Bikman - Genetic Disorders

Question 1

Chromosomal mutations

Answer 1

Any inherited alteration of genetic material.

1. Base pair substitution
2. Frameshift mutation

Question 2

What is base pair substitution and what are possible outcomes?

Answer 2

One base pair is substituted for another

Possible outcomes:

1. Silent
2. Missense
3. Nonsense

Question 3

What is a frameshift mutation?

Answer 3

Insertion or deletion of one or more base pairs.

Causes a change in the entire “reading frame”

Question 4

What are non-mutation alterations in chromosomes?

Answer 4

1. Polymorphisms
2. Epigenetic changes
3. Alterations in non-coding RNAs
4. Translocation

Question 5

What is a polymorphism? (SNP and copy number variation)

Answer 5

(Non mutation alteration)

Single nucleotide polymorphisms: Common variation at a single nt position

Copy number variations: Abnormal # of copies of one or more sections of the DNA

Question 6

What is the difference between SNP and point mutation?

Answer 6

If it occurs in <1% of people, it’s a point mutation; occurs in >1%, it’s a SNP

Question 7

Epigenetic changes

Answer 7

(Non mutation alteration)

Non-DNA changes; i.e. alterations in gene or protein expression

Question 8

Alterations in non-coding RNAs

Answer 8

(Non mutation alteration)

Regulatory genes that do not code for proteins

Question 9

Translocation

Answer 9

(Non mutation alteration)

Exchanging genetic material between non-homologous chromosomes.
Occurs when two chromosomes break and the segments are rejoined in an abnormal fashion.

Question 10

Chromosome aberrations

Answer 10

Euploid
Polyploid
Aneuploid
Disjunction
Non disjunction

Question 11

Euploid cells

Answer 11

(Chromosome abberation)

Have normal # of chromosomes
Different for haploid vs. diploid

Question 12

Polyploid cells

Answer 12

(Chromosome aberration)

Cell has a multiple of 23

Question 13

Triploidy

Answer 13

Three copies of every chromosome

3*23 = 69

Embryonic lethal; ~10% of known miscarriages

Question 14

Tetraploidy

Answer 14

Four copies of every chromosome

4*23 = 92

Embryonic lethal; ~10% of known miscarriages

Question 15

What is aneuploidy and what are some examples of aneuploidy?

Answer 15

(Chromosome aberration)

Somatic cell that doesn’t have a multiple of 23 chromosomes.
One too many, or one too few

Trisomy
Monosomy

Question 16

Trisomy

Answer 16

3 copies of one chromosome

Question 17

Monosomy

Answer 17

1 copy of any one chromosome

*Lethal, but infants can survive with trisomy of certain chromosomes

Question 18

Disjunction

Answer 18

(Chromosome aberration)

Normal separation of chromosomes during cell division.

Question 19

Non-disjunction

Answer 19

(Chromosome aberration)

Usually the cause of aneuploidy.

Failure of homologous chromosomes or sister chromatids to separate

Question 20

If a human fetus has 45 chromosomes, it would be called…

Answer 20

Aneuploidy

Question 21

What are some examples of autosomal aneuploidy?

Answer 21

Trisomy 13
Trisomy 18
Trisomy 21

Question 22

Trisomy 13

Answer 22

(Autosomal aneuploidy)

Patau Syndrome
Polydactyly
Mental retardation
Microcephaly

Usually lethal early in life due to heart deformities

Question 23

Trisomy 18

Answer 23

(Autosomal aneuploidy)

*Edwards Syndrome*
Kidney malformations
Protruding intestines
Mental retardation
Small size

Usually lethal early in life due to heart deformities.

Question 24

Trisomy 21

Answer 24

(Autosomal aneuploidy)

Down Syndrome
Risk increases with maternal and/or paternal age.
Best known example of aneuploidy

Question 25

What are some examples of sex chromosome aneuploidy?

Answer 25

Trisomy X Turner Syndrome Klinefelter Syndrome

Question 26

Trisomy X

Answer 26

(Sex Chromosome Aneuploidy) Little physical manifestation - Lyonization. Symptoms can vary from no overt symptoms to sterility, menstrual irregularity, and/or mental retardation - can worsen with each additional X chromosome

Question 27

Turner Syndrome

Answer 27

(Sex Chromosome Aneuploidy) XO female ``` Undeveloped ovaries (sterile) Short stature Webbing of neck Edema Underdeveloped breasts; wide nipples (Shield's chest) Out-turned arms at elbows Low hairline at back of neck ```

Question 28

Klinefelter Syndrome

Answer 28

(Sex Chromosome Aneuploidy) XXY males ``` Male appearance Can be fertile Possible modest breast development at puberty Underdeveloped male genitals Sparse body hair Long limbs ``` XXXY, XXXXY - Abnormalities increase with each X

Question 29

Which of the following is an example of trisomy? A. Fragile X B. Turner Syndrome C. Klinefelter Syndrome D. Cris du chat Syndrome

Answer 29

C. Klinefelter

Question 30

Autosomal dominant vs. Autosomal recessive disorders

Answer 30

Dominant doesn't skip generations doesn't generate carrier progeny, only normal and affected. Recessive may skip generations and may produce carrier progeny, in additional to normal or affected.

Question 31

If both parents are affected with autosomal dominant disorder, what is the recurrence in the offspring?

Answer 31

~3/4

Question 32

If one parent is normal and the other parent is affected with autosomal dominant disorder, what is the recurrence in offspring?

Answer 32

~1/2

Question 33

What are some examples of autosomal dominant disorders?

Answer 33

Marfan syndrome Ehlers-Danlos Syndrome Treacher Collins Syndrome

Question 34

What is Marfan Syndrome and what are the features of it?

Answer 34

(Autosomal Dominant Disorder) A disorder of CT, manifested principally by changes in the skeleton, eyes, and CV system. Features: - Unusually tall with long extremities - Ectopica lentis: bilateral subluxation of eye lens - CV lesions: Mitral valve prolapse

Question 35

What is Ehlers-Danlos Syndrome and what are the features of it?

Answer 35

(Autosomal Dominant Disorder) A group of diseases characterized by defects in collagen synthesis or structure. Features: - Skin and joint hypermobility - Easy bruising Gorlin's Sign is can be an indicator

Question 36

What is Treacher Collins Syndrome and what are features of it?

Answer 36

(Autosomal Dominant Disorder) Results from the abnormal development from the first and second branchial arches. Features: - Underdeveloped mandible - Downward slating palpebral fissures - Possible cleft palate

Question 37

What is penetrance?

Answer 37

The percentage of individuals with a specific genotype who also express the expected phenotype.

Question 38

What is incomplete penetrance? What is an example of incomplete penetrance?

Answer 38

Someone who has the gene for a disease but doesn't express the disease, i.e. Retinoblastoma

Question 39

What is expressivity? What is an example?

Answer 39

The variation in a phenotype associated with a particular genotype. i.e. von Recklinghausen disease (neurofibromatosis)

Question 40

What is von Recklinghausen disease?

Answer 40

Example of expressivity. Autosomal dominant. Disease can vary from dark spots on skin to malignant neurofibromas, scoliosis, gliomas, neuromas, etc.

Question 41

What can increase the risk of expressing autosomal recessive disorders?

Answer 41

Consanguinity

Question 42

What are the two types of autosomal recessive storage diseases?

Answer 42

Lysosomal | Glycogen

Question 43

What autosomal recessive diseases are classified as lysosomal storage diseases?

Answer 43

1. Gaucher's disease 2. Tay-Sachs disease 3. Niemann-Pick disease

Question 44

What are the deficient enzymes, accumulating metabolites, and affected cells of Gaucher's Disease? What are histologic signs of it?

Answer 44

Deficient enzyme: Glucocerebrosidase Accumulating metabolite: Glucocerebroside Affected cells: Macrophage Histologic sign: Enlarged macrophages in the spleen

Question 45

What are the deficient enzymes, accumulating metabolites, and affected cells of Tay-Sachs disease? What are histologic signs of it? What population is Tay-Sachs most prevalent in?

Answer 45

Deficient enzyme: Hexosaminidase A Accumulating metabolite: G Ganglioside Affected cells: Neurons Histologic sign: Enlarged pale neurons. Leads to motor and mental deficits, blindness, dementia. Particularly prevalent among Ashkenazi Jews.

Question 46

What are the deficient enzymes, accumulating metabolites, and affected cells of Niemann-Pick disease? What are histologic signs of it?

Answer 46

Deficient enzyme: Sphingomyelinase Accumulating metabolite: Sphingomyelin Affected cells: Neurons and phagocytes Histologic sign: Kuppfer cells have foamy appearance

Question 47

What diseases are classified as autosomal recessive glycogen storage diseases?

Answer 47

1. Type I: von Gierke's 2. Type II: Pompe's 3. Type III: Cori's 4. Type IV: Brancher Glycogenosis/Anderson's 5. Type V: McArdle's Syndrome

Question 48

What are the deficient enzymes, affected tissues, and histiologic signs of von Gierke's disease (Type I)?

Answer 48

Deficient Enzyme: Glucose-6-phosphatase Affected tissue: Liver and kidney Histiologic sign: Foamy hepatocyte

Question 49

What are the deficient enzymes, affected tissues, and histiologic signs of Pompe's disease (Type II)?

Answer 49

Deficient Enzyme: Lysosomal glucosidase Affected tissue: Heart Histiologic sign: Large vacuoles in cardiomyocytes

Question 50

What are the deficient enzymes, affected tissues, and histiologic signs of Cori's disease (Type III)?

Answer 50

Deficient Enzyme: Debranching enzyme Affected tissue: Heart, liver, skeletal muscle Histiologic sign: Enlarged hepatocytes

Question 51

What are the deficient enzymes, affected tissues, and histiologic signs of Brancher Glycogenosis/Anderon's (Type IV)?

Answer 51

Deficient Enzyme: Branching enzyme Affected tissue: Heart liver, skeletal muscle, brain Histiologic sign: Enlarged hepatocytes

Question 52

What are the deficient enzymes, affected tissues, and histiologic signs of McArdle's Syndrome (Type V)?

Answer 52

Deficient Enzyme: Muscle phosphorylase Affected tissue: Skeletal muscle Histiologic sign: Large vacuoles in myocytes

Question 53

What is Chediak-Higashi Syndome and what are some features of it? What are histiologic signs?

Answer 53

(Autosomal Recessive Disorder) Arises from a mutation of a lysosomal trafficking regulator gene (LYST). - Partial albinism - Photophobia - Compromised immunity - Neuropathy Histiologic sign: Fusion of lysosomal granules

Question 54

What are some examples of sex-linked disorders?

Answer 54

Hemophilia A and B Duchenne Muscular Dystrophy Red-green color blindness