Week 1 Flashcards
Pharmacogenetics
the area of biochemical genetics concerned with the impact of genetic variation on drug response and metabolism
What are the two major physiological responses to drugs?
1) achieving desired effect
2) removing/inactivating the drug
Pharmokinetics
rate at which the body absorbs, transports, metabolizes, and excretes drug
ATME
“whether/how much drug reaches target”
Pharmakodynamics
response of drug binding to its target and downstream targets
“what happens when drug reaches target”
Phase I drug metabolism
attach polar group onto compound to make more soluble - hydroxylation step
Phase II drug metabolism
attach sugar/acetyl group to detoxify drug and make it easier to excrete
Cytocrome P450
CYP450
responsible for phase I metabolism
Most are associated with inactivation of drug, but CYP2D6 is associated with activation
CYP2D6
drug necessary to convert codeine into morphine
Frameshift mutation in CYP2D6
non function - no conversion to morphine
Splicing of CYP2D6
skin exons or alter reading frame - non functional - no conversion to morphine
Missence of CYP2D6
alter protein function - reduced activity - less conversion of morphine
Copy number alleles in CYP2D6
increased gene copies is increased activity!
Poor, Normal, or ultrarapid/ultrafast
CYP3A
Cyclosporine
Inhibitors: ketoconazole, grapefruit juice
Activators: rifampicin
CYP2D6
Codein, tricyclic, antidepressants
CYP2C9
warfarin
TMPT
6-mercaptopurine
6-thioguanine
Chemotherapeutic, but bone marrow toxicity
ranges from high to virtually indetectaable enzymatic activity. Those with low (1:400) have extreme bone marrow suppression that causes fatality if not dosed correctly.
must give 1/10 of standard dose for those patients.
G6PD
Sulfonamide, dapsone
X-linked enzyme
susceptible to hymolytic anemia after drug exposure.
VKORC1
Warfarin
blood thinner
Warfarin
Both a CYP2C9 and VKORC1
Anti-coagulant
prescribed at standard dose of 5 mg and pt is watched over next few moths for excessive bleeding or clotting and dose id adjusted.
NAT
isoniazid for TB
if quickly digested: no liver problems but not adequate TB treatment
if slowly digested: good TB treatment, but liver problems.
Haplotype
a group of allele sin coupling at closely linked loci, usually inherited as a unit
Pleitropic
multiple phenotypic effects due to a mutation(S) in a single gene. Often used when phenotypes are seemingly unrelated and/or in different tissues.
Incomplete dominance
phenotype is intermediate between two homozygous phenotypes
trait inherited in dominant manner, but is more severe in homozygous than heterozygote.
semidominant
1st law of segregation
At meiosis, alleles separate (or segregate) from each other such that each gamete (egg or sperm) receives one copy from each allele pair.
have a 50:50 chance of getting the gene
Mende’s 2nd law of independent assortment
At meiosis, the segregation of each pair of alleles is independent. [Note: genes physically near each other
(‘linked’) on the same chromosome violate this law]
Co-dominant traits
if both alleles/traits are expressed in heterozygous state
Hemizygous
male with mutated X
X-Inacivation
one chromosome is largely inactivated in somatic cells, to equalize expression of X-linked Genes between sexes.
Penetrance
fraction of individuals with a trait genotype who manifest the disease
Can be either 100% penetrant or Incomplete penetrance.
Analogous to light switch
Expressivity
degree to which a trait is expressed (measure of severity)
analogous to dimmer
influenced by sex, environmental factors, stochastic events, and modifier genes
Phenocopies
Diseases that are due to non-genetic factors
ie. thyroid cancer due to radiation exposure vs. thyroid cancer due to RET mutation
Four factors that influence allele frequency
1) natural selection
2) genetic drift
3) nutation
4) gene flow
Genome mutation
Due to chromosome missegregation
2-4 x 10^-2/cell division
Chromosome mutation
due to chromosome rearrangement
6x10^-4 / cell division
Gene mutation
due to base pair mutation
10^-5 to 10^-6
Polymorphism
genetic mutations that is common in more than 1% of the population
Genetic Drift
random fluctuation of allele frequencies, usually in small populations
Gene Flow
when populations with different allele frequencies mix
Incidence rate of autusomal domiant
2* mutation rate
Assumptions of Hardy-Weingberg
Large populations are randomly mating
Allele frequency remains constant because
1) there are no new mutations
2) no selection for/against alleles
3) no immigration/emigration with new allele frequencies
Stratification
populations containing two or more subgroups preferentially mate within own subgroup
(AA) with sickle cell anemia
Assortive Mating
Choice of mate is dependent on particular trait (ie height, intelligence, dwarfism, blindness)
Mitosis vs. Meiosis
1) paternally and maternally derived homologous chromosomes pair at onset of meiosis, where as they segregate independently in mitosis
2) reciprocal recombination events occur in meiosis, but are rare in mitosis
chiasmata
crossing of chromatid strands of homologous chromosomes
a physical linkage
Bivalent
pair of homologous chromosomes in association, as seen in metaphase of first meiotic division
Synaptonemal complex
The synaptonemal complex is a protein structure that forms between homologous chromosomes (two pairs of sister chromatids) during meiosis and is thought to mediate chromosome pairing, synapsis, and recombination.
Disassembled during end of prophase.
Reciprocal Recombination
generate physical linkages between homologs
2-3 crossover events occur per pari of chromosomes
Genetic consequences of meiosis
1) reduction of chromosome number
2) recombination during meiosis I prophase giving 2^23 possibilities
3) independent assortment of maternal and paternal chromosomes
Non-disjunction in meiosis I
100% abnormal cells
2 (N+1) and 2(N-1)
Non-disjunction in Meiosis II
50% abnormal cells
2 N and 1 (N+1) and 1(N-1)
What increases rates of non-disjunction?
1) Maternal Age
2) crossing over events that occur too near (entanglement) or too far from centromere (less effective in spindle attachments)
3) Reduction of recombination events
what percentage of genetic abnormalities cause first semester spontaneous abortions?
50%
what percentage of live born infants have congenital abnormalities?
3%
What percentage of sperm is abnormal?
1-3%
What percentage of ova are abnormal?
> 3%
increasing with advanced maternal age
metacentric
central centromere
submetacentric
off center and arms are clearly of different lengths
Acentric
centromere nearly at the end
includes 13, 14, 15, 21, 22
small masses of chromatin called Satellites
Satellites
a small mass of chromosome containing genes for rRNA at the end of the short arm of acentric chromosomes
Highly polymorphic and variable
Telocentric
centromere at one end and only a single arm
not observed in humans
ploidy
number of homologous chromosome sets present in a cell or organism
Euploidy
true ploidy
full sets of chromosomes
Triploid
3 sets of chromosomes - 69
Tetraploid
4 sets of chromosomes - 92
mechanism that causes tetraploidy
DNA duplication but not cell division (endomitosis)
Aneuploidy
abnormal chromosome number due to the extra or missing chromosome
arrises during meiosis I or II, could be paternal or maternal
or post zygotically
Tolerated aneuploidies at conception
45,X
Trisomy 16, 21, 22
Tolerated aneuploidies at live birth
trisomy 13, 18, 21
sex chromosome aneuploidy
When should cytogenic studies be ordered?
1) multiple congenital abnormalities
2) developmental delay + minor abnormalities
3) historical familial chromosomal abnormality
4) intrauterine growth reduction
5) history of miscarriages
Postnatal cytogenic studies
peripheral blood
skin biopsy
Cytogenic Studies with acquired cancer
Bone Marrow
tumor
peripheral blood
lymph node
Trisomy 21 Phenotype:
1) brachycephaly (shorter head) 2) midface hypoplasia 3) up slanting palpebral fissures 4) spicanthal folds (extra skin on inside of eyes) 5) small ears 6) large appearing tongue 7) increased joint mobility 8) brushfield spots 9) incurving 5th finger 10) increased space between 1st and 2nd toe 11) horizontal fissure
Clinical Features of Down Syndrome: cardiac
50% have congenital heart defect
mostly atrioventricular canal
GI defects in Down Syndrome
10-15% of DS babies
esophageal or duodenal atresias
Hirshprungs disease
non anatomical defects: feeding problems, gastro esophageal reflux disease, celiac
How are esophageal and duodenal atresias detected
extra amniotic fluid becuase baby can’t swallow
called polyhydramnios
Ophthalmologic problems in Down Syndrome
60% of DS patients have there
1) conjuntivitis (blocked tear ducts) 2) myoptia (near sightedness) 3) lazy eye 4) nysagmus (jiggly eye) 5) cataracts
Ear, nose and throat problems in Down Syndrome
Chronic ear infections
deafness (both sensorineural and conductive)
chronic nasal congestion
enlarged tonsil and adenoids leading to sleep apnea
Percentage of hearing loss in Down Syndrome
75%
Endocrine disorders in Down Syndrome
25% Thyroid Disease (hypothyroidism) Insulin dependent diabetes Alopecia Reduced fertility (normal puberty) females can be fertile, but males are almost never
Orthopedic problems in Down Syndrome
Hips and joint subluxation
Atlantoaxial subluxation
Blood issues in Down Syndrome
Myeloproliferation disorder
Increase risk of leukemia (12-20X) in perinatal period
iron deficiency due to feeding issues
Neurological/Psychiatric problems in down Syndrome
Hypotonic Seizures (infantile spasms) Depression Early onset AD autism (1/10)
Development and behavioral phenotype of Down Syndrome
Delayed gross motor development due to hypotonia
Intellectual disability IQ -50
Speech problems due to small mouth/large tongue
Recurrence risk of Down Syndrome
1/100 + risk of maternal age
Risk for having DS child in 20s
1/1000
Risk of having DS child at 35
1/200
risk of having DS child at 40
1/100
risk of having DS child at 45
1/20 to 1/10
Types of trisomy 21
Complete 90%
Acentric translocation 3-4%
Mosaic: 1-2%
Maternal Age effect
1) diminished recombination due to lack of chiasmata or mislocalization
2) decreased segregation
less able to overcome non-disjunction detection
Prevalence of Trisomy 21
1/800 to 1/900 live births
Only 20-25% of conceptuses survive to birth
Trisomy 18
Edwards Syndrome
Trisomy 18 phenotype
small for gestation age, microcephaly, clenched hands/overlapping fingers, rocker bottom feet, heart/brain abnormalities
Trisomy 13
patau syndrome
Phenotype of Trisomy 13
growth retardation, severe mental retardaton, sloping forehad, misformed ears, cleft palate, clenched and overlapping fingers, rocker botton feet, congenital heart defects, urogenital defects, ocular abnormalities
Turner Syndrome
45, X
most common abnormalities in spontaneous abortions
99% of fetuses do not survive to term
1/2500 female births
Turner Phenotype
prenatal lymphedema, cystic hygroma, congenital heart defect, coarctation of aorta, gonadal dysgenesis, short stature, webbed neck, low set ears, normal intelligence, infertility due to non-functioning ovaries, hormone dysfunction(requires hormone replacement)
karyotypes of Turners
45, X (50%) 46, X, i(Xq) Three long arms 1 short mos 45X/46 X i(Xq) mos 45, X/ 46 XX (truncated long arm) all surviving births are through to be mosaic
Klinefelter Syndrome
47, XXY
common 1/1000 males
Klinefelter syndrome phenotype
tall, hypogonadism, atrophic testis (infertile), underdevelopment of 2nd sexual characteristics, learning disability, poor psychosocial development, delayed speech and langauge, quiet, not broard shoulders, wide hips
At puberty: small tests, reduced facial and body hair, infertility, hypospadias (uretrha underside penis), gynecomastia (enlarged breasts)
Origin of Klinefelter
50% due to paternal meiosis I (failure of Xp/Yp recombination)
50% de to maternal meiosis I errors (75% occur in meiosis I)
Klinefelter Mosaicism
25% are mosaic
most common are 47, XXY/ 46 XY (with normal testicular development maybe)
48 XXYY, 48 XXXY, 49 XXXXY
when are structural chromosomal abnormalities visible by cytogenetics?
changes greater than 5 megabases
Reciprocal Translocation
translocation between two non-homologous chromosomes
Quadrivalent
structure that forms the gametocyte in meiosis I, divides chromosomes of one daughter cell and chromosomes to the other daughter cell.
Alternative segregation
alternate centromeres to the same pole
centromere of homologues to opposite poles
always leads to normal and balanced translocation
occurs 50% of the time
Adjacent 1 Segregation
adjacent nonhomologous centromeres to the same pole
Top from bottom
each contains duplications and deletions,
50% of the time
results in trisomy or monosomy
Adjacent 2 segregation
adjacent homologous centromeres to same pole
seldom occurs
Separation from right and left
Reciprocal Translocation
BALANCED
partner homologues arrnges themselves to maximize pairing to from quadravalent and separated by alternate and adjacent separtion
Robertsonian
Structural chromosomal rearrangment that cuases acrocetnric chromsome to fuse to make double centromere or single centromere
almost always leads to unbalanced because they have 45
can be homologous or non homologous
Human acrocentric chromosomes
13, 14, 15, 21, 22 most common is 13:14 75% also 14:21 and 21:21 can be de novo or familial
Homologous acrocentric chromosomes
pairing of both of the same sister chromatids
ie. 13 with 13
Non-Homologous Acrocentric chromosomes
between two different acrocentric chromatids
13 and 14
how many trisomy 13 are due to roberstonian translocation
20%
Pericentric Inversion
inversion that include the centromere
non-consequential unless break in gene
Familial
not associated with increased SAB, infertility, or recombinant offspring
Crossing over in pericentric inversion
if crossing over occurs between two non-sister chromatids gives rise to:
1) two complimentary recombinants
2) duplication of long arm, deletion of short
3) deletion of long arm, duplication of short arm
Gamete possibilities of pericentric inversion
1) normal, unrearranged
2) inversion, balanced (combined about 50%)
3) two complimentary recombinants (one compatible one lethal)
Paracentric Inversion
Excludes centromere
Familial and Sporadic
Crossing over in Paracentric Inversion
results in 1/2 balance and 1/2 unbalanced
Products are either dicentric (two centrosomes) or acentric
both unstable.
Anirdia
poor iris development due to paracentric inversion of 11
Balanced Translocation Carriers
Risk of having unbalanced progeny of 0-30% depending on type of translocation
risk of unbalanced is due to: Size of exchange material, tolerated monosomies or trisomies, maternal translocations are more likely to have unbalanced offsprings
TBX-1
due to a deletion and duplication in chromosome 22
Disturbance in migration of neural crest cells in pharyngeal arches and pouches results in cleft lip, palate, heart defects
influence parathyroid, thyroid, and thymus.
Isochromosome
abnormal chromosomes in which one arm is duplicated (forms two arms of equal length with the same loci in reverse sequence) and the other arm missing.
AML
Acute myelogenous Leukemia
seem mostly in adults
Diagnosed by Auer Rod in Bone Marrow and elevated Blast in Bone marrow and peripheral blood.
Two main fusion proteins: PML-RARalpha and BCR-ABL
How is AML diagnosed
Auer rod in Bone Marrow
Elevated blasts in bone marrow and peripheral blood
CML
Chronic Myeloid Leukemia
Night sweats, fatigue, weightloss, anemia, splenomegaly
diagnosed by longulated large cells in peripheral blood and bone marrow is hypocellular
characterized by BCR-ABL protein (9 and 22)
Symptoms of CML
night sweats, fatigue, weight loss, anemia, splenomegaly
diagnosis of CML
longulated large cells in blood, bone marrow in hypocellular
BCR-ABL
in CML
translocation between Ch 9 (ABL) and Ch 22 (BCR)
What is other characteristics of CML
BCR-ABL fusion
gain of ch 8
deletion of 22
Treatment of CML
Gleevec
targets BCR-ABL fusion protein and inhibits by binding to ATP binding site
tyrosine kinase inhibitor
APL
Acute Promyelocytic leukemia
PML-RARAlpha
translocation of 15:17
PML-RARalpha
PML (ch15) and RARalpha (Ch 17)
creates novel transcriptionf actor that prevents differentiation of myeloid hematropeoetic precursors past promyloctypic stage.
Treatment of APL
with trans-retinoic acid (vitamin A) overcomes inhibition and allow differentiation and APL goes into remission.
Types of leukemia that Down Syndrome patients develop
ALL, AML, 20 to 100 fold increase
AMKL 500x more likely
ALL
hyperdiploidy in bone marrow and peripheral blood
FISH
specific clones >200 bp DNA sequences are covalent bound to Fluorescent dye.
hybridized in either interphase or metaphase conditions
can be used to identify number of specific chromosomes or identify translocation
Various types of probes for FISH
1) centromere
2) locus specific
3) dual Fusion/fusion
4) break Apart
5) whole chromosome pain
Centromere probes
used for enumeration
Locus Specific probes
used to detect deletions or duplications
Dual Fusion and Fusion probes
used to detect translocation
Break Apart Probes
used in detecting translocation rearrangements
Whole Chromosome Pain Probes
used to identify markers and translocations
Two types of translocations
1) right next to strong promoter and enhancer that up regulates expression
2) novel fusion
Chromosomal Microarray
high volume, automated analysis of many pieces of DNA at once.
CMA chips use labels or probes that bond to specific chromosome regions.
can detect deletions, duplications (great than 200 kbases) , but not translocations
Cytogenetics:
genome screen; mitotic selected cells, gain/loss, balanaced rearrangements, highly dependent on technological expertise.
CMA
genome screen, interphase on all cells, gain or loss only, technology dependent, detects runs in homozygosity by detecting SNPs.
Copy Number Variants
structural variation that results in the cell having an abnormal or normal variation in the number of copies of one or more sections of DNA.
Specific duplications
may be inherited or de novo
Runs of Homozygosity
indicates that child is born from a father and mother who are first degree relatives.
Procedure for testing children with developmental and learning disorders, autism, dysmophic features, failure to thrive
1) CMA detects deletion or duplciation
2) parental FISH to determine if finding is rare, normal or family variant
3) if found in parents, test family to see if genetic component
4) if not found in parent, look in genetic variants databse
Epigenetics
mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence but by
1) reversible post-translational modifications of histones by DNA methylation
2) Generalized, not sex specific
Genetic Imprinting
1) normal process due to alterations chromatin structure that occur in the germ line that is unique to one of your parents.
2) methylation of cytoseine, modification of histone code
3) effects expression
4) reversible gene inactivation
5) occurs in less than 10% of genome
MeCP2
interacts with methylated DNA and undergoes ATP hydrolysis to promote continued histone de-acytylation and histone methylation.
Methylation is..
1) established in the gamete
2) stably maintained after fertilization
3) reversible, so that it can be reset during gametogenesis to transmit appropriate sex-specific imprinting to progeny
Hemi-methylated DNA
during DNA replication, when the old strand is methylated but new strand is not
Methyltransferase
enzyme that methylates the new strand to create fully methylated DNA
Where does epigenetic programming occur
in germ cells sex specific methylation of imprinted loci is specific to sperm or egg.
when fertilized, zygote has unique methylation pattern from both mom and dad
somatic cells maintain this methylation pattern for the remainder of life.
Erasure of genetic imprinting
in germ cells this methylation is erased until you have kids, where the methylation pattern will persist based on sex of baby.
if erasure does not occur, there will be an imbalance because you will either have no active copies or two active copies. you need the alteration.
Prader Willi Syndrome
excessive eating, short stature, hypogonadism, some degree of intellectual disability
due to deletion in paternal p15, uniparental disomy, imprinting center mutation
what are the causes of Prader Willi syndrome
70% due to deletion in paternal p15
28% due to maternal uniparental disomy
2% imprinting error to cause maternal allele to be persistant
Angelman Syndrome
short stature, severe intellectual disability, spasticity, seizures
maternal gene methylation/deletion on Ch15
Causes of Angelman syndrome
70% deletion of maternal gene on qch15
4% due to paternal uniparental disomy
8% imprinting center mutation to make paternal persistent
8% mutation in UBE3A mutation
How do deletions in imprinting centers occur?
presence of low copy repeats near common breakpoints that arise from large genomic duplications of HERC2. These make it more likely to have inter and intra-chromosomal misalignments and homologous recombinations resulting in deletions.
Uniparental disomy
presence of a disomic cell line containing two chromosomes or portions of either parental imprinted allele.
trisomic conceptus
when you have 2 paternal allels and 1 from the other during fertilization. Normally this inviable, but then undergoes trisomy rescue that removes one of chromatids. to leave with either two maternal or paternal chromosomes.
Testing for Prader-Willi
Methylation testing of Ch15
FISH or microarray
Prader Willi physical features in infancy
hyptonic, almond shaped eyes, lighter pigmentation, undescended testicle, severe feeding problems (need G tube)
Phenotype of Prader Willi in toddlers
feeding becomes voracious, obescity, strabismus (lazy eye), nysagmus
medical problems with PWS
strabismus, nystagmus, scoliosis, sleep apnea, obesity
Development and behavioral phenotype of PWS
mild/moderate cognitive diabilites
behavioral issues
motor delays due to hypotonia
excessive compulsion disorders
Other disorders with Ch 15q
1) marker chromosome - inverted duplications
2) interstitial duplications
3) linkage disequilibrium
Marker Chromosome - inverted duplicaiton of Ch15q
forms extra tiny chromosome that is made up of part of p and q so you have 4 copies of gene.
Autism, NOT dysmporphic, hypotonic, seizures
Interstitial duplications of 15q
to make a partial trisomy
autism, not dysmorphic, sqizures, hypotonia
how does genetic variation beneif organisms?
1) allows them to exist in constantly changing environment
2) encounter and need to fend off bacteria, viruses, parasites
3) need to purge deleterious mutations
Sexual dimorphism
1) phenotypic differences between male and female
2) induces reproductive organs as well as body habitus differences
X-inactivation
no matter how many Xs in you have, there is still only one active X.
The other X is turned off but phenotypes occur in Aneuploidy because of pseudo-autosomal regions that remain active in inactivated X.
Post-Puberty signs of Kleinfelter
Small testes, reduced facial hair and body hair, infertility, hypospadias (urethra underside of penis), gyneocmastia (enlarged breasts)
47, XYY
Jacob’s Syndrome
learning diabilities, speech delay, developmental delay, behavior and emotional difficulties, autism, tall, still fertile!
1/1000
Triple X
47,XXX
Tall, increased risk of learning disabilities, delayed speech, delayed motor dvpt, seizures, kidney abnormalities.
1/1000
Primary Sex Determination
determined by gonads
Presence of Y - male
Presence of X is female
we have the potential to be both, and testes and ovaries result from common biopotenail gonad and are differentiated.
Mesonephric ducts
Wolffian
results in male structures
under influence of testosterone, elongate to form epididymis, seminal vesicles, ductus deferens
Promoted by SRY gene and SOX9
SOX 9
on autosomal Ch.
a TF that produces anti-mullerian hormone.
cause regression of mullerian ducts and progression of mesonephric or wolffian duct
FGF9
chemotactic factor that causes tubules to form mesonephric duct to penetrate gonadal ridge
testis differentiation
SF1/NF5A1
stimulates differentiation of sertoli and leydig cells
Paramesonephric Duct
Mullerian ducts
result in female structures
estrogen stimulates formation of uterus, cervix, broad ligament, fallopian tubes, upper 1/3 of vagina
WNT4
protein
extracellular signaling factor
differentiation of ovary
inhibited by SOX9
DHH
gene
nuclear hormone receptor
unregulated by WNT4
down regulates SOX9
RSPO1
gene
coactivator of WNT
Week 3 embryology
mesenchymal cells in primitive streak migrate to form genital tubercle and genital swellings
Males secondary genetalia
androgen exposure and dihydrotestoserone from testis results in formation of glands, shaft and scrotum
what forms glands of penis
genital tubercle
what forms shaft of penis
urogential folds
Female secondary genetalia
estrogen from mother and father results in formation of clitoris, labia major and minora
labia minora
urogential folds
labia majora
labioscrotal swellings
Prader Scale
0 is no virilization and 5 is full virilization
AIS
46 XY
normal or elevated testosterone or DHT
X linked androgen receptor
mild under virilization to full sex reversal
5-alpha reductase deficiency
46 XY
normal/elevate testosterone or DHT
mutation causes decreased ability to convert testosterone into DHT
under virilized male, but increased at time of puberty.
Disorders of SRY gene
either 46 XY or 46 XX (when SRY is transposed on X)
Decreased Testosterone or DHT in male, increased in female
under virilization of male if deleted or mutated
male phenotype if ectopic presence in 46 XX
Denys Drash and Fraiser
46 XY decreased DHT or Test sex reversal mutation in WT1 gene chronic kidney disease, increase wilms tumor risk WT1 is TF for SRY
Congenital Adrenal hyperplasia
ambiguous genitalia 46, XX
12-hydroxylase deficiency
Type I Gaucher
most common, non-neuropathic, childhood-adulthood
9/10 cases
prevalent in ashkenazi jews
Phenotype of Type I Gaucher
anemia, hepatosplenomegaly, osteopneia, bone p ain, osteoprosis, thrombocytopenia, epixaxis (nose bleeds)
less than 30% glucocerebrosidase activity
Type II Gaucher
infantile
rare, sever, neurological
1/100,000 births
severe brainstem abnormalities
Type II gaucher phenotype
same as I, but also mental retardation, apnea, dementia, seizures, rigidity
Type III gaucher
presents after infancy, some neuro components
all phenotype of I, but also mental retardation, dementia, convlusions
Thrombocytopenia
abnormal drop in platelets involved in clotting.
pts bruise easily
due to:
1) decreased production of platelets by bone marrow
2) increased destruction of circulating platelets
3) increased trapping in spleen
4) loss due to hemorrhage
How is Gaucher diagnosed?
1) Glucocerebrosidase activity
2) Genotyping
3) bone marrow for glycolipid laden macrophages
4) prenatal testing
How are RBC removed?
1) 90% are removed by phagocytic activites in liver, spleen and lymph
2) 10% hemolyze in circulation
3) macrophages break down chemical components
Clincial manifestation of Gacher
in absence of glucerebrosidase, glucocerebroside accumulate in macrophages and lysosomes fill up. IT gives it a wrinkled cigarette paper appearance. These build up in the liver, spleen and bone marrow.
