Chapter 5 - Genetic Disorders Flashcards
1
Q
mutations that alter the meaning of the sequence of the encoded protein
A
missense mutation (type of point mutation)
2
Q
what type of mutation is the sickle cell mutation
A
missence mutation - CTC for glutamic acid is changed to CAC for valine
3
Q
mutation that changes an amino acid codon to a chain terminator
A
stop codon or nonsense mutation (type of point mutation)
4
Q
what type of mutation is the B0-thalassemia mutation
A
stop codon nonsense mutation (CAG for glutamine is changed to UAG stop codon)
5
Q
small deletion or insertions that lead to an altered reading of DNA
A
frameshift mutations (insertion/deletion mutations)
6
Q
Tay Sachs is what type of mutation
A
frameshift mutation
7
Q
amplification of a sequence of three nucleotides
A
trinucleotide repeat mutations
8
Q
fragile X syndrome is what type of mutation and what is this disorder?
A
tandem repeats of CGG within the fene called familial mental retardation 1 (FMR1)
9
Q
how do mendelian disorders affect genes
A
they are a result of mutations in single genes
10
Q
G6PD follows what type of genetics
A
X-linked recessive; red cell hemolysis in patients receiving certain types of drugs
11
Q
Vitamin D-resistant rickets has what type of genetics
A
X-linked dominant
12
Q
what type of genetics does Marfan syndrome have?
A
autosomal dominance
13
Q
what is the mutation in marfan syndrom
A
fibrillin-1
14
Q
role of fibrillin in the extracellular matrix
A
fibrillin microfibrils in the ECM provide a scaffolding on which tropoelastin is deposited to form elastic fibers
15
Q
what chromosome is the fibrillin gene mapped on
A
15q21.1 (FBN-2 is on 5q23.31, not in rapid review)
16
Q
skeletal deformities present in marfan syndrome
A
exceptionally long extremities and long, tapering fingers and toes
17
Q
what organs may be affected in marfan syndrome
A
skeletal, eye, cardio
18
Q
what is the ocular change associated with marfan syndrome
A
ectopia lentis - bilateral subluxation/dislocation of the lens
19
Q
what cardiovasuclar malformations are present in marfan syndrome, which is a leading cause of death
A
MVP and dilation of the ascending aorta due to cystic medionecrosis, dilation of aorta is most serious
20
Q
major cause of death in Marfan syndrome
A
rupture of an anortic dissection
21
Q
ehlers danlos syndrome has a defect in _________
A
fibrillar collagen
22
Q
symptoms of ehlers danlos syndrome
A
Skin is hyperextensible, stretchy, fragile, and vulnerable to trauma. Joints are hypermobile
23
Q
internal complications associated with ehlers danlos syndrome
A
(1) rupture of thhe colon and large arteries (vascular EDS) (2) ocular fragility with rupture of cornea and retinal detachment (kyphoscoliosis EDS) (3) diaphragmatic hernia (classical EDS)
24
Q
which type of collagen manifests as the vascular type of EDS
A
type III collagen
25
the arthrochalasia type of ehlers danlos is a defect in what type of collagen
collagen type I, procollagen to collagen
26
mutation in familial hypercholestolemia
gene encoding receptor for LDL
27
features of heterozygoes with familial hypercholesterolemia
2x/3x elevations in plasma cholesterol, skin xanthomas and premature atherosclerosis in adult life
28
features of homozygotes with familial hypercholestorlemia
5x/6x elevations in plasma cholesterol, skin zanthomas, coronary/cerebral/peripheral vascular atherosclerosis at an early age, MI possible before age 20
29
what is the LDL receptor's role physiologically
binding of IDL to the liver cell membrane and it recognizes both apoprotein B-100 and apoprotein E
30
how many mutations of the LDL receptor in familial hypercholesterolemia
more than 900 mutations involving the LDL receptor gene
31
what is there an accumulation of in tay-sachs disease
Gm2 gangliosides
32
the mutation in tay-sachs disease causes a deficiency of:
hexosaminidase A
33
what group of people is tay-sachs disease prevalent in
Ashkenazi Jews
34
what is the genetics of tay-sachs disease
autosomal recessive
35
symptoms of tay-sachs disease
progressive neurodegeneration, developmental delay, cherry-red spot on macula, lysosomes with onion skin, no hepatomegaly (unlike niemann-pick)
36
What disease is this seen? and what is it?
37
What disease is this seen in?
Tay-sachs; portion of a neuron with prominent lysosomes whorled configurations
38
39
pattern of inheritance in niemann-pick disease
AR
40
which type of niemann-pick disease does organomegaly present without CNS involvement
type B
41
what are some characteristics of of Niemann-Pick Disease Type A
severe infantile form with extensive neurologic invovlement with marked visceral accumulations of sphingomyelin, and progressive wasting and early death within the first 3 years of life
42
electron microscopy of niemann-pick disease reveals
engorged secondary lysosomems that often contain membranous cytoplasmic bodies that resemble concentric lamellated myelin figures (zebra bodies)
43
what organs are enlarged with niemann pick disease
hetosplenomegaly
44
what disease is this
niemann pick disease in liver with hepatocytes and kupffer cells with a foamy vacuolated appearance because of lipid deposition
45
what is the build up in niemann pick diseases A and B
sphingomyelin due to an inherited deficiency of sphingomyelinase
46
most common type of niemann pick disease
type C niemann pick with NPC1, sometimes NPC2 mutation
47
inheritance pattern of gaucher disease
autosomal recessive
48
mutation invovles what enzyme for gaucher disease
glucocerebrosidase
49
where does the glucocerebrosides accumulate in gaucher disease
distended phagocytic cells in the spleen, bone marrow, lymph nodes, tonsils, thymus, and peyer's patches
50
histologic appearance of cells in gaucher disease
fibrillary type of cytoplasm like crumpled tissue paper
51
what organ is mostly involved in gaucher disease
splenomegaly
52
what disease do you see these types of cells in
gaucher disease; gaucher cells - cytoplasm with the appearance of crumpled cytoplasm
53
general features of mucopolysaccharidose disorders
progressive disoders characterized by coarse facial features, clouding of the cornea, joint stiffness, and mental retardation
54
pattern of inheritance for hurler syndrome
AR
55
deficiency in hurler syndrom
alpha-1-iduronidase
56
in adition to the MPS symptoms, what are some characterisitics of hurler syndrome
growth is retarded with coarse facial features and skeletal deformities
57
when/how does death occur in hurler syndrome
death bye 6-10 years due to carciovascular complications
58
accumulating metabolite in hurler syndrome (MPS I H)
dermatan sulfate, heparan sulfate
59
inheritance pattern for hunter syndrome
X-linked recessive
60
what is the enzyme deficiency of Hunter syndrome
L-Iduronosulfate sulfatase
61
how does hunter syndrome differ from hurler syndrome
it is a milder form of hurler's syndrome with aggressive behavior and no corneal clouding
62
what accumulates in hunter's syndrome
heparan sulfate and dermatan sulfate
63
inheritance pattern of alkaptonuria
autosomal recessive
64
enzyme deficency in alkaptonuria, and what is this enzyme in control of
lack of homogentistic oxidase which converts homogentistic acid to methylacetoacetic acid in the tyrosine degradation pathway
65
what is excreted in alkaptonuria
urine turns black if its allowed to stand and undergo oxidation when the built up homogentisic acid is secreted
66
what is the most serious consequence from alkaptonuria
homogentisic acid deposits in the articular cartilages of the joints causing the cartilage to lose its normal resiliency and become brittle and fibrillated
67
what regions of the body is ochronosis seen in alkaptonuria
blue black pigmentation most evident in ears, nose, and cheeks
68
what is the deficient enzyme of metachromatic leukodystrophy
arylsufatase A
69
what builds up in metachromatic leukodystrophy
sulfatide
70
what is the deficient enzyme in krabbe disease
galactosylceramidase
71
what builds up in krabbe disease
galactocerebroside
72
enzyme deficiency in von gierke disease
G6PD - type 1 glycogen storage disease
73
what organs are involved in von gierke diseases
hepatomegaly and renomegaly
74
clinical manifestation of von gierke disease
hypoglycemia
75
enzyme deficiency in McArdle syndrome
Muslce phosphorylase - type V glycogen storage disease
76
morphologic changes wih McArdle syndrome
skeletal muscle accumulations only
77
clinical manifestations of McArdle syndrome
painful cramps associated with strenuous exercise
78
what is the age of onset in McArdle syndrome and explain lactate levels in this disease
in adulthood (greater than 20 years); muscular exercise fails to raise lactate level in venous blood
79
enzyme deficiency in pompe disease
enzyme deficiency of lysosomal glucosidase (acid maltase) - miscellaneous type of glucagen storage disease
80
morphologic changes in pompe disease
massive cardiomegaly and cardiorespiratory failure within 2 years
81
the important glycogen storage disease have what mode of inheritance
AR
82
in what disease will this change occur in the myocardium
pompe disease (glycogen storage disease type II) - normal is on left. right picture has myocardial fibers full of glycogen which is seen as clear spaces
83
most common cause of trisomy and down syndrome
nondisjunction
84
what has a strong influence on the incidence of trisomy 21
maternal age
85
how often does trisomy occur in births in women under age 20 and over 45
1150 live births in women under 20 and 1/25 for mothers over 45
86
other than nondisjunction, what is the genetic abnormality found in Down syndrome
robertsonian translocation
87
how much mosaicism goes on with down syndrome?
1% of patients are mosaics
88
what type of down syndrome does maternal age affect
nondisjunction; translocatioin or mosaic down syndrome are not affected by maternal age
89
diagnostic clinical features of down syndrome (4)
flat facial profile with epicanthic folds, abundant neck skin, simian crease on hand, hypotonia, mental retardation, congenital herat defects, predisposition to leukemia
90
what is responsible for the majority of death in infancy/childhood of Down syndrome patients?
cardiac problems
91
what cardiac abnormalities are commonly present with Down syndrome
defects of the endocardial cushion (most common) like ASDs and VSDs.
92
what congenital malformations other than cardiac problems are present with Down syndrome
atresias of the esophagus and small bowel
93
children with trisomy 21 have an increased risk of developing \_\_\_\_\_\_\_
acute leukemia, ALL and AML (megakaryoblastic leukemia commonly)
94
Down syndrome patients that are older than 40 can develop
Alzheimer disease
95
edwards syndrome is trisomy \_\_\_
18
96
clinical features of edwards syndrome
mental retardation, overlapping fingers, congenital heart defects (VSD)
97
patau syndrome is trisomy \_\_
13
98
clinical features of patau syndrome
early death, mental retardation, polydactyly, cleft lip and palate, cardiac defects (VSD), renal defects (cystic kidneys)
99
genetic abnormality of DiGeorge syndrome
22q11.2, small deletion of band q11.2 on the long arm of chromosome 22
100
symptoms of DiGeorge syndrome
thymic hypoplasia with T-cell immunodeficiency, parathyroid hypoplasia (hypocalcemia), cardiac malformations with the outflow tract, and mild facial anomalies
101
clinical features of velocardiofacial syndrome (subtype of DiGeorge)
facial dysmorphism (prominent nose, retrognathia), cleft palate, cardiovascular anomalies, learning disabilities
102
what determines male sex
presence of a single Y chromosome
103
klinefelter syndrome is genetically defined as
male hypogonadism occurring with 2 or more X chromosome and 1 or more Y chromosome
104
clinical features of klinefelter syndrome
eunuchoid body habitus with abnormally long legs, small atrophic testes associated with a small penis, lack of secondary mal characteristics like a deep voice, beard, and male distribution of pubic hair, gynecomastia, lower mean IQ but not mental retardation
105
abnormal hormone levels found in klinefelter syndrome
elevated FSH and reduced testosterone levels
106
appearance of testes with klinefelter syndrome
some patients have totally atrophied testicular tubules that are replaced by pink, hyaline, collagenous ghosts; others have atrophic tubules that are interspersed
107
appearance of leydig cells with klinefelter syndrome
leydig cells appear prominent as a result of atrophy and crowding of tubules and increased gonadotropin concentrations
108
classic klinefelter karyotype, and what does it result from
47,XXY from nondisjunction
109
turner syndrome results from ____ and is characterized by ____ in phenotypic females
complete/partial monosomy of the X chromosome, hypogonadism
110
most common karyotype of turner syndrome
45, X karyotype
111
most severely affected patients with turner syndrome present in infancy with these clinical features:
edema of the dorsum of the hand and foot because of lymph stasis, swelling of the nape of the neck (markedly distended lymphatic channels producing cystic hygroma), b/l neck webbing, persistant looseness of the skin on the back of the neck, congenital heart disease (preductal coarctation of the aorta and bicuspid aortic vlve most common)
112
clinical features seen in the adolescent andd adult form of Turner syndrome
failure to develop normal secondary sex characteristics, short stature (lower than 150cm), amenorrhea
113
most important cause of primary amenorrhea (1/3 of cases)
turner syndrome
114
most common sex chromosome abnormality in females
turner's syndrome
115
describe what happens to the oocytes and what do the ovaries look like in turner's syndrome
without the second X chromosome there is an accelerated loss of oocytes which is complete by age 2 years; ovaries are reduced to atrophic fibrous strands devoid of ova and follicles called streak ovaries
116
most common form of male pseudohermaphroditism and what is its cause and mode of inheritance
complete androgen insennsitivity syndrome (testicular feminization) from mutations in the gene encoding the androgen receptor, X-linked recessive
117
fragile-x syndrome gene, protien, and repeat
FMR1 (familial mental retardation-1 gene), FMR-1 protien, CGG
118
friedreich ataxia gene, protein, repeat
FXN, frataxin, GAA
119
myotonic dystrophy gene, protein, repeat
DMPK, myotonic dystrophy protein kinase (DMPK), CTG
120
spinobulbar muscular atrophy/kennedy disease gene, protein, repeat
AR, androgen receptor AR, CAG
121
huntington disease gene, locus, protein, repeat
HTT, 4p16.3, huntingtin, CAG
122
spinocerebellar ataxia trinucleotide repeat
CAG
123
second most common genetic cause of mental retardation (after Down syndrome)
fragile-x syndrome
124
clinical features of fragile-X syndrome in males
mentally retarded males, with a long face with a large mandible, large everted ears, and large testicles (macroorchidism - 90% of post-pubertal males!)
125
how often is it to have a carrier female be affected in fragile x-syndrome
30% to 50% of carrier females affected with mental retardation which is a higher number than that of other x-linked recessive disorders
126
mode of inheritance for fragile-x syndrome
x-linked
127
choice for diagnosis of fragile-x syndrome
PCR-based detection of the repeats
128
example of a disease with mitochondrial inheritance
leber hereditary optic neuropathy - a neurodegenerative disease that manifest as a progressive b/l loss of central vision
129
what is genomic imprinting
imprinting selectively inactivates either the maternal or paternal allele; occurs in the ovum/sperm before fertilization and then is transmitted to all somatic cells through mitosis
130
prader-willi syndrome characteristics
mental retardation, shrot stature, hypotonia, obesity, hypogonadism
131
genetic abnormality in prader-willi syndrome
deletion in the paternally derived chromosome 15 (paternal imprinting)
132
angelman syndrome genetic abnormality
deletion of maternally derived chromosome 15 (maternal imprinting)
133
symptoms found in angelman syndrome
mental retardation, ataxic gait, seizures, inappropriate laughter
134
what are angelman syndrome patients sometimes referred to as?
happy puppets :/
135
what does PCR do to DNA and what are the steps invovled
amplifies a desired fragment of DNA; denaturation (heat to generate 2 strands), annealing (in cooling, excess premade DNA primers anneal to specific sequeneces on the DNA needing to be amplified), elongation (heat stable DNA polymerase replicates following each DNA primer)
136
blotting procedures: each blot is used for what molecule?
SNoW DRoP (southern = DNA, northern = RNA, western = protien)
137
process of southern blotting
DNA sample electrophoresed to gel then to filter --\> filter soaked in denaturant and exposed to radiolabeled DNA probe --\> DNA probe recognizes the sample and anneals to the complementary strand --\> ds DNA is visualized when filter is exposed to film
138
when would you use a southern blot over PCR
if the affected DNA segment is too large
139
process of microarraying
thousands of nucleic acid sequences arranged in grids on glass/silicon --\> DNA/RNA probes hybridize to the chip and scanner detects the amount of complementary binding
140
what is microarray used for? what is it able to detect?
you look at thousands of genes simultaneousl; they detect single nucleotide polymorphisms (SNPs)
141
use of FISH! (flluorescence in situ hybridization)
specific localization of genes and direct visualization of anomalies at a molecular level (if the deletion is too small to be visualized on a karyotype)
142
what does the fluorescence indicate on FISH
fluorescence is present when the gene is present, if there is no fluorescence the gene has been deleted
143
FISH method
fluorescent DNA or RNA probe binds to specific gene site of interest on chromosomes
