebrand disease
What gene is associated with Von Willebrand disease?
VWF gene
Most people with Von Willebrand disease are what?
asymptomatic
What is the inheritance pattern associated with Von Willebrand Disease?
mostly autosomal dominant with variable penetrance
What can follow an autosomal recessive pattern but is less common and causes more severe symptoms in this form?
Von Willebrand Disease
How many types of Von Willebrand disease classifications are there?
3:
- type 1, 2 and 3
What is the defect associated with type 1 Von Willebrand disease?
quantitative defect; not enough VWF
What is the defect associated with type 2 Von Willebrand disease?
qualitative disease; dysfunctional VWF
What is the defect associated with type 3 Von Willebrand disease?
profound quantitative defect; total or near absence of VWF
What is the inheritance of type 1 Von Willebrand disease?
autosomal dominant
What is the inheritance of type 2 Von Willebrand disease?
autosomal dominant (common)
autosomal recessive (uncommon)
What is the inheritance of type 3 Von Willebrand disease?
autosomal recessive
What type of Von Willebrand disease is associated with barely any bleeding and is the most mild?
type 1
What type of Von Willebrand disease is associated with moderate to severe bleeding?
type 2
What type of Von Willebrand disease is associated with severe bleeding and is clinically similar to hemophilia A?
type 3
What are some clinical bleeding symptoms associated with type 1 Von Willebrand disease?
- epistaxis
- postoperative bleeding
- gastrointestinal bleeding
- ecchymosis and hematomas (brusing)
- joint bleeding
- menorrhagia, hematuria, postpartum bleeding
Sickle cell anemia is more common with ancestry connected to?
sub-Saharan Africa (african americans)
Sickle cell anemia is associated with mutations on what gene?
HBB gene for hemoglobin
Sickle cell anemia is what type of substitution at the 6th codon?
single substitution
The single substitution on the 6th codon in sickle cell anemia results in what?
sickled hemoglobin
Who requires newborn screening for sickle cell anemia?
all states
Normal hemoglobin in adults is comprised of what?
- two alpha polypeptide chains
- two beta polypeptide chains
Within each chain of hemoglobin, what is there?
a heme group which contains iron
Hemoglobin is responsible for what?
oxygen transport
When you lose hemoglobin, what else do you lose?
iron
If an older individual is suddenly anemic, what should you check for?
colorectal cancer; they’re suddenly losing hemoglobin and iron
Normal hemoglobin is very (1) and (2), but HgbS (sickle) is not
- pliable
- deformable
How do sickled cells flow?
they do not flow freely and lead to pain and vaso-occlusive infarction of organs
Sickled cells get what?
stuck places
How is sickle cell anemia inherited?
autosomal recessive pattern
Heterozygous individuals are carriers of sickle cell anemia and are referred to as having what?
the sickle cell trait
What has been found to provide a 60% protection against malaria?
- most of the benefit occurs before age 16
- higher frequency of carries are in malaria regions
Sickle cell anemia
Mice that were genetically engineered to be sickle cell carriers were protected against what?
cerebral malaria
The protective effect of the sickle cell train occurs why?
because sickled hemoglobin is a strong inducer of heme-oxygenase 1 (HO-1)
What produces the gas carbon dioxide which protects host from cerebral malaria without interfering with malaria parasites in RBCs?
Heme-oxygenase
What can lead to severe neurologic complications such as:
- neurocognitive impairments
- coma
- death
cerebral malaria
Manifestations of sickle cell anemia occur due to what?
hemolysis and vasoocclusion
What are these manifestations in infants and children associated with:
- failure to thrive
- anemia
- splenomegaly (enlarged spleen)
- multiple infections
- swelling of extremities from vasoocclusion
Sickle cell anemia
What are these manifestations associated with?
- chronic anemia from RBC destruction
- jaundice and scleral icterus
- aplastic crisis
sickle cell anemia
What results in tissue ischemia?
chronic anemia
What is due to the cessation of RBC production and is often results from acute infection (shut down factory for RBC production)?
Aplastic crisis
What is the biggest complaint associated with sickle cell anemia?
chest pain
Acute chest syndrome is associated with?
sickle cell anemia
What are these associated with:
- fever
- chest pain
- tachypnea
- wheezing
- cough
- changes on chest imaging
acute chest syndrome of sickle cell anemia
What are these manifestations associated with:
- severe abdominal pain
- stroke
- renal necrosis
- leg ulcers
- priapism (sustained erection)
- vision loss due to infarction
sickle cell anemia
What type of testing is used for sickle cell anemia?
- prenatal testing through amniocentesis
- hemoglobin electrophoresis
What is high cholesterol known as?
hypercholesterolemia, dyslipidemia, or hyperlipidemia
What can uncontrolled high cholesterol lead to?
- atherosclerosis
- myocardial infarction
- sudden cardiac death
To reduce the risk of heart disease, we regularly monitor lipid panels, which includes what?
- total cholesterol
- triglycerides
- high-density lipoprotein (good)
- low-density lipoprotein (bad)
The majority of dyslipidemia is?
polygenic in origin (polygenic high cholesterol)
What disease is a strictly inherited form of high cholesterol and is less common than polygenic cases?
familial hypercholesterolemia
Familial hypercholesterolemia is due to mutations on which gene specifically?
LDLR
What is the inheritance pattern of familial hypercholesterolemia?
Either AD or AR depending on the variant
What acts as a carrier for cholesterol, which is needed for many metabolic functions?
LDL
Cells require LDL for use through their what?
LDL receptors
What do normal LDL receptors do?
remove LDL from circulation and “give” it to the cell
What encodes for a protein on the LDL receptor?
LDLR gene
In familial hypercholesterolemia, what is wrong with the LDL receptors?
they are either defective or completely absent
- if completely absent, the disease will be very serious
If the LDLR gene is defective, what can happen to LDL levels?
they can be 2-8 times higher than normal
What disease poses a very high risk of coronary heart disease from atherosclerosis (can result in angina and MI)?
familial hypercholesterolemia
What medications are used to reduce atherosclerosis in familial hypercholesterolemia?
cholesterol medication “statins”
What is tendon xanthomas associated with?
familial hypercholesterolemia
What are cholesterol deposits in tendons called?
tendon xanthomas
What is xanthelasma associated with?
familial hypercholesterolemia
What are yellow, cholesterol build-up growths that appear around the eyes called?
xanthelasma
Atherosclerosis, tendon xanthomas, and xanthelasma are all associated with what?
familial hypercholesterolemia
It is recommended that individuals should be screened for familial hypercholesterolemia if?
- family member presents with FH
- plasma total cholesterol level in adult is greater than 310 in an adult or 230 in a child
- premature CHD or sudden cardiac death
- tendon xanthomas
What is a disorder of the connective tissue of multiple systems such as:
- eyes
- aorta
- skin
- long bones
marfan syndrome
What is one of the most common disorders of connective tissue?
Marfan syndrome
Marfan syndrome has no predilection of what?
race, ethnicity, or gender
What is the gene associated with Marfan syndrome?
FBN1 (fibrillin-1 gene)
What is the inheritance pattern of Marfan syndrome?
autosomal dominant
75% of Marfan syndrome cases are ______
inherited
25% of Marfan syndrome cases are due to what?
do novo mutations
What varies between affected individuals with Marfan syndrome?
expression
What is the function of the FBN1 gene?
encodes for glycoprotein fibrillin
What is the principal component of microfibril which is part of the structure of collagen?
microfibril
What does collagen provide?
- elasticity
- stability
- strength
Where in the body are microfibrils particularly abundant?
- aorta
- periosteum
- alveolar walls
- skin
Patients with Marfan’s have abnormally functioning fibrillin, so their connective tissues will become overly _____
elastic
What is the main cause of morbidity and morality in Marfan syndrome?
aortic dissection
What manifests as aortic aneurysms, aortic regurgitation, and aortic dissection?
Marfan syndrome
Dilation of the aorta in Marfan pts is found in who?
- 50% children
- 60-80% adults
- progressively worsens with time/age
Because aortic dissections in pts with Marfan syndrome has such a high fatality rate, what should be done at diagnosis and at regular intervals?
echocardiograms (cardiac ultrasounds)
What are these skeletal abnormalities associated with:
- excessive linear bone growth with joint laxity (tall with long arms)
- arachnodactyly (spider fingers)
- dolichostenomelia (arm span>body height)
Marfan syndrome
What is dolichostenomelia?
arm span>body height
Positive thumb sign and positive wrist sign is associated with?
Marfan syndrome
What is pectus carinatum?
pigeon chest (chest sticks out)
What is pectus carinatum associated with?
Marfan syndrome
What is pectus excavatum?
funnel chest (chest folds inwards)
What is pectus excavatum associated with?
Marfan syndrome
What is hindfoot valgus?
“too many toes” sign; ankle and foot curves inward allowing you to see many toes on the lateral side of the legs
What is hindfoot valgus associated with?
Marfan syndrome
What is pes planus?
flat foot
What is pes planus associated with?
Marfan syndrome
What are these spine abnormalities associated with:
- paradoxical reduced joint mobility of elbows and digits
- scoliosis
- kyphosis
Marfan syndrome
What are these eye abnormalities associated with:
- dislocated lens (ectopia lentis)
- myopia (nearsightedness)
Marfan syndrome
What are these manifestations associated with:
- spontaneous pneumothorax
- skin striae (stretch marks)
- recurrent incisional hernias
Marfan syndrome
How is Marfan syndrome diagnosed?
- Ghent criteria and family history
- genetic testing to confirm diagnosis
What can occur in any portion of the aorta and is defined as having >50% increase in the expected diameter for that portion of the aorta?
aortic aneurysm (widened aorta)
What percentage of aortic aneurysms are sporadic?
80%
What are the risk factors associated with aortic aneurysms?
- hypertension
- smoking
- hypercholesterolemia
What percentage of aortic aneurysms are related to genetics and can be related to Marfan syndrome familial thoracic aortic aneurysm?
20%
What is the inheritance pattern of familial thoracic aortic aneurysms (familial TAA)?
autosomal dominant with variable expression
In familial TAA, how many genes are are linked and identified on 4 separate chromosomes?
4
In familial TAA, what part of the aorta is involved 80% of the time?
ascending aorta
What is the average age of onset of aneurysm dissection in pts with Marfan syndrome?
38 years
What is the average age of onset of aneurysm dissection in pts with familial TAA?
56 years
What is the average age of onset of aneurysm dissection in pts with sporadic aneurysm?
64 years
What is the mortality rate of aortic dissection?
1-2% per hour (same as in the 1950s, haven’t been able to figure this out)
Aneurysms that produce symptoms are usually large and dangerous, so pts can present with what symptoms?
- chest pain
- upper band and/or left shoulder pain
- hypertension, shock if severe
Most patients that have aortic aneurysms are ________
asymptomatic until they begin to dissect
What are the four “P’s” associated with aortic aneurysms/dissections?
- Pallor (pt appears pale)
- Pulseless (blood not perfusing well)
- Paresthesia (lack sensation in extremities)
- Paralysis (unable to move one or several extremities)
What should you ask yourself if a pt presents with symptoms that may be related to aortic aneurysms?
- does the pt’s family have a history of aortic dissection?
- does the patient have Marfan syndrome?
- do physical findings suggest the patient may have undiagnosed Marfan syndrome?
What tests are available for diagnosis of familial TAA?
- genetic testing
- screening of all first-degree relatives in FTAA
What should be known prior to pregnancy due to high-risk of dissection and rupture in pregnant women?
if the pregnant mother has familial TAA
Cardiomyopathies are a heterogenous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually exhibits inappropriate ___________ and are due to ____________
- ventricular hypertrophy or dilation
- variety of causes that frequently are genetic
What are the leading cause of sudden cardiac death in athletes, even young athletes?
hereditary cardiomyopathies
What helps detect cardiomyopathy abnormalities?
sports physicals
What should you pay attention to in pts with hereditary cardiomyopathy?
- murmurs
- pay attention to symptomatology and family history of sudden cardiac death
What are the different types of cardiomyopathies?
- dilated cardiomyopathy
- hypertrophic cardiomyopathy
- arrhythmogenic cardiomyopathy
- restrictive cardiomyopathy
What is the dilation of at least one of the ventricles of the heart which results in impaired contraction of one or both ventricles?
dilated cardiomyopathy
What occurs when the ventricular myocardium of the left ventricle becomes thickened and doesn’t fill all the way?
hypertrophic cardiomyopathy
What occurs when the ventricular myocardium of the right ventricle is replaced with fibrofatty scare tissue so the nodes are affected and will have abnormal heart rhythms?
arrhythmogenic cardiomyopathy
What is the stiffening and rigidity of both ventricles due to the replacement of normal myocardium by scar tissue but there is NO hypertrophy of the ventricle?
restrictive cardiomyopathy
Left ventricular abnormality is associated with what?
hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy is associated with genetic mutations of what?
sarcomere genes
Hypertrophic cardiomyopathy has what type of inheritance pattern?
usually autosomal dominant but de novo mutations can occur
Right ventricular abnormality is associated with what?
arrhythmogenic right ventricular dysplasia/cardiomyopathy
Eight genes are known to be associated with what can can affect desmosome (aid in cell adhesion)?
arrhythmogenic right ventricular dysplasia/cardiomyopathy
Arrhythmogenic right ventricular dysplasia/cardiomyopathy has what type of inheritance pattern?
usually autosomal dominant
What are the two most common forms of hereditary cardiomyopathies?
- hypertrophic cardiomyopathy
- arrhythmogenic right ventricular dysplasia/cardiomyopathy
Dyspnea on exertion is associated with what?
hypertrophic cardiomyopathy
Arrhythmias (abnormal heart rhythms) are clinical manifestations of what?
arrhythmogenic right ventricular dysplasia/cardiomyopathy
What are these clinical manifestations associated with:
- chest pain
- palpitations
- syncope (passing out when they exert themselves)
- hypertrophic cardiomyopathy
- arrhythmogenic right ventricular dysplasia/cardiomyopathy
Hereditary cardiomyopathy has multiple genes involved, particularly those that affect?
sarcomere function
Hypertrophic cardiomyopathy has what type of inheritance pattern?
autosomal dominant
Dilated cardiomyopathy is inherited in what manner?
AD or AR
Hereditary cardiomyopathy can have what type of penetrance?
incomplete penetrance
What should you consider in a young person or athlete with syncope especially during sports/exertion or pronounced chest pain with exertion?
hereditary cardiomyopathy
