Unit 2 Day 3 Flashcards
chromosome and fish studies are impt. in investigating what?
leukemia and lymphoma
choromosome microarray
standard of complementary to chromosome and fish studies
for individuals with developmental delays
what specimens are used in cytogenetic studies?
bone marrow
blood (unstimulated, constitutional)
tissue (lymph node, solid tumor, poc)
fluids (CNS, amniotic fluid)
what tissues are used in cancer diagnostics
bone marrow unstimulated blood lymph node solid tumor CNS
FISH
fluorescence in situ hybridization single strand probes diffusion signals specific, cloned DNA sequences that enumerate # of specific chromosomes or identify translocations ~200kbp
types of fish probes?
centromere (identifies enumeration)
dual fusion, fusion (identifies translocation)
also: locus specific, break apart, whole chromosome paint
chromosomal in cancer translocations can result in
usually balanced
can end up in site with strong promoters-overexpressed
novel protein creation
where are APMLs seen?
acute myeloid leukemia
granular clumps that form elongated “needles”
what is AML?
acute melodeons leukemia
adults, sometimes children/young adults
translocation 15;17 or translocation 9;22
how do you treat APML?
vitamin a treatment puts into transmission
cleaves conformation of the novel protein that is preventing downstream transcription-allows differentiation to go through
What is CML?
chronic myeloid leukemia
has large lobulated cells
packed bone marrow
how do you treat CML?
targeted, biological therapies
molecular antagonists that bind ATP binding site in abl tyrosine kinase and bcr/abl tyrosine kinase
inhibits cell proliferation
what is the risk for cancer in DS patients?
infants and children have 20-100 fold elevated risk for ALL or AML
500x’s more likely to get AMKL
what is CMA?
Chromosomal Microarray target DNA on slide/chip single stranded oligomers detects gains/losses only limited mosaicism detection (10-15%)
what are the advantages of CMA?
can detect “submicroscopic” gains and losses not seen in FISH
detects hot spot abnormalities
detect abnormalities in backbone of genome
characterize chromosomal anomalies by karyotyping
CNV
copy number variant
CNC
copy number change
what does CMA report?
size, location of deletions/duplications
thresholds of deletions are >200kb, duplications >400kb
evaluate ROH
cannot detect mosaicism, hterodisomy, balanced chromosome rearrangements
Causes of DS
trisomy 21 (95% of patients) unbalanced translocation btw. 21 and acrocentric chromosome (3-4% patients) mosaic tri 21 (1-2% patients), milder phenotype
prenatal counseling approach for DS
- caused by nondisjunction error
- risk increases with maternal age
- 1st trimester prenatal screening (1st trimester, ultrasound measures) (82-87% detection)
- 2nd trimester screening (80% detection), quad screen, unconjugated estriol, inhibit level, ultrasound
- if screen 1st and 2nd, 95% detection
common medical issues of DS
- cardiac issues in 50% patients (Atrioventricular canal, but any heart defect)
- gastrointestinal (10-15% structural anomalies, functional GI issues)
- ophthalmic (v. common)
- ENT problems
- Endocrine problems
- ortho problems
- hematologic issues
- neurologic issues
developmental issues DS
- hypotonia and gross motor defects
- spectrum of intellectual disabilities
- speech issues
what is the spectrum for disability development?
profound (don’t develop past baby)
severe (talk, but not well)
moderate (develop at 1/3 normal rate)
mild (develop at 2/3 normal rate)
Prader-Willi Syndrome medical issues
eyes (strabismus, nystagmus)
ortho (scoliosis)
respiratory (sleep apnea, contraindicates of HGH)
developmentally (mild-mod. cognitive disabilities)
Chromosome 15Q abnormalities
marker chromosomes-inverted duplication
interstitial duplication
deletions (angleman syndrome)
-linkage disequelibrium btw. pts w/ autism and plymorphism on GaBa-b3 locus on 15q.
15q11-q13 anomalies
maternally derived
supernumerary marker chromosomes
phenotype: autistic, not dysmorphic, hypotonic, seizures
is 15q maternally derived?
Yes
angelman syndrome
15q deletion from PWS/AS region from maternal allele
detect FISH
imprinting errors seen with methylation studies
mildly dysmorphic features, hypotonia, spasticity, seizures, autism
What abnormalities are found on Chromosome 15?
Prader Willi (paternal deletion) angelman (maternal deletion) IDIC 15 (associated autism, hypotonia, seizures, ID) maternally inherited duplication (associated autism, hypotonia, seizures, ID)
what is the current model for pharmacology?
one size fits all
some benefit, many don’t.
medication stopped in those who survive adverts events
pharmacogenetics
- study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, toxicity
- variable response due to individual genes
pharmacogenomics
- genomic approach to pharmacogenetics, concerned with assessment of common genetic variants in aggregate for impact on outcome of drug therapy
- variable response to multiple loci across the genome
once a drug is taken, it must do what?
A-reach target
B-exert effect
C-do the above before being inactivated/eliminated
remember-all people do this differently!
pharmacokinetics
describes absorption, distribution, metabolism, excretion of drugs
(ADME)
pharmacodynamics
the relationship btw the concentration of a drug at its site of action and observed biological effects
how effective are drugs in patients?
25-60%
graduation of responses
CYP450 complex
gene products active in liver and intestinal epithelium 3 families (CYP 1-3) CYP3A4 is 40% of all common drugs
What do most CYPs do?
inactivate drugs
rarely are needed for activation
detoxifying proteins/genes, work on drugs (pill form)
CYP3A
- Mechanism: genetically less imp. than other drug metabolism genes (pop distribution of activity is continuous, unimodal)
- most impt of all drug metabolizing enzymes b/c abundant in liver and intestine
- can be up-regulated some drugs, or down regulated independently of underlying genotype
- cyclosporine
inhibited: ketoconazole, grapefruit juice
induced: rifampin
CYP2D6
- mechanism: multiple
- phenotype of extensive/ultra rapid metabolism=genetically determined
- addition of inhibitor converts individuals to poor metabolizers
- tryciclic antidepressants
inhibited: quinidine, fluoxetine, paroxetine
CYP2C9
- mechanism: 2 variant has 20% activity, 3 has 10% activity
- substrates=warfarin
NAT
- isoniazid for tuberculosis
- mechanism: rate acetylation determined genetic polymorphisms, 3 genes, 1 and 2 responsible for phenotype variation
- modifies risk of cancers through acetylation differences
TMPT
- 6-mercaptopurine, 6-thioguanine
- mechanism: missense mutations destabilize
- often presented as classic example of pharmacogenic mechanism that is fatal if ignored (childhood leukemia)
G6PD
- substrates: sulfonamide, dapsone
- mechanism: x-linked enzyme
- deficient individuals susceptible to hemolytic anemia after drug exposures
VKORC1
- warfarin
- mechanism: reduces vitamin K, single nucleotide polymorphisms
- one of the most commonly prescribed medicines for over 20 million pts in US annually
