Chapter 5 Flashcards
What percentage of spontaneous abortions have chromosomal abnormalities
50%
What percentage of newborns contain a gross chromosomal abnormality
1%
Will mutations in somatic cells cause defects in progeny
No
What is a single base nucleotide substitution
The base is changes, potentially resulting in the change of a single amino acid
What is a missense mutation
Single base mutation resulting in the change of amino acid
What is conservative amino acid base substitution
The change in amino acid is so similar, that the function of the protein causes little change
What is the amino acid sequence change that results in Beta-globin chain sickle cell anemia
CTC (GAG in mRNA) which is a glutamate —> CAC (GUG in mRNA) which is a valine
What is a nonsense mutation
The base change results in a stop codon
What is B0-thalassemia
Beta-globin chain is prematurely stoped due to nonsense mutation, resulting in immediate degradation
In the Beta-0 globin allele, what amino acid die the change occur and what amino acid stops
38 is the amino acid change and stops there resulting from a change to a stop codon
What is a frameshift mutation
Change in amino acid number (addition or deletion) of a nonmultiple of 3
What is the usual result of a frameshift mutation
Variable number of incorrect amino acids followed by a premature stop codon
Which bases do almost all trinucleotide repeats incorporate
Cytosine and Guanine
What type of mutation results in taysachs disease
Frameshift mutation (addition of 4 amino acids)
What type of mutation results in the blood allele Group O
Frameshift mutation from the addition of a single nucleotide
What are the conditions that are incorporated into single gene disorders with nonclassical patterns of inheritance
1) Triple-repeat mutations
2) mutations in mitochondrial DNA (mtDNA)
3) genomic imprinting and gonadal mosaicism
What does the term congenital mean
Means born with, but does not have to be familial (ex congenital syphilis)
What are virtually all Mendelian disorders
Mutations in single genes that have large effects
What percentage of non expressive recessive mutations arefamilial
80-85%
Sickle cell anemia is caused by what
Substitution of normal hemoblobin (HbA) with hemoglobin S (HbS)
Under which conditions with a heterozygous individual for sickle cell express the RBC sickling (aka sickle cell trait)
Under lower oxygen tension
What are two examples of codominance
Blood group compatibility and MHC
What is pleiotropism
A single gene mutant leads to many effects
What is genetic heterogeneity
Mutations at several genetic can produce the same trait
Sickle cell mutation is described as what
Pleiotropism
How is sickle cell an example of pleiotropism
The disfigured sickle cells can log jam vessels, leading to splenic fibrosis, organ infarcts, and bone changes
Mutations involving a single gene follow which of three patterns
1) Autosomal dominant
2) Autosomal recessive
3) X-linked
How is it possible to have an autosomal dominant gene expressed in a chid but not in a parent
There is a new mutation in either the sperm of the egg they were derived from
In the case of a child who inherited an autosomal dominant trait from unsympotomatic patients, how likely are subsequent siblings to develop the disease
Not at all, as siblings are not effected not at higher risk
If a disease causes a decrease in reproductivity, how is the trait passed on
Usually a result of a new mutation. Commonly seen in germ cells of older father
What is incomplete penetrance
Inheriting the mutant gene, but phenotypically normal
Neurofibromatosis type 1 presents what type of expressivity
Variable expressivity
What is the result of loss of 50% of LDL receptors
Secondary elevation of cholesterol that predisposes pt to atherosclerosis
What is dominant negative
In genes that are autosomal dominant, the loss of one gene impacts the functionality of the working gene such that there is no viable product
How is collagen an example of dominant negative
Collagen is a trimeric structure. Loss of function on one of the strands leads to the inability to form the whole structure
Transmission of a disorder produced by a gain of function mutation is almost always what
Autosomal dominant
How is Huntington disease an example of gain of function disease
Mutation gives rise to abnormal protein called Huntington, which is toxic to neurons, so even a heterozygote can develop disease
What type of disorder makes up the largest category of disorders
Autosomal recessive
Almost all inborn errors of metabolism are what kind of disorder
Autosomal recessive
What are the characteristic findings of autosomal recessive that separate them from other disorders
- Complete penetrance
- onset early in life
- more uniform expression
- New mutations are rarely seen clinically
- Many of the genes encode enzymes
Why is the there no Y linked inheritance
Because disorders on Y chromosome usually lead to infertile males
Males are considered what with regards to X chromosome
Hemizygous for X linked mutant genes
What is the rate of inheritance of a positive X linked disorder male
Will not pass to male sons, all daughters are carriers
How is a heterozygous female able to express phenotypically the X linked disorder
Random inactivation of an X chromome could cause the normal X to be silenced
What is the heritability of G6PD deficiency
X linked
How does G6PD deficiency affect females who are heterozygous
X linked trait, so affects males via hemolysis. Females will have some RBCs that are enzyme deficient and can still result in hemolysis
What is the heritability pattern of an X linked dominant disorder from the father
Gives to all of the daughters, and none of the sons
What is the example of X llinker dominant disorders
Vitamin D resistant rickets
What is type of heritability disorder for Huntington disease
Autosomal dominant
What is type of heritability disorder for Neurofibromatosis
Autosomal dominant
What is type of heritability disorder for Myotonic dystrophy
Autosomal dominant
What is type of heritability disorder for Tuberous sclerosis
Autosomal dominant
What is type of heritability disorder for Polycystic kidney disease
Autosomal dominant
What is the result from a mutation resulting in the decreased synthesis of an enzyme with reduced activity or reduced amount of normal enzyme
Metabolic block
The mutation in galactose-1 phosphate uridyltransferase results in the buildup of which product
Galactose
What is the result in the defect in tyrosinase
Deficiency in melanin, leading to albinism
What is the result of the metabolic block in alpha1-antitrypsin deficiency
Failure to inactivate neutrophil elastase in lungs
What is the result of a mutated LDL receptor in familial hypercholesterolemia
Reduced synthesis of LDL, decreased transport of LDL into cell, increased cholesterol in blood, increased cholesterol synthesis
What is the general characteristics of thalassemias
Mutations in globulin genes that result in a decrease in the amount of globulin chains made
What drug is contraindicated in G6PD deficiency
Primaquine
What is the result of administration of antimalarial drug primaquine to a G6PD deficient patient
Hemolytic anemia
What the three systems mainly affected by Marian syndrome
Skeleton, eyes, and cardiovascular system
What is the prevalence of Marian syndrome
1 in 5000
What is the percentage of Marian syndrome cases that are familial and transmitted by autosomal dominant inheritance
70 to 85%
What does the pathogenesis of Marfan come from
Defect in extracellular glycoproteins called fibrillin 1
What are the two general mechanisms that Marfans syndrome results in weakened connective tissue
- Loss of structural support in micro fibril rich connective tissue
- Excessive TGF beta signaling
The fibrils that are affected in Marfans serve which purpose
Act as scaffolding for tropoelastin, which is deposited to from elastic fibers
What are the main locations of elasticity loss in Marfans
Aorta, ligaments, ciliary zonules (supporting the lens)
FBN1, which codes for fibrillin-1, is located on which chromosome location
15q21.1
FBN2, which codes for fibrillin-2, is located on which chromosome location
5q23.31
Mutations in which gene is the underlying mechanism of pathogenesis in Marfans
FBN1
What does a mutation in FBN2 cause
Congentical contractural arachnodactyly
What is congenital contractural arachnodactyly caused by and what is the pattern of inheritance
Autosomal dominant, mutation in FBN2
What is haploinsufficiency
Reduction of fibrillin content below threshold, resulting in connective tissue weakness
What is the correlation between TGFbeta levels and Marfans
Marfans has excessive TGFbeta due to loss of microfibrils. Increases MMP and the loss of ECM
What are the normal clinical features of a healthy patient with Marfans
-Tall, with long extremities, tapering fingers and toes. Double jointed with a hyperextended thumb. Frontal eminences and prominent supraorbital ridges.
What will a patient with Marfans present with regards to spinal deformities
Kyphosis, scoliosis, rotation or slipping of the lumbar vertebra
What will a patient with Marfan present with regards to the chest
Lecture excavatum is pigeon breasted
What will a patient with Marfan present with regards to ocular changes
Ectopia lentis, aka bilateral subluxation or dislocation of the lens
A patient presenting with ectopic lentis, or outward and upward dislocation of the lens should be checked for which condition
Marfans
What are the commonly seen CV findings in a pt with Marfans
Mitral valve prolapse, dilation of the ascending aorta (due to cystic medionecrosis)
What is the common cause of death in Marfans patients and what is the percentage
Aortic dissection/hemorrhage in 30-45% of pts
What is required for the diagnosis of Marfans
Major involvement of two organ systems (MSK, CV, Ocular, Skin) and minor involvement of another organ
What is the main treatment for Marfans
Beta blockers to decrease HR and aortic stress
Ehlers-Danlos Syndrome (EDS) is caused by which general underlying condition
Defect in the synthesis or structure of collagen
Which of Mendelian patterns does Ehlers-Danlos Syndrome (EDS) encompass
All 3 principles
What are the locations of structures most affected by Ehlers-Danlos Syndrome (EDS)
skin, ligaments and joints
What are the serious complications seen in patients with Ehlers-Danlos Syndrome (EDS)
-Rupture of colon and large arteries, cornea and retinal detachment, diaphragmatic herniation
What is the most common form of Ehlers-Danlos Syndrome (EDS)
Lyphoscoliosis type
What is the heritability of Ehlers-Danlos Syndrome (EDS) type 1
Aka classic
Autosomal dominant
What is the heritability of Ehlers-Danlos Syndrome (EDS) type 2
Autosomal dominant
What is the herititability of Ehlers-Danlos Syndrome (EDS) type 3
Aka hypermobility’
Autosomal dominant
What is the heritability of Ehlers-Danlos Syndrome (EDS) type 4
Aka vascular
Autosomal dominant
What is the heritability of Ehlers-Danlos Syndrome (EDS) type 6
Aka hyphoscoliosis
Autosomal recessive
What is the heritability of Ehlers-Danlos Syndrome (EDS) type 7a/b
Aka arthrochlasias
Autosomal dominant
What is the heritability of Ehlers-Danlos Syndrome (EDS) type 7c
Aka dermatosparaxis
Autosomal recessive
What is the mutation coding in Ehlers-Danlos Syndrome (EDS) kyphoscoliosis
Lysyl hydroxylase (can not hydroxylate lysine residues)
What is the mutation code in Ehlers-Danlos Syndrome (EDS) vascular type
COL3A1, giving rise to abnormalities in collagen type 3
What is the defect in Ehlers-Danlos Syndrome (EDS) arthrochalasia type
COL1A1 and COLA1A2, which is defect in conversion from procollagen to collagen via defect in the pro-alpha chains (resist cleavage)
What is the defect in Ehlers-Danlos Syndrome (EDS) dermatosparaxis type
Mutations in procollagen-N-peptidase gene, preventing cleavage from procollagen to collagen
What is the defect in Ehlers-Danlos Syndrome (EDS) classic type
COL5A1 and COL5A2
What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 1/2
Skin and joint hyper mobility, strophic scars, easy bruising
What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 3
Joint hypermobility, pain, dislocations
What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 4
Thin skin, arterial and uterine rupture, bruising, small joint hyperextendability
What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 6
Hypotonia, joint laxity, congenital scoliosis, ocular fragility
What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 7a/b
Severe joint hyper mobility, skin changes, scoliosis, bruising
What are the clinical presentation for Ehlers-Danlos Syndrome (EDS) Type 7c
Severe skin fragility, cutis lata, bruising