Genetic Disorders Part 1 Flashcards
1
Q
what is genetics
A
- study of heredity
- study of function and composition of a single gene
2
Q
what is genomics
A
study of ALL GENES and their relationships to identify their combined influence on and development of the organism
3
Q
what are hereditary disorders
A
derived from the parents = familial
4
Q
define congenital
A
-present at birth
5
Q
does congenital imply heredity
A
no!
6
Q
nature of genetic abnormalities contributing to human disease
A
- mutations in protein-coding genes
2. alterations in protein-coding genes other than mutations
7
Q
what are mutations
A
permanent change in DNA
8
Q
mutations of germ cells are transmitted to who
A
progeny
9
Q
mutations of germ cells may give rise to what type of diseases
A
inherited disease
10
Q
are mutations of somatic cells transmitted to progeny
A
no!
11
Q
mutations of somatic cells cause
A
- cancer
- congenital malformations
12
Q
what mutations can occur in protein-coding genes
A
- point mutations
- frameshift mutations
- trinucleotide repeat mutations
13
Q
name 2 point mutations
A
- missence mutations
- nonsense mutations
14
Q
what are missence mutations
A
change in SINGLE nucleotide base
15
Q
example of a missence mutation
A
sickle cell disease
A–>T
16
Q
what are nonsense mutations
A
termination codon; interrupt translation
17
Q
what are the termination codons
A
UAA
UAG
UGA
18
Q
what are frameshift mutations
A
- deletion and insertion
- one or 2 base pairs
- reading frame is altered
19
Q
what are trinucleotide repeat mutations
A
-amplification sequence of 3 nucleotides
20
Q
example of trinucleotide repeat mutations
A
Fragile X syndrome
CGG amplification
21
Q
what are other alternations in protein-coding genes oter than mutations
A
- polymorphisms
- epigenetic changes
- alternations in non-coding RNAs
22
Q
what are 2 most common types of polymorphism
A
- single nucleotide polymorphism (SNP)
- copy number variation (CNV)
23
Q
what are single nucleotide polymorphism (SNP)
A
- variation at a single nucleotide position
- anywhere in the genome
24
Q
1% of SNP occurs in
A
coding regions therefore alters gene product
25
are SNPs inherited
coinherited with a disease
26
what are copy number variations (CNVs)
large stretches of DNA
27
what % of CNSs are involved with gene-coding sequences
50%
28
CNVs contribute to
human phenotypic diversity
29
CNVs affect
CNS and immune system! (EXAM)
30
what are epigenetic changes
- modulation of gene
| - absence of mutation
31
how can epigenetic changes occur
- methylation of gene promoter
- silencing of tumor suppressor gene
- acetylation of histone
32
what is imprinting
physiologic epigenetic silencing (gene in that particular chromosome is silent or not expressed)
33
name 2 alternations in non-coding RNAs
1. microRNA
| 2. long non-coding RNA
34
what do long non-coding RNA do
- do not encode protein
| - inhibit translation
35
what are the 3 major categories of genetic disorders
1. mendelian disorders: disease caused by single-gene defects
2. complex multigenic disorders
3. cytogenetic disorders
36
what are the transmission patterns of single gene Mendelian disorders
1. autosomal dominant
2. autosomal recessive
3. X-linked
37
what are the characteristics of an autosomal dominant gene
- heterozygous state
- at least 1 parent is affected
- M an F are affected
- 1 chance in 2 (50%) **
- delayed age at onset
38
example of an autosomal dominant disease
Huntington disease (mutation at birth, but doesn't manifest until adult)
39
do autosomal dominant genes encode enzymes
NO!
40
autosomal dominant genes are involved in
1. regulation of metabolic pathways (eg. Familial Hypercholesterolemia)
2. structural proteins (eg. collagen), cytoskeletal components (eg. ankyrin)
41
clinical features of autosomal dominant inheritance are affected by
- variable expressivity
| - reduced penetrance
42
what type of disease is Familial Hypercholesterolemia
an autosomal dominant inheritance
| 1 in 500 affected
43
what does Familial Hypercholesterolemia effect
intracellular transport of LDL
| catabolism of LDL
44
where is the mutation in Familial Hypercholesterolemia
in LDL receptor
45
what class of Familial Hypercholesterolemia is most common
class II
46
what is class II Familial Hypercholesterolemia
defective folding of protein
- receptor is present
- impaired transport of LDL
47
what are the clinical manifestations of Familial Hypercholesterolemia
- atherosclerosis
- coronary artery disease
- xanthoma
48
what type of disease is Marfan syndrome
autosomal dominant
49
Marfan syndrome affects what gene
FBN1 gene
50
characteristics of marfan syndrome
- affects structural protein fibrins
- skeletal abnormalities
- ecotopia lentis
- CHF
51
what is the most common cause of death in Marfan syndrome
aortic rupture
52
Marfan syndrome results in a loss of
microfibrils
- excessive activation of TGF-beta
- affects vascular smooth muscle
53
what drugs are used to treat Marfan syndrome
-angiotension receptor blockers (ARBs) may improve cardiac function in MFS
54
what tyep of disease is Ehlers-Danlos syndrome
autosomal dominant
55
what are the 3 types of Ehlers-Danlos Syndrome
1. Classic EDS
2. Vascular EDS
3. Kyphoscoliotic EDS
56
what is the mutation in classic EDS
-COL5A1 and COL5A2 (type V collagen defect)
57
what is the mutation in vascular EDS
-COL3A1 gene (type III collagen defect)
58
what is the mutation in Kyphoscoliotic EDS
- deficient enzyme: Lysyl hydroxylase
| - type I and III colagen
59
EDS causes the skin to be
hyperextensible
- vulnerable to trauma
- poor wound healing
60
EDS also affects
- cornea
- blood vessels
- colon may rupture
61
characteristics of autosomal recessive inheritance disorders
- both alleles are mutant
- trait does not affect parents
- 25% recurrence risk
- low frequency mutant gene = strong likelihood of consagunitiy (related by blood)
- uniform expression
- complete penetrance
- early in life
- new mutations rarely detected
62
do autosomal recessive disorders affect enzymes
yes! enzyme proteins are affected
63
what is the mutation in cystic fibrosis
mutation in CFTR (cystic fibrosis transmembrane conductance regulator gene)
64
what is the most common cystic fibrosis mutation
change in F508
65
what are complications of CF in pancreas
- pancreatitis
- hyperglycemia
- biliary atresia
- neonatal obstructive jaundice
- cholelithiasis
- Vit. deficiency
* Meconium Ileus
66
complication os CF in lungs
- pneumonia
- bronchiectasis
- lung abscess (S. aureus, P.aeru, H.influ_
- Sinusitis
- mucoid impaction
- nasal polyps
- respiratory failure
67
what are other complications of CF
- congenital bilateral atrophy of vas deferens (CBAVD)
- infertility
- strictures in the colon
68
how can CF be diagnosed
- quantitive sweat test
| - CFTR mutation lab evidence
69
what factors can give a false positive or negative sweat test
false positive: eczema, Klftr
| false negative: hyponatremia, malnutrition
70
how is CF treatment managed
- team approach
| - supportive
71
who does Phenylketonuria affect
Scandinavian
72
what is phenylketonuria
phenylalanine hydroxylase deficiency
73
what is hyperphenylalainemia
- normal levels at birth
- few weeks: plasma levels increase
- 6mo: mental retardation
- seizures, eczema
74
what are maternal PKU syndrome
- heterozygous infant
- microcephaly
- mental retardation
- congential heart disease
75
what type of disease is galactosemia
an autosome recessive
76
galactosemia affects what gene
galactose -1-phosphate uridyl transferase (GALT)
77
galactosemia affects what part of the body
- brain
- eyes
- liver
- spleen
- kidneys
78
in newborns, galactosemia causes
- vomiting
- diarrhea
- jaundice
- hepatomegaly
79
what type of disease is a lysosomal storage disease
autosomal recessive
80
who does lysosomal storage affect
infants, children
81
what is mutated in lysosomal storage disease
- gene that codes for specific enzymes
- therefore lack of specific enzymes
- mononuclear phagocytes
82
Tay-Sachs disease affects
Ashkenazi Jews
83
tay-sachs disease is deficient in
hexosaminidase A
84
describe the progression of Tay-Sachs disease
at birth: normal
3-6 mo: motor weakness
2-3 yrs: progressive disease; death
85
Tay-Sachs disease affects
brain, spinal cord, retina
86
under a microscop Tay-Sachs is characterized by
- neuron, with lipid vacuolation
| - lysosomes with whorled configuration
87
Tay-sachs disease has a mutation in what gene
HEXA
88
how can you diagnose the mutation in HEXA gene
- plasma levels or WBS
- prenatal Dx: CV sampling, amnioscentesis
- carriers: genotyping
89
what is characteristic of a mutation in HEXA gene
retina: cherry red spot
90
Niemann-pick disease (NPD) affects
Ashkenazi Jews
91
NPD is deficient in what
acid sphingomyelinase
92
what is type A NPD
neurodegenerative
- results in organomegaly
- fatal in 3 yrs
93
what is type B NPD
no CNS involvement
+ organomegaly
survival to adulthood
94
what microscopic features are characteristic of NPD
vacuolated hepatocytes and Kupffer cells with accumulated sphingomyelin
95
what genes are affected in type C NPD
NPC1 and NPC2
96
type C NPD is defective in
intracellular cholesterol/lipid transport
97
type C NPD causes
ataxia, dystonia
| -vertical supranuclear gaze palsy
98
what type of disease is Gaucher disease
autosomal recessive
99
what enzyme is Gaucher disease deficient in
glucocerebrosidase
100
what type of Gaucher Disease is most comon
type 1
101
what does Gaucher disease affect
Ashkenazi Jews
102
what symptoms does Gaucher disease cause
- osteopenia (radiographic bone disease; Erhlenmyer flask deformity)
- hepatosplenomegaly
103
is Gaucher disease neuronopathic
no; no CNS manifestation
104
what is type II Gaucher disease
acute infantile
- cause seizures
- incompatible with life
105
what is type III Gaucher disease
- chronic neuronopathic
- causes mental retardation
- seizures
106
what is the pathogenesis of Gaucher disease
- senescent RBC release glycosphingolipids
| - degraded in spleen liver, bone marrow
107
function of glucocerebrosidase
cleaves glucose from ceramide
108
what happens in a glucocerebrosidase deficiency
-glycosphingolipids accumulate
109
what cytokines are activated in glucocerebrosidase deficiency
IL-1, IL-6, TNF
110
what microscopic features are characteristic of Gaucher disease
- lipid laded Gaucher cells in bone marrow
| - Gaucher cell with distended lysosome
111
what therapy is given for Gaucher disease
- IV recombinant glucocerebrosidase for life
- oral drugs that inhibit glucocerebroside synthase
- gene therapy - normal gene transfected autologous hematopoietic stem cells (HPC)
112
what accumulates of Mucopolysaccharidoses (MPS)
- dermatan
- heparan
- keratan
- chondroitin sulfate
113
what are the symptoms of mucopolysaccharidoses
- skeletal abnormalities
- hepatomegaly
- cardiovascular disease
114
what is Hurler Syndrome
MPS Type 1
115
MPS type 1 is deficinet in
L-iduronidase
116
what is the life expectancy of MPS type 1
6-10yrs
117
what enzymes build up in MPS type 1
- dermatan
| - heparan
118
what are the effects of MPS type 1
- mental retardation
| - affects vascular endothelium, neurons, cornea
119
what is Hunter syndrome
MPS type II
120
what type of disease is MPS type II
X-linked!
| all other MPS = autosomal recessive
121
what enzyme is deficient in MPS type II
L-iduronate sulfatase
122
what is the clinical corse of MPS type II
MILD
123
what is affects is absent in MPS type II
corneal clouding
124
what type of disease is glycogen storage disease (glycogenoses)
autosomal recessive inheritance
125
what are the 3 forms of glycogen storage disease
hepatic, myopathic, miscellaneous
126
describe the hepatic form of glycogen storage disease
- organomegaly
- hypoglycemia
- Von Gierke = type 1
- glucose 6 phosphatase
127
describe the myopathic form of glycogen storage disease
```
McArdle disease =Type V
Muscle phosporylase
Skeletal muscle only
Painful cramps
Myoglobinuria
Onset: 20 y.o.
```
128
describe the miscellaneous glycogen storage disease
```
Pompe disease = Type II
Generalized glycogenosis
Lysosomal glucosidase
(acid maltase)
Hepatomegaly: mild
Massive CARDIOMEGALY
```
129
all sex linked disorders are
x-linked
130
what are the characteristics of x-linked disorders
- heterozygous female carriers transmit only to sons
- rarely express phenotypic change
- sons: 1 chance in 2 of receiving mutant gene from heterozygous mother
- son manifest the disease
131
in x-linked disorders affect males do not transmit disorder to
- sons
| - all daughters are carriers
132
what are the 3 most common X-linked recessive inheritance
- hemophilia A
- Duchenne/Becker muscular dystrophy
- Fragile X syndrome
133
what type of disease is hemophilia A
x-linked
134
what gene is mutation in hemophilia A
F8 gene
| -results in inversion of 22 sequence (40%)
