BMS Exam 2 Diseases Flashcards
1
Q
Allelic Heterogeneity
A
Distinct mutations in the same gene, producing same phenotype.
CFTR
- Multiple mutations/genotypes produce the same phenotype (Absent functional CFTR)
*B-thalassemia
2
Q
Phenotypic Heterogeneity
A
Distinct mutations in the same gene producing very different phenotypes
We can have different mutations in the same gene that can produce tremendous differences in expressions of the disease.
CFTR
- Different mutations in same gene all cause CF but depending on the mutation you will have varying severity of dz
3
Q
Locus Heterogeneity
A
Mutations at different loci that produce the same phenotype
Same dz can be caused by more than one gene mutation
- Long QT phenotype caused by mutations in more than one gene
- Albinism
4
Q
Pleiotropy
A
Single gene mutations producing multiple diverse phenotypic effects in multiple systems.
One gene affects multiple traits. Single gene defect that: - affects multiple organ systems - produces multiple diverse phenotypes - variety S&Sx
Ex. VHL - symptoms in multiple organ systems. Difficult to dx
*PKU
5
Q
Polygenic
A
Multiple genes affect one trait
Ex. Male baldness
6
Q
Cystic Fibrosis Inheritance
A
Autosomal Recessive
- Individual MUST HAVE 2 mutant
- No WT
- Type of mutation in each allele can be different (compound heterozygote)
- Affects enzymes
- Risk of inheritance is 1/4
- Risk of carrier is 1/2
- Risk of unaffected is 3/4
- Risk of unaffected child being carrier –> 2/3**
On a pedigree
- Parents unaffected, asymptomatic carriers
- Males = females
- Phenotype found in siblings
- Rare traits often found in related parents (two lines connecting parents)
7
Q
Wilson’s Disease
A
Autosomal recessive
- affects copper processing and liver
8
Q
Familial Hypercholesterolemia
A
Autosomal dominant
- Xanthomas
- Risk that child will be affected 1/2 (Bb x bb)
- Risk of phenotypically normal child with mutant allele is zero unless there is incomplete penetrance
- Every affected individual has affected parent
- No skipping of generations
- Males = females
- male to male transmission
- Normal individuals will have unaffected children
- Also achrondroplasia
(Short limbed dwarfism) - Incomplete dominance
An individual that is homozygous will be more severely affected than heterozygous ppl
9
Q
Reduced penetrance
A
Complete penetrance - everyone who has mutation is affected
Reduced (or incomplete) - less than 100%
- AD form of split-hand foot malformation has reduced penetrance of 70%. Skips generation and hard to interpret pedigree
10
Q
Variable expressivity
A
Varying phenotype among individuals with same dz
genotype
- All individuals affected but severity is different
- Neurofibromatosis has age-dependent penetrance and variable expressivity
11
Q
Male-limited precocious puberty
A
Sex-linked AD
- Mutation in LHR gene that keeps it active all the time
- ONLY EXPRESSED IN MALES
- Secondary sex characteristics with growth spurt by age 4
- Females unaffected but can pass to male child
Pedigree: male to male transmission exludes x-linked recessive disorder
12
Q
Hemochromatosis
A
Sex-linked AR
***most common single gene inherited dz in the US
Phenotype dependent
- More common in males who have no physiologic process to reduce excess iron
- Woman can reduce iron through bleeding
13
Q
Hemophilia A
A
X-linked recessive
- Risk bw unaffected M and carrier F - 1/2 F carry and 1/2 M affected
- Risk bw affected M and unaff F - All F carry, All M normal
- -> Never male to male transmission in X-linked disorder
- Males»_space;> female
- Hetero F are unaffected; depends on x-inactivation
- Phenotype in homo, hemi, or compound hetero
14
Q
X-linked Dominant
A
- Trait never from father to son
- Affected M and normal F –> All daughters affected and all sons are normal
- Doesn’t skip generations
15
Q
Mosaicism
A
After zygote is fertilized and cell division begins, can have mutations develop along the line and then the cells in the individual are not genotypically the same.
- Pure somatic (present in some tissues in the embryo but not the germ cells)
- Pure germline
Depends on if mutation occurred before or after separation of germline cells from the somatic cells
16
Q
Germline Mosaicism
A
- Typically, a person with only germline mosaicism will not be affected with the disorder caused by the mutation because the mutation is not in the other cells of the body. Genetic testing using blood or tissue samples (other than germline tissue) from individuals who only have a germline mutation will be negative for the mutation.
- Most commonly seen with autosomal dominant and X-linked disorders.
- Osteogenesis imperfecta
- Hemophilia A/B
- Duchenne muscular dystrophy
17
Q
Somatic Mosaicism
A
- A person who is mosaic for a somatic mutation may or may not be affected by the disorder caused by that mutation. Individuals will express the phenotype depending on how many and which cells are affected.
- Down Syndrome
- Neurofibromatosis (NF)
- Cancer
18
Q
Genetic Lethal
A
Diseases are produced by dominant alleles with effects so severe that persons with them do not have children
- Severe forms of osteogenesis imperfecta (AD)
- Duchenne MD (XLR; genetic lethal)
19
Q
Prader willi
Angelman
A
PW
- Loss of paternal genes
- 20 maternal imprinted genes affected
A
- loss of maternal genes
- 1 paternal imprinted gene affected
Chromosome 15
20
Q
Leigh Syndrome
A
No Ragged Red Fibers (RRF)
- Progressive childhood mitochondrial encephalopathy.
- mean age of death 5 yo
Inheritance:
- Mutations of many mt and nuclear genes that encode proteins involved in energy metabolism.
- Most cases AR but some are x-linked and maternally inherited.
21
Q
LHON (Leber Hereditary Optic Neuropathy)
A
No Ragged Red Fibers (RRF)
- Painless progressive loss of central vision
Inheritance:
- Maternally inherited
- Male prevalence
*mtDNA point mutations in protein coding regions
22
Q
Diseases with RRF
A
KSS and CPEO
- ataxia, pigmentary retinopathy, short stature
- -> KSS mtDNA deletion (progresses with age)
MELAS
- dementia, ataxia, pigmentary retinopathy, short stature
MERRF
- ataxia, dementia
- -> Base substituion in tRNA of mtDNA
Most of these will be in organs that have a high energy requirement.
23
Q
Recombination between repeated sequences
A
Repeats create “hot spots” for recombination, increasing the chance of structural change in chromosomes and the frequency of some genetic conditions.
Recombination may cause inversion, duplication, or deletion
DZ Ex:
- Red green color blindness
- –> during meioisis, recomb misaligns genes for R and G so on one allele you get only R and the other you get R and 2 Gs (would still see normal). Only in males bc only one X chromosome
- Rh Factor
- Velocardiofacial syndrome
- Hemophilia A (x-linked)
24
Q
Contiguous gene syndromes (Recombination)
A
Recombination occurs between large repeats resulting in deletion of a block of DNA that contains multiple genes.
DiGeorge (Velocardiofacial Syndrome)
- Failure of pharyngeal pouches to develop
- Parathyroid, thymus, cardiac defects
- del 22q11
Prader-Willi and Angelman Syndromes
Dx by FISH with probe for deleted region
25
Down Syndrome
Trisomy 21
Male: 47, XY, +21
Can also occur from Isochromosome 21
45, XX, t(21;21)(q10, q10)
- Almond eyes, epicanthal folds
- Brachycephaly
- Transverse palmar crease
- Heart defect
26
Kleinfelter Syndrome
Male with 2 X
47, XXY
- Tall, hypogonadism, gynecomastia
- Social dysfunction, mental retardation
27
Turner Syndrome
Female with Monosomy
45,X
*All other monosomies are lethal
- Cystic hygroma
- Gonadal dysgenesis
- Short stature
28
Isochromosome 21
45, XX, t(21;21)(q10, q10)
29
Edwards syndrome
47, XX, +18
- Heart/CNS /Renal abnormalities
- Growth restriction
- Micrognathia
- Omphalocele
- Equinovarus
- Clenched hands
30
Patau Syndrome
47, XY, +13
- CL/P
- CNS, Renal, Heart, Omphalocele, Equinovarus
- Polydactyly
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41
Huntington's Chorea
- Autosomal dominant
- Paternal expansion (spermatogenesis)
- Polyglutamate disorder (CAG repeats) > 39
- TNR expansion occurs in the first exon leading to protein misfolding
**Caused by excess misfolded protein due to glutamine insertions
Clinical Features
- Movement disorder (chorea) or dystonia (PD)
- Dysarthria
- Abnormal eye movements (saccadic eye movements)
- Ataxic gait
- Neurodegenerative dz
- Dementia
Normal: 6-35 CAG repeats
Intermediate: 27 - 35, normal but tendency to expand
Borderline (Premutation): 36-39
Disease: > 39
* Can use PCR to detect this --> Inc size of PCR product
42
Fragile X Syndrome
- X linked inheritance
- Maternal expansion (oocyte)
- TNR expansion in 5' UTR
- Transcription affected with full mutation (FMR protein is lost *methylation*)
- Premutation has distinct phenotype (2ary excess RNA) and sequesters other nearby transcripts?
- Premature ovarian failure***, cerebellar ataxia and dementia (Tremor ataxia syndrome)
** Disease caused by diminished or absent protein
Clinical Features
- Intellectual disability (low IQ)
- Typical faces, hyperextensibility of joints, macroochidism
- Autism spectrum disorder
X-tra large testes, jaws, ears
*When transmitted by female, there is high risk for expansion
43
Friedreich's Ataxia
- Autosomal recessive inheritance
- TNR expansion in the first intron
- Transcriptional suppression results in diminished protein expression
** Disease caused by diminished or absent protein
Clinical Features
- Ataxic gait initially, followed by progressive weakness in extremities
- dysarthria
- dysphagia
- cognitive dysfx
CLINICAL TRIAD
- Neurologic dysfx
- Cardiomyopathy (palpitations and CHF)
- DM (beta cells die)
44
Myotonic Dystrophy, Type 1
- Autosomal dominant inheritance
- Maternal expansion for most severe phenotype
- Expansion in the 3' UTR
- RNA tox due to sequestered RNA splicing proteins by the hairpin loop
Clinical Features
- Adult onset muscular dystrophy (muscle weakness & wasting)
- Myotonia
- DM2
- Cardiomyopathy
45
Hereditary Spherocytosis
- Inherited disorder with defects in membranes of erythrocytes
- RBC more spherical, less deformable, and more susceptible to destruction by phagocytic cells in the spleen.
- Spectrin mutation
- Cells more sensitive to mild hypertonic solution (more shriveled)
46
Cystic Fibrosis Receptor
Chloride Ion channel mutation
- Leads to abnormal salt transport across epithelial cell membranes, resulting in thick mucus-build up in respiratory epithelial cells.
- Ligand is ATP
- ABC protein example
47
Tetrodotoxin
Found in pufferfish or Fugu
| - Sodium ion channel blocker (blocks action potentials in nerves)
48
Estrogen Receptor
- Overexpressed in cancer cells (BREAST)
| - Also Addison's, Cushing, precocious puberty, obesity
49
Neurofibromatosis Type 1
- Mutation in NF1 gene which encodes a Ras - GAP
| - -> overactive Ras
50
Noonan Syndrome
- Mutation in PTPN11 gene which encodes SHP2
| - -> gain of fx and hyperactive Ras
51
Cholera Toxin
GM1 ganglioside used for entry of cholera toxin
| - Glyclolipid with Sialic acid (NANA) sugar instead of phosphate
52
Lidocaine
Na channel blocker
| - anesthetic, tachycardia tx
53
Curare
Antagonist at Ach binding site
54
Chloroquine Resistance
ABC transporter --> MDR
55
Tau
Microtubule tau
| - in alzheimer's it can cause neurofibrillary tangles
56
Phalloidin
Binds and stabilizes actin filaments
- Found in death angel mushrooms
- Amanita phalloides
57
Colchicine
Depolymerizes microtubules
| - From the autumn crocus
58
Taxol
Binds and stabilizes microtubules
- Pacific yew (tree) is a natural source
- Used for cancer
59
Primary Ciliary Dyskinesia (PCD)
| Kartagener Syndrome
Cause: mutation in outer arm ciliary dynein heavy chain
Effect: Dynein outer arms in cilia are missing; cilia are immotile
Clinical features:
- Chronic infection of respiratory tract
- Infertility in males
- Situs inversus (organs flip flopped)
60
Griscelli Type I and Elejalde Syndromes
Mutations in:
- Myosin Va
- Melanophilin
- Rab27a
- In skin, melanosomes stay in the basal level of epithelium
- In hair, pigment is clumped and not evenly distributed
Clinical features:
- Silvery hair
- Light skin of dark skinned parents
- Severe neurological defects
61
Zellweger Syndrome
- Lethal condition caused by defective assembly of peroxisomes due to lack of transport of enzyme proteins (but not membrane proteins) into the peroxisome.
- Newly synthesized peroxisomal enzymes remain in the cytosol and eventually are degraded. Cells in patients with Zellweger syndrome contain empty peroxisome.
62
Botulinum and Tetanus toxin
Cleave SNARES
| - Prevent vesicle fusion and NT release
63
Human I Cell Disease
- M6P modification of mannose on lysosomal proteins does not occur because the phosphotransferase required is mutated.
- Since m6P modified lysosomal proteins are not produced, the lysosomal proteins cannot be recognized by M6P receptor and are not packaged into vesicles bound for lysosomes.
- Instead, ALL lysosomal enzymes are secreted
64
Legionairre's Disease
Phagosome hijacks host vesicles
- Becomes like RER
- Blocks delivery to lysosome and can replicate
65
Familial Hypercholesterolemia
LDL receptor protein has a defective coated-pit binding site, so you can't internalize cholesterol and stays in plasma
66
Claudin 16 and 19 mutations
In the kidney
- Serum Mg --> LOW
- Urinary Ca --> HIGH
- Kidneys will have calcification
in the thick ascending limb
67
P-Cadherin Mutation
- Expressed in retinal pigment epithelia --> progressive blindness
- hair follicles --> can cause hair loss
68
Pemphigus Foliaceus
Autoantibody mediated blistering dz in which antibodies against desmoglein 1 cause a loss of adhesion of keratinocytes in the superficial layers of the epidermis.
--> Blister within the epidermis and epithelial tissue
69
Bullous Pemphigoid
- Antibody to bullous pemphigoid antigen (BPAG1 or 2) triggers local response that induces mast cells to release eosinophil chemotactic factor (ECF) to attract eosinophils.
- Eosinophils release proteases causing the breakdown of anchoring filaments linking the attachment plaque of the hemidesmosome to the basal lamina
--> blister develops underneath the epidermis
70
Connexin 26 mutation
Expressed in cochlear hair cells
| --> mutation causes deafness
71
Connexin 32
Expressed in peripheral myelin
| --> mutation leads to peripheral neuropathies
72
Collagen mutations
Type I - Osteogenesis imperfecta
Type II - Chondrodysplasia
Type III - Ehler Danlos syndrome --> aneurism (BV)
Type VII - epidermolysis
Type XI - Epiphyseal Dysplasia --> arthritis
Type VII - Bullous pemphigoid
73
Marfan Syndrome
Fibrillin 1 mutation
- Autosomal dominant
- Patients are tall, long arms, legs fingers and toes (arachnodactyly)
- -> lack of recoil during development thought to lead increased length of appendages
- Mitral valve prolapse, dilation of aortic root, aortic dissection
74
Elastin disorders??
Hyperextendable skin
- Type III collagen
- Susceptible to aneurism
Altered elastin - elastoderma
- reduced coiling
Epidermolysis bullosa
- epithelium and basement membrane peel away
- Type VII anchoring fibrils disrupted
75
Integrin mutations
B2 mutation - leukocyte adhesion deficiency, inability of WBC to bind endothelium
B3 - Glanzmann's dz -- inability to bind fibrinogen during clotthing --> bleeding
76
Trisomy 13
- Midline defects
- Cleft lip, palate
- CNS malformations
- Micropthalmia
- Holoprosencephaly (single ventricle)
(~ 1 year expected survival)
77
Trisomy 18
- Intrauterine growth restriction
- Clenched hands; low set ears
- Rocker bottom feet
- Prominent occipital lobe
- females tend to survive longer
(~ 1 year expected survival)
78
Cyclopamine
- INhibits smoothened pathway
In calfs --> holoprosencephaly
- Cancer tx?
79
Jervine
Antagonize smo
| - Cancer therapy?
80
Holoprosencephaly (HPE)
- Developmental disorder characterized by incomplete midline formation during forebrain development.
Range of severity (severe to mild)
- Cyclopia
- Single forebrain vesicle
- Absence of pituitary, corpus callosum, or optic nerves-
- Midline clefting of palate
- Single maxillary central incisor (more mild form but can still pass severe onto kids).
Cause:
- Shh protein haploinsufficiency or other singaling pathway reducing mutation
- can also affect limb formation (Not humans)
81
Smith-Lemli-Opitz Syndrome
- Loss of function of DHCR7 gene
- Codes for critical enzyme in cholesterol synthesis
- Lack of cholesterol can produced same phenotype as lack of Shh i.e. HPE
- Do not give statins or cholesterol reducing meds to preggos as this can create a lack of cholesterol --> HPE
82
GLI3 mutations
Autosomal Dominant
- Reduction in Gli3 repressor protein can cause:
```
Greigh Cephalopolysyndactyly (GCPS)
Pallister-Hall (PHS)
Postaxial Polydactyly (PPS)
- Extra digit on pinky side of hands or feet
- GLI3 haploinsufficiency (+/-)
```
83
Medulloblastoma
HH receptor pathway mutation
- PTCH1 lof mutation
- nevoid BCC also have PTCH1
84
Vismodegib
Inhibits smo
85
Colorectal cancer
Can be caused by APC mutation --> Wnt pathway
