Bikman - Genetic Disorders Flashcards
Chromosomal mutations
Any inherited alteration of genetic material.
- Base pair substitution
- Frameshift mutation
What is base pair substitution and what are possible outcomes?
One base pair is substituted for another
Possible outcomes:
- Silent
- Missense
- Nonsense
What is a frameshift mutation?
Insertion or deletion of one or more base pairs.
Causes a change in the entire “reading frame”
What are non-mutation alterations in chromosomes?
- Polymorphisms
- Epigenetic changes
- Alterations in non-coding RNAs
- Translocation
What is a polymorphism? (SNP and copy number variation)
(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
What is the difference between SNP and point mutation?
If it occurs in <1% of people, it’s a point mutation; occurs in >1%, it’s a SNP
Epigenetic changes
(Non mutation alteration)
Non-DNA changes; i.e. alterations in gene or protein expression
Alterations in non-coding RNAs
(Non mutation alteration)
Regulatory genes that do not code for proteins
Translocation
(Non mutation alteration)
Exchanging genetic material between non-homologous chromosomes.
Occurs when two chromosomes break and the segments are rejoined in an abnormal fashion.
Chromosome aberrations
Euploid Polyploid Aneuploid Disjunction Non disjunction
Euploid cells
(Chromosome abberation)
Have normal # of chromosomes
Different for haploid vs. diploid
Polyploid cells
(Chromosome aberration)
Cell has a multiple of 23
Triploidy
Three copies of every chromosome
3*23 = 69
Embryonic lethal; ~10% of known miscarriages
Tetraploidy
Four copies of every chromosome
4*23 = 92
Embryonic lethal; ~10% of known miscarriages
What is aneuploidy and what are some examples of aneuploidy?
(Chromosome aberration)
Somatic cell that doesn’t have a multiple of 23 chromosomes.
One too many, or one too few
Trisomy
Monosomy
Trisomy
3 copies of one chromosome
Monosomy
1 copy of any one chromosome
*Lethal, but infants can survive with trisomy of certain chromosomes
Disjunction
(Chromosome aberration)
Normal separation of chromosomes during cell division.
Non-disjunction
(Chromosome aberration)
Usually the cause of aneuploidy.
Failure of homologous chromosomes or sister chromatids to separate
If a human fetus has 45 chromosomes, it would be called…
Aneuploidy
What are some examples of autosomal aneuploidy?
Trisomy 13
Trisomy 18
Trisomy 21
Trisomy 13
(Autosomal aneuploidy)
Patau Syndrome
Polydactyly
Mental retardation
Microcephaly
Usually lethal early in life due to heart deformities
Trisomy 18
(Autosomal aneuploidy)
*Edwards Syndrome* Kidney malformations Protruding intestines Mental retardation Small size
Usually lethal early in life due to heart deformities.
Trisomy 21
(Autosomal aneuploidy)
Down Syndrome
Risk increases with maternal and/or paternal age.
Best known example of aneuploidy
What are some examples of sex chromosome aneuploidy?
Trisomy X
Turner Syndrome
Klinefelter Syndrome
Trisomy X
(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
Turner Syndrome
(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
Klinefelter Syndrome
(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
Which of the following is an example of trisomy?
A. Fragile X
B. Turner Syndrome
C. Klinefelter Syndrome
D. Cris du chat Syndrome
C. Klinefelter
Autosomal dominant vs. Autosomal recessive disorders
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.
If both parents are affected with autosomal dominant disorder, what is the recurrence in the offspring?
~3/4
If one parent is normal and the other parent is affected with autosomal dominant disorder, what is the recurrence in offspring?
~1/2
What are some examples of autosomal dominant disorders?
Marfan syndrome
Ehlers-Danlos Syndrome
Treacher Collins Syndrome
What is Marfan Syndrome and what are the features of it?
(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
What is Ehlers-Danlos Syndrome and what are the features of it?
(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
What is Treacher Collins Syndrome and what are features of it?
(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
What is penetrance?
The percentage of individuals with a specific genotype who also express the expected phenotype.
What is incomplete penetrance? What is an example of incomplete penetrance?
Someone who has the gene for a disease but doesn’t express the disease,
i.e. Retinoblastoma
What is expressivity? What is an example?
The variation in a phenotype associated with a particular genotype.
i.e. von Recklinghausen disease (neurofibromatosis)
What is von Recklinghausen disease?
Example of expressivity.
Autosomal dominant.
Disease can vary from dark spots on skin to malignant neurofibromas, scoliosis, gliomas, neuromas, etc.
What can increase the risk of expressing autosomal recessive disorders?
Consanguinity
What are the two types of autosomal recessive storage diseases?
Lysosomal
Glycogen
What autosomal recessive diseases are classified as lysosomal storage diseases?
- Gaucher’s disease
- Tay-Sachs disease
- Niemann-Pick disease
What are the deficient enzymes, accumulating metabolites, and affected cells of Gaucher’s Disease? What are histologic signs of it?
Deficient enzyme:
Glucocerebrosidase
Accumulating metabolite: Glucocerebroside
Affected cells: Macrophage
Histologic sign: Enlarged macrophages in the spleen
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?
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.
What are the deficient enzymes, accumulating metabolites, and affected cells of Niemann-Pick disease? What are histologic signs of it?
Deficient enzyme: Sphingomyelinase
Accumulating metabolite: Sphingomyelin
Affected cells: Neurons and phagocytes
Histologic sign: Kuppfer cells have foamy appearance
What diseases are classified as autosomal recessive glycogen storage diseases?
- Type I: von Gierke’s
- Type II: Pompe’s
- Type III: Cori’s
- Type IV: Brancher Glycogenosis/Anderson’s
- Type V: McArdle’s Syndrome
What are the deficient enzymes, affected tissues, and histiologic signs of von Gierke’s disease (Type I)?
Deficient Enzyme: Glucose-6-phosphatase
Affected tissue: Liver and kidney
Histiologic sign: Foamy hepatocyte
What are the deficient enzymes, affected tissues, and histiologic signs of Pompe’s disease (Type II)?
Deficient Enzyme: Lysosomal glucosidase
Affected tissue: Heart
Histiologic sign: Large vacuoles in cardiomyocytes
What are the deficient enzymes, affected tissues, and histiologic signs of Cori’s disease (Type III)?
Deficient Enzyme: Debranching enzyme
Affected tissue: Heart, liver, skeletal muscle
Histiologic sign: Enlarged hepatocytes
What are the deficient enzymes, affected tissues, and histiologic signs of Brancher Glycogenosis/Anderon’s (Type IV)?
Deficient Enzyme: Branching enzyme
Affected tissue: Heart liver, skeletal muscle, brain
Histiologic sign: Enlarged hepatocytes
What are the deficient enzymes, affected tissues, and histiologic signs of McArdle’s Syndrome (Type V)?
Deficient Enzyme: Muscle phosphorylase
Affected tissue: Skeletal muscle
Histiologic sign: Large vacuoles in myocytes
What is Chediak-Higashi Syndome and what are some features of it? What are histiologic signs?
(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
What are some examples of sex-linked disorders?
Hemophilia A and B
Duchenne Muscular Dystrophy
Red-green color blindness
