Genetic diseases II Flashcards Preview

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Flashcards in Genetic diseases II Deck (180):
1

actual genetic code present at a gene locus

genotype

2

the observable physical characteristic seen expressed by the genetic
code.

phenotype

3

Each gene is located at the same locus in each of the paired constituent chromosomes

allele

4

any permanent change in the DNA.

mutation

5

mutations are caused by?

ionizing radiation, chemicals or drugs, microbes (namely viruses), and advancing age

6

Patterns of Inheritance of Mendelian Disorders

autosomal disorders
X-linked disorders
Dominant disorder
Recessive disorder
codominance
pleiotropy genetic heterogeneity

7

isease is caused by mutation of a gene located on one of the 44 autosomes (non-sex chromosomes).

Autosomal Disorders

8

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.)

X-linked Disorders

9

disease that is expressed in the phenotype if the mutation is present in the genotype, i.e., both heterozygotes and homozygotes express the disease.

Dominant Disorder

10

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.

Recessive Disorder

11

both alleles of the gene pair are fully expressed in the heterozygote.

Codominance

12

a single-gene mutation may cause many phenotypic effects.

Pleiotropy

13

a single-gene mutation at any of several different gene pairs may cause the same phenotypic disease.

Genetic Heterogeneity

14

what are the autosomal dominant mendelian disorders?

Familial hypercholesterolemia
Marfan syndrome
Neurofibromatosis

15

Prevalence – 1:500

Familial Hypercholesterolemia

16

autosomal dominant defect is caused by a mutation in a receptor protein.

Familial Hypercholesterolemia

17

mutation involves the gene that specifies the receptor for low-density
lipoprotein (LDL).

Familial Hypercholesterolemia

18

esults in impaired intracellular transport and catabolism of LDL, and thus LDL cholesterol accumulates in the plasma.

Familial Hypercholesterolemia

19

Premature atherosclerosis and coronary artery disease

Familial Hypercholesterolemia

20

Elevated serum cholesterol – heterozygotes have 2-3 fold increase
homozygotes have >5 fold increase

Familial Hypercholesterolemia

21

famous example is Abraham Lincoln.

Marfan Syndrome

22

Prevalence – 1:5,000

Marfan Syndrome

23

autosomal dominant defect is caused by mutations in structural
proteins.

Marfan Syndrome

24

Mutations in the fibrillin-1 (FBN1)

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