Genetic diseases II Flashcards
1
Q
actual genetic code present at a gene locus
A
genotype
2
Q
the observable physical characteristic seen expressed by the genetic
code.
A
phenotype
3
Q
Each gene is located at the same locus in each of the paired constituent chromosomes
A
allele
4
Q
any permanent change in the DNA.
A
mutation
5
Q
mutations are caused by?
A
ionizing radiation, chemicals or drugs, microbes (namely viruses), and advancing age
6
Q
Patterns of Inheritance of Mendelian Disorders
A
autosomal disorders X-linked disorders Dominant disorder Recessive disorder codominance pleiotropy genetic heterogeneity
7
Q
isease is caused by mutation of a gene located on one of the 44 autosomes (non-sex chromosomes).
A
Autosomal Disorders
8
Q
isease is caused by mutation of a gene located on the X-chromosome. (There are no known disorders due to a mutation on the Y-chromosome.)
A
X-linked Disorders
9
Q
disease that is expressed in the phenotype if the mutation is present in the genotype, i.e., both heterozygotes and homozygotes express the disease.
A
Dominant Disorder
10
Q
Disease that is expressed in the phenotype only if both gene loci of the chromosome
pair have the pathologic mutation (homozygotes).
- Heterozygotes for the gene mutation are clinically normal, but are disease carriers.
A
Recessive Disorder
11
Q
both alleles of the gene pair are fully expressed in the heterozygote.
A
Codominance
12
Q
a single-gene mutation may cause many phenotypic effects.
A
Pleiotropy
13
Q
a single-gene mutation at any of several different gene pairs may cause the same phenotypic disease.
A
Genetic Heterogeneity
14
Q
what are the autosomal dominant mendelian disorders?
A
Familial hypercholesterolemia
Marfan syndrome
Neurofibromatosis
15
Q
Prevalence – 1:500
A
Familial Hypercholesterolemia
16
Q
autosomal dominant defect is caused by a mutation in a receptor protein.
A
Familial Hypercholesterolemia
17
Q
mutation involves the gene that specifies the receptor for low-density
lipoprotein (LDL).
A
Familial Hypercholesterolemia
18
Q
esults in impaired intracellular transport and catabolism of LDL, and thus LDL cholesterol accumulates in the plasma.
A
Familial Hypercholesterolemia
19
Q
Premature atherosclerosis and coronary artery disease
A
Familial Hypercholesterolemia
20
Q
Elevated serum cholesterol – heterozygotes have 2-3 fold increase
homozygotes have >5 fold increase
A
Familial Hypercholesterolemia
21
Q
famous example is Abraham Lincoln.
A
Marfan Syndrome
22
Q
Prevalence – 1:5,000
A
Marfan Syndrome
23
Q
autosomal dominant defect is caused by mutations in structural
proteins.
A
Marfan Syndrome
24
Q
Mutations in the fibrillin-1 (FBN1)
A
Marfan Syndrome
25
FBN1 has been
| mapped to which chromosome
chromosome 15
26
Mutation produces qualitative and quantitative defects in fibrillin-1, a
glycoprotein component of
microfibrillar connective tissue fibers
27
Fragmentation of elastic tissue is characteristic.
Marfan Syndrome
28
Major collagen fibers and elastic fibers are structurally normal
Marfan Syndrome
29
lipid masses are present in what syndrome and what are they called?
Familial Hypercholesterolemia
| called Soft tissue Xanthomas
30
what is the problem with marfan syndrome?
the microfibers that hold the collagen fibers and elastic fibers together thats that problem
31
Loss of microfibrils leads to abnormaland excessive activation of what?
transforming
| growth factor beta (TGF-β), which in turn affects integrity of ECM.
32
syndrome where you lose elasticity which can cause valves to tear and decrease rebound
Marfan syndrome
33
Elongated slender habitus
Marfan syndrome
34
Arachnoid fingers
Marfan syndrome
35
hyper extendable joints
Marfan syndrome
36
floppy heart valves
Marfan syndrome
37
aortic dissection and dilation
Marfan syndrome
38
bilateral dislocation of lenses
Marfan syndrome
39
TX for marfan syndrome
monitor vascular changes
antihypertensives
angiotensin receptor blockers (inhibit TGF-B)
40
Neurofibromatosis Type I was previously known as?
Recklinghausen disease of skin
41
Neurofibromatosis type 1 accounts for what % of cases of neurofibromatosis?
90%
42
Neurofibromatosis is transmitted via what disorder?
autosomal dominant disorder
43
Caused by mutation in NF1 gene
Neurofibromatosis Type I
44
NF1 gene is what type of gene?
tumor supressor gene
45
NF1 gene codes for neurofibromin, which negatively regulates what?
RAS
| oncoprotein.
46
mutation in NF1 causes
overactivity of the RAS protein, resulting the growth of tumors.
47
cafe au last spots
Neurofibromatosis Type I
48
Pigmented hamartomas of the iris = Lisch nodules
Neurofibromatosis Type I
49
Malignant transformation occurs in about 3% of patients.
Neurofibromatosis Type I
50
Incidence – 1:2,500 live births in US
Cystic fibrosis
51
Prevalence – 1:3,200 US Caucasians
Cystic fibrosis
52
Carrier frequency – 1:20 US Caucasians
Cystic fibrosis
53
autosomal recessive disorder is caused mutations of the_____ gene which
is located at chromosome ___
CFTR gene
| chromosome 7
54
What does the CFTR gene code for?
membrane associated protein that serves as a chloride channel
55
CFTR genes produce defects in what?
transport of chloride ions across epithelial surfaces.
56
what is the result in cystic fibrosis?
- epithelial cells relatively impermeable to Cl ions.
- This causes mucus secretions to be abnormally viscid, and
- sweat gland secretions to be abnormally salty.
- Affects products of all exocrine glands.
57
can produce problems in the pancreas- cysts in ductal system and fibrosis in acing structures and stroma and respiratory system
Cystic fibrosis
58
what is used to diagnose cystic fibrosis?
elevated sweat chloride test
| DNA probe- used to test carrier state and for prenatal diagnosis
59
what disorder is typically diagnosed due to MECONIUM ILUS?
Cystic fibrosis
| -bowel obstruction at birth bc bile secretions that for meconium of fetus is thicker and can't pass
60
which disorder presents with recurrent and chronic pulmonary infections and pancreatic insufficiency and malabsorption?
Cystic fibrosis
61
which disorder presents with mucous plugs malabsorption of fats (steatorrhea) and biliary cirrhosis (viscosity of bile)
cystic fibrosis
62
Tx for cystic fibrosis?
Antimicrobial therapy
pancreatic enzyme replacement
bilateral lung transplant
new treatment include medication targeting CFTR function
63
life expectancy for cystic fibrosis?
nearly 40 years
64
when you can't convert phenylalanine to tyrosine 2 things happen ...
1. accumulate phenylalanine in cells that normally metabolize it and can reach toxic levels
2. deficiency in tyrosine
65
Prevalence – 1:10,000 Caucasians
Phenylketonuria (PKU)
66
autosomal recessive disorder is caused by mutations in enzyme proteins.
Phenylketonuria (PKU)
67
severe lack of phenylalanine hydroxylase preventing
| conversion of phenylalanine to tyrosine
Phenylketonuria (PKU)
68
age onset for phenylketonuria?
within weeks of birth
69
why do you get severe mental retardation in phenyketoneuria?
BBB not yet formed (BBB formed by glial cells) excess serum phenylalanine enters brain tissue causing impaired brain development
70
Infant will have severe mental retardation witting 6 months if not treated IQ 50-60 seizure disorder
phenykeonturia
71
decreased pigmentation of skin and hair
phenylketonuria - due tyrosine necessary for melanin synthesis ( phenylalanine hydroxylase which is lacking in phenylketonuria prevents conversion of phenylalanine to tyrosine
72
diagnosis for phenylalanine
biochemical tests done frequently
73
treatment for phenylalanine
- dietary restrictions phenylalanine early in life
- enzyme replacement therapy with phenylalanine ammonia lyase
- tetrahydrobioterin (BH4) helps break down phenylalanine
74
what has large doses of phenylalanine?
asides have aspartate(equal sugar) which increases phenylalanine
75
what bacteria is responsible for recurrent and chronic pulmonary infections in cystic fibrosis?
pseudomonas aeruginosa and staphylococcus aureus
76
Prevalence – 1:60,000 live births
Galactosemia
77
autosomal recessive disorder of galactose metabolism is caused by
mutations in enzyme proteins.
Galactosemia
78
Lactose from milk is metabolized to
glucose and galactose.
79
what is there a lack of in galactosemia?
total lack of galactose-1-
| phosphate uridyl transferase
80
what does the lack of galactic-1 phosphate uridyl transferase cause?
preventing further metabolism of galactose-1-
| phosphate.
81
where does Galactose-1-phosphate and galactitol accumulate in tissues –
especially liver, eyes
| and brain.
82
Failure to thrive, with vomiting and diarrhea clinical feature of what?
galactosemia
83
hepatomegaly and jaundice
galactosemia
84
cataracts
galactosemia
85
CNS changes – loss of nerve cells, gliosis, edema
galactosemia
86
E. coli sepsis
galactosemia
87
Tx for galactosemia?
galactose-free diet for first 2 years of life
88
diagnosis deform galactosemia?
urine test for reducing sugar other than glucose \
| -test for rbc's for reduced transferase levels
89
what are the lysosomal storage diseases?
Tay sachs disease
Niemann pick disease (type A,B and C)
Gaucher disease
Mucopolysaccharidoses
90
caused by mutations in lysosomal enzyme proteins
lysosomal storage disease
| -autosomal recessive
91
what are the autosomal recessive disorders?
```
cystic fibrosis
phenylketonuria
galactosemia
lysosomal storage diseases
Glycogen storage diseases
```
92
why can lysosomal storage diseases be deadly?
lysosome being released into cytoplasm of cell has to be engulfed kills more lysosomes and can reach toxic levels and therefore death of the whole cell
93
Prevalence – 1:3,500 US Ashkenazi Jews, French Canadians (~1:30 Ashkenazi
Jews are carriers.)
Tay sachs disease
94
Deficiency of hexosaminidase A prevents degradation of GM2.
Tay-Sachs Disease
95
what is GM2
gangliosides- stored in axon neuronal bodies, glial cells, peripheral nerve fibers and in autonomic system
96
GM2 gangliosides are stored excessively in CNS
Tay-Sachs Disease
97
Infants develop severe mental retardation, blindness and severe neurologic
dysfunction.
Tay-Sachs Disease
98
Death occurs at 2-3 years of age.
Tay-Sachs Disease
99
Diagnosis of tay sachs disease?
- Heterozygotes are determined by serum hexosaminidase A level.
- Prenatal biochemical testing is possible.
100
Tx for Tay sachs disease
No effective treatment, can only manage complications
101
accumulation of sphingomyelin and/or
| cholesterol in phagocytic cells and sometimes in the CNS.
Niemann-Pick Disease
102
deficiency of acid sphingomyelinase
Niemann-Pick Disease type A and B
103
what does deficiency of sphingomyelin cause?
prevents conversion of sphingomyelin to ceramide and phosphorylcholine
104
which disease has predilection for
| the Ashkenazi Jewish population
Niemann pick Type A and B
| tay sachs disease
105
Characterized by severe deficiency of acid sphingomyelinase.
Niemann pick Type A
106
Most severely affected organs are the spleen, liver, bone marrow,
lymph nodes and lungs, leading to severe visceromegaly.
Niemann pick Type A
107
The entire CNS is involved, leading to severe neurologic
| deterioration.
Niemann pick Type A
108
Death occurs by age 3 years.
Niemann pick Type A
109
Mutated sphingomyelinase has some residual activity.
Niemann pick Type B
110
Affects the organ systems producing visceromegaly, particularly
hepatomegaly and splenomegaly.
Niemann pick Type B
111
CNS is not affected.
Niemann pick Type B
112
Most common type of Niemann pick disease
Niemann pick Type C
113
Caused by mutation of NPC1 (95%) or NPC2
Niemann pick Type C
114
what does amutation of NPC1 (95%) or NPC2 code for?
code for transport of
| cholesterol out of lysosomes. Cholesterol accumulates in lysosomes.
115
Affects the viscera and the CNS, leading to organ enlargement and
neurologic deterioration
Niemann pick Type C
116
Onset is in childhood. Survival is variable.
Niemann pick Type C
117
Patients survive into late childhood or early adulthood.
Niemann pick Type B
118
Prenatal or postnatal testing of sphingomyelinase activity of WBC or cultured fibroblasts is possible. Carrier state can also be determined.
Niemann Pick disease
119
Caused by deficient activity of glucocerebrosidase
Gaucher Disease
120
what does glucocerebrosidase do?
cleave the glucose residue from ceramide.
121
Glucocerebrosides accumulate in phagocytic cells forming what?
Gaucher cells
122
gaucher cells are large and have what type of pathognomonic cytoplasm?
"wrinkled tissue paper" cytoplasm
123
accumulation of gaucher cells also activates what cells?
macrophages
124
what are the variants of gaucher disease
Type I (99%), Type II and type III
125
chronic non-neuropathic form features bone involvement
and Hepatosplenomegaly, but NO CNS involvement. It is compatible with
long life.
Gaucher disease Type I
126
severe CNS involvement characterizes this highly lethal variant
that manifests by age 6 months.
Gaucher disease Type II
127
this juvenile form involves CNS and viscera.
Gaucher dises Type II
128
20x risk of devoting Parkinson disease
Gaucher disease
129
Diagnosis for Gauchers disease?
testing glucocerebrosidase levels in WBC or cultured fibroblasts. Heterozygotes can be detected
130
Tx for Type I Gauchers disease?
a) Life-long infusions enzyme replacement of recombinant glucocerebrosidase
b) Oral glucosylceramide synthase inhibitor – reduces substrate
c) Gene therapy is emerging therapy – hematopoietic stem cells containing
corrected enzyme
131
revalence – 1:25,000 (all types combined)
Mucopolysaccharidoses
132
abnormal degradation and
| subsequent accumulation of mucopolysaccharides in tissues.
Mucopolysaccharidoses
133
dermatan sulfate, heparan sulfate,
| keratin sulfate and sometimes chondroitin sulfate accumulation
Mucopolysaccharidoses
134
Multiple organs systems are involved including liver, spleen, heart and
blood vessels
Mucopolysaccharidoses
135
Mental retardation, cataracts, joint stiffness and coarse facial features present.
Mucopolysaccharidoses
136
Prevalence – 1:50,000 (all types combined)
Glycogen Storage Diseases (Glycogenoses)
137
All are caused by deficiency of a specific enzyme involved in glycogen synthesis or
degradation, resulting in excessive accumulation of glycogen in tissues.
Glycogen Storage Diseases (Glycogenoses)
138
missing enzyme is from liver
Hepatic form of Glycogen Storage Diseases (Glycogenoses)
139
Major clinical manifestations are hepatomegaly (from glycogen stored in
liver) and hypoglycemia.
Hepatic form of Glycogen Storage Diseases (Glycogenoses)
140
what is the most important example and results from lack of glucose-6-phosphatase.
Von Gierke disease in hepatic form of glycogen storage disease
141
enzymes of glycolysis are deficient in muscles
Myopathic forms of glycogen storage disease
142
Major clinical manifestations are muscles cramps and reduced production of
lactate following exercise.
Myopathic forms of glycogen storage disease
143
results from reduced muscle phosphorylase.
McArdle syndrome in Myopathic forms of glycogen storage disease
144
generalized glycogenosis
Pompe disease in misc. types of glycogen storage disease
145
what does generalized glycogenesis result from?
resulting from lysosomal
| glucosidase (acid maltase) deficiency
146
what disease can be classified as both glycogen storage and lysosomal storage disease?
Pompe disease
147
bulky muscles from glycogen but cant use it bc can't convert glycogen to glucose when you need it
Myopathic forms of glycogen storage disease
148
Major findings include hepatomegaly, cardiomegaly and skeletal muscle
glycogen deposits
Pompe disease in misc. types of glycogen storage disease
149
Death typically occurs by 2 years of age due to cardiorespiratory failure.
Pompe disease in misc. types of glycogen storage disease
150
what is an example of an X-linked dominant disorder
vitamin D-resistant rickets.
151
Examples of X-linked Recessive Disorders
a. Glucose-6-phosphate dehydrogenase deficiency
b. Hemophilia A and B
c. Agammaglobulinemia
d. Duchenne and Becker muscular dystrophies
152
what is an disease that displays a variable Mendelian mode of transmission?
Ehlers Danlos Syndromes
153
Incidence – 1:5,000 to 1:10,000
Ehlers Danlos Syndromes
154
group of syndromes are all caused by mutations in structural proteins leading to
defects in collagen synthesis or structure.
Ehlers Danlos Syndromes
155
Loss of tensile strength
Ehlers Danlos Syndromes
156
Inheritance of Ehlers Danlos Syndromes
1) All variants are inherited as single-gene defects.
2) Some are autosomal dominant.
3) Others are autosomal recessive.
4) At least one is X-linked recessive.
157
skin, ligaments and joints are affected i
Ehlers Danlos Syndromes
158
Hyper movable joints
Ehlers Danlos Syndromes
159
Hyperextensible skin shows extraordinary stretchability yet is extremely fragile and vulnerable to trauma.
Ehlers Danlos Syndromes
160
Pulls collagen apart but elastic tissue is ok so rebounds well
Ehlers Danlos Syndromes
161
skin and subcutaneous tissues are highly vulnerable to trauma
-hemorrhages easily and excessively
have collagen in bv's so traumatized tissue bleeds like crazy
Ehlers Danlos Syndromes
162
Structural failure of internal organs in t's with Ehlers Danlos Syndromes
̈ Rupture of colon
̈ Rupture of large arteries due to vascular fragility
̈ Rupture of cornea and retinal detachment
̈ Diaphragmatic hernia
163
Deficient synthesis of type III collagen is caused by?
Mutation in the COL3A1 gene
164
what does deficiency in type III collagen and Mutation in the COL3A1 gene cause?
This defect causes the vascular type of EDS and is transmitted in an
autosomal dominant fashion.
165
characterized by weakness of blood vessels and the bowel wall.
Deficient synthesis of type III collagen in EDS
166
what does deficiency of lysyl hydroxyls enzyme cause?
Causes decreased hydroxylation of type I and III collagen thus preventing
normal cross-linking
167
deficiency of lysyl hydroxyls enzyme causes
causes kyphoscoliosis EDS and is transmitted in an autosomal recessive fashion.
168
Deficiency of type V collagen causes mutation in what gene?
Mutation in COL5A1 or COL5A2 causes deficient synthesis.
169
Inherited in an autosomal dominant fashion and Produces classical EDS.
Deficiency of type V collagen
170
1) 1:1,500 males
| 2) 1:8,000 females
Fragile X- syndrome
171
Caused by mutation in the FMR1 gene
Fragile X- syndrome
172
associated with long repeating
| sequences of three nucleotides.
Fragile X- syndrome
173
What is the only disease that causes mental retardation thats genetically based that is more common than fragile x- syndrome?
Down syndrome
174
T/F down syndrome is not familial?
true
175
mutation maps to Xq27.
fragile X- syndrome
176
diagnosis for fragile x-syndrome
discontinuity in staining or constriction in q arm of X on karyotype.
177
Mental retardation – moderate to severe in males
fragile x- syndrome
178
Long face, large mandible, large everted ears, large testicles (macro-orchidism)
fragile x- syndrome
179
Males are generally affected. 20% of males with defect are clinically normal
carriers, and may pass the defect to their grandchildren
fragile x- syndrome
180
30-50% of carrier females have mental retardation, though not usually as severe
as in affected males.
fragile x- syndrome
