Genetic Disorders Flashcards
1
Q
Mutation in a single gene (Mendelian DOs) characteristics:
A
Large effects.
Rare, high penetrance.
2
Q
Chromosomal DOs characteristics:
A
Structural or numerical alterations in autosomes, sex chromosomes.
Rare, high penetrance.
3
Q
Complex multigenic DOs characteristics:
A
More common, low penetrance.
Involves environmental and gene interactions.
4
Q
Germ cell mutations give rise to:
Somatic cell mutations give rise to:
A
Inherited diseases.
Cancers and congenital malformations.
5
Q
Missense vs. nonsense mutations
A
Missense - alter meaning of sequence of encoded protein (sickle cell).
Nonsense - replaced w/ a stop codon (B-thalessemia).
6
Q
What do mutations in noncoding sequences include?
What is the outcome?
What transcription factors are involved?
A
Mutations in promoter, enhancer, splicing, etc.
Failure to form mRNA.
MYC, JUN, p53.
7
Q
Trinucleotide-repeat
A
Amplification of a sequence of 3 nucleotides (G and C)
8
Q
Anticipation
A
A genetic disorder, when passed down, has symptoms that become more apparent at an earlier age in each generation.
Ex: Huntington disease, myotonic dystrophy.
9
Q
Types of point-mutations in:
CF
ABO
Tay-Sachs
A
CF - 3 base deletion (no frameshift)
ABO - single base deletion (frameshift)
Tay-Sachs - 4 base insertion (frameshift)
10
Q
Codominance
Pleitropism
Genetic heterogeneity
A
Codominance: both alleles contribute to phenotype.
Pleitropism: single mutant gene causes many end effects.
Genetic heterogeneity: mutations at several loci may produce the same trait.
11
Q
New autosomal dominant DOs tend to occur in:
A
Germ cells of older fathers.+3
12
Q
Ex of loss of function AD disease
A
Familial hypercholesterolemia
13
Q
Ex of gain of function AD disease
A
Huntington disease (proteins that are toxic to neurons)
14
Q
2 patterns of DZ with Autosomal Dominant DOs
A
- Regulation of metabolic pathways that are subject to feedback inhbition. Ex - less receptors, increase in cholestrol in vessels –> hypercholesterolemia.
- Key structural protein damage. Ex - collagen and cytoskeletal elements of RBC membranes (OI).
15
Q
When do symptoms onset in autosomal dominant DOs?
A
The age of onset is delayed. Sx tend to appear in adulthood.
16
Q
Largest category of genetic DOs
A
Autosomal recessive
17
Q
If a AR mutation arises out of nowhere, what should be a consideration?
A
Consanguinous marraige
18
Q
What is the chance of developing a AR disease if both parents are carriers?
A
25%
19
Q
What do AR diseases have in contrast w/ AD diseases? (5)
A
More uniform expression than AD.
Complete pentrance is more common.
Early onset.
Many of the mutations are involved in metabolism.
New mutations are rarely detected clinically.
20
Q
What is the primary defect in CF?
What gene is involved?
Where on the chromosome?
A
Abnormal function of an epithelial Cl- channel protein.
CFTR
7q31.2
21
Q
In what areas does the abnormal epithelial Cl- channel affect?
A
Affects fluid secretion in exocrine glands and epithelial lining of the respiratory tract, GI tract and reproductive tracts.
22
Q
In CF, chronic lung disease is secondary to: (6)
A
Recurrent infections Pancreatic insufficiency Male infertility Meconium ileus Atelectasis Rectal prolapse
23
Q
CF has an incidence in:
It is the most common lethal genetic disease in what population?
A
1/2500 live births.
Caucasion populations.
24
Q
Inheritance pattern in CF
Heterozygote carriers have an increased incidence of:
A
Autosomal recessive.
Respiratory and pancreatic diseases as compared to general pop.
25
Most common bacterial infections in a patient w/ CF:
Pseudomonas aeruginosa, Staphylococcus aureas.
26
What test is used to detect CF?
Sweat chloride test
27
Incidence of PKU:
In what populations?
1/10k.
Mostly Scandinavian descent.
28
What is the inheritance pattern of PKU?
What is the enzymatic pathology?
What else can't be made?
AR.
Phenylalanine hydroxylase (PAH) deficiency, which leads to hyperphenylalaninemia.
Phe can't make Tyr, which is a precursor for melanin.
29
Presentation of PKU
TTM
Normal at birth.
At 6 mo, severe retardation, hypopigmentation and eczema.
Strong musty odor in urine and sweat.
Dietary restrictions.
30
Most X-linked DOs are:
Where at in the chromosome? What is the relevance of this location?
Recessive.
Male-specific region of Y chromosome. Makes males usually infertile.
31
In X-linked recessive DOs, why are all daughters of affected males carriers?
Father can only pass down an X and his is recessive.
32
What 2 conditions are also present in a patient with CF?
What is generally the cause of death?
Emphysema
Bronchiectasis
COPD in 80-90% of cases.
33
What kind of inheritance is G6PD deficiency?
What occurs in G6PD?
X-linked recessive.
Drug induced hemolytic reactions.
34
Mechanism of mitochondrial inheritance
All children of an affected mother is affected.
35
Alterations in single gene mutations lead to:
4 main categories:
Abn products or decreased normal product.
1. Enzyme defects
2. Membrane defects
3. Alterations in nonenzyme proteins
4. Mutations leading to unusual drug reactions
36
3 major consequences of mutations leading to decreased activity (or abn function) of an enzyme and example diseases
1. Acummulation of substrate: the build up protein or precursor is toxic. Ex - galactosemia (Gal 1-phosphate uridyltransferase deficiency).
2. Decreased amount of end product. Ex - albanism (low tyr decreases melanin) and Lesch-Nyhan (increased intermediates and protein breakdown).
3. Failure to inactivate a tissue-damaging substrate. Ex - a1-antitrypsin deficiency (can't inactivate neutrophil elastase in the lung leading to emphysema).
37
Pathology of familial hypercholesterolemia
Decreased synthesis or function of LDL receptor -> defective transport of LDL into cells -> secondary increase in cholesterol.
38
Pathology of sickle cell disease
Defect in structure of globin molecule
39
Pathology of Thalassemias
Mutation in globin gene affects amount of globin chains synthesized
40
What causes the hemolytic anemia in G6PD?
Antimalarial primaquine
41
Inheritance pattern of Marfan's disease:
Gene(s) involved and chromosome locations:
What protein is defective?
Incidence of Marfan's:
AD.
FBN1 (15Q21.1) and less commonly FBN2 (5q23.31).
Fibrillin-1.
1/5k, 70-85% familial.
42
2 fundamental mechanisms oby which loss of fibrillin-1 leads to clinical manifestations
1. Loss of structural support in microfibril rich CT.
| 2. Excessive activation of TGF-beta signaling.
43
Clinical features of Marfan's (6)
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Unusually tall, long LE.
Double-jointed.
Frontal bossing.
Pectus excavatum.
Ectopia lentis (dislocation of lens).
Aortic dissection, MV prolapse, dilation of ascending aorta, etc.
```
44
What is the pathology of Ehlers-Danlos syndrome?
Defect in synthesis or structure of fibrillar collagen.
45
Clinical features of EDS
Skin is hyperextensible/stretchable.
Hypermobile joints.
Gaping defects
46
What are internal complications from EDS?
Rupture of the colon, large arteries, rupture of cornea and retinal displacement, diaphragmatic hernia.
47
If a AD disease decreases reproductive fitness, where do most of the mutations come from?
Most of them are new mutations. If they lower reproductive fitness, the individual will not likely be able to survive to reproductive age or be able to have children.
48
Incomplete penetrance
Variable expressivity
Pt. has the mutation, but does not exhibit the phenotype.
Pt. has the mutations but they exhibit them differently.
49
Neurofibromatosis type 1 features (3)
Cafe au lait spots
Skeletal deformities
Neurofibromas
50
What happen in a mutation to cause Osteogenesis imperfecta?
The mutant allele can interfere w/ assembly of functionally normal multimer (dominant negative).
51
What 2 features will be present in a baby with CF?
Pulmonary manifestations
| Neonatal meconium ileus
52
Musty diaper/urine is what disease?
PKU
53
AD DOs to know (6)
```
Huntington disease
Neurofibromatosis
Marfan syndrome
EDS
Osteogenesis imperfecta
Familial hypercholesterolemia
(HOME NF)
```
54
AR DOs to know (6)
```
CF
PKU
Lysosomal storage diseases
alpha1-antitrypsin
Glycogen storage diseases
Alkaptonuria
(PC LAG)
```
55
X-linked recessive DOs to know (3)
G6PD deficiency
Lesch-Nyhan
Fragile X
56
Familial hypercholesterolemia
AKA
Incidence
Heterozygotes vs. homozygotes
Presentations
Receptor disease
1/500.
Hetero - 2 to 3 fold increase in cholesterol.
Homo - 5 to 6 fold increase in cholesterol.
Xanthomas (tendinous, skin, around eyes, etc). Coronary, cerebral and vascular athersclerosis at early age. Suspect if young pt.has an MI.
57
Lysosomal storage diseases - primary accumulation
No enzymes within the lysosome to complete catabolism of substrate -> primary accumulation.
Leads to lysosomes being stuffed w/ incompletely digested macromolecules.
58
Lysosomal storage diseases - secondary accumulation
Lysosomes are needed for autophagy, so the impaired autophagy leads to secondary accumulation of substrates.
59
3 approaches for TTM of lysosomal storage diseases
1. Enzyme replacement therapy.
2. Substrate reduction therapy (might be a little enzyme to catabolize what is left behind).
3. More recently, strategy is to better understand the molecular basis of enzyme deficiency.
60
```
Tay-Sachs disease
Cause:
Mutation and enzyme deficiency:
Pops. most effected:
Presentation (birth and 6 mo):
Classic feature:
Where do substrates build up?
What stains are positive in a cell?
```
Pt. cannot catabolize the GM2 gangliosides.
Mutation in alpha-subunit on chr 15 leading to deficiency of hexosaminidase.
Easter European (Ashkenazic Jews).
NL at birth. At 6 mo, motor and mental retardation, obtunded, flaccidity, blindness, dementia. Death by age 2-3.
Cherry red spot on macula.
GM2 gangliosides accumulate in neurons, retina, heart, liver and spleen.
Fat stains oil red O and Sudan black B.
61
What builds up in Niemann-Pick disease?
What pops. most effected?
What chromosome? Inheritance type?
Cell morphology:
Clinical features:
Sphingomylelin due to deficiency in sphingomyelinase.
Ashkenazi Jews.
Chr 11p15.4, AR.
Cells enlarged due to buildup of sphingomyelin and cholesterol -> foamy cytoplasm and zebra bodies.
Massive spleen and many have a cherry red retinal spot.
62
Niemann-Pick DZ
Type A
Type B
Type C
A: most severe. Extensive neurological involvement. Sx by 6 mo and death by 3.
B: Organomegaly. No CNS involvement. Mildest form.
C: most common. NPC1 gene effected and cannot transport free cholesterol from lysosomes to cytoplasm. Leads to progressive neurological damage.
63
Gaucher disease
What accumulates and in what cells?
What becomes activated as a result?
Presentations:
TTM:
Glucocerebroside in phagocytes.
IL-1, IL-6 and TNF is +.
Enlarged spleen and pantocytopenia and thrombocytopenia.
TTM is hematopoietic stem cell transplant.
64
Gaucher DZ
Type I
Type II
Type III
I: chronic. 90% of cases. No CNS involvement. European Jews/
II: severe. Infantile cerebral pattern. Progressive CNS involvement, early death. NOT Jewish.
III: intermediate. Progressive CNS involvement beginning in adolescence and early adulthood.
65
Look of cells' cytoplasm in Gaucher DZ
Crumpled tissue paper
66
Mucopolysaccharidosis (MPS) is a defect in what?
Universal features (3)
What are the 2 subtypes and their inheritance patterns?
Where does the substrate build up?
COD:
What else do the cells contain?
Deficiency in enzymes degrading glycosaminoglycans (in CT).
Course facial features, joint stifness and mental retardation.
Hurler (AR) and Hunter (XLR)
Spleen, liver, BM, LN, BVs, heart.
COD is MI and cardiac failure.
Lamellated zebra bodies.
67
How to differentiate between Hunter's and Hurlers?
Hunter's is XLR and does not have corneal clouding. Hurler's is AR and HAS corneal clouding.
68
Glycogen storage diseases (3)
von Gierke dz (hepatic form)
McArdle dz (myopathic form)
Pompe dz
69
von Gierke DZ
Increased glycocen in liver leading to hypoglycemia.
Deficiency in G6Phosphatase.
70
McArdles DZ
Increased glycogen in skeletal muscle leading to muscle weakness and cramps after exercise. No increase in lactate after exercise.
Deficiency in muscle phosphorylase.
71
Miscellaneous glycogen storage DZs are associated w/?
1. Deficiency in glucosidase (acid maltase).
2. Lack of branching enzymes.
Early death.
72
Pompe DZ
Cardiomegaly.
Acid maltase deficiency.
73
3 common malformations in multifactorial inheritance
Cleft lip
Cleft palate
Neural tube defects
74
Euploid
Aneuploid
E: exact multiple of 23.
A: not exact multiple of 23.
75
Anaphase lag
During cell division, one chromatid lags behind and is left out of nucleus.
76
Mosaicism
MItotic errors in early development leads to many different populations of cells in the same individual.
Most commonly effects sex chromosomes.
77
Ring chromosome
Break occurs at both ends of chromosome w/ fusion fusion of damaged ends.
78
Paracentric vs. pericentric inversions
Para: inversion involving only one arm of chromosome.
Peri: breaks on opposite of centromere.
79
Isochromosome
One arm of a chromosome is lost and remaining arm is duplicated leaving only 2 short arms or 2 long arms.
80
Robertsonian translocation
Translocation between 2 acrocentric chromosomes (1 large chromosome and 1 small one, etc).
Contributes to 3-4% of trisomy 21 cases.
81
Trisomy 21 (Down syndrome)
```
Incidence:
Strongest influence on developing DZ:
Diagnostic clinical features:
40% of pts. have:
10-20 fold increased risk in developing:
What disease will they look like they have in their 20s?
What else is at a high risk to develop?
```
1/700.
Maternal age.
Flat facial profile, eyelid abnormalities, low IQ.
Congenital heart DZ.
Increased risk of developing acute leukemia (10 to 20 fold).
Alzheimer's disease
Serious infections due to abnormal immune responses and thyroid autoimmunity.
82
Trisomy 18
Trisomy 13
18: Edwards. Mental retardation, low ears, neck, renal malformations.
13: Patau: Mental retardation, cleft lip, polydactaly.
83
Chr 22q11.2 deletion syndromes (2)
1. Digeorge syndrome
| 2. Velocardiofacial syndrome
84
Chr 22q11.2 deletion syndrome incidence:
Presentations:
1/4000.
```
Variable.
Cardiac abnormalities
Abnormal faces
Thymic aplasia
Cleft palate
Hypocalcemia
CATCH 22
```
85
Digeorge syndrome presentations
Thymic hypoplasia -> T cell deficiency.
Parathyroid hypoplasia -> hypocalcemia.
Mild facial abnormalities.
Heart problems.
86
Velocardiofacial syndrome presentations
Facial dysmorphism, cleft palate, CVS problems, learning disability.
87
Klinefelter syndrome
Incidence:
Presentation:
Associated problems:
20x increased risk for:
47, XXY.
1/660.
Long legs, small testes and penis, low IQ.
Increased risk for T2DM and metabolic syndrome, mitral valve prolapse, osteoporosis.
Male infertility.
20x increased risk for breats cancer.
88
Turner syndrome
45, X.
1/2500.
Cystic hygroma: infant w/ edema and swelling of nape of neck due to lymph stasis -> neck webbing.
CVD, shortness, amenorrhea, menopause before menarche -> streak ovaries, glucose intolerance, obesity, low thyroid, insulin resistance.
89
Fragile X syndrome is what type of genetic DO?
What is the length of that region?
Effected gene:
Incidence for men/women:
Phenotype:
Most distinctive feature:
Nucleotide repeat mutation.
Very large expansion of repeat region.
FMR1.
1/1550 for males. 1/800 for females.
Mental retardation, long face, facial abnormalities, MV prolapse.
Macro-orchidism.
90
Huntington disease
AD DZ w/ nucleotide repeat mutation component (prototype of it).
91
Heteroplasmy
Tissues and individuals have both wild-type and mutant mtDNA.
92
Threshold effect
Minimum number of mutant mtDNA must be present in a cell/tissue before oxidative dysfunction occurs.
93
Leber hereditary optic neuropathy
Prototype of mtDNA DO.
| Neurodegenerative DZ that manifests as a progressive BL loss of central vision.
94
Prader-Willi syndrome
Location of mutation:
Paternally imprinted.
Mental retardation, short stature, obesity, always hungry, small hands, hypogonadism.
Deletion of band q12 in long arm of chr 15. Del(15)(q11.2q13).
95
Angelman syndrome
Maternal imprinted on same location as Prader-Willi (Deletion of band q12 in long arm of chr 15. Del(15)(q11.2q13)).
Mental retardation, ataxia, seizures, laughter. "Happy puppets".
96
Why are patients with Gaucher's disease have a tendency towards fractures?
Because the Mo eat away the bone and can cause fx.
97
Why do patients with Gaucher's disease have a higher incidence of infections?
The diseased Mo push out the normal WBCs and can lead to an abnormal immune response.
98
What is the enzyme deficiency in Hurler's disease?
Alpha1-iduronidase
99
What is the enzyme deficiency in SCID (Bubble Boy disease)?
Adenosine deaminase
100
Acid maltase is the same as:
Lysosomal glucosidase
101
In patients w/ Down's syndrome, what disease most commonly occurs by 20?
What about by 50?
By 20: Acute leukemia
By 50: AD
102
Presentation of patients with von Gierke:
Seizures, small size, pale, hepatomegaly.
103
Types of EDS: clinical findings, inheritance, gene defects.
Classic (I)
Vascular (IV)
Kyphoscoliosis (VI)
Classic (I): skin and joint hypermobility, scars, easy bruising. AD. COL5A1, COL5A2.
Vascular (IV): thin skin, arterial or uterine rupture, bruising, small joint hypermobility. AD. COL3A1.
Kyphoscoliosis (VI): hypotonia, joint laxity, scoliosis, ocular fragility. AR. Lysyl hydroxylase.
104
One huge clinical feature of patients w/ DS:
Simian crease
105
How can a Robertsonian translocation cause DS?
The long arm of chr 13, 14, 15 translocates to chr 21 or 22.
