Unit 2 Day 6 Flashcards
karyotype of turners
- XO
- loss of second sex chromosome
- widely spaced nipples, broad chest, underdeveloped ovaries
abnormalities of CVS in TS
Bicuspid Aortic Valve Coarctation of the aorta Systemic Hypertension Prolonged QTc Syndrome Partial anomalous pulmonary venous connection Persistent left SVC
abnormalities of Eye with TS
inner canthal folds
ptosis
blue sclera
abnormalities skeletal system with TS
cubitus valgus
short 4th metacarpal
short stature
abnormalities of neck with TS
webbed neck
low hairline
cystic hygroma
learning abnormalities TS
difficulty math
visual spatial skills
low non-verbal scores
other abnormalities TS
lymphatics: prenatal =cystic hygroma, newborn is neck webbing
urinary system
loss of hearing/vision
endocrine: hypothyroidism, gonadal dysgenesis
what are the challenges TS patients experience across their lifetime?
- infertility
- stature
- sexual development
- concerns regarding health and aging
what are common pitfalls in disclosure?
secret keeping
difficulty communicating infertility diagnosis
perceived negative experiences with physicians
Hb F (alpha2gamma2)
birth: 60-90%
>2yrs:
Hb A (alpha2beta2)
birth: 10-40%
>2 years: >95%
-most common in adults
HbA2 (alpha2sigma2)
birth: 2 yrs:
when do you see sickle cell disease?
- symptoms show 6 months of age since still have HbF.
- at 6 months, spleen doesn’t function well
SB0 thalassemia
don’t make any hb
SB+ thalassemia
make some hb
Hb S
sickle cell
Hb C
-amino acid substitution–> lysine for glutamic acid
Hb E
- beta chain substitution
- gene has been genetically fixed
- in some SEAsia areas, almost 100% penetrant, combination with thalassemia is increased severity
qualitative hemoglobinopathies
Hb S
Hb C
Hb E
quantitative hemoglobinopathies
α thalassemia β thalassemia γ thalassemia Δ thalassemia delta and gamma can change clinical presentation
hemoglobinopathies
- 15% of Africans are S carriers
- 7% of SE Asians are E carriers
- 4-5% of SE Asians and Mediterranean population are beta thal carriers
- 350,000 babies are born throughout the world each year with major hemoglobin disorders
mutations by region
#1 – Southeast Asia: α, β thalassemia and E #2 Africa – S, C, α and β thalassemia #3 West Pacific – α and β thalassemia and E #4 East Mediterranean – β thalassemia and S
thalassemia
reduced rate of 1 or more of global chain synthesis. leads to imbalanced/defective global chain production, damage to RBC and precursors
alpha thalassemia types
α thalassemia major α thalassemia 3 gene deletion α thalassemia 2 gene deletion α thalassemia 1 gene deletion α thalassemia + Hgb Constant Spring
beta thalessemia types
β thalassemia major “Cooley’s anemia” β thalassemia intermedia β thalassemia trait SB° thalassemia SB+ thalassemia
differences btwn African and Asian alpha thalassemia
Africa: haplotypes are different
- One always have normal allele
- Always inherit one or two
SE asia, there is incomplete allele
-So there is a chance of getting 2 abnormal alleles
autosomal recessive disorders
- homozygote expression
- males and females equally affected
- horizontal inheritance
- parents=carriers
- recurrence risk for children is 1/4, unaffected is 2/3
- frequency is q^2
- frequency of mutant allele=q
frequency of wild type allele
p (p+q=1)
frequency of normal
p^2
carrier frequency
most of the time q is so small you can approximate p as 1
find q by taking square root of q^2
tay sachs carrier frequency
1/300 general population
risk: 1/300 x 1/300 x 1/4 =1/360000
if parents are carriers: 1/2 x 1/2= 1/4
allelic heterogeneity
presence of multiple common mutant alleles of the same gene in a population
compound heterozygote
individual who carries 2 diff mutant alleles of the same gene
phenylketonuria phenotypes
PKU
- high phenylalanine love in the blood
- high levels metabolites in urine
- hyperactivity and epilepsy
- metal retardation, microcephaly
- babies affected by this
PKU defects in PAH
- high allelic heterogeneity. 7 alleles account for 2/3 of all PAH mutations in European populations. 6 alleles account for 80% of PAH mutations in Asian populations
- compound heterozigysity
- varied phenotype severity
PKU newborn screening
- done with tandem mass spectrometry
- sorts molecules by size, weight, quantity
- multiple molecules measured simultaneously
- timing is critical, baby carries enzymes from mom, once digesting food it builds up, test late enough but not too late
PKU treatment
- low phenylalanine diet
- BH4 supplementation
- neutral amino acid supplementation, enzyme replacement therapy, gene therapy
PKU maternal effect
- off low Phe diet in pregnancy
- increases risk of miscarriage
- malformations/retardation
alpha 1 antitrypsin deficiency (ATD)
- more common in people with northern European ancestry
- disease is 1/2500, carrier frequency ~4%
- underdiagnosed
- risk of emphysema, liver cirrhosis and cancer
- more severe symptoms in smoker
- caused by mutations in alpha 1-AT gene
- made in liver, transported to lungs in blood
ATD defects
- deficiency in ATD, protease inhibitor
- SERPINA 1=suicide substrate of serine protease elastase
- imbalance elastase and SERPINA 1
- cycles of elastase release and lung damage in ATD
- eventually lung loses elasticity
elastase
released by activated neutrophils at airway, destroy elastin in connective tissues
ATD Z allele
- most common mutant allele
- Z/Z phenotype have ~15% normal SERAPINA level
- make protein that isn’t folded properly and tends to accumulate in ER of liver cells
ATD S allele
makes unstable SERPINA1 protein
-S/S genotype has 50/60% normal level
ATD M allele
encode functional proteins (wild type)
ATD treatment
current treatments:
- bronchodialators/inhaled steroids
- vaccinations
- pulmonary rehab
- lung transpant
- treatments in development: enzyme replacement therapy, gene therapy, release misfolded AAT from liver to blood w/ chemicals
Tay-Sachs
- genetic fetal disorder
- progressive destruction CNS
- T-S babies die by 2-4 years
- first signs: muscle response
tay-sachs biochemical defects
- lysosomal storage defects, too much Gm2 builds up
- synthesized in neurons and cell membrane
- unable to degrade it
- Hexosaminidase A consists of alpha/beta subunits (encoded HEXA/B genes)
- T-S have mutations in HEXA gene
- hex b causes sandhoff disease
hemoglobin as tetramer
- 2 alpha beta hetrodimers
- lots of salt bridges
- heme group has iron in center, linked to histidine
human global gene clusters
- beta locus codes for beta and beta genes
- switch from beta to alpha, switch from gamma to alpha
- majority of adult hemoglobin is alpha 2 beta 2
globin switching
- change of expression patterns during development
- theta to epsillon to beta
- alpha has one switch, stays on
- beta has 2 switches, controlled around time of birth
- gamma plus beta is similar to alpha
Locus control region
- regulates globin transcription
- each gene has own promoters 20-40kb upstream
genetic disorders of hemoglobin
- structural variants (synthesize normally, different globin)
- thalassemeias (low to zero synthesis of chain)
- defective globin switching (persistance fetal hemoglobin)
sickle cell disease: HbSS
single gene disease
point mutation-codon 6, exon 1 of beta global
glutamate –>valine
can’t deform
hemoglobin C disease: HbCC
- affects same codon as HbSS
- glutamate–>lysine
- first codon (sickle is second)
- form crystals
- altered solubility
DNA diagnosis sickle cell
- restriction enzyme Mst 2 recognizes code
- sickle cell changes A to T, destroys site
- larger chunk
Speed of Hemoglobin electrophoresis
- Wt is HbA
- S is slower
- C is slowest (+ charge)
polycythemia (Hb Kempsey)
- higher O2 affinity
- less O2 to tissues
- overproduction RBC
cyanosis (Hb kansas)
- lower Hb-O2 affinity
- lower O2, level RBC
- bluish skin
alpha thalassemia
- low/zero alpha globulin, excess beta and gamma
- fetal/postnatal defects
- deletion alpha globin gene
- only when you go below 50% are going to have problems
- h disease=beta 4
- some areas SEAsia mutant is less frequent, baby dies b/c gamma 4 is not sufficient
beta thalassemia
- low/zero beta globulin, excess alpha and precipitates
- postnatal defects
- point mutations in beta globin
- caused by deletions in LCR region of beta gene cluster
hemolysis
the rupture or destruction of red blood cells.
microcytosis
red blood cells are unusually small as measured by their mean corpuscular volume
hypochromia
anemia in which the red blood cells (erythrocytes) are paler than normal
alpha thalassemia
SEAsia: alpha thal 1
–/– hydrops fetalis
alpha -/– HbH disease
aa/– mild anemia
Africa, Med, Asia: alpha thal 2
a-/a- mild anemia
alpha thalessemia traits
beta thalassemias
- beta locus, affects beta globin
- not turned on till after birth
- switch from gamma to beta occurs gradually
major-need treatment/transfusion
minor-little/no symptoms
beta + some expression but not enough
beta 0 - no detectable beta
HPFH mechanisms and implications
- large deletions or promoter mutations
- large deletions bring enhancers downstream closer to beta locus–> gamma expressed after birth
- promoter mutations shut off expression of gamma
- less beta, substitute expression of beta
- try to keep gamma from shutting off: prevent from happening by using BCA 1, gene silencing w/ RNA and mRNA, 2 micro RNA present on 13
