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*MOD Exam 1 > Lecture 5: Genetic Disorders (Martin) > Flashcards

Lecture 5: Genetic Disorders (Martin) Flashcards

1
Q

What are the three categories of human genetic disorders?

A
  1. Single gene mutation
  2. Chromosomal disorder
  3. Complex multigenic disorder
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2
Q

What is an example of a single gene mutation disorder?

A

Sickle cell anemia

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3
Q

What is the most common type of human gentic disorder?

A

Complex multigenic disorders

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4
Q

What are some examples of complex multigenic disorders?

A

Atherosclerosis, diabetes, hypertension, autoimmune diseases, height, weight

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5
Q

What is the definition of a mutation?

A

Permanent change in DNA

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6
Q

Germ cell mutations give rise to ___________

A

Inherited diseases

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7
Q

Somatic cell mutations give rise to __________ and ____________

A

Cancer

Congenital malformations

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8
Q

Define:

Missense

A

Alter the meaning of a sequence of the encoded protein

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9
Q

Define:

Nonsense

A

Pre mature STOP CODON

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10
Q

***

What are the major 3 transcription factors associated with noncoding sequences?

A

MYC, JUN, p53

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11
Q

What happens if 3 base pairs, or multiple of 3 occurs in a DNA strand?

A

Reading frame remains intact, however get an abnormal protein

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12
Q

What happens if a deletion or insertion does NOT occur in a multiple of 3?

A

Alteration in reading frame = frameshift mutation

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13
Q

What is a trinucleotide-repeat?

What do they contain?

A

Amplification of a sequence of 3 nucleotides

*nearly all contain guanine (G) and cytosine (C)

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14
Q

What are a couple of diseases that are examples of trinucleotide-repeat?

A

Huntingtons Disease

Myotonic dystrophy

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15
Q

What is anticipation in relation to genetic disorders?

A

“A genetic disorder is passed on to the next generation, the symptoms become apparent at an earlier age with each generation. In most cases, an increase in severity of symptoms is also noted.”

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16
Q

State what type of deletion or insertion is occuring with the following disorders:

Cystic Fibrosis

ABO (blood type)

Tay-Sachs

A

Cystic Fibrosis = 3 base deletion

ABO (blood type) = Single base deletion

Tay-Sachs = 4 base insertion

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17
Q

Define:

Codominance

A

Both alleles contribute to phenotype

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18
Q

Define:

Pleiotropism

A

Single mutant gene

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19
Q

Define:

Genetic heterogeneity

A

Mutations at several loci may produce the same trait

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20
Q

Autosomal dominant disorders

New mutations seem to occur in germ cells of _________________

A

Relatively older fathers

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21
Q

What is incomplete penetrance?

A

(+) mutation

Normal phenotype

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22
Q

What is variable expressivity?

A

(+) for trait

however

EXPRESSED differently

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23
Q

What is an example of a loss-of-function mutation?

A

Familial hypercholesterolemia

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24
Q

What is an example of a gain-of-function mutation?

A

Huntingtons protein toxic to neurons

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25
Q

What are the two main patterns of disease with autosomal dominant disorders?

A
  1. Regulation of complex metabolic pathways
  2. Key structural proteins: collagen and cytoskeletal elements of RBC membrane
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26
Q

What is an example of an autosomal dominant disorder that demonstrates the “regulation of complex metabolic pathways” pattern of disorder?

A

LDL receptor in familial hypercholesterolemia

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27
Q

What is an example of an autosomal dominant disorder that demonstrates the “key structural protein compromise” pattern of disorder?

A

Osteogenesis imperfecta

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28
Q

How do autosomal dominant disorders keep getting passed on if they are so detrimental?

A

Age of onset is delayed in many of these conditions

This allows the genes to continue to get passed onto offspring

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29
Q

What are the major autosomal recessive disorders we discussed in lecture?

A

Cystic Fibrosis

Phenylketonuria

Niemann-Pick

MPS (Hurler)

Gaucher

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30
Q

Describe the characteristics of autosomal recessive disorders

A

Largest category of disorder

Both alleles are mutated

Trait usually does NOT affect parent

If mutation is low frequency in population, strong likelihood proband product of consanguineous marriage

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31
Q

How can you differentiate autosomal dominant vs autosomal recessive disorders?

A

Autosomal recessive disorders demonstrate:

  • Uniform expression of defect
  • Complete penetrance
  • Onset is early in life
  • Many mutatations involve enzymes
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32
Q

What is the primary defect in cystic fibrosis?

What gene?

What chromosome?

A

Abnormal function of an epithelial chloride channel protein

CFTR gene

Chromosome 7q31.2

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33
Q

What is the most common lethal genetic disease that affects Caucasian populations?

A

Cystic fibrosis

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34
Q

What is the major bacteria associated with cystic fibrosis?

A

Pseudomonas aeruginosa

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35
Q

What are the major GI indications for Cystic Fibrosis?

A

Meconium ileus

Pancreatic insufficiency

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36
Q

What is a major manifestation of cystic fibrosis specifically in males?

A

Male urogenital abnormalities

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37
Q

What are the cirteria for diagnosis of cystic fibrosis?

A

One or more characteristic phenotypic features;

  • OR a history of CF in a sibling
  • OR a positive newborn screening test result

AND

An increased sweat chloride concentration on two or more occasians

  • OR identification of two CF mutations
  • OR demonstration of abnormal epithelial nasal ion transport
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38
Q

What type of inheritance does Phenylketonuria (PKU) follow?

What is the mechanism of Phenylketonuria?

A

Autosomal recessive disorder

Deficiency in phenylalanine hydroxylase (PAH) which leads to HYPERPHENYLALANINEMIA

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39
Q

What is the typical profile of a patient with phenylketonuria (PKU)?

A

Scandinavian descent

Light skinned

6mo severe mental retardation, hypopigmentation

Strong musty or mousy odor in urine and sweat

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40
Q

What are the two major X-linked recessive disorders covered in lecture?

A

Glucose-6-phosphate dehydrogenase dificiency

Fragile X syndrome

41
Q

What does an X-linked disorder pedigree look like?

A

Only males are affected

42
Q

What does mitochondrial inheritance look like on a pedigree?

A

*Remember, mitochondrial inheritance ALWAYS comes from the mother.

43
Q

What is a mendelian disorder?

A

Alterations in a single gene which produces

an abnormal product or decrease in normal product

44
Q

What are the three potential outcomes of having an enzyme defect?

A
  1. Accumulation of substrate
  2. Decreased amount of end product
  3. Failure to inactivate a tissue-damaging substrate
45
Q

Name the main example associated with the 3 potential outcomes of enzyme defects

  1. Accumulation of substrate
  2. Decreased amount of end product
  3. Failure to inactivate a tissue-damaging substrate
A
  1. Accumulation of substrate : Galactosemia
  2. Decreased amount of end product : Lesch-Nyhan
  3. Failure to inactivate a tissue-damaging substrate : Alpha1-antitrypsin
46
Q

What is the mechanism behind familial hypercholesterolemia?

A

Decreased synthesis or decreased function of LDL receptor

leads to defective transport of LDL into cells

Which causes increase of cholesterol synthesis

47
Q

What is the

inheritance pattern

gene

product defect

in MARFANS?

A

Autosomal dominant

FBN1 (more common), FBN2 (less common)

Fibrillin-1

48
Q

What is the phenotype of someone with Marfans?

A

Unusually tall

Exceptionally long extremities

“Double jointed”

Long headed

Prominent supraorbital ridges

Ectopia lentis

Aortic dissection

49
Q

Describe Ehlers-Danlos Syndromes (EDS)

A

Defect in the synthesis or structure of fibrillar collagen

Skin is hyperextensible and joints are hypermobile

Skin is extremely stretchable–> vunlerable to trauma

50
Q

How do patients with Ehlers-Danlos Syndromes typically die?

A

Rupture of the colon and large arteres

51
Q

What are the UNIQUE clinical findings with

EDS CLassic (I/II)

Vascular (IV)

Kyphoscoliosis (VI)

*When I say “unique” I mean additional features in these subtypes that are not found in other types

A

EDS CLassic (I/II) : Easy bruising

Vascular (IV): Arterial rupture

Kyphoscoliosis (VI): Ocular fragility

52
Q

What is a primary accumulation lysosomal storage disease?

A

Catabolism of the substrate of the missing enzyme remains incomplete, leading to the accumulation within the lysosomes

53
Q

What causes a secondary accumulation lysosomal storage disorder?

A

Impaired autophagy

54
Q

Tay-Sachs disease

What chromosome?

Severe deficiency of?

Common in what population?

A

What chromosome –> Chr 15

Severe deficiency of–> Hexosaminidase A

Common in what population –> Ashkenazic jews

*Way to remember the chromosome number: Tay, shes a basic teenage girl and she had SEX (Tay-Sachs) at age 15.

55
Q

What is a hallmark clinical finding for Tay-Sachs disease?

A

Cherry-red spot in the macula

56
Q

Describe the mechanism of Niemann-Pick disease

A

Lysosomal accumulation of sphingomyelin

due to inherited deficiency of sphingomyelinase

57
Q

What is population is Niemann-Pick disease commonly found with?

A

Ashkenazi Jews

58
Q

What is the inheritance pattern of Neimann-Pick disease?

What chromosome is it found on?

A

Autosomal recessive

Chromosome 11p15.4

59
Q

What are the three types of Neimann-Pick disease?

What are the characteristics of each?

A

Type A: Severe infantile, death before 3

Type B: No CNS development

Type C: MOST COMMON due to NPC1

60
Q

What is the morphology of Niemann-Pick disease cells?

A

Foamy cytoplasm

Zebra bodies

61
Q

Gaucher disease

Genetic inheritance?

Type of mutation?

Where does material collect?

A

Autosomal recessive

Glucocerebrosidase mutation

Glucocerebroside in phagocytes

62
Q

What is the morphology of Gaucher disease cells?

A

Crympled tissue paper

63
Q

What is the inheritance pattern for Mucopolysacchariodoses (MPS)?

A

All are autosomal recessive

EXCEPT Hunter syndrome which is X-linked recessive

64
Q

What are the clinical manifestations of Mucopolysaccharidoses (MPS)?

A

Coarse facial features

Clouding of cornea

Joint stiffness

Mental retardation

65
Q

What are the two most common types of Mucopolysaccharidoses?

A

Hurler

Hunter

66
Q

Cute mneumonic for remembering Hunters vs Hurler’s?

A

Children with Hunter’s syndrome do not have corneal clouding because you need to “see” in order to hunt

To remember that it is X-linked, picture a hunter with a bow and arrow. The box and arrow cross each other making an X

67
Q

Glycogen storage diseases:

What are the 3 major sub groups?

A
  1. Hepatic forms
  2. Myopathic forms
  3. Miscellaneous
68
Q

Glycogen storage diseases:

What is an example of each of the three sub groups?

A

Hepatic forms: Von Gierke

Myopathic form: McArdle disease

Misc: Pompe disease

69
Q

What is the enzyme involved in:

McArdle disease

Pompe disease

Von Gierke disease

A

McArdle: Phosphorylase (V, VI)

Pompe: Lysosomal acid maltase

Von Gierke: Glucose 6 phosphatase

70
Q

What is multifactorial inheritance?

A

Interaction of enviornmental influences with two or more genes

71
Q

What are common examples of Multifactorial inheritance?

A

Cleft lip

Cleft palate

Neural tube defects

72
Q

Define:

Euploid

Aneuploid

A

Euploid: any exact multiple of haploid number (23)

Aneuploid: NOT an exact multiple of 23

73
Q

Define:

Mosaicism

A

Mitotic errors in early development give rise to two or more populations of cells with different chromosomal complement in the same individual

74
Q

What is a Robertsonian translocation?

A

(Centric fusion)

Translocation between 2 acrocentric chromosomes ; typically breaks appear closer to the centromeres of each chromosome

75
Q

Robertsonian translocations account for 3-4% of __________

A

Trisomy 21 cases

76
Q

What is a strong influence of trisomy 21?

A

Maternal age

77
Q

What are the clinical manifestations of trisomy 21?

A

Flat facial profile

Oblique palpebral fissures

Epicanthic folds

40% have congenital heart disease

10-20 fold increased risk of developing leukemia

simian crease

78
Q

What syndrome does this baby have?

A

Trisomy 13: Patau syndrome

79
Q

What syndrome does this baby have?

A

Trisomy 18: Edwards syndrome

80
Q

What syndrome does this baby have?

A

Trisomy 21: Down Syndrome

81
Q

What is chromosome 22q11.2 deletion syndrome

A

DiGeorge Syndrome/Velocardiofacial syndrome

Congenital heart defects, abnormalities of the palate, facial dysmorphism

82
Q

What is lyonization?

A

Inactivation of all but one X chromosome

Results in barr body

83
Q

What is the genetic makeup of someone with Klinefelter syndrome?

A

47, XXY

84
Q

What are Klinefelter syndrome patients at higher risk for aquiring?

A

Type 2 DM

Breast cancer

Male inferfility

Osteoporosis

85
Q

What is the genetic makeup of a patient with Turner syndrome?

A

45, X

86
Q

What is oberved upon birth of a patient with Turner syndrome?

A

Cystic hygroma

Bilateral neck webbing

87
Q

What is the clinical presentation of a Turner’s patient?

A

Short stature

Webbing of neck

Cardiovascular malformations

Amenorrhea

Lack of secondary sex characteristics

FIbrotic ovaries

88
Q

What is the difference between a true hermaphrodite and a pseudohermaphrodite?

A

True: presence of both ovarian and testicular tissue

Pseudo: have phenotypes of both

89
Q

Describe a trinucleotide-repeat mutation

A

Expansion of trinucleotide repeats is an important genetic cause of human disease…

Particularly Neurodegenerative disorders

90
Q

What is a morphologic hallmark of trinucleotide repeat mutations?

A

Accumulation of aggregated mutant proteins inside large intranuclear inclusions

91
Q

Fragile X Syndrome

Gene?

Most distinctive feature?

A

Gene: FMR1

Distinctive: Macro-orchidism

92
Q

What syndrome do these dudes probably have?

A

Fragile X Syndrome

  • Broad forehead
  • Elongated face
  • Large prominent ears
  • Srabismus
  • Highly arched palette
93
Q

Huntington’s disease is an autosomal _________ disease

A

Dominant

94
Q

What are the clinical manifestations of Huntington’s disease?

A

Progressive movement disorders

Dementia

95
Q

What is the key prototype of mtDNA disorder?

A

Leber hereditary optic neuropathy

–> Progressive bilateral loss of central vision

96
Q

What does the vision pattern on the right reveal?

Bonus points: What type of inheritance pattern does this have?

A

Leber Hereditary Optic Neuropathy (LHON)

*has a mitochondrial inheritance pattern

97
Q

How do you remember how prader-willi syndrome and angelman syndrome is inherited?

A

Prader-willi = Paternal

Angelman= Maternal

98
Q

The term “Happy puppets” refers to?

A

Angelman syndrome

Mental retardation w/ ataxic gait, seizures and inappropriate laughter

Due to their laughter and ataxia, they have been called “Happy Puppets”

99
Q

You can do it

A

You filthy animal

*MOD Exam 1 (15 decks)

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