Genetic Disorders Flashcards
(175 cards)
1
Q
what is genetic disease?
A
the price humankind pays for the tendency of genes to change
2
Q
congenital disorder
A
present/manifest at birth
3
Q
is congenital disorder genetic?
A
may be genetic or non-genetic (trauma, infection)
4
Q
when does a genetic disorder manifest?
A
the moment the egg is fertilized (picked the wrong parents ;))
5
Q
when can genetic disorders manifest?
A
may or may not manifest at birth
6
Q
examples of genetic diseases that result from post-fertilization somatic mutations
A
can’t be inherited
McCune-Albright syndrome (rare)
Neoplasms (“acquired” genetic disease, common)
7
Q
hereditary disease
A
“genetic disease” except those you can’t trust
8
Q
familial disease
A
“diseases that cluster within families”
9
Q
examples of familial disease
A
genetic diseases polygenic disease nutritional stuff environmental stuff (lead poisoning) behavioral stuff (child abuse, obesity)
10
Q
vertical transmission
A
parent to child (genetic disease)
11
Q
horizontal transmission
A
within cells of single person (tumors)
12
Q
what are chromosomal disorders?
A
cytogenic disorders
13
Q
what causes a chromosomal disorder?
A
wrong number of copies of a chromosome or alterations of one or more chromosomes
14
Q
what percentage of newborns have a chromosomal disorder?
A
1%
15
Q
what percentage of chromosomal disorders result in spontaneous abortions?
A
50%
16
Q
how are chromosomal disorders described?
A
as total chromosomes, sex chromosomes, abnormality
i.e. 47 XY +21; 47 XXY
17
Q
haploid
A
number of chromosomes in sex cell
18
Q
diploid
A
exactly twice haploid (i.e. somatic cells)
19
Q
euploid
A
exact multiples of haploid (2x, 4x, etc.)
20
Q
aneuploid
A
any other number (45, 47, etc.)
21
Q
what does aneuploid usually result from?
A
nondisjunction
22
Q
what is nondisjunction?
A
failure of duplicated chromosomes to separate in meiosis 1
OR
failure of chromatids to separate in meiosis II
23
Q
what does nondisjunction result in?
A
gametes carrying 2 copies of a chromosome or none
24
Q
what can also causes nondisjunction?
A
anaphase lag
sister chromatids do not properly separate from each other
25
what can DNA breaks result from?
radiation
chemicals
viral infections
26
chromosomal disorders mechanisms of action
deletion/substitution
inversion
translocation
27
deletion/substitution
terminal or interstitial piece of chromosome deleted/duplicated
28
inversion
broken chromosome segment replaced "backwards"
29
translocation
2 chromosomal breaks with exchange of segments
30
balanced translocation
even exchange of genetic material, no extra or missing DNA
31
unbalanced translocation
unequal exchange, extra or missing genes
32
robertsonian translocation
one large and one extremely small (usually lost) chromosome result
33
what type of autosomal disorders can cause abortion?
autosomal monosomy or no X chromosome causes early abortion
34
what do trisomies normally produce?
infants who will usually die during the first few months of life
35
exception trisomy that is viable
trisomy 21
36
what can cause autosomal disorders to recur?
parent carries a balanced translocation
| advanced parental age
37
what is trisomy 21 also known as?
down syndrome
38
how do you express down syndrome?
47XX (or XY) + 21
39
how does trisomy 21 commonly occur?
maternal nondisjunction of 21
40
what causes maternal nondisjunction of 21?
advanced maternal age
41
what is the most common aneuploidy to reach birth?
trisomy 21
42
what markers indicate trisomy 21?
a-fetoprotein
pregnancy-associated protein A
human chorionic gonadotropin
43
clinical features of trisomy 21
```
lack of muscle tone at birth ("floppy")
flat face, open, big tongue
slanted eyes and epicanthic folds ("mongolism")
low-set, funny-looking ears
single palmar crease ("simian")
heart defects (40%)
brushfield's spots on iris
```
44
trisomy 21 future problems
```
mental retardation
hypothyroidism
conductive hearing loss
various leukemias
Alzheimer's disease
```
45
when do you recognize trisomy 21?
usually recognizable at birth
46
lifespan trisomy 21
most die before 30s
47
what is trisomy 18 known as?
edward's syndrome
48
how to express edward's syndrome
47XX (or XY) + 18
49
prevalence edward's syndrome
second most common trisomy to reach term
50
what causes edward's syndrome
maternal nondisjunction during meiosis II
51
trisomy 18 prognosis
most stillborn or die within first month
52
trisomy 18 clinical features
```
growth retardation
prominent occiput
micrognathia
overlapping fingers
rocker-bottom feet
choroid plexus cysts (prenatal US)
```
53
sex chromosome disorders-y chromsome
necessary and sufficient for phenotypic maleness, assuming the body can also make and use testosterone
54
sex chromosomal disorders x chromosome characteristics
the more X chromosomes, the more abnormal the person
55
sex chromosomal disoders
diagnosis usually missed at birth
56
what are sex chromosomal disorders better tolerated than?
autosomal aneuploidy
57
example of klinefelter syndrome
47XXY, 48XXXY, etc.
58
what causes klinefelter syndrome
maternal (or paternal) (or both) nondisjunction
59
what slightly increases risk of klinefelter's
advanced maternal age
60
when is klinefelter syndrome detected?
usually detected at puberty
61
symptoms of klinefelter's
```
small testes and penis
long limbs
diminished body hair, rarely go bald
"female" hips
gynecomastia
```
62
hormone levels klinefelter's
low plasma testosterone, high estrogen
63
reproductive ability klinefelter's
almost all are sterile
| infertility
64
IQ klinefelter's
slightly lower IQ's than XY dudes
65
what are people with klinefelter's prone to?
osteoporosis
66
do people with klinefelter's have a propensity for violent crimes?
no!
67
what can help klinefelter's?
androgen replacement
68
what is turner syndrome?
monosomy of Xp, 45X0
69
percentage of spontaneous abortions turner syndrome
99% spontaneously abort
70
turner syndrome prevalence
most frequent genetic disorder in females (1 in 2000)
71
when is turner syndrome detected and why?
usually detected at puberty, lack feminization
72
symptoms of turner syndrome
```
nonfunctional ovaries
primary amenorrhea
lack of breast development
no pubic hair
"menopause occurs before menarche"
```
73
turner physical features
```
short stature
multiple pigmented nevi
webbed neck
shield-shaped chest
valgus deformity of elbows (turned out)
coarctation of aorta
infertile
```
74
what can help turner's syndrome?
hGH and estrogen therapy help
75
how is genetic (chromosomal) sex determined?
presence/absence of Y chromosome
76
what actually determines intersex states?
SRY genes (sex determining region on Y)
77
what happens when dudes have SRY on X?
46XX
78
what is gonadal sex determined by?
histology of gonads
79
what indicates gonadal sex?
follicles vs. tubules vs. both (hermaphrodites) vs. neither (Turner)
80
what determines phenotypic (genital) sex
external genitalia
81
what indicates phenotypic sex?
vulva vs. penis vs. can't tell
82
what do true hermaphrodites have?
ovaries and testes
83
how to express true hermaphrodites?
46XX with translocation of Y to another chromosome-very rare
84
what do pseudohermaphrodites have disparity between?
gonadal and phenotypic sex
85
female pseudohermaphrodites
penis and ovaries
| "penis" is really an enlarged clitoris
86
what causes female pseudohermaphrodites?
usually due to error of metabolism
| Adrenogenital syndrome
87
male pseudohermaphrodites
vulva and testes
88
what causes male pseudohermaphrodites?
problems with testosterone synthesis and responsiveness
| "testicular feminization"
89
autosomal dominant disorders
single gene of a pair affected
90
what do autosomal dominant disorders result in?
defective or decreased amounts of protein product
91
what is variable in autosomal dominant disorders?
variable penetrance and expressivity
92
when do autosomal dominant disorder manifest?
later in life (after carrier has had chance to reproduce)
93
what chance of passing on autosomal dominant disorders?
affected parents have 50% chance of passing to offspring regardless of gender
94
mechanisms of autosomal dominant disorders
problems with the quantity or arrangement of structural proteins
problems with regulator proteins or receptors
deficiency in proteins that are in short supply even in health
anti-oncogene deletion syndromes
the mutant gene makes a harmful protein ("gain of function")
95
anti-oncogene deletion syndromes
a "second hit" on the normal allele turns it to a tumor cell
96
autosomal dominant disorders-structural proteins
Marfan's syndrome (connective tissue proteins)
Ehlers-Danios (connective tissue proteins)
Hereditary spherocytosis (red cell membrane)
Familial hypertrophic cardiomyopathy (heart muscle proteins)
Familial psoriasis
Achondroplastic dwarfism (fibroblast growth factor receptors)
Hereditary hemorrhagic telangiectasia (several)
Osteogenesis imperfecta (collagen)
97
autosomal dominant disorders-connective tissue proteins
Marfan's syndrome
| Ehlers-Danlos
98
autosomal dominant disorders-receptors
```
Familial hypercholesterolemia (LDL receptor)
Benign familial tremor
Ion channel problems
```
99
example of ion channel problems autosomal dominant
malignant hyperthermia susceptibility syndromes
100
autosomal dominant disorders-short supply proteins
von Willebrand's disease (vWF)
Maturity onset diabetes of the young (glucokinase)
Acute intermittent porphyria
101
autosomal dominant disorders-tumor genes
```
retinoblastoma
neurofibromatosis I and II
familial polyposis coli
lynch's hereditary non-polyposis colon cancer
multiple endocrine neoplasia syndrome I, Ila, Ilb
Li-fraumeni cancer syndrome
Tuberous sclerosis
Von Hippel-Lindau disease
Peutz-Jegher's syndrome
Adult polycystic kidney disease
```
102
autosomal dominant disorders-harmful proteins
prion diseases
Huntington's disease ("Huntington's chorea")
familial dysplastic nevus syndrome (melanin generates rather than protects from free radicals)
the common thrombophilias (hypercoagulability)
103
examples of the common thrombophillias (hypercoagulability)
Antithrombin III deficiency
Protein S deficiency
Protein C deficiency
Factor V Leiden
104
what is Marfan syndrome?
heterogenous group of disorders affecting connective tissue matrix
105
Marfan-mutations
many different mutations known, many unknown
106
what does Marfan syndrome usually involve?
fibrillin I
15q21
associates with elastin fibers
107
what types of manifestations in Marfan syndrome?
ocular, cardiovascular and musculoskeletal manifestations
108
Marfan syndrome symptoms
```
tall, long extremities
long "spider" fingers
hyperextensible "loose" joints
chest wall deformities
-pectus excavatum or carinatum
spinal curvatures
-kyphosis, scoliosis
funny-looking face
```
109
Marfan syndrome eye symptoms
```
ectopia lentis
-lax suspensory ligaments
-virtually pathognomonic
elongated globe, cornea loses convexity
-severe myopia
```
110
Marfan syndrome heart sx
```
lax aortic valve ring
-aortic insufficiency
-severe heart failure
"cystic medial necrosis" of thoracic aorta
-aortic dissections
1/3 of Marfan deaths
```
111
familial hypercholesterolemia
most common mendelian disorder
1 in 500 (or less)
many mutations known, usually 19p13
112
what is family hypercholesterolemia characterized by?
deficiency or defect in apoprotein B-100 ("LDL") receptors
| -the "bad" serum cholesterol
113
basic mechanism familial hypercholesterolemia
decreased liver clearance of LDL from the plasma with high plasma LDL levels
increased receptor-independent uptake of LDL by macrophages
chaotic uptake of LDL by macrophages leads to manifestations
114
familial hypercholesterolemia lab results
high serum cholesterol levels 300-500mg/dL
115
xanthomas
masses of lipid-stuffed macrophages
116
familial hypercholesterolemia induced precocious atherosclerosis leads to
heart attacks
| strokes
117
how is familial hypercholesterolemia treated?
statins
118
familial hypercholesterolemia homozygotes
die in teens
119
autosomal recessive disorders
both genes of pair affected
120
what do autosomal recessive disorders result in?
absence or lack of function of gene product
121
autosomal recessive penetrance
usually complete penetrance
122
when do autosomal recessive disorders manifest?
early in life
123
how are autosomal recessive disorders passed on?
affected parents always pass gene to offspring regardless of gender
124
what increases risk of autosomal recessive disorders?
consanguineous mating increases risk (don't kiss your cousin)
125
what are autosomal recessive disorders?
deficiencies or defects in highly specialized proteins
| -enzymes, membrane transport proteins
126
what are autosomal recessive disorders characterized by?
hemoglobinopathies
127
what are most inborn errors of metabolism?
autosomal recessive
128
what can common disorders often confer?
survival advantage to heterozygous carriers
129
examples of survival advantages autosomal recessive disorders
- sickle cell carriers can resist malaria
- hemochromatosis carriers maintain body iron stores easier
- cystic fibrosis carriers are resistant to gram-negative intestinal infections
130
autosomal recessive disorders-specialized proteins
```
albinism
cystic fibrosis
phenylketonuria
galactosemia
maple syrup urine disease
a-1 protease ("antitrypsin") inhibitor deficiency
Wilson's disease
most glycogen storage diseases
most lysosomal storage diseases
```
131
autosomal recessive disorders-hemoglobinopathies
sickle cell anemia
hemoglobin C disease
B-thalassemia major
a-thalassemia syndromes
132
albinism
inability to synthesize melanin
133
how many autosomal loci known for albinism?
at least 12
134
what deficiency from albinism most common?
deficiency of tyrosinase
135
what body parts are affected by albinism?
skin, eyes, hair affected
136
light sensitivity-albinism
highly photosensitive
137
what are albinos predisposed to?
skin and eye cancers
138
what is phenylketonuria a deficiency of?
phenylalanine hydroxylase
139
what does an accumulation of phenylalanine cause?
CNS toxicity
140
phenylketonuria sx
mental retardation
microcephaly
delayed speech development
hypopigmentation
141
phenylketonuria screening
all US infants screened at birth
142
what can prevent brain damage with phenylketonuria?
dietary restrictions
143
what are lysosomal storage diseases?
failure to catabolize large molecules within lysosomes
144
how many lysosomal storage diseases are known?
lots
145
what is the prototype lysosomal storage disease?
tay-sachs "amaurotic family idiocy"
146
what is tay-sachs a deficiency of?
hexosaminidase
147
what builds up in tay-sachs?
buildup of GM2 ganglioside (cell membrane component) within lysosomes
148
what is mostly affected in tay-sachs?
CNS and retinal neurons
149
what population is tay-sachs common in?
Ashkenazic Jews (1 in 30 is a carrier)
150
tay-sachs infants
normal at birth
151
what do tay-sach infants develop?
mental retardation, blindness, incoordination
152
tay-sachs brain and head sx
enlargement of brain and head
| -lipid accumulation within neurons
153
tay-sachs macula
cherry red spots on macula
| surrounding yellow indicates lipid accumulation
154
tay-sachs prognosis
death occurs within years
| no cure
155
sex-linked disorders
little to no homology between X and Y
156
how do defects on one X work sex-linked disorders?
defects on one X are overridden by normal allele on other X
| -no true x-linked dominant disorders
157
allele requirement sex-linked disorders
males (Y) require one abnormal allele (hemizygous), females require two (homozygous)
158
usual genders affected by sex-linked disorders
females are carriers
| males manifest disease (usually)
159
sex-linked disorders how many males with the gene are affected?
all males with the gene are affected
160
when will sex-linked disorders affect a woman?
she has two affected x-chromosomes
she suffers from really unfortunate lyonization
disease is expressed when individually lyonized cells are affected (G6PD deficiency)
she has turner's syndrome (XO) or testicular feminization (XY)
161
are sex-linked disorders transmitted from father to son?
never
162
sex-linked daughters of affected males
all carriers
163
sex-linked disorders
```
hemophilia A (factor VIII deficiency)
hemophilia B (factor IX deficiency)
G6PD deficiency ("favism")
Lesh-Nyhan syndrome
Duchenne's muscular dystrophy (Jerry's kids)
Emery-Dreifuss muscular dystrophy
Fragile X syndrome
Fabry's disease
Red-green color-blindness
testicular feminization (common type)
nephrogenic diabetes insipidus
Bruton's agammaglubulinemia
"David the Bubble Boy's" immunodeficiency
```
164
Lesch-Nyhan Syndrome
deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
needed for purine synthesis (salvage pathway)
leads to buildup of uric acid (gout)
intellectual disability
writhing movements
self-mutilating behaviors
165
polygenic disorders
disorders in which heredity plays a dominant role but there is no single gene
166
what do most cases of polygenic disorders involve?
environmental factors
167
polygenic disorders inheritance
do not follow clear-cut rules of inheritance
168
how can polygenic disorders represent?
congenital or later in life
169
polygenic disorders index patient
the sicker the index patient, the greater the risk to close relatives
170
polygenic disorders-siblings
the more sibs that are affected, the greater the risk to the next child
171
polygenic disorders-what is tricky to distinguish between?
single-gene diseases with incomplete penetrance
genetic diseases modified by environment
genetic heterogeneity
172
polygenic disorders examples
```
alcoholism
asthma
atherosclerosis
attention-deficit disorder/hyperactivity
baldness and hirsutism
breast cancer risk
cleft palate
diabetes mellitus (type I, type II)
hypertension
pyloric stenosis
schizophrenia
obesity (appetite out-of-sync with bodyweight)
```
173
acquired genetic disorders
a fertilized egg with the disease is non-viable
| a post-zygotic mutation involving only some cells occurs
174
expression acquired genetic disorders
expression variable depending on what/where affected cells are
McCune-Albright syndrome
Proteus syndrome
175
what is the great acquired genetic disease?
neoplasms
