Chapter 5 - Genetic Disorders Flashcards
Trisomy 21:
1) what do 40% of patients end up having? why?
2) what do they have a 10-20x increased risk of compared to normal?
3) all patients end up having what? how can you see this histologically?
4) what about their immune systems?
5) what is their usual cause of death?
congenital heart disease –> atrial septal defects of the endocardial cushion (usually osmium primum)
developing acute leukemia
characteristic changes of Alzheimer disease when above 40 yers old
abnormal so they get serious infections usually in the lungs and thyroid. plaques and tangles
cardiac problems
Ehlers Danlos Syndrome:
what internal complications can these people have that result in death?
what type leads to blindness?
what. type leads to diaphragmatic hernias?
rupture of the colon and large arteries (vascular EDS)
ocular fragility rupture of cornea and retinal detachment (kyophoscoliosis EDS)
Classic EDS
Phenylketonuria
1) what is the incidence of it? what race? be specific
2) what is the inheritance?
3) what’s the problem?
4) because of this problem, what accumulates?
1/10000 live born caucasians of Scandinavian descent
Autosomal recessive
Phenylalanine hydroxyls (PAH) deficiency –> changes phenylalanine to tyrosine
hyperphenylalaninemia
What is codominance?
Pleiotropism?
genetic heterogeneity?
both alleles contribute to the phenotype
single mutant gene has many different end effects with it
mutations at several loci produce the same trait
Tay Sachs Disease:
1) what is the problem
2) what chromosome is it located on?
3) what is the deficiency?
4) what is the carrier rate and race associated?
you can’t catabolize Gm2 gangliosides
15
hexosaminidase A
1/30, Eastern European –> Ashkenazic Jew
Velocardiofacial syndrome:
1) what’s causing it?
2) what is seen on the patient?
Chromosome 22q11 deletion
super long face, super prominent nose (pear shaped), overfolded helix on their nose
Other than the “miscellaneous diseases”, What are the different organs that have glycogen storage disease? what’s the mechanism? explain these briefly
what are examples of each?
——- Hepatic forms –> liver is the key to glycogen metabolism, so if you have a deficiency, you’ll have INCREASED STORAGE of glycogen and DECREASED blood glucose concentrations.
Von Gierke
——- Myopathic forms: skeletal muscle –> glycogen storage is INCREASED in the muscle leading to muscle weakness and cramping after exercise.. even after you’re done exercising there’s no increase in blood lactate due to block
McArdle disease
Marfan syndrome:
1) what inheritance pattern
2) what things are affected?
3) what chromosome?
4) what does this code for?
1) Autosomal Dominant
2) FBN1 / FBN2 (less common)
3) 15Q21.1 / 5q23.31 (less common)
4) Fibrillin 1
What is incomplete penetrance?
What is variable expressivity? What’s the big example?
you have the mutation, but a normal phenotype
we can have the positive trait, but it’s expressed differently. –>
big example is neurofibromatosis type 1.. some have cafe-au-lait spots, skeletal deformities and or neurofibroma.
What is the inheritance of most classic Ehlers Danlos syndrome?
what’s the one exception? what is the defect in this case?
Autosomal Dominant
Kyphoscoliosis which is autosomal recessive. –> Lysyl hydroxylase
What is a prime example of anticipation?
what is anticipation again?
Huntington’s disease –> passed through the male. so we have an unstable spermatogenesis and adds increase in base pairs.
genetic disorder passed on to the next generation, the symptoms come at an even earlier case.. severity of symptoms is also increased too.
How do we know if a baby has CF at birth?
meconium ileus –> first bowel movement you have at birth.
when they have meconium ileus –> children with CF do not have that first bowel movement within the first few days of birth. so it’s DELAYED
when they do have it, it smells awful.
For glycogen storage diseases (glycogenesis), what is the general problem?
what’s the result?
deficiency of one of the enzymes involved in synthesis or sequential degradation of glycogen
storage of normal or abnormal forms of glycogen, PREDOMINANTLY in the liver or muscle.
Hepatic forms
Explain aortic dissection
1) what is it simply?
2) what is it physically separating?
3) what can it “occlude”?
4) what is the name of the space it creates?
the actual layers of the aorta separate
you have tears through the lining of the endothelium and the blood separates the endothelium from the adventitia from the outer layers of the aorta and dissect that lining away from the rest of the aorta
so as the blood separates it, it occludes the arteries going to the intercostals, or occlude the main trunks to the UE and the brain, or it can occlude off the kidneys if it goes lower.
“false lumen”
Fragile X:
1) what’s unique regarding this that doesn’t associate with other diseases?
2) what happens if they transmit to a female, what’s the problem with this?
3) what makes affected females different in this disease vs others?
4) what big process is happening with fragile X?
there are normal Carrier males! –> 20% of males are known to carry fragile X mutation and are COMPLETELY NORMAL –> they only transfer it to their phenotypically normal daughters to affected GRANDCHILDREN.
the female has a high probability of DRAMATIC amplification of CGG repeats that occur during OOGENESIS but not spermatogenesis
most it’s a small chance to be affected, but this is 30-50% chance.
Anticipation –> gets worse with each successive generation FROM THE FEMALE
What are examples of alterations in structure, function, or quantity of non-enzyme proteins?
2 clinical stuff
what overarching structural proteins do we see affected?
Sickle Cell disease –> defect in structure of global molecule
Thalassemias –> globin again
Collagen disorders, spectrin problems, dystrophin,
Ring Chromosome? How is it going to be denoted?
Inversion? what are the two types?
there’s a break that occurs at both ends of the chromosome with the fusion of the damaged ends
“r(chromosome” –> 46,XY,r(14)
you get two breaks within a single chromosome and it just flips
if inversion of one arm –> paracentric, if breaks are on opposite sides of the centromere –> pericentric
What are the three trisomies to know?
Trisomy 21 = Down Syndrome
Trisomy 18 = edwards
Trisomy 13 = Patau syndrome
Marfan syndrome
1) what do people with this issue present with vascularly?
2) which one is the cause of death
1) mitral valve prolapse
2) dilation of the ascending aorta
3) AORTIC DISSECTION
aortic dissection!!!
What happens if babies have CF?
they have failure to thrive (protein-calorie malnutrition) because of the pancreatic problems and bowel issues.
mendelian disorders… what are examples of problems because we have a decreased amount of end product?
what about something where you have an accumulation of an intermediate product?
1) albinism –> we don’t have tyrosinase so we have lower melanin (end product).
2) Lesch-Nyhan –> increased intermediated product and their breakdown is what leads to toxicity.
What are two examples of defects in receptors and transport systems? what are two examples and what happens in each?
Familial Hypercholesterolemia –> lower synthesis or lower function of LDL receptor –> leads to defective transport of LDL into cells –> increased cholesterol synthesis because of this –> atherosclerosis
Cystic fibrosis –> chloride ion transport in exocrine sweat glands, sweat ducts, lungs defective and pancreas defective
What are the 3 types of Gaucher Disease?
Type 1: what is it? how common is it? what group has it? is it fatal?
Type 2: what is it? what hallmarks? what group has it? is it fatal?
Type 3: what is it? what do they have? when does it present?
what’s the worst, what’s the best?
Type 1: CHRONIC –> 90% of the cases. NO CNS involvement. European Jew. slight decrease in life span
Type 2: ACUTE NEURONOPATHIC –> infantile cerebral pattern –> hepatosplenomegaly and EARLY death. NOT JEWISH
Type 3: intermediate. systemic involvement mostly, but some CNS involvement. presents in adolescence or early childhood.
1 = best 2 = worst
When does cystic fibrosis present?
is it treatable?
what race does it affect? what is it considered in this frame?
what genetics?
before birth to early childhood or even in adolescence
pretty much lethal
Caucasian population –> most common lethal genetic disease involving caucasian populations.
autosomal recessive
We have an autosomal dominant disorder that has killed someone within a few years of life, what was the cause?
who gave it to them?
since the disease had a low reproductive fitness, it would have had to come from a new mutation
new mutations occur in germ cells of relatively OLDER fathers.
When to suspect a genetic syndrome.. what’s the mnemonic?
VACTERL (Vater)
Vertebral Anal anomalies Cardiac Trachea-Esophageal fistula Renal anomalies Limb anomalies
Someone with super thin skin and bruising comes in to give birth.
upon giving birth, they end up dying due to a uterine rupture.
what is your diagnosis?
what is the gene defect in this case?
what is the inheritance?
Vascular EDS
COL3A1
autosomal dominant
What’s to know about mitochondrial inheritance?
what effect happens because of the mitochondrial inheritance
all the children from the female are going to be + because that’s where the mitochondria comes from.. it does NOT come from the male. –> affected males do not pass on their mitochondria, so a positive male and nothing else afterwords.
threshold effect –> need a minimum # of mtDNA present in a cell or tissue before oxidative dysfunction gives rise to the disease
X-linked disorders:
1) what is the inheritance, where is it located?
2) What’s going to happen if a man has it?
3) what about a mother that’s the carrier?
1) almost all are recessive
2) all of his daughters will be carriers.. but his sons won’t have it (duh, x linked)…
3) if the mother is heterozygote, the son WILL be affected if it gets the X, the daughters will be carriers.
What do you see on the physical eyeball of people with familial hypercholesterolemia?
what about this same problem in old people?
there’s a little arc of white –> this is “arcus Cornelius” –> it’s a deposit of this material in the cornea.
arcus senilis –> a circular ring around the iris of the xanthoma stuff
Tay Sachs:
1) cytoplasmic inclusions stain positive for what?
2) What do we see on an H and E of a neuron?
3) what do we see on EM? ***
the fat stains Oil Red O and Sudan Black B
a large lipid vacuole filling up the space of the neuron
whorled lysosomes –> look like onions
What’s mostly happening in lysosomal storage disease?
what two things are happening during this?
they’re missing the catabolism of the substrate because of the missing enzyme
so you have an accumulation of stuff that isn’t digested in the lysosome –> PRIMARY ACCUMULATION, so the lysosomes are super large.
autophagy is interrupted as well in lysosomal storage diseases, so we also get a “SECONDARY ACCUMULATION” of the autophagic substrates
Someone comes in, super tall, long dangly fingers.. they describe a “tearing” feeling.
what happened?
will they survive? in what scenario?
aortic dissection in marfans
usually toast
however if it ruptures back into the lumen, blood will come back in and go back to normal processes
Turner syndrome:
1) what is the typical genotype?
2) what are the 3 types of karyotypic abnormalities?
3) what is the key feature to Turner syndrome? what happens because of this?
4) as someone with this grows older, what happens to #3?
45X or 45Xo
complete or partial monosomy of X chromosome. –> it’s gotta be a female
- 57% missing entire X, so 45X
- partial monosomy of X
- mosaic types
Cystic hygroma!!! –> infant with edema –> swelling of the nape of the neck due to LYMPH STASIS, can’t drain it!
the swelling subsides but the skin stays put, so you have bilateral neck webbing
Say we have a mendelian disorder, we know that it leads to an abnormal product or decreased normal product.. what increases?
what’s an example of this? what’s the problem?
accumulation of the substrate (or precursor)
Galactosemia –> galactose 1 phosphate uridyltransferase deficiency leads to tons of galactose.
What are the two most common Mucopolysaccharidoses?
1) which one HAS corneal clouding? when does it present? what is the first sign of presentation? is it fatal?
2) which one does not have corneal clouding? What inheritance? is it fatal?
mnemonic?
Hurler (MPS I-H) –> corneal clouding.. Normal at birth, hepatosplenomegaly by 6-24 months, dead at 6-10 years old
Hunter –> no corneal clouding, X linked, Milder clinical course
Hunter needs to see so no corneal clouding, and the bow and arrow cross making an “X” for x-linked
What is the incidence of heterozygote Familial Hypercholesterolemia?
what do you see on these people?
because of the hypercholesterolemia, what do you see? what does this give you a risk of?
1 in 500 –> they have 2-3 fold increase in cholesterol
Tendinous xanthoma (lipid deposits, so you’ll see yellowish stuff
premature atherosclerosis
increased risk of MI
Difference between von gierke and drug primaquine?
von Gierke is G6Phosphatase
Primiquine is G6PD
a 19 year old man comes in complaining of not having a child and thinks it’s him. on further inspection, he complains that he has been having some epigastric pain, a chronic cough with sputum, and fatty stools. He complains somewhat of respiratory problems but he says it hasn’t bothered him before.
what can explain his problem?
Cystic Fibrosis
male urogenital abnormalities resulting in obstructive azoospermia (no vas deferens)
Klinefelter syndrome:
1) what are they at an increased risk for? (4 things)
hints: 50% of people with these have one, and they are 20x higher risk for something.
what don’t they have that would be characteristic of someone without Klinefelter?
Type 2 DM / metabolic syndrome***
Mitral Valve Prolapse
Osteoporosis (because of hormone issues, so fracturing is easy)
20x risk of breast cancer
no beard, no deep voice, no male pubic hair
What are the differences between niemann-pick disease, type a, b, and C?
1) Start with C. where’s the defect at? what do they present with?
2) Type B, what is to know about this?
3) Type A, what’s to know about this?
4) which is the best prognosis? worst prognosis?
Type C –> most common. defect in NPC1.. which usually transports free cholesterol from lysosomes to cytoplasm but can’t do that
–> get progressive neurological damage, ataxia, stuff like that
Type B –> NO CNS involvement; they reach adulthood.
Type A –> SEVERE infantile form. extensive neuro involvement. it has a COMPLETE lack of sphingomyelinase.. present by 6 months, dead before 3.
A is worst, B is best
Explain Point mutations:
1) what is it?
2) what are the three types?
3) what is the best example with regards to two of these types? explain why
a change in a single nucleotide base
can be silent –> single change but same amino acid
missense –> can be a little change in functionality “conservative”, or nonconservative where it changes the function.
nonsense –> changes to a stop codon
Sickle Cell –> B chain is changed from glutamate to valine –> gives rise to sickle cell anemia
B - thalassemia (severe form of anemia) glutamine in the B chain is changed to a stop codon.
