Chapter 5 Flashcards
(146 cards)
1
Q
Traits of Mendelian Disorders (4)
A
- Highly Penetrant
- Single gene mutations
- Follow mendelian inheritance
- Generally rare unless there is strong selection (sickle cell)
2
Q
traits of Chromosomal Disorders (2)
A
- Structure or number problems
2. Highly penetrant
3
Q
traits of Complex Multigene disorders (3)
A
- AKA polymorphisms (each mutation add a little to problem)
- More common
- Low penetrance/highly variable
4
Q
Point Mutations (1)
A
- Single BP switch
5
Q
Types of point mutations? (2)
A
- Missense (conservative and non-conservative)
2. Nonsense mutations
6
Q
This mutation forms a stop codon.
A
Nonsense mutation
7
Q
This mutation changes one Amino Acid
A
Missense
8
Q
B-thalassemia is what type of mutation?
A
Nonsense mutation
anemia due to reduced b-globulin?
9
Q
Example of non-conservative missense, deals with blood cell shape.
A
Sickle cell
10
Q
Intron related mutations are in …?
A
non-coding sequences
11
Q
Effects of mutations in non-coding sequences? (2)
A
- Transcription problems (effect regulatory sequences
2. mRNA processing and splicing issues
12
Q
2 outcomes of deletions/insertions?
A
- Frame shift (often premature stop codon arises)
2. Multiple of 3 (add/subtract AA)
13
Q
Tay-sachs is an example of what type of insertions?
A
4 BP insertion
14
Q
Trinucleotide-repeat mutation traits (2)
A
- Amplification of 3 NT sequences (mostly GC)
2. Non-classic inheritance pattern (increases with generations) aka dynamic
15
Q
Pleotropism
A
1 genes => many effects (sickle cell)
16
Q
Genetic Heterogeneity
A
Multigens => 1 effect
17
Q
Autosomal Dominant Disorders characteristics (2 to really know)
A
- Patients w/o effected parents = new mutation
2. Penetrance can vary
18
Q
Autosomal Recessive Disorders (2)
A
- Early onset relative to dominant disorders
2. Complete Penetrance
19
Q
X-Linked Disorders
A
- Most are recessive
- Males are affected and pass to daughter carriers (no sons)
- Daughter carriers pass to sons
20
Q
Biochemical and Molecular basis of single Gene - 4 mechanisms
A
- Enzyme defects and consequences
- (metabolic block, Lack of feedback, failure to inactivate tissue damaging substrate) - Defects in R + transport systems (ex. Familial hypercholesterolemia)
- Alterations in structure, Function or quality of nonenzyme proteins
- Genetically Determined Adverse Reactions to drugs.
21
Q
Marfan Syndrome: Defect in?
A
Fibrillin
22
Q
Where is Fibrillin found? (3)
A
Marfan Syndrome:
1. Eyes
- Skeleton
- Cardiovascular system
23
Q
Marfan Syndrome: Fibrillin mutation?
A
FBN1 (can be FBN2)
24
Q
Fibrillin scaffolding for?
A
Elastin
25
Marfan Syndrome: What else plays a factor (not fibrillin).
Excessive TGF-B activation
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Excessive TGF-B activation leads to?
1. bone overgrowth
| 2. Myxoid changes in MITRAL VALVES
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What causes TGF-B problems?
Reduced microfibril activation (normal microfibrils cage TGF-B)
28
Marfan Syndrome: Morphologic changes
1. Skeletal abnormalities
2. Ocular changes
3. Cardiovascular
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Marfan Syndrome: Skeletal abnormalities
1. Tall, long limbs, tapering fingers and toes
- Joints are lax, tongue can be hyperextended to wrist
- dolichocephalic (longheaded)
- Spinal deformities
30
Marfan Syndrome: Ocular Changes
1. Bilateral luxation or dislocation (up or out)
| - Ectopia lentis bilaterally
31
Marfan Syndrome: Cardiovascular changes
1. Mitral Valve prolapse
2. Dilation of ascending Aorta
- diagnosed via echocardiograph
32
Marfan Syndrome: Diagnosis
2/4 organ systems
33
Marfan Syndrome: Treatment
B-blockers: angiotensin 2 blockers in humans
34
Ehlers-Donlos Syndromes (EDS): main problem?
Collagen
-Post transcriptional
35
Tissues rich in collagen?
1. Skin
2. Ligaments
3. Joints
36
Ehlers-Donlos Syndromes (EDS): Clinical presentation
1. Extreme Flexibility
2. Minor injuries => gaping
3. Rupture of colon or Large A.
4. Ocular fragility and retinal detachment
5. Diaphragmatic Hernia
37
Ehlers-Donlos Syndromes (EDS): Types?
1. Kyphoscoliosis (most common-Type 6)
2. Vascular EDS (Type 4 EDS and type 3 collagen)
3. Arthrochalasia and dermatosparaxis (type 7 EDS and Type 1 collagen-procollagen to collagen)
4. Classic type (type 1/2 and Type 5 collagen)
38
Ehlers-Donlos Syndromes (EDS): Recessive or Dominant?
Recessive
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Ehlers-Donlos Syndromes (EDS): Kyphoscoliosis mutation?
Lysyl Hydroxylase
40
LDL receptor mutation is seen in?
Familial Hypercholesteralemia
41
Familial Hypercholesteralemia: What are the 3 proteins on VLDL
1. ApoC
2. B-100
3. ApoE
42
Familial Hypercholesteralemia: What protein remains on IDL
1. ApoE
| 2. B-100
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Familial Hypercholesteralemia: What protein remains on LDL
1. B-100
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VLDL and IDL contain
Cholesterol and Triglycerides
-IDL has less triglycerides
45
LDL contains
Just cholesterol
46
Familial Hypercholesteralemia: 5 classes
```
class 1: synthesis
class 2: transport
class 3: binding
Class 4: Clustering
Class 5: Recycling
```
47
Percent of IDL to liver?
50%
48
What does LDL receptor recognize?
ApoE and B-100
49
Synthesis of cholesterol requires what enzyme?
HMG CoA reductase
50
NPC does what?
Removes cholesterol from lysosome.
51
NPC is related to what disease?
Nieman-Pick Disease
52
What stimulates storage of cholesterol esters?
acyl-coenzyme A
| and oversupply of cholesterol
53
Familial Hypercholesteralemia: Results in? (5)
1. decreased LDL catabolism
2. increased Plasma LDL (2x or 5x)
3. Increased LDL synth
4. Impaired IDL transport => increased LDL formation
5. Scavangers/monocytes can't handle load => Xanthomas
54
Familial Hypercholesteralemia: is what type of disease?
Autosomal Dominant
Polygenic: requires multiple polymorphisms
55
Familial Hypercholesteralemia: Treatment?
Statins (2ndary prevention of ischemic heart disease)
56
Lysosomal storage diseases: (5)
1. Tay-sachs
2. Nieman-Pick Type A and B
3. Nieman-Pick Type C
4. Gaucher Disease
5. Mucopolysaccharidoses (MPS)
57
Lysosomal storage diseases: Lysosomal marker?
Mannose-6-phosphate
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Lysosomal storage diseases: 2 consequences
1. Primary accumulation: Incomplete catabolism
2. Secondary accumulation: Impaired Autophage (accumulation of cell organelles and can trigger apoptosis)
- Accumulation of mitochondria can develop free radicals = death
59
Lysosomal storage diseases: 3 Tx
1. Enzyme replacement therapy
2. Substrate reduction therapy
3. Molecular Chaperone Therapy -exogenous competitive inhb used as template for misfolded proteins (Gaucher
60
Lysosomal storage diseases: Mucopolysaccharide degradation effects what organ?
All organs
61
Lysosomal storage diseases: Phagocytic rich organs are?
1. Spleen and liver
| - Often enlarged
62
Whorled configurations of lysosomes is associated with a defect in what enzyme? What accumulates?
1. Tay-sachs Disease
2. Hexosaminidase deficiency
3. GM2 Gangliosidosis build up
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Tay-Sachs: Prevelent among?
Eastern European Jews
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What type of cells will you fined ganglioside filled vacules?
Tay-sachs effects Neurons (ANS + CNS)
65
Common characteristic of Neural storage diseases found in most Tay-sachs cases?
Cherry red macula (swollen Retina ganglia)
66
Clinical features of Tay-Sachs?
1. Mental/motor deteriation at 6 months
| 2. Protein misfolding (chaperone therapy potential Tx)
67
Pt with foamy cytoplasm, neuro issues and death in 3 yrs. Defect in what is most likely?
1. Niemann-Pick Disease Type A
2. Deficiency in sphingomyelinase
3. Build-up of sphingomyelin
68
Niemann-Pick Type A: Clinical features? (5)
1. Foamy cells
2. Zebra bodies (concentric bodies)
3. Death in 3 yrs (severe infantile)
4. Neuro issues
5. Failure to thrive, vomiting, fever
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Niemann-Pick Type B: Clinical features (3)
1. No Neural issues!
2. Organomegaly (Protuberant abdomen due to hepatosplenomegaly-huge spleen!)
3. Brain gyri shrunk
70
This disease causes a buildup of cholesterol in lysosomes. What is the mutation?
1. Niemann-Pick Disease Type C
| 2. Mutation in NPC1 (and 2 but mostly 1)
71
Niemann-Pick Disease Type C: May present as?
1. Hydrops fetalis
2. Neonatal Hepatitis - still birth
3. Chronic (most common): Neuro damage, ataxia and supranuclear gaze
72
Pt with hepatosplenomegaly, Bone Erosion and fibrillary type cells that look like tissue paper:
What is the disease/weird cells? What Enzyme deficiency is most likely? What builds up?
1. Gaucher disease-Gaucher cells
2. Glucocerebrosidase
3. Phagocyte accumulation
73
Gaucher disease: 3 types?
Type 1 Non-neuropathic:
-Limited to Macrophages-still some glucocerbrodase activity. Jews w/slightly shortened lifespan
Type 2 Acute Neuropathic:
-No glucocerebrodase acitvity = early death
Type 3 Intermediate: begins in adolesence
74
Gaucher Disease Type 1: Clinical features (2)
1. Adult splenomegaly/bone issues
| 2. 2ndary pancytopenia and thrombocytopenia (spleen related)
75
Gaucher Disease Tx?
Replacement therapy. Expensive!
76
Gaucher Disease Type 2/3: Clinical features? (2)
1. Gaucher cells in Virchow-Robin spaces
| 2. No lipids in Neurons (cytokines damage Neurons)
77
Pt with joint stiffness, mental retardation, course facial features and clouding of cornea:
Disease?
Deficiency?
Build up?
1. Mucopolysaccharidoses (MPS)
2. Mucopolysacharide degradation deficiency
3. Sulfate (heparin-sulfate) based stuff accumulates
78
Mucopolysaccharidoses (MPS): Type of disease?
Autosomal recessive
Hunter syndrome is x-linked!
79
Mucopolysaccharidoses (MPS): Where is it found?
1. Phagocytes
2. Endothelium
3. Smooth Muscle
4. Fibroblasts
80
Mucopolysaccharidoses (MPS): Will you find zebra bodies?
some but not as much as in Gaucher disease
81
Mucopolysaccharidoses (MPS): two types?
1. Hurler syndrome (MPS-I)
- manifests 6-24 months and death in 6-10 yrs
2. Hunter Syndrome (MPS-II)
- X-linked, Milder, MPS-II
82
Mucopolysaccharidoses (MPS): Morphologic features?
1. Balloon cells (cleared cytoplasm-small vacules w/acid schiff)
2. Some Zebra bodies
3. Spleen/Lover
4. Skeletal deformaties
5. Arterial deposits (effecting brain and coronary arteries)-think MI
83
Types of Glycogen Storage Diseases? (3)
Hepatic:
-Type 1-Von Gierke
Myopathic:
- Type 5- McArdle
- Type 7-M. Phosphofructokinase activity
A-glucosidase/branching enzyme deficiency:
-Pompe Disease
84
Cardiomegaly and death in early life associated with what disease?
Pompe disease: acid maltase deficiency (branching enzyme)
85
Increased glycogen storage in liver and decreased blood glucose in what disease?
Von Gierke (type 1 hepatic)
86
Muscle cramps after exercise and M. Phosphorylase activity down
McArdle disease: Type V
87
Deficiency in glycolytic pathway enzymes results in what?
reduced ATP to muscles
88
Type VII disease?
M. Phosphofruktokinase related. Myopathic
89
Multigenic Disorders can...
range in severity because they are polymorphisms. home BOYEEE!!!!!!!
90
Chromosomal disorders: multiple of 23
Euploid
91
Chromosomal disorders: not multiple of 23
aneuploidy
92
What causes Aneuploidy??
Nondisjunction and anaphase lag
93
What happens when I have 2 or more populations of cells and what type is this mostly seen with?
1. Mosaicism
| 2. Sex chromosomes
94
How do we see chromosomal changes?
we FISH for them (FISH is a test duh).
95
5 types of chromosomal changes:
1. Translocations
2. Isochromosomes
3. Inversions
4. Deletion
5. Ring Chromosome
96
What the F are Translocations? 2-types
2 types:
1. Balanced/recipricol
2. Centric fusion/Robertsonian
97
Whats a robertsonian? (3)
Translocation/Centric fusion:
1. Acrocentric (happens around edges of chromosome)
2. break into 1 small and 1 V. Large chromosome. small usually lost
3. Phenotype generally normal
98
What is a balanced recipricol?
Translocation:
1. No loss of genetic material
2. High risk of abnormal gametes
99
Isochromosomes? (3)
1. 1 arm of chromosome lost and remaining duplicated
2. get a large or small chromosome
3. Xq gives us the only live birth with this
100
2 types of inversion
1. Paracentric (swap places on 1 side of chromosome)
| 2. Pericentric (swap places on oppo sides of chromosome
101
Deletions are...
rarely terminal
102
Ring chromosome?
1. Deletion at both ends and the ends fuse to make a ring
103
Epicanthic folds, Oblique palpebral fissures, flat facial profile are all a result of what?
1. Nondisjunction leading to trisomy 21 and downs syndrome
104
Downs syndrome risk increases with...?
...increased maternal age
105
What other additional risks for downs syndrome? (4)
1. Increased risk of Leukemia
2. After 40, downs Pts likely to get Alzheimers like diseases
3. Increased infection rate (especially thyroid and lung)
4. 40% have congenital Heart Disease (endocardial cushion)
106
How is downs tested for?
1. DNA of maternal blood derived from fetus used
107
Downs is a trisomy of what chromosome
21
108
Trisomy 18 is...
Edwards syndrome
109
Edwards syndrome Pts...
1. Die w/in 1 yr
2. Have simian crease on hand
3. Interstitial stenosis
110
Pt has cleft lip, polydactyly and rocker bottom feet.
Patqu Syndrome-trisomy 13
More severe that downs.
111
Pt has cleft palate, schizophrenia, decreased T-cell count, learning disabilities.
Disease/cause of?
1. DiGeorge Syndrome
| 2. Deletion in Chromosome 22q11.2
112
DiGeorge Syndrome also associated with?
1. Bipolar disorders
2. Thymichypoplasia (causes decreased T-cells)
3. Cardiovascular abnormalities
113
Factor associated with DiGeorge syndrome?
TBX-1 targets PAX9 and is associated with DiGeorgy syndrome phenotype
114
decreased spermatogenesis region?
MSY region on the Y chromosome
115
Heteropyknosis:
the inactivation of 1 x chromosome
116
What is an inactive X called?
Barr body
117
What forms Barr Body?
XIST will cover w/long repeats and silence x via methylation
118
Females are generally...
CRAZY!! kidding!! they are mosaics. hahahahahaahahaahahhaahahaha who is crazy now hahahaaa jesus.
119
More x =>
increased mental retardation
120
Pt with type 2 diabetes, mitral valve prolapse, small penis, increased FSH and hypogonadism:
Disease?
Cause?
1. Klinefelter syndrome
| 2. Multiple x, 1 or more Y (XXY)
121
Klinefelter Syndrome: clinical features (6)
1. Hypogonadism
2. Elongated body
3. Lack of 2ndary sex Character
4. Mitral valve prolapse (50%)
5. Male infertility
6. Increased FSH and decreased testosterone
122
Klinefelter Syndrome: Increased risk?
1. Type 2 diabetes
| 2. Breast cancer
123
Klinefelter Syndrome: Hypogonadism causes
1. increased x expression
124
Pt has webbed neck, primary amenorrhia, short stature, broad chest and streak ovaries:
Disease?
Cause?
Types of structural abnormalities possible?
1. Turner syndrome (45X)
2. Missing one x chromosome or structural abnormalities
3. Isochromosome, Ring chromosome, Deletions
125
What causes short stature?
loss of SHOX gene
126
Turner syndrome clinical features (5)
1. Short stature
2. Neck Webbing
3. Broad chest
4. Streak ovaries
5. Peripheral lymphedema at birth
127
Types of single-gene disorders (4)
1. Trinucleotide repeats
2. Mutations in mitochndria
3. Genomic Imprinting
4. Gonadal Mosaicism
128
Trinucleotide repeat diseases? (2)
1. Fragile X syndrome and Fragile x tremor/ataxia
| 2. Huntingtons
129
Trinucleotide diseases are common in?
Neodegenerative disorders
130
General principles of trinucleotide diseases?
1. Expansion of G/C trinucleotide regions
2. Proclivity of expansion depends on sex of transmitting parent (Fragile x = mom, huntington = dad)
3. 3 key mechs (loss/gain of function and Toxic gain of mediation by mRNA
4. Coding regions are CAG repeats
131
CAG repeats will accumulate in?
Intranuclear inclusions
132
Pt is male with long face and macroorchidism.
Disease?
Cause?
1. Fragile X syndrome
| 2. Mutation in FMR1 mutation
133
Fragile x Clinical features:
1. Long face
2. Macroorchidism
3. Abnormal inheritance patterns (increased rink downstream generations)
134
What parent is at fault for Fragile X?
Mother: CGG repeats expand during oogenesis but females are generally unaffected.
-More female carriers are effected than in normal x-linked diseases
135
FMR1 mutation occurs when and what does it cause?
1. CGG > 230
2. Mental retardation caused by lack of FMRP
3. FMRP also regulates intracellular transport to dendrites
136
mRNA toxic gain of function is related to...
Fragile X Tremor/Ataxia
137
Fragile X Tremor/Ataxia: clinical characteristics
1. Neurological disorder later in life
| 2. May progress to parkinsons.
138
Fragile X Tremor/Ataxia: cause?
FMR1 is failed to be silinced
139
This diseases require a threshold of mutations to be met and is a progressive bilateral loss of vision.
Leber heredity optic neuropath
-Mitochondrial mutation
140
Heteroplasmy definition:
Indv w/wild type and mutant mtDNA
141
Why is mtDNA mutation diseases so variable?
Division of mutant DNA passed on is highly variable
142
CG repeat methylization that occurs in sperm or ovum before fertilization.
Genomic Imprinting
143
Male pt that cant stop eating has small trump hands, and a deltion in chrom 15:
disease?
Cause?
1. Prader-willi
| 2. Loss of SNORP and deletion in PATERNALLY derived chrom 15 (mother 15 is imprinted)
144
Pt can't stop laughing and walks like a drunk person (ataxic gate) (2)
1. Angelman Syndrome
| 2. Ubiquitin ligase defect and deletion in MATERNAL chrome 15
145
Uniparental disomy definition
2 copies, 1 parent
146
Mutations that occur after zygote formation are typical of... (3)
Gonadal Mosaicism
- Effect only gametes so parent appears normal
- more than 1 child can get mutation
