Lecture 4: Mendelian Diseases Part Two Flashcards
What mutation is hemophilia caused by?
F8 or F9 on X chromosome
Hemophilia A is a disorder of what gene?
factor 8 gene
Hemophilia B is a disorder of what gene?
factor 9 gene
Which hemophilia is considered classis hemophilia and is most common?
Hemophilia A; factor 8 gene
How is hemophilia A and B inherited?
X-linked recessive
How common is it that patients do not have family history and have a de novo mutation of hemophilia?
1/3 of hemophilia patients have a de novo mutation
What is a manifestation of hemophilia in newborns?
intracranial hemorrhage with seizures; this is increased with the use of forceps or vacuum in delivery
When do the majority of children with sever hemophilia become symptomatic?
within the first two years of life and are typically diagnosed by age 6
What are some manifestations of hemophilia?
bruising, hemarthrosis (bleeding in the joint tissue), epistaxis, hematuria, blood in the stool
What is von willebrand factor?
large glycoprotein; involved in platelet adhesion to the subendothelium; receptors in platelets bind to the VWF; acts as a carrier for factor 8 in circulation
What is the most common inherited bleeding disorder?
von willebrand disease
What is characteristic about Von Willebrand Disease?
has low factor 8 activity with missing or dysfunctional VWF activity
How is von willebrand disease inherited?
mostly autosomal dominant; some autosomal recessive
What is type 1 von willebrand disease
has low VWF; most common; mostly autosomal dominant
What is type 2 von willebrand disease?
normal levels of VWF but the VWF does not work correctly
What is type 3 von willebrand disease?
has little or no VWF; the least common; causes the most severe symptoms; usually autosomal recessive; has mutations that result in an abnormally short nonfunctional von willebrand factor
On which chromosome is VWF gene located?
chromosome 12
How is hemophilia C inherited?
autosomal recessive pattern
How many oxygen’s can each iron in a heme group bind?
one oxygen
In what ancestry is sickle cell anemia more common?
sub-Saharan and Africa
What is normal hemoglobin comprised of?
two alpha polypeptide chains and two beta polypeptide chains
What is the difference in normal hemoglobin and sickle cell hemoglobin?
there is a single substitution at the 6th codon of the beta hemoglobin chain that causes the amino acid glutamic acid to be replaced with valine
What are the distinguishable characteristics of HbS?
sickle cells form long inflexible chains and is not very pliable
How is sickle cell anemia transmitted?
autosomal recessive pattern
Why does sickle cell trait protect against malaria?
protective affect occurs because sickled hemoglobin is a stronger inducer of heme-oxygenase 1; this enzyme has been shown to protect host from cerebral malaria
What are some manifestations of sickle cell anemia?
related to hemolysis and vaso-occlusion; failure to thrive, anemia, splenomegaly, infections, swelling of extremities, jaundice, cholelithiasis, stroke, chronic anemia, acute chest syndrome, renal necrosis, leg ulcers, priaprism, vision loss
What does lipid monitoring typically include?
total cholesterol, HDL, triglycerides, LDL
What is the gene and chromosome identified with familial hypercholesterolemia?
LDR gene on chromosome 19
What is LDR gene?
encodes a protein for the low density lipoprotein receptor… LDL typically functions as the carrier for cholesterol in the blood; LDL receptors regulate total cholesterol by reducing LDL
What happened to LDL receptors in familial hypercholesterolemia?
in a defective LDLR gene the receptors are either defective of absent leading to an increase in LDL in circulation
Which is more common for the LDLR gene, heterozygous form or homozygous form?
homozygous form is rare and consists on atherosclerosis of child having serum cholesterol 8X normal; heterozygous form is more common having LDL 2-3 X normal
What are some manifestations of familial hypercholesterolemia?
CHD from atherosclerosis, tendon xanthomas (fatty deposits on the skin), xanthelasma around eyes,
When should a person be screened for FH?
if a family member presents with FH, plasma cholesterol level in adult is > 310 or in a child is > 230, premature CHD or sudden cardiac death, or tendon xanthomas
How is marfan syndrome inherited?
in an autosomal dominant pattern
What is the mutation involved in marfan syndrome?
fibrillin-1 gene (FBN1) on chromosome 15
What percent of cases of marfan syndrome are de novo?
25%
What is Fibrillin-1?
encodes for glycoprotein fibrillin which is the principle component of the microfibril and therefore part of the structure of collagen
Where are microfibrils particularly abundant?
in aorta, periosteum, alveolar walls, and skin
what is the most concerning manifestation in marfan syndrome?
aortic dilatation (aortic root disease) as the major cause of morbidity and mortality in marfan’s
What is the effect of the mutation on Fibrillin-1 in Marfan’s?
patients do not have normal functioning fibrillin which causes the connective tissue to be overly elastic; there is also weakening in the connective tissues
What are the cardiac manifestations of marfan’s syndrome?
aortic root disease, aortic aneurysm, aortic regurgitation, aortic dissection, mitral valve prolapse
What are the skeletal manifestations associated with Marfan’s syndrome?
excess linear bone growth, tall with long arms, arachnodactyl (spider fingers), and dolichostenomelia (arm span is greater than body height), positive wrist sign, positive thumb sign, scoliosis, kyphosis
What are the two different manifestations that have to do with the chest in marfan’s?
pectus carinatum- funnel chest
pectus excavatum- pigeon chest
What are the ocular manifestations associated with marfan’s syndrome?
ectopia lentis- dislocated lens
What is typically used to diagnose marfan’s syndrome?
genetic testing is not always needed and Ghent criteria can be used
What is an aortic aneurysm?
widening or bulging of the wall of the aorta; defined as having > 50% increase in the diameter for that portion of the aorta
What are risk factors for aortic aneurysms?
genetic defects such as marfan’s, also smoking, hypertension, and hypercholesterolemia
What is an aortic dissection?
a tear forms in the inside layer of the aorta and blood begins to fill between the layers; blood fills in the false lumin -> can lead to massive hemorrhage
What are some symptoms that can present with an aortic aneurysm?
chest pain, upper back and left shoulder pain, hypotension; but most patients that have aneurysms are asymptomatic
What are the four P’s in the clinical presentation of an aortic aneurysm or dissection?
Pallor, Pulselessness, Parasthesias, and Paralysis
How is familial thoracic aortic aneurysms inherited?
autosomal dominant inheritance
How many genes have been identified for involvement in FTAA?
4 genes on 4 different chromosomes
What is the difference between patients with FTAA and Marfan Syndrome?
in FTAA patients present at a much later age than patients with Marfan Syndrome
What is important to remember with genetic testing in FTAA?
genetic testing is available for all 4 genes; all first degree relatives should be screened; knowledge prior to pregnancy is important due to the high-risk of dissection and rupture in pregnant women with this condition
What are the different types of cardiomyopathies?
dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic cardiomyopathy
What is hypertrophic cardiomyopathy?
the myocardium becomes thickened; especially in the left ventricle
What is restrictive cardiomyopathy?
walls become stiff and rigid but not thick; usually because of replacement of normal myocardium by scar tissue
What is arrhythmogenic cardiomyopathy?
right ventricular myocardium replaced with scar tissue
what are two of the most common hereditary cardiomyopathies?
hypertrophic cardiomyopathy (HCM)-disorder of the left ventricle arrhythmogenic cardiomyopathy (ARVD/C)- disorder of the right ventricle
How is hypertrophic cardiomyopathy most commonly inherited?
in an autosomal dominant pattern
What are the mutations involved in HCM? (hypertrophic cardiomyopathy)
12 or more genes linked to over 1400 mutations; the mutations involve coding for the tick or thin filaments of the sarcomere; sometimes called disease of the sarcomere
What are some manifestations of HCM?
left ventricular hypertrophy, impaired left ventricular contractility, dyspnea on exertion, palpitation, chest pain, syncope
What is arrhythmogenic right ventricular dysplasia/ cardiomyopathy characterized by?
fibro fatty replacement of right ventricle myocardium and myocardial thinning
What are the clinical manifestations of ARVD/C?
arrhythmias, palpitations, chest pain, syncope
How many genes are known to be associated with ARVD/C?
8!
