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Genetics Exam 2 Lecture 1
Terms in this set (134)
Diabetes has __________ inheritance meaning simultaneous presence of several
abnormal genes or polymorphisms
needed for the disease state
Type 1 DM
most common 80-90% of all cases
Type 2 DM
Once known as juvenile diabetes
Insulin is insufficent
Has genetic link and usually develops in children but may have adult onset
Type 1 DM
Once known as NIDDM
Type 2 DM
Type 2 DM is a _________ disorder with poorly understood _______
Type 2 DM develops because of _________
_________ ( not just one or the other!)
Impaired glucose tolerance diabetes
insulin deficiency in Type 2 DM
The genetics of Type 2 DM is hard to differentiate since the disease development is influenced by what other things?
T/F The genes involved in common forms of NIDDM are still uncertain
Genes regulating appetite, energy expenditure, and intraabdominal fat accumulation
these are basically genetically determined risk factors
diabetes related genes
Directly impact insulin secretion/sensitivity
Glucokinase mutations and insulin receptor mutations are two of the many candidate genes
Mutation in HBB (hemoglobin B) gene aka beta globulin
sickle cell anemia
Sickle cell anemia is __________ passed in the ______
When did newborn screenings begin checking for sickle cell and trait?
Symptoms of sickle cell anemia usually manifest within the _______
__________ offers a heterozygote advantage and provides
protection against malaria parasite Plasmodium species.
Sickle Cell Carrier
Prevalence of the heterozygote mutation HgbS is highest in _______, _____ and _______ where malaria is endemic
sub-Saharan Africa, India, Middle East
If sickle cell is recessive autosomal, what are the chances of being affected?
one in four, 50% are carriers
Novel protein property of HgbS results from __________ mutation in sickle cell hemoglobin
Occurs due to simple point mutation
In sickle cell, the protein forms long inflexible polymer chains that deform _______. A sickle cell _____ is formed.
are all found on
beta globin gene cluster
are all found on ________
alpha globin gene cluster
Made of heme and globin proteins
Normal version contains 2 alpha chains and 2 beta chains
hemoglobin A HgbA
Normal version has 2 alphase and 2 delta chains
Hemoglobin A2 HgbA2
Normal version is produced by the fetus and have 2 alpha and 2 gamma chains
hemoglobin F HgbF
Mutated sickle cell hemoglobin;
both beta chains are replaced with HbS
Treatment of Sickle Cell with _______ decreases the number and severity of attacks and possibly prolongs life as it reactivates fetal hemoglobin production
Higher ________ prevent sickling of cell and prevents exertion
higher oxygen levels
sickle cell anemia
Painful vaso occlusive crises
Symptoms aggravated by hypoxia due to polymerization change in Hb so they must avoid overexertion
Sickle cell anemia homozygote
Jaundice-accelerated RBC turnover
Enlarged heart/systolic murmurs
Pulmonary Arterial Hypertension
Acute Chest Syndrome
Delayed Growth/ delayed puberty
Multiple Organ Failure
are all possible compliactions of _________
sickle cell anemia homozygote
What 2 agents often cause septicemia in those with sickle cell anemia?
90% of septicemias occur before 3 years old
Vomiting and/or diarrhea
signs of ________
septicemia in sickle cell
Another complication of sickle cell is rapid turnover of sickle cells. They live ______ (normal RBCs 90-120 days)
Abnormal forms of hemoglobin
A variety of mutations (point mutations, deletions, etc) in ______ globin gene can lead to variant
Several hundred hemoglobin variants have been documented but only a few are clinically significant
Most are _________ variants
sickle cell anemia
8.3% of african americans
mild chronic hemolytic anemia
30% of southeast asians
mild chronic hemolytic anemia
3% of african americans
mild chronic hemolytic anemia
2% of north indian and descendants from Pakistan and Afganistan
What is hemoglobin SC disease?
combo of Hemoglobin C and Hemoglobin S that causes sickle cell
Characterized by episodes of abdominal and joint pain, splenomegaly and mild jaundice
without severe crises
has excellent prognosis
Results from a mutation (GA) at codon 26 of the beta globin gene
Which Hb variant can combine with beta thalessemia and lead to intermediate presentation?
Most common single gene disorder in humans
hemoglobinopathies (not just sickle cell)
Which hemoglobin variant is increasing in the US due to immigrantion of Southeast Asians?
Mutations of hemoglobin that lead to unusually low level of beta or alpha globin
Thalassemias have what type of inheritance pattern?
Most common thalassemia in Southeast Asia
Most common thalassemia in the Mediterranean region, and in portions of Africa, Asia, South Pacific, and India
Alpha thalassemia will have an excess of ______
beta chains (b/c alpha is screwed up)
Beta thalassemia will have an excess of _______
Where is alpha thalassemia found? Beta?
Alpha- chromosome 16
Beta- chromosome 11
What would a blood smear of a patient with thalassemia look like under microscope?
hypochromic because it has less hemoglobin
4 clinical conditions of alpha thalassemia:
1) __________: clinically normal, haemtologically normal
2) __________: microcytosis, hypochromia, and mild anemia
3) __________: moderate to severe microcytic, hypochromic, haemolytic anemia, mild jaundice, moderate hepatosplenomegaly
4) ___________: severe anemia, generalized edema, ascites, marked hepatosplenomegaly, skeletal and cardio malformations,
usually die in utero
1) silent carrier
3) HbH disease-major presenting form
4) Bart's hydrops fetalis
Incompatible with life; absolutely NO alpha chains made
The degree of pathology in alpha thalassemia is based on the number of ________ from chromosome 16
alpha chains deleted
Variant form of hemoglobin that consists of a tetramer of beta chains and reduced alpha chains
unstable and precipitates in RBCs leading to hemolysis
major form of alpha thalassemia
Tetramer of delta chains and NO alpha chains
Hemoglobin Barts aka hydrops fetalis
Impaired growth and development
Endocrine disorders-hypogonadism, type 2 Dm
Venous and arterial thromboembolic events
main clinical issues in alpha thalassemia
Clinical presentation of beta thalassemia depends on the degree of __________. Diagnosis is based on hematologic and molecular genetic testing
beta chain deficiency
Prevalent in Mediterranean, Middle East, Central Asia, India, Southern China, Far East as well as countries along north coast of Africa and in South America
Highest carrier frequency in Cyprus, Sardinia, and Southeast Asia
One mutated beta gene
Increased Hemoglobin A2
Normal HbA and HbF
beta thalassemia minor aka trait
Makes some beta but low expression level
No normal beta genes; beta not expressed at all
HbE combined with beta thalassemia
prevalent in Southeast Asia and carrier frequency is around 50%
What complications are seen in beta thalassemia major or intermedia?
over stimulation of bone marrow
iron overload from regular transfusions
Life threatening anemia
Die within 5 years of life if left untreated
beta thalassemia major
Occurence of gallstones, leg ulcers, and thrombosis
beta thalassemia intermedia
If one parent is a carrier of beta thalassemia, what is the risk for the child?
If both parents are carriers of beta thal, what is the risk for the child?
25% to have disease
If one parent has beta thal and the other is a carrier, what is the risk for the child?
50% have disease
If a parent has beta thalassemia and the other parent has another hemoglobin variant, what might happen?
25% chance the two might combine causing a child to have both
bleeding disorder with slow blood clotting; typically has a family history
more common in boys since x-linked recessive
Most cases of hemophilia are treated with recombinant factor ____ or _____
8 or 9
What is the leading cause of death in those with hemophilia?
2 types of hemophilia
1) hemophilia A-classic or factor VIII 8 deficiency due to
F8 gene mutation
2) hemophilia B-Christmas disease or factor IX 9 deficiency
F9 gene mutation
What royal family suffered from hemophilia?
Queen Victoria-had 14 children
Most common type of hemophilia
1% of normal factor= _________
1-5% of normal factor= ________
6-40% of normal= __________
Bleeding into joints with associated pain and swelling.
Blood in the urine or stool.
Gastrointestinal tract and urinary tract hemorrhage.
Prolonged bleeding from cuts, tooth extraction, and surgery.
are symptoms of ________
PT, CBC/platelet count, bleeding time, plasma fibrinogen concentration will all be
in hemophilia. What test will be diagnostic and show abnormality?
-measures intrinsic and common clotthing pathway-
will be prolonged
To confirm a diagnosis of hemophilia what should you do?
measure factor 8 or 9
Most common bleeding disorder
; affects 1% of US
Von Willebrand Disease
Genetic disorder caused by missing or defective Von Willebrand factor encoded on
, a clotting protein important in platelet plug formation
Most Type 1 and 2 Von Willebrand is ________.
Type 3 (some type 1&2) Von Willebrand is _______
PTT-prolonged or normal
CBC/platelet-can be normal but may show microcytic anemia or low platelet count
Type 1 is most common with the patient having _______ VWF levels.
Type 2 has ___________ VWF levels but the do not work properly.
Type 3 has ________ VWF.
tumor suppression gene mutation
50% occurs due to spontaneous mutation
Most common type of NF
30-50% due to spontaneous mutation-not inherited but may be passed on
Highly variable expressivity and dependent on age
Most common tumors of NF1; benign peripheral nerve tumors
Diagnosing NF1 for those > 8
_____ cafe au lait spots > 5 mm prepuberty, > 15 mm post puberty
______-freckling in the inguinal and axillary
_____ Lisch nodules
_____ neurofibromas or 1 plexifrom neurofibroma
Optic Nerve glioma
Bone deformities and _______
First degree relative with NF1
6+ cafe au lait
Presentation of NF2
Tumors in _____
__________-affects 8th cranial nerve bilaterally in late adolescent; 90% get this
2nd most common tumor in NF2
Cafe au lait spots, axillary freckling, and Lisch nodules are uncommon in patients with ________
Brittle bone disease or Osteogenesis Imperfecta has ______ forms based on the type of collagen affected
Most commonly ________ collagen is affected in osteogenesis imperfecta
Vast majority of osteogenesis imperfecta has what type of inheritance pattern?
dominant mutation (dominant negative)
Most common cause of death in OI
dominant negative mutation
produces protein that hinders function of the normal protein from the normal allele
Type 1 collage is made of 2 _______ and 1 _______
pro alpha 1 chain
pro alpha 2 chain
Most common and mildest form of OI
Bones easily fracture-usually before puberty
Loose joints, muscle weakness
Normal or near normal stature
Hearling loss possible
Collagen normal but
don't make enough
Type 1 OI
Localized or diffuse dilation of an artery with diameter at least 50% greater than normal size
fusiform is most common
Bulging in section of aorta due to weakened aortic wall
Equal likelihood in males/females
Leading cause is HTN
Descending associated with atherosclerosis
thoracic aortic aneurysm
More common than thoracic
Usually asymptomatic until rupture
More common in men and people 65+
Leading cause is atherosclerosis
Smokers 3-5 x greater risk
abdominal aortic aneurysm
Tear in the intima of the artery
75% of people with aortic dissection have history of _______. 2/3 are male.
Risk factors for aortic dissection
prior cardiac sx
are biggest 3
When aortic dissection occurs in those < 40, _______ is usually present
Classifications of aortic dissection:
__________-60%, involves ascending aortia
_________-10-15% involves ascending aortia
_________-25-35% involves distal aorta; originates distal to subclavian
Aortic dissection is often overlooked or considered an ________. EKG will help differentiate.
What is aortic dissection commonly misdiagnosed as in younger people?
Thoracic Aortic Aneurysm Dissection is typically diagnosed with _____ or ______.
CT or MRI
Only 20% of those with TAAD have a first degree relative with thoracic artery disease. Most don't have a family history
Risk factors for TAAD
Pregnancy 3rd trimester, post partum
Connective tissue disorder-Marfan's Ehlers-danlos
T/F No one sign or symptom is sufficient for diagnosis of TAAD
38% are missed on initial eval
Abrupt, sharp chest pain
Pulse deficit or BP difference > 20 mmHg
thoracic aortic aneurysm dissection
Bundle questions to assess risk for TAAD?
1) family hx
2) Marfan's or family hx of it
3) do clinical findings suggest undiagnosed Marfan's
if yes to any do CT to rule out
4 P's associated with TAAD
Most patients with TAAD will be hypertensive but some may become _________
96% of acute dissection were identified based on a combination of the following 3 features
1) immediate onset of ________
2) ________ on CXR
3) variation in __________
if all 3 present 100% diagnosis, if any 2 83%
pulse and/or BP > 20 mmHg
Does a normal CXR rule out TAAD?
nope 12-15% have normal CXR must do CT or MRI
Usually autosomal dominant condition most commonly linked to
ACTA2 gene mutation
Has variable penetrance/expressivity
Autosomal on chromosome 10
Presence of iris flocculi and livedo reticularis can be associated with a mutation of this gene
When diagnosing Familial TAAD what things must be present?
presence of dilation and/or dissection of thoracic aorta
presence of family hx
absence of other causes like Marfan's, Turner's, Ehler's-Danlos
First degree relatives of probands with TAAD should have _________ of the ascending aorta beginning in _________
Treatment for Familial TAAD
beta blockers to reduce shearing forces
If ascending aorta is dilating by 0.5 cm per year or is between ________, elective surgical repair is recommended
A person with FTAAD should avoid:
Sports that can lead to chest blow
Isometric, heavy exercise
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