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Inherited Diseases > Exam 1 > Flashcards

Exam 1 Flashcards

1
Q

Mendel’s Laws

A

Independent assortment - Alleles of one gene segregate independently from alleles of another gene

Equal segregation - Alleles of a gene segregate into gametes at equal ratios

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2
Q

Human Genome

A 
20-30k genes (30%)
Extragenic DNA (70%)
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3
Q

Hardy-Weinberg Assumptions

A
  1. Population is infinitely large and effects of random genetic drift are negligible
  2. Mating is random with respect to genotypes
  3. No new mutation is introduced
  4. Natural selection does not affect geneotype frequency
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4
Q

Hardy-Weinberg equation

A

p^2+2pq+q^2=1

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5
Q

Founder Effect

A

A high frequency of a specific gene mutation in a population founded by a small ancestral group

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6
Q

Population Bottleneck

A

Population is reduced, survivors with mutation spread the mutation resulting in a high mutation frequency in the newly burgeoning population.

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7
Q

Jewish Related Diseases

A 
Bloom syndrome
Breast cancer
Canavan disease
Dysautonomia
Factor IX deficiency
Gaucher disease
Idiopathic torsion dystonia
Niemann-Pick disease
Tay Sachs
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8
Q

Patterns of Inheritance - Mendelian

A 
Autosomal Dominant
Autosomal recessive
XLR
XLD
Y-linked
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9
Q

Patterns of Inheritance - Non-Mendelian

A 
Imprinting
Mitochondrial
Multifactorial
Sporadic
Conitguous gene syndromes
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10
Q

Nucleotide vs Nuceloside

A

Nucleotide - sugar, nitrogenous base, phosphate

Nucleoside - sugar, nitrogenous base

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11
Q

Pyrimidines - smaller

A

Thymine, Cystosine, Uracil

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12
Q

Purines - larger

A

Adenine, Guanine

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13
Q

Chargaff’s Rule

A

[A]=[T]

[C]=[G]

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14
Q

RNA vs DNA

A

2’ OH on Ribose absent on Deoxyribose

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15
Q

TATA Box

A

Promoter region

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16
Q

5’ Cap and Poly A tail

A

Help in stability and transport of mature mRNA

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17
Q

RNA Splicing

A

Donor site, acceptor site, branch site, lariat.
Lariat is donor plus branch end formed into a loop
Spliceosome splices out intron and carries it away
Splicesome contains small nuclear RNAs and small nuclear riboproteins

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18
Q

Post translational protein modification

A
  1. Protein cleavage
  2. Ubiquitination - can mark a protein for degradation
  3. Addition of small chemical groups - phosphorylation, acetylation, methylation
  4. Addition of other types of chemical groups - Glycosylation, palmitoylation
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19
Q

Point mutations

A

Transitions - A>G, G>A or T>C, C>T (more common)
Transversions - A>T, C>G, G>C, T>A
Deamination - C>U

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20
Q

Pyrimidine Dimers

A

Ultraviolet light can create kinks in DNA, pyrimidines bond together which bends the DNA at that spot (kink)
Interferes with DNA replication and can lead to mutation

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21
Q

Large scale del/dups

A

Often caused by errors in recombination and replication

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22
Q

Insertions

A

Transposons can insert into stretches of DNA and disrupt transcription
-Alu elements most common transposable element in genome

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23
Q

Repeat expansions

A

Short highly repetitive sequences are prone to slippage

-Increase in number of repeats leads to mutation

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24
Q

Stop Codons

A

UAG
UGA
UAA

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25
Q

Mutation Nomenclature

A

Numbering begins at start codon ATG/AUG (1)

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26
Q

Analysis of complex DNA

A

PCR, Cloning - Selective replication of a segment of DNA

Molecular hybridization - detection within a complex micture

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27
Q

Cloning - Formation of Recombinant DNA

A
  1. Purification of DNA vector
  2. Purification of complex DNA target
  3. Digestion of both by restriction enzyme
  4. Ligation of target DNA to vector
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28
Q

Cloning - Steps 2, 3, and 4

A
  1. Transform recombinant DNA into host cells
  2. Grow individual transformants to form colonies
  3. Further expand clones and isolate recombinant DNA
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29
Q

PCR

A
  • Need template DNA, oligo primers, DNTPs, thermostable DNA polymerase
  • Can genotype repeat expansion diseases
  • Allele-specific PCR is useful for detecting nucleotide variants
  • 3 uses - SNP detection, large del/dups, repeat expansion diseases
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30
Q

Hybridization

A

In a complex mixture, can use a probe for a known nucleic acid or oligonucleotide. Hybridizes to sequence of interest.

  • Southern Blot
  • Microarray
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31
Q

Genotyping

A

ASOH - Allele specific oligonucleotide hybridization

  • One oligonucleotide matches normal sequence, once matches mutant
  • Used to find common mutations: CF, Achondroplasia, Sickle cell, Gaucher
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32
Q

Sequencing

A

Used when there is not a common mutation

-DMD, Breast cancer, NF

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33
Q

Dideoxy sequencing (Sanger)

A

Use di-deoxy nucleotides, chain can’t continue. Colors correspond to bases.

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34
Q

Pyrosequencing

A

Luciferace and dNTPs - lights up when new base added

-used for genotyping, short sequencing, and massively parallel sequencing

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35
Q

Massively Parallel Sequencing

A

Simulatneously sequence a panel of genes for genetic heterogenous disorders

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36
Q

Forward genetics

A

Study mutant phenotype, identify corresponding genotype

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37
Q

Reverse genetics

A

Known gene, generate mutant organism to study the gene’s function in vivo

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38
Q

Gene knock-out

A

Removal of an essential part of, or the entire, gene

-no active gene present

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39
Q

Gene knock-in

A

Insertion of a mutation into a gene

-Both mutation and wt are active

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40
Q

Gene replacement

A

Only mutant gene is active

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41
Q

RNAi

A

miRNA (natural mechanism) and siRNA (a tool for experimental gene modification)

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42
Q

CRISPR/Cas9 genome editing

A

Removes mutation and replaces with a functional copy

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43
Q

Muller’s morphs

A

+ = wt, m = mutant, Df = gene deletion, Dp = gene duplication, > = more severe than

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44
Q

Amorph

A

complete loss of gene function

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45
Q

Hyopmorph

A

Partial loss of gene function

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46
Q

Hypermorph

A

Increased gene function

47
Q

Antimorph

A

Dominant mutation acting to oppose normal gene function

48
Q

Neomorph

A

Dominant gain of function that is different than normal gene function

49
Q

Morpholino knockdown

A

Morpholino hybridizes to mRNA, blocks translation

50
Q

Transgenic organisms

A
  1. Inject foreign DNA into one of the pronuclei of prior fertilized mouse egg
  2. Transfer injected eggs into female mouse
  3. 10-30% of offspring will exhibit foreign DNA, will be present in all tissues
  4. Breed mice containing foreign DNA to continue mutation in germ line
51
Q

Gene KO in mice

A

Mutant alleles introduced via injection of embryonic stem cells into developing embryo, injected embryo is placed in to “pseudo pregnant” mouse, creates chimera mice which can be bred

52
Q

Conditional gene targeting

A

LoxP/Cre mice will only express Cre recombinase at a certain time or place in development

53
Q

Garrod’s Views

A

Concepts. What diseases are and why they exist. How to think about medicine.

54
Q

Osler’s Views

A

Facts. How to practice medicine. Treatment and management.

55
Q

ACMG NBS criteria

A
  • Clinical characteristics (incidence, burden of disease if untreated, phenotype in newborn)
  • Analytical characteristics of the screening test (availability, platform)
  • Diagnosis, treatment and management of disease in both acute and chronic form
56
Q

Sensitivity

A

Proportion of people with the target disease who have a positive test

57
Q

Specificity

A

Proportions of people without the target disease who have a negative test

58
Q

Positive Predictive Value

A

Proportion of people with a positive test who have the disease

59
Q

Negative Predictive Value

A

Proportion of people with a negative test who don’t have the disease

60
Q

Tandem Mass Spectrometry

A

Allows for focusing of mass spec for defined disorders, adaptable to most substrate disorders.

61
Q

Uniform Screening Panel

A
  • 29 core conditions (20 by mass spec)
  • 25 secondary conditions (22 by mass spec)
  • Later additions
62
Q

Goals of NBS

A
  • Sensitivity should be high
  • Specificity and PPV vary by disorder
  • Timing matters
  • NBS is a SCREENING program to detect infants in need of a diagnostic test
63
Q

ACT Sheets and Algorithms

A

Stepwise processes for NBS positives that help practitioners determine the next direction to take

64
Q

PKU

A

Deficiency of levels of Phenylalanine Hydroxylase
AR inheritance
PAH works in liver, but liver is unaffected
Sometimes caused by BH4 mutations (biopterin, cofactor to PAH)

65
Q

PKU Incidence

A
  • 1/10,000 to 1/16,000

- 300 new cases per year

66
Q

PKU Phenotype

A
  • Severe - serum Phe >1200 microMolar
  • Moderate - serum Phe >600 to <600
  • Intellectual disability and autistic behaviors
  • Seizures
  • White matter hyperintensities
  • Genotype/Phenotype correlation
67
Q

PKU Phenotype part 2

A
  • Fair hair (tyrosine is a pigment precursor)
  • Pale skin, blue eyes
  • Developmental delays
  • Microcephaly
  • Eczema
  • Musty order (phenylketones in urine)
68
Q

Tyrosine

A

Precursor to pigment and neurotransmitters

69
Q

PKU History

A

Folling - First description of the disease
Jervis - Showed that PKU was due to liver PAH deficiency
Bickel - Reported the reduced Phe diet
Guthrie - Newborn screening

70
Q

Guthrie

A

Guthrie bacterial inhibition assay

  • Blood spots from newborns plated with bacteria that requires Phe to grow
  • Bacteria only grows on spots containing excess Phe
71
Q

Maternal PKU

A
  • Structural birth defects - cardiac defect, esophageal atresia
  • Microcephaly, intellectual disability
  • Craniofacial effects - elongated philtrum, medial epicanthal folds, thin upper lip
72
Q

PAH

A

Chromosome 12q

73
Q

PKU Treatment/Therapies

A
  • Low phe diet
  • Vitamin supplementation/amino acid supplementation
  • Tyrosine supplementation
  • Prevent fasting/catabolism
  • 225-450 mg Phe/day (normal person consumes 4000 mg)
74
Q

PKU New Therapies

A
  • Kuvan - large doses of biopterin - may stabilize poorly functioning PAH
  • LNAA therapy - bombard blood brain barrier with other amino acids to prevent Phe uptake
75
Q

PKU Barriers to compliance

A 
Peer pressure
Costs of specialty food
Insurance companies
Intolerance to supplements
Limited variety
76
Q

Structural proteins of the ECM

A
  • Form a large percentage of bulk body protein
  • Large multi-domain homo/heteropolymers
  • Extensively modified (oxidation, crosslinking, glycosylation)
  • Directly influence cell behavior via integrin receptors
  • Regulate the activity of and are regulated by growth factors
77
Q

Inheritance of connective tissue diseases

A

Mostly dominant

  • Haploinsufficiency - amorph/hypomorph (Marfan, SVAS)
  • Dominant negative - antimorph (Osteogenesis imperfecta)
  • Gain of function - hypermorph (Achondroplasia)
78
Q

Marfan Syndrome

A
  • 2-3/10,000 incidence
  • 1/4 to 1/3 are de novo
  • Skeletal, ocular, cardiovascular, pulmonary, skin and integument, dura
79
Q

Ocular features of Marfan

A

Major - ectopia lentis
Minor - Abnormally flat cornea, myopia, increased globe length, hypoplastic iris
Other - open angle glaucoma, nuclear cataract

80
Q

Cardiovascular features of Marfan

A

Major - dilation of ascending aorta with/without aortic regurgitation
Minor - Mitral valve prolapse, dilation of pulmonary artery before age 40, calcification of the mitral valve before age 40, dilation of descending thoracic or abdominal aorta before the age of 50
Other - arrhythmia, dilated cardiomyopathy, diastolic dysfunction

81
Q

Management of Marfan

A

Skeletal

  • Surgical stabilization of scoliosis
  • Surgical correction of pectus excavatum
  • Hormonal treatment with estrogen to reduce growth

Visual

  • Corrective lenses to prevent amblyopia
  • Ectopia lentis: surgical removal and artificial lens replacement
  • Laser eye surgery

Cardiovascular

  • Annual echo
  • B-andrenergic blockade to reduce rate of dilation/dissection
  • Avoid exertion
  • Replacement of aortic root when moderately dilated (>50mm)
  • Mitral valve repair
82
Q

Pleiotropy

A

A gene or mutation in a gene causes phenotypic changes in multiple organs or tissues
Mechanisms:
-Toxic metabolite with multiple target tissues
-Gene product required for homeostasis of multiple organs
-Gene is necessary for a function of a developmental precursor of multiple organs

83
Q

FBN1 mutations and Marfan

A

Chromosome 15

  • Fibrillin microfibrils in ECM
  • Most missense mutations located in calcium-binding EGF-like domains
  • Some genotype phenotype correlation
84
Q

Disease mechanisms in Marfan

A

Dominant negative

  • overexpression of mutant protein in cells results in abnormal microfibrils
  • mutant cells do not assemble microfibrils

Haploinsufficiency

85
Q

Marfan and TGFBeta

A

TGFbeta antagonism rescues Marfan syndrome in mice

Losartan antagonizes TGFbeta to rescue MFS in mice - possible medicine for Marfan

86
Q

Diseases related to Marfan

A

Some FBN1 mutations cause isolated Marfan symptoms

Weill-Marchesani Syndrome

  • AD
  • Short stature, muscular build, brachycephaly, severe myopia, ectopia lentis, joint stiffness

Stiff skin syndrome
-Mutations in Arg-Gly-Asp of FBN1

FBN2
-congenital contractural arachnodactyly

87
Q

Homocystinuria

A

AR

  • CBS deficiency
  • tall stature, long limbs, arachnodactyly, limited joint mobility, pectus deformity, osteoporosis
  • highly arched palates, crowded teeth
  • ectopia lentis, myopia
  • mitral valve prolapse, MI
  • fine, brittle hair, hernia
  • intellectual disability, seizures
  • fatty liver disease, pancreatitis
88
Q

Treatment homocystinuria

A
  • 50% of patients are responsive to pyrixodine (vitamin B6), usually they are mildly affected
  • Pyrixodine nonresponders - low methionine, cystein supplementation, betaine treatment
89
Q

Elastin characteristics

A 
Secreted as soluble monomer tropoelastin
Lacks internal Met
Contains 2 cysteines at C-terminus
Insoluble, highly stable crosslinked polymer
Produced early in life
90
Q

Supravalvular Aortic Stenosis

A

Narrowing of the ascending aorta
Mortality - Sudden Death (severe biventricular obstruction)
Can be non-syndromic
Associated with Williams-Beuren syndrome

91
Q

Familial supravalvular aortic stenosis

A

AD
Arterial stenosis
1/200,000

92
Q

Williams-Beuren Syndrome

A 
Rare AD
1/20,000
Sporadic
Characteristic facial features
Intellectual disability, developmental delay
Gregarious personality
Hypercalcemia
93
Q

Mechanism of ELN mutations in SVAS

A

Less elastin
Increased vascular smooth muscle cell proliferation
Leads to SVAS

94
Q

Cutis Laxa

A

AD

  • emphysema
  • hernias
  • pulmonary artery stenosis
  • aortic aneurysms
  • 30% mutations are de novo
95
Q

Mechanism of ELN mutations in ADCL

A

Mutant tropoelastin has impaired association with fibrilin microfibrils, increased aggregations with wildtype tropoelastin

  • unfolded protein response and increased apoptosis
  • Increased TGFbeta signaling
96
Q

Collagens

A

Most abundant protein in the body

  • makes up 70% of bone protein
  • There are 28 types of collagen encoded over 45 genes
  • long chains with glycine-proline-hydroxyproline
  • often form a triple helix
97
Q

Collagen I

A

Encoded by COL1A1 and COL1A2 genes

Exists as trimer

98
Q

Proline Hydroxylation

A

Proline hydroxylation requires vitamin C
Proline hydroxylation stabilizes collagen triple helix
Scurvy results from vitamin C deficiency (James Lind)

99
Q

Osteogenesis Imperfecta

A 
1/20,000
Bone fragility, blue sclerae, short stature
Collagen Type I mutations
AR
"Brittle bone syndrome"
100
Q

Mechanisms of OI

A
  • most are missense replacements of Gly

- Loss of function mutations result in AD OI

101
Q

Treatment of OI

A

Bisphosphonates to increase bone mineral content
Rodding
Bone marrow transplantation (experimental)
Animal studies point to TGFbeta antagonism

102
Q

Ehlers Danlos Syndrome

A

Skin hyperextensibility and joint hypermobility
Easy bruising
Abnormal
Cigarette paper scarring

103
Q

FGFR3 mutations

A

Achondroplasia

Hypochondroplasia

104
Q

Mechanisms of FGFR3 mutations

A

Too much differentation and too little cell division of growth plate

105
Q

Causes of Hypertyrosinemia

A
  1. Transient tyrosinemia of newborn
  2. Severe hepatocellular dysfunction
  3. Inborn errors of tyrosine catabolism
  4. Scurvy
  5. NTBC Treatment
  6. Hyperthyroidism
  7. Postprandial state
106
Q

Hereditary Tyrosinemia Type I

A

Rare AR
Life threatening

Phenotypes

  • Acute with liver failure at infancy
  • Subacute/chronic with a protracted course
  • Renal tubular dysfunction
  • Rickets (liver failure leads to lack of vitamin D activation)
  • 80-90% mortality in childhood
107
Q

HTT1 Cause

A

Block at the conversion of fumarylacetoacetate, causes it to be converted to succinyl acetone instead

Succinylacetone is a product inhibitor of the enzyme that converts Tyrosine to 4-OH Phenylpyruvate, resulting in excess tyrosine

108
Q

Untreated prognosis of HTT1

A
  • Liver disease
  • Renal Tubular dysfunction
  • Neurological crises similar to pts with porphyria
  • Liver cancer
109
Q

Conventional treatments of HTT1

A

Diet

Liver transplant

110
Q

NTBC

A

Initially an herbicide
Caused eye lesions in rats due to excess of tyrosine
Causes a block in the chain that prevents conversion of 4-OH phenylpyruvate but ALLOWS conversion of tyrosine
Made into a medicine for HTT1 patients called Orfadin

111
Q

NTBC effect on HTT1

A
  • Reverse acute symptoms of liver failure
  • Allows for normal growth
  • Reverse/prevent renal dysfunction
  • Prevents rickets
  • Prevents neurological crises
  • Prevent or delay need for liver transplant
112
Q

4-hydroxphenylpyruvate dioxygenase (4PPD)

A

Also called tyrosinemia III
AR
Leads to hypertyrosinemia

113
Q

Tyrosine aminotransferase (TAT) deficiency

A

Characteristic: Keratosis palmoplantaris
-hyperkaratosis of palms and feet
Ocular and cutaneous symptoms
Half of pts have intellectual disability

Treatment: Dietary restriction of Phe and Tyr

114
Q

Alkaptonuria

A 
Rare AR
Homogentisic acid cannot be broken down
(Defects in homogentisic acid oxidase)
Ochronosis (blackening of joints)
Arthritis
Spinal narrowing leading to back pain
Blackened stool/urine
Possible can be treated by NTBC

Inherited Diseases (2 decks)

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