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130 Cards in this Set
- Front
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Down Syndrome genetics
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Trisomy 21:
47,XY,+21 |
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Down syndrome cause
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Maternal Meiosis 1 Non disjunction = 95%
5% = roberstonian translocation or mosaicism for Trisomy 21 |
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Down syndrome clinical presentation
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Redundant skin, short fingers, hypopigmented patches (brush field spots) in iris of the eye , simean crease
Severe retardation Gastrointestinal obstruction 3% Respiratory infections Common Leukemia 15-20 X Congenital heart defect 40% Moderate to severe mental retardation 100% Development: |
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Edward Syndrome
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Trisomy 18
47,XY,+18 |
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Edward syndrome appearance
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"Little Old man"
a. •Prominent occiput b. •Micrognathia c. •Microcephaly d. •Low set malformed ears e. •Characteristic clenched fists f. •Rocker-bottom feet g. •Congenital anomalies of lungs, diaphragm, and kidneys |
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Trisomy 18 incidence
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1:6000 live births
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Trisomy 21 incidence
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1 in 800 live births
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Trisomy 13 appearance
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Distinctive malformation pattern
i. (Craniofacial and Central Nervous System) Cleft lip +/- palate Low set ears with abnormal helices Holoprosencephaly Cardiac defects Polydactyly of the hands and feet |
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Trisomy 13 incidence
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1: 10,000 live births
95% spontaneously abort |
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Turner syndrome cytogenics
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45x - 50%
45x/46XY (mosaic)- 30-40% Structural x abnormalities -10-20% 80% due to paternal meiotic error 15-20% abort |
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What trisomy is the most common abnormality in stillbirths with mulitple congenital abnormalities?
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Trisomy 18
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Turner syndrome incidence
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1:5000 female births (but many spontaneously abort)
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Turner syndrome appearance
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c. Individuals are very short, they are usually infertile. Characteristic body shape changes include a broad chest with widely spaced nipples and may include a webbed neck
i. Coarctation of aorta 20% ii. Structural kidney defects 50% |
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Turner syndrome RX
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Growth hormone & estrogen
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Klinefelter syndrome cytogenics
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47xxy
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Klinefelter incidence
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1:1000 males
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Klinefelter syndrome inheritance
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50% maternal/50% paternal in origin
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Linefelter syndrome phenotype
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c. Small testes, poorly developed secondary sex features due to low testosterone
d. Tall and thin, slightly lower IQ |
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Wolf-hirschhorn syndrome cytogenics
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Deletion 4p16.3 Karyotpe
(loss of tip of 4p) - terminal portion |
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Wolf-hirschhorn incidence
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1 in 50,000
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Wolf-hirschhorn phenotype
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c. Fetal growth restriction
d. Microcephaly e. Hypotonia f. Characteristic facial appearance (greek helmut facies) g. Severe mental retardation h. Seizures i. Posterior midline scalp defects |
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DiGeorge/Velo-cardio-facial syndrome
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Most common MICRODELETION syndrome in humans
22q11 microdeletion syndrome |
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DiGeorge/Velo-cardio-facial syndrome phenotype
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i. Very variable
ii. DiGeorge = more severe iii. Velo-Cardio-faicial syndrome = less severe (hole in soft palate) iv. Appearance: Hypernasal speech, characteristic facial appearances, specific learning disabilities |
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DiGeorge/Velo-cardio-facial syndrome Incidence
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1 in 4000
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Short arm name
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P arm
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Long arm name
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Q arm
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Sub-metacentric
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P arm is shorter than Q arm
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Heterochromatin
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Not transcribed
Large heterochromatin regions on 1,9,16, and Y arm |
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Euchromatin
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Transcribed
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Achrocentric
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Specialized very small P arm that has repetitive RNA sequence and ribosomal RNA genes (satellites)
Occurs on 13,14,15,21,22 |
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When can you see chromosome?
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Metaphase
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G-Banding
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Routine Banding method in the US
GTG: G bands produced with Trypsin using Giemsa Standard G-banding karyotype scans whole genome for deletions/duplications at least 5mb |
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Q banding
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First banding developed
Uses fluorochromes that bind to DNA and flourescence - requires flourescence microscope |
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C Banding
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Stains constitutive heterochromatin around the centromeres and other heterochromatin regions (1, 9, 16, Y)
CBG - C bands produced with Barium using Giemsa |
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R banding
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Opposite (Reverse) of G banding
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What's more lethal? Monosomy or Trisomy
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Monosomy
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Aneuploidy
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Complete: Gain or loss of whole chromosome
Partial: Gain or loss of part of chromosome |
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Polyploidy
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Extra set of chromosomes ex 69XXX
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Triploidy
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i. One complete extra set of chromosomes.
ii. Caused by polyspermy, fertilization of an egg by more than one sperm. iii. Usually spontaneously abort. iv. Fetus with IUGR and very small placental when complement is maternal (digyny) v. Well grown fetus and large cystic complement is paternal (diandry) |
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Abnormalities related to advanced maternal age?
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Trisomy 13, 18, and 21 and Monosomy X
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Sex chromosome aneuploidy
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Because of X-inactivation and the paucity of genes on the Y chromosome, aneuploidies involving the sex chromosomes are far more common and less severe than those involving autosomes.
Some genes on the X-chromosome are also present on the Y chromosome (pseudoautosomal regions) and some escape X-inactivation. ex Klinefelter |
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Unipatental disomy (upd)
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Both genomes originate from the same parent
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Hydatidiform moles
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Parental origin Uniparental diploidy
No fetal parts only trophoblast hyperplasia Sperm reduplicates its genome and fertilizes empty egg - 46xxis most common karyotype |
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Ovarian teratormas
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Maternal origin UPD
Disorganized embryonic material Activated unovulated oocyte |
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Uniparental disomy
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two of same chromosome from one parent and none from the other, will give you a phenotype if one of the ones that carry imprinted genes – 6, 7, 11, 14, 15, 16
Affects a SINGLE PAIR of chromosomes |
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Trisomy Rescue
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a genetic phenomenon in which a fertilized ovum containing three copies of a chromosome loses one of these chromosomes to form a normal, diploid chromosome complement. If both of the retained chromosomes came from the same parent, then uniparental disomy results.
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Robertsonian Translocation
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Translocation between acrocentric chromosomes. Short arms are lost and long arms fuse at centromere (5% of Down syndrome cases) [46,XX,der(14;21)(q10;q10),+21]
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Inversion
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a. An inversion consists of two breaks in one chromosome. The area between the breaks is inverted (turned around), and then reinserted and the breaks then unite to the rest of the chromosome.
i. Pericentric: includes centromere ii. Paracentric: does not include centromere |
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deletions
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Loss of a chromosomal segment
partial deletion can be viable: ex 4p Wolf-Hirschhorn Syndrome |
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Microdeletions
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Not visible by routine Karyotype analysis
Recurrent sporadic rearrangement Partial monosomy or trisomy (1-4 MB of DNA) DOSAGE SENSITIVE |
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Contiguous gene deletion syndrome
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syndrome caused by a microdeletion that spans two or more genes tandemly positioned along a chromosome. Microdeletion is often too small to be visualized using conventional cytogenetic techniques; detection often requires fluorescent in situ hybridization (FISH).
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Isochromosomes
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a. two P arms go to one daughter and two Q arms go to the other… splitting of chromatids during miosis, can happen that you misdivide the centromere and two p arms go to one and two q arms go to the other and then get an ISOCHROMOSOME of either P or Q arm
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Ring Chromosome
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Chromosomes
a. Break on P arm and Q arm leading to “sticky ends” b/c you lose the telomeres, in order to protect the chromosome, a ring will form to keep chromosome from being degraded ex Ring X - r(X) is most common cause of Turner syndrome |
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Supernumary marker chromosomes (SMCs)
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Additional piece of a chromosome - too small to identify w/ molecular methods; if it has euchromatin, will have phenotype associated w/ it
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FLOURESCENCE IN SITU HYBRIDIZATION (FISH)
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a. FISH is a physical DNA mapping technique in which a DNA probe labeled with a marker molecule is hybridized to chromosomes on a slide, and visualized using a fluorescence microscope
b. The marker molecule is either fluorescent itself, or is detected with a fluorescently labeled antibody. |
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Interphase FISH
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Prenatal diagnosis aneuploidy by FISH looks at interphase nuclei derived from direct chorionic villi or amniocytes
FISH investigates small regions of the genome for deletions/duplications of about 50-500 kb, but is targeted. |
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Metaphase FISH
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Performed on CULTURED cells and probe will hybridize to both nuclei and metaphase chromosomes
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FISH Applications
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Chromosome identification
ii. • Aneuploidy Detection in prenatals iii. • Marker chromosome identification iv. • Total chromosome Analysis v. • Translocation Analysis vi. • Microdeletion Syndrome Analysis vii. • Gene Amplification Analysis in cancer |
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Unique Sequence Probes
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Identifies a specific region on a particular chromosome
1.Microdeletion syndrome analysis 2.Translocations 3.Oncology/Pathology\ |
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Telomeric Specific Probes
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Identifies the subtelomeric region of a particular chromosome
1. Translocations 2. Cryptic translocation 3. Terminal deltions/duplications |
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Array CGH (comparative genomic hybridization)
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In situ hybridization of differentially labeled specimen DNA & normal reference DNA to DNA targets spotted onto glass slides
The relative amounts of specimen & reference DNA hybridized at a particular chromosome position are contingent on the relative excess of those sequences in the two DNA samples & can be quantified by calculation of the ratio of their different fluorescent colors. |
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Copy number variant (CNV)
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a. range from 1 kb to several Mb in size
b. up to 12% of the genome c. thousands present in the human genome d. contribute to human genetic variation and complex disease – but not yet well understood |
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What percent of first trimester spontaneous abortions are chromosome abnormalities?
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2/3
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What percent of patients w/ mental retardation have chromosomal abnormalities?
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20-30%
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Incidence of liveborns w/ chromosomal abnormalities?
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1 in 125
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What diseases are disorders of Protein Metabolism
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Amino Acid Metabolism: PKU
Organic Acidemias: Propionic Acidemia Urea Cycle defects: OTC deficiency |
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What diseases are disorders of carbohydrate metabolism
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Disorders of galactose metabolism: Galactosemia
Disorders of glycogen storage: GSD1A |
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Disorders of fat metabolism?
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Fatty acid oxidation defects: MCAD
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Disorders of lysosomal storage?
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Sphingolipid metabolism: gaucher disease
Disorders of MPS metabolism: Hurler's disease |
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Mitochondrial Diseases
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Respiratory chain defects: MELAS, NARP, MERF, Leigh's disease
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PKU pathology
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Lack of Phenylalanine Hydroxylase ergo cannot convert Phenyalanine into Tyrosine (or subsequently dopamine or melanin)
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Treatment of PKU
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Restrict Phenyalanine
Provide BH4 cofactor (tetrahydrobiopterin) Provide Tyrosine *clinical trials to replase enzyme |
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Outcome of treated PKU
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If stop treatment after six years: executive fxn problems, concentration problems, memory problems
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Maternal PKU (fetal exposue to high levels of Phenylalanine)
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Microcephaly
Congenital heart disease Craniofacial abnormalities Small for gestational age PHE IS A TERATOGEN!!!! |
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Pathwayws effected by Tetrahydrobiopterin deficiency
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Phe--> Tyr
Tyr --> Dopa Tryptophan --> serotonin |
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What is an organic acid?
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Essentially an acid w/ no amino group on it??
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Propionic labs?
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High ammonia
High acid in baby's bood Not responsive Baby's vomiting... and ill appearing and low level of consciousness |
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What enzyme is effected in Propionic Acidemia?
What are the substrates? |
Propionyl-CoA Carboxylase
VOMIT Valine, OCFA, Methionine Isoleucine, Threonine, |
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Treatment for Propionic Acidemia
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Restrict VOMIT & provide antibiotics to decrease gut bacteria
Provide Biotin cofactor Use Carnitine to bind & eliminate propionic acid Treat secondary effects: ammonia detox & bicarbo to neutralize acid |
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Outcomes of Propionic Acidemia
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Mental Retardation
Recurrent metabolic decompensation: Infection Protein load Essential amino acid deficiency Severe injury Surgery Fasting End organ failure Basal Gangliar Infarcts Renal Failure Pancreatitis Cardiomyopathy |
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Case report of what disease?
Male infant DOL # 3, refused to breast feed Given one bottle of infant formula Within one hour of finishing bottle, became apneic Brought to ER, noted to have seizures Became unresponsive Ammonia extremely elevated Admitted to PICU for hemodialysis, intravenous medications Despite heroic efforts, the infant died 12 hours after admission |
OTC
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OTC pathology
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A mutant enzyme protein impairs the reaction that leads to condensation of carbamyl phosphate and ornithine to form citrulline. This impairment leads to reduced ammonia incorporation, which, in turn, causes symptomatic hyperammonemia (see Hyperammonemia). The gene for this enzyme is normally expressed in the liver and is intramitochondrial.
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OTC treatment
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restrict all protein
Provide Citrulline (product) Replace enzyme via LIVER TRANSPLANT Dialysis & ammonia scavenging medicine to reduce ammonia Gene therapy trial - fail |
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OTC symptoms
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some mental retardation
Recurrent metabolic decompensation - infection, protein load, injury, surgery, fasting, etc Males can have less severe forms of OTC might have hyperammonemic crisis with stressor |
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OTC GENETICS
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X - LINKED RECESSIVE!!!
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Galactosemia pathology
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Missing UDP-GLC-Gal1-puridyltrandferase
Galactose -1 -phosphate -->glucose 6 phosphate |
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Galactosemia symptoms
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Newborn coagulopathy
Liver dysfunction/failure Cataracts E. Coli sepsis Primary ovarian failure Learning disabilities |
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Galactosemia Treatment
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Restict lactose & galactose
Treat Secondary effects via antibiotics for E. Coli (b/c they feed off the galactose) |
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GSD1A labs
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VERY low blood sugar
Blood lactate elevated Blood triglycerides elevated Blood uric acid elevated |
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GSD1a pathology
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Most common is G6Phosphatase deficiency so cannot rip 6 phosphate off to make glucose
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Von Gierke's Disease
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GSD 1a
Cannot convert G6P to Glucose |
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GSD 1a Treatment
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Frequent feedings of cornstarch
Treat secondary effects Treat uric acid w/ allopurinol Maintain normal base status Antilipidemic medications |
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Long term outcome of GSD 1a
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Severe hypoglycemia
Lactic acidosis Growth restriction because of lactic acidosis Osteopenia Hypertriglyceridemia Pancreatitis Hepatic steatosis Hyperuricemia (HIGH URIC ACID) Gout Kidney stones Glycogen accumulation In liver: Hepatic adenomas In kidneys: Nephromegaly |
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MCAD INCIDENCE
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1: 6500 to 1: 17,000
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MCAD symptom
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Sudden death (18% of all pediatric age groups)
Fasting HYPOKETONIC and HYPOGLYCEMIA!! - low ketones! Neurologic: lethargy, coma, seizures |
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Treatment of MCAD
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Avoid Fasting
Low fat, high carb diet Give Carnitine to bind and eliminate fatty acid intermediates |
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What are sphingolipids
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Found in neural tissue
Play a role in signaling & involved in cell recognition |
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What disease is a disorder of sphingolipid metabolism?
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Gaucher Disease
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Gaucher Disease symptoms
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Hepatosplenomegaly
Pancytopenia Thrombocytopenia can be severe Skeletal disease Osteoporosis Bone infarcts Fractures Erlenmeyer Flask deformity of femur (storage inside marrow) |
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Gaucher Type 1
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More common in Ashkenazi Jews
Non-neuronpathic Visceral and skeletal disease Older people |
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Gaucher Type 2
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Neurodegenerative disease, fatal by 2 years of age
Brain disease Type 2 = death by 2 |
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Gaucher Type 3
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Intermediate phenotype
More common in Sweeds |
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Gaucher pathology - what is wrong
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mutations in ß-glucocerebrosidase
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Treatment for Gaucher
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Replace enzyme - Cerezyme
Restrict substrate via ZAVESCA (inhibits the pathway) Treat secondary effects - Bisphosphate for osteopenia; pain management |
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HURLER'S DISEASE
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MSP 1
Disorder of Mucopolysacccahride Metabolism |
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What is accumulated in Hurler's disease?
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Dermatan and Heparan sulfate
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Symptoms of Hurler's
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Corneal clouding
Organomegaly - spleen & liver Heart disease Mental retardation Death in childhood Alpha-Iduronidase Deficiency |
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Treatment of Hurler's
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Bone Marrow Transplant
Recombinant enzyme (aldurazyme) Secondary tx: physical therapy, cardiac care, hearing aids, management of respiratory difficulties |
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What is Replicative Segregation
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Random allotment of daughter cells during replication
Mitochondrial populations may change in the same tissue --> cause genetic Drift |
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MELAS DISEASE
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NORMAL then come in paralyzed and or blind
Mitochondria encephalopathy Lactic acidosis Stroke like episodes |
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How is newborn screening done?
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Heelstick NBS test performed w/in 48 hours and results back in 4- 7 days
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Common Disease-Common Variant (CD-CV) versus Common Disease-Rare Variant (CD-RV) Hypothesis
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Originally thought common diseases had a common set of polymorphisms associated w/ those disease, when look through common varients, don’t explain a lot of disease…opposite of mendelian where things are rare but highly penetrant.
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GWAS
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Genome Wide Association study - – select huge pool of SNPs up to 2.5million SNPs; genotype all at once, and applying unbiased approach to analyze the multiple SNPs in the cases (NO HYPOTHESIS)
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Candidate disease approach
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Biologic candidate genes (pathways);
Candidate genes from animal [knockout] models; Look at SNPs in pathways and see if associated w/ disease |
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Limitations of Association studies
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Require large sample sizes (thousands of individuals)
Require phenotypically homogeneous groups of cases and controls Sensitive to populations stratification Produce false positive results Hard to replicate |
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Genome-wide significance (GWS):
(value) |
0.05/1,000,000=5*10-8
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What are interactions?
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When other factors modify genetic effect
Gene-Environment interactions: Gene-Diet (nutrigenomics) Gene-Drug (pharmacogenetics) Gene-Life style (e.g., smoking, exercise) |
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Principles of Natural selection
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More organisms are produced than can survive and reproduce
Organisms differ in their ability to survive and reproduce, based on genotypic differences The genotypes that promote survival are favored and are reproduced |
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Hardy Weinberg Equation
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P+Q = 1
P^2 +2PQ+ Q^2 = 1 |
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What causes deviation from Hardy weinberg equation?
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Genotyping error
Mutation Migration (immigration and emigration) Natural selection Nonrandom Mating/Inbreeding Genetic drift |
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What is stabilizing selection?
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Extremes have decreased fitness
(second generation is higher peak in middle w/ fewer outliers) |
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What is Disruptive selection?
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Intermediates have decreased fitness
Two hump second generation |
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What is directional selection?
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Extremes have increased fitness
- moves in one direction |
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Genetic Drift
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Genetic drift affects the genetic makeup of the population but, unlike natural selection, through an ENTIRELY RANDOM PROCESS
--> DOESN'T PRODUCE ADAPTIONS, RANDOM ex huntington's disease in south african settlers |
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Haplotype
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is a combination of alleles (DNA sequences) at different places (loci) on the chromosome that are transmitted together.
collection of alleles together in a physical block – over generations haplotypes get smaller and smaller and smaller, so when populations have different linkages of equilibrium, older population – more recombination in population = haplogype smaller; more recent population through bottle neck = reset the clock = longer haplotype blocks |
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Linkage Disequilibrium
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Likeliness that it will be inherited as a block - shorter LD means not homogenous
Can be measured by D' or r^2 When r2 = 1, two SNPs are in perfect LD; allele frequencies are identical for both SNPs, and typing one SNP provides complete information on the other D' varies from 0 (complete equilibrium) to 1 (complete disequilibrium) |
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Linkage Disequilibrium uses
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Knowledge of patterns of LD can be quite useful in the design and analysis of genetic data
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How are Linkage disequilibriums used in GWAS
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By using LD they can identify a few SNPs that represent a block and therefore don't have to sequence entire genome
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GWAS susceptibility?
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GWA studies are susceptible to population stratification which occurs when there are differences in:
1) disease prevalence 2) allele frequencies i.e. When allele frequency is more common in one population than other, screening for the population not disease… The problem arises if case and control populations have different frequencies of ethnic groups |
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Ancestry-Informative Markers
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polymorphisms, which exhibit substantially different frequencies between populations from different geographical regions.
By using a number of AIMs one can estimate the geographical origins of the ancestors of an individual and ascertain what proportion of ancestry is derived from each geographical region. |