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.
Digeorge syndrome:
1) what’s causing it?
2) what are the 2 main problem?
3) what does this result in? (2 things)
4) what is the mnemonic?
Chromosome 22q11.2 deletion
2) thymic hypoplasia and parathyroid hypoplasia
3) T-cell immunodeficiency and hypocalcemia
Catch 22 –> Cardiac abnormality, Abnormal faces, Thymic aplasia, cleft palate, hypocalcemia/hypoparathyroidism
Ehlers Danlos Syndrome:
1) what’s the problem?
2) what about range of motion?
3) what about their skin in general. why is this a problem?
defect in the structure fibrillar collagen for connective tissue
hyperextensible skin, joints are hypermobile
skin is EXTRAORDINARY stretchable. –> they are super vulnerable to trauma.. so when we get minor injuries they produce GAPING defects and surgical repair is extremely DIFFICULT because it doesn’t have the normal tensile strength
Robertsonian Translocation? what do we see?
what is the rate of robertsonian translocations?
what is the most classic robertonian translocation and how does it work?
2 acrocentric chromosomes translocate, typically breaks appear closer to the centromeres of each chromosome.
we see 1 very large chromosome and 1 extremely small one.
1/1000 people –> even though its pretty normal
Trisomy 21, q arm of chromosome 21 is translocated onto another chromosome.. so the fetus has 46 chromosomes but 3 copies of the long arm of chromosome 21.
Von Gierke Disease:
1) what’s the deficiency and where is it typically seen
2) what’s the type of disease?
3) what do patients present with?
1) G6Phosphatase –> in the liver
2) Hepatic glycogenoses
3) hepatomegaly (more but I don’t know if it will be tested)
What are the two main patterns of disease with autosomal dominant? examples of each?
what is the age of onset usually? why?
1) regulation of complex metabolic pathways –>
LDL receptor in familial hypercholesterolemia… we have 50% less receptors, which means increased cholesterol which leads to early atherosclerosis
2) key structural proteins are screwed up –> collagen and cytoskeletal elements of the RBC membrane –>
Osteogenesis imperfecta –> people have fractures in utero.. they break their bones super easily. it’s a lack of collagen!
delayed onset –> we need it to remain silent for it to be passed on.
Euploid?
Aneuploid? What 2 things can create this?
Mosaicism? where is it common most in?
any exact multiple of haploid number (23)
NOT an exact multiple of 23
1) nondisjunction (+/- 1 chromosome)
2) anaphase lag –> during meiosis or mitosis one chromatid lags behind and is left out of the nucleus.. so one normal, one monosomy cell
–> mitotic errors in early development give rise to two or more populations of cells with different chromosomal complement in the same individual –> sex chromosomes
what are the four mutation types that can give inherited disease?
point mutations in coding sequences
mutations in noncoding sequences
deletions and insertions
trinucleotide repeat mutations
What does it mean for complex multigenic disorders to be multifactorial?
what are the common malformations of these disorders?
is it always going to be super severe?
they’re going to have two or more genes and environmental influences.
clef lip, cleft palate, neural tube defects
no. there’s a range of severity.
Say we have anaphase lag, what would most certainly result in death?
if you have a monosomy of an autosome. we need autosomes to survive.
Isochomosome? what can you only get then?
Translocation?
One arm of the chromosome is lost, remaining arm is duplicated..
you can have a chromosome with 2 short arms ONLY or 2 long arms ONLY
segment of one chromosome is transferred to another one.
Trisomy 21:
1) what is the strongest influence on incidence of trisomy 21?
2) 4% of the cases have what cause for Down syndrome?
3) what do the final 1% have? what’s to note about this version?
maternal age
robertsonian translocation of the q arm of 21 to another acrocentric chromosome (22 or 14)
mosaics! mixture of cells with either 46 or 47 chromosomes –> symptoms are variable and generally milder
Genomic Imprinting is what?
what are the two characteristic syndromes to know for this?
we get selective inactivation of maternal or paternal genes
it’s deletions of the SAME gene, it’s just how the imprinting goes that changes things up
Prader Willi and Angelman
Prader-Willi syndrome:
1) what’s happening?
2) what is it characterized with?
Paternal deletion of chromosome 15
Obesity, mental retardation, short stature, hypotonia (lack of tension in extremities), small hands and feet
Marfan Syndrome
1) what physical characteristics do they have? (4)
2) what about flexibility?
3) what about their eyes***
Extremely long arms compared to their legs.. so very disproportionate
unusually tall
long fingers and toes
pectus excavatum
Hyperflexibility (double jointed)
Ectopia lentis –> dislocation of the lens!!!
What are the three broad categories of human genetic disorders?
what penetrance does each have?
which is the most common?
what is the classic for each (if applicable)
Disorders related to mutations in a single gene with large effects –> highly penetrant –> sickle cell
Chromosomal disorders –> highly penetrant but uncommon
Complex multigenic disorders –> low penetrance
complex multigenic is most common –> atherosclerosis, diabetes, autoimmune, height and weight
Fragile X:
1) what is the gene affected? what is the sequence that is being repeated and how many repeats can be seen?
2) what’s the rate in males and females? who’s more affected?
3) what if males are affected
4) phenotypic features?
5) hallmark?
FMR1, CGG repeats, up to 4000 repeats
1 in 1550 for males, in females its 1 in 8000
males are mentally retarded (super small IQ)
long face, large mandible, LARGE everted ears, LARGE TESTICLES, hyper extensible problems.. mitral valve prolapse
hallmark is macro-orchidism (extremely large testicles)
Marfan Syndrome
1) how many people get this? what about familial wise?
2) what are the mechanisms by which this issue leads to clinical manifestations
1) 1 in 5000, 70-85% familial
2)
- loss of fibrillin means loss of structural support in the microfibril rich connective tissue
- excessive activation of TGF-B signaling
Leber hereditary Optic Neuropathy
1) what kind of disease is it
2) what’s happening?
3) when does it present?
4) what does it lead to?
mitochondrial disease
progressive bilateral loss of central vision –> so people will be doing their head around trying to see what’s going on. ONLY THE CENTER IS OUT
15-35 years old
complete blindness
why do clinicians say “kiss your baby” with regards to CF?
what test do we do? how does it work?
the baby will taste salty because of the increased ion transport
sweat chloride test –> put a chemical on them and an electrical current, collect the sweat and see how much chloride they have.. obviously if it’s higher than normal it’s an indication
Explain why one sickle cell anemia patient can have full blown sickle cell and another can only exhibit symptoms in lowered oxygen environments like on a mountain?
If you’re heterozygous for sickle cell, only a portion of the cells is HbS, the rest being HbA, then you are only going to sickle under unusual circumstances like described
if you’re homozygous, all of the hemoglobin is abnormal, HbS type, and even with normal saturation of oxygen the disorder is FULLY expressed.
Explain Trinucleotide repeat mutations
what is in almost all sequences with these mutations?
what happens with these mutations across generations? what is this called?
what is considered it’s “distinguishing feature”?
what are two famous trinucleotide repeat mutations to know?
amplification of a sequence of three nucleotides
almost all affected sequence share the nucleotides G and C!
usually when you get these you have an earlier age when you have an increase in number of nucleotides or repeats –> anticipation (appears at an earlier age with each generation)
they’re dynamic –> degree of amplification increases during gametogenesis
Fragile X syndrome + Huntingtons
What is the gene defect in classic EDS?
COL5A1, COL5A2
Explain what’s happening in CF?
1) what is causing this?
2) what are the two major processes do we see in the lungs? –> what cell type is at a higher presence?
3) what happens in the pancreas? be specific
4) what about the small intestines?
5) what about genitals?
this is due to a chloride ion channel transport issue –> VISCOUS SECRETIONS–> plugs everything up in the body…. called “insipated”
these blockages are called Bronchiectasis, where instead of wedging like there would be in infarction, it’s instead staying large the whole way.
emphysema ends up with one big round wall, we lose a bunch fo surface area so decreased oxygenation
increased goblet cell development –> more mucus, even worse breathing.
PANCREATIC INSUFFICIENCY –> cystic dilations of those ducts because the mucus is too thick. enzymes aren’t going to come out, it leads to fibrosis, chronic pancreatitis, a lot of pain. TONS OF problems
distended small intestines because of the mucus –> STEATORRHEA (smelly), INTESTINAL OBSTRUCTION
male infertility
Phenylketonuria
1) what is tyrosine a precursor of? so people with PKU present with what?
2) when do you see symptoms? why at this point?
3) what’s the main characteristic of this besides the above?
4) what’s the therapy?
1) melanin, so no melanin, they are super pale –> albinism
2) normal at birth, but severe mental retardation, hypopigmentation and severe eczema at 6 month.. it takes that long for toxic products to start building.
3) diaper smells like a “mouse” or “musty”
4) dietary restrictions (no Diet Coke) to keep them from progressing!
Neural tube defects are reduced by intake of what in the diet?
Folic Acid
Klinefelter syndrome:
1) what’s the genotype
2) what do you see?
3) what’s the rate? when does it present
4) clinical stuff
47,XXY (90%)
Male Hypogonadism
1/660 live male births, but usually not diagnosed until puberty
abnormally long legs, atrophic testes and small penis, enlargement of breast tissue In males
in autosomal dominant disorder, what state is usually manifested? how many genes? so how many parents are affected?
heterozygous, one gene affected, so one parent is usually affected
Huntington Disease:
1) what is the inheritance of Huntington’s? what is degenerating?
2) what do you get eventually?
3) what do they present with?
4) what’s the lifespan of the disease? when are you diagnosed?
5) anticipation in this case is through the male or female?
1) autosomal dominant, head of the caudate nucleus –> eventually to the globus palladus
eventually we get brain atrophy
dance like movements (chorea), and they have 3x more calorie intake because they’re constantly moving.
later in life, but 15 years
male
Trisomy 21:
1) what do you see on fish?
2) what are the gross morphologic features we see?
3) what is to note about Down syndrome? what is it the major cause of?
4) what is the incidence? how many cases have this trisomy?
3 red signals
flat facial features, epicanthal folds, single palmar crease, wide gap between toes, fissured tongue
most common chromosomal disorder + major cause of mental retardation
1/700, 95%
What mutations can we see with regards to adverse reactions to drugs?
1) what deficiency?
2) what drug was used?
3) what people were affected?
4) what did they end up getting because they took this drug?
G6PD –> Antimalarial drug called primaquine.. came out in Korean War to prevent malaria..
people of mediterranean and middle eastern descent had this deficiency and didn’t know it. as they took this drug they got SEVERE hemolytic anemia
What is the problem with being homozygotic for familial hypercholesterolemia?
what do you see on these people?
what’s super significant to know?
you have a 5-6x higher increase in cholesterol than normal
instead of tendinous xanthomas, you see skin xanthomas.. deposits often on the eyelids.
you also have cerebral, peripheral and vascular atherosclerosis at early age –> MI before 20 y/o
Angelman Syndrome:
1) what’s happening
2) what are the hallmarks of this?
3) what are people with this called?
maternal deletion of chromosome 15
mentally retarded, but present with ataxic gait, siezures, and INNAPROPRIATE LAUGHTER
happy puppets
Chromosome 22q11.2 deletion syndrome
1) where’s the deletion?
2) what is kind of the hallmark that discerns this from others?
3) what’s the incidence?
4) what are the two pathologies associated with it?
small deletion of band q11.2 on the long arm of Chr 22
T cell immunodeficiency and hypocalcemia
1/4000
DiGeorge syndrome, Velocardiofacial syndrome
2 basic approaches to treatments of lysosomal storage diseases?
enzyme replacement therapy
substrate reduction therapy (don’t eat the stuff that we can’t eat, then the reduced enzyme activity will be enough to work on its own)
Mendelian Disorders encompass what?
what does it result in? 2 things
what are the 4 main categories?
alterations in a single gene –> leads to an abnormal product or decreased normal product
enzyme defects
defects in membrane receptors/transport systems
alterations in structure, function, or quantity of non-enzyme proteins
mutations resulting from reactions to drugs
Say you’re a carrier for cystic fibrosis but you don’t have cystic fibrosis because of its inheritance pattern. are you going to have any issues/
higher incidence of respiratory and pancreatic diseases than a normal individual
What are the two glycogen storage diseases that don’t necessarily correlate with the liver or skeletal muscle?
why don’t these correlate?
Acid maltase deficiency (Pompe disease)
problems with lack of branching enzyme
overlapping symptoms –> they often associate with glycogen storage in MANY organs and death in early life.
what’s the difference between mendelian problems and sex chromosome problems
What is one major process that is happening with Sex chromosome disorders? how does it work?
How can we see this inactivated X stain wise?
sex chromosome problems are much better tolerated than autosomal problems. –> not necessarily lethal.
1) lyonization (inactivation) of all but one X chromosome –> we end up with mosaics with two populations of cells going on. (can be maternal or paternal origin that gets inactivated) –> activated early in life.
the inactivated x is turned into a Barr body
Barr body –> inactive X is going to be a mass connected to nuclear membrane in interphase
Tay Sachs Disease:
1) when does it present?
2) is it lethal?
3) what hallmark do we see?
4) what accumulates and where does it accumulate?
1) Normal at birth, at 6 month you have motor and metal deterioration. blindness
1-2 year old vegetative state, death by 2-3 years
cherry-red spot in the macula
Gm2 gangliosides –> neurons, retina
Explain the cherry red spot
1) what disease process
2) why does it look the way it does?
all the ganglion cells around it are swollen and pale, but the macula stays red because no ganglion cells.
CF:
1) what’s the problem
2) what gene is the problem
3) what chromosome?
chloride channel
CFTR gene
7q31.2
In CF, what are the three major organisms that we see in this pathology?
two big organisms –> Staph aureus, and Pseudomonas aeruginosa, Haemophilus Influenzae
what are the 3 features of autosomal recessive disorders?
25%
1) trait is usually NOT affecting the parent
2) siblings have a 25% risk at birth
3) if mutation is low frequency in a population, it means that it’s part of consanguineous marriage (if it’s something super rare but all the sudden we see it.. look at family history)
Hermaphroditism and Pseudohermapthroditism?
true hermaphrodite –> presence of ovary and testicular tissue
pseudo –> disagreement between phenotypic and gonadal sex
female pseudo has ovaries, but male external
Male has testicular tissue, but female type genitalia
What do people with Mucopolysaccharidoses (MPS) usually have morphologically? what’s the exception with one of them?
Coarse facial features, joint stiffness, mental retardation, clouding of the cornea
hunter syndrome DOES NOT have clouding of the cornea
Pompe Disease:
1) what is the deficiency?
2) what is the KEY characteristic in this pathology? how do you see this on a slide?
3) how do they die?
acid maltase deficiency
cardiomegaly (die at early age). –> you’ll see normal myocardium but in Pompe it’s glycogen filled myocardial cells
3) cardiorespiratory failure within 2 years of onset.
Mutations with noncoding sequences are found where usually? what happens because of this?
what are three transcription factors associated with these mutations?
promotor or enhancer sequences (part of the intron)
failure to form mRNA (so no translation)
MYC, JUN, p53
What is usually the Cause of Death for those with MPS?
what is the cell to know? what is this similar to?
what do we have on EM?
myocardial infarction and cardiac decomposition.
Balloon cells –> clear cytoplasm with multiple vacuoles.. similar to niemann pick
lamellate zebra bodies, similar to NP
What is the usual pathogenicity resulting of an autosomal dominant disorders?
What are the two possible mutations seen in autosomal dominant diseases?
examples of each?
lower product, dysfunctional or inactive protein produced
loss of function –> familial hypercholesterolemia
Gain of function –> Huntington
Gaucher Disease:
1) what is the inheritance?
2) what’s the deficiency?
3) what results because of this deficiency?
4) because of this problem, what is released?
1) autosomal recessive
2) glucocerebrosidase
3) accumulation of glucocerebrosides in phagocytes primarily, but sometimes CNS too.
4) it activates the macrophages, which leads to IL1, IL6, and TNF
Why is sickle cell anemia still in the population? it’s kind of its key feature too
it strongly selects for people to not contract malaria (their blood type doesn’t allow them to contract malaria)
Niemann-Pick Disease, what are the cells going to look like? what is this sometimes called?
what are these also called if seen on an EM image?
anything to note about their organs? be specific this is important!!
what is similar with this and Tay Sachs that you’ll need to know how to distinguish?
what happens in the brain?
really enlarged because of the sphingomyelin and cholesterol accumulation –> foamy cytoplasm
“Zebra bodies” –> lysosomes with concentric lamellations
massive splenomegaly! 10x the normal weight of a spleen
1/3 to 1/2 of NPD have cherry red retinal spot
we have ballooning of neurons (like tay Sachs) but then brain atrophy
Gaucher Disease:
1) what is the distinct morphology seen on a slide?
2) what about organs? what about this vs niemann pick?
3) what happens if these cells are in the bone marrow? (2 things)
you see “Gaucher cells” which are distended phagocytic cells
the cytoplasm is elongated distended lysosomes and noted as “CRUMPLED TISSUE PAPER”
2) enlarged spleen, greater than 10kg.. not 10x greater, only above 10kg.
3) if it hits the bone marrow, it leads to bone erosion –> so we have pathological fractures because of weakening of the bones.
also because of bone marrow involvement we have pancytopenia and thrombocytopenia (low red and white blood cells, also platelets)
What is common between Edwards (trisomy 18) and Patau (trisomy 13) but NOT seen in trisomy 21?
What does Trisomy 13 (Patau syndrome) have that 18 and 21 don’t have?
What does Trisomy 18 (Edwards) have that 13 and 21 don’t have?
21 rather than 18 and 13?
rocker bottom feet
Cleft lip and palate, microphthalmia, microcephaly, POLYdactyly
short neck, OVERLAPPING fingers, micrognathia (small mouth)
gap between first and second toe, epicanthic folds, simian crease in hand. INESTINAL STENOSIS
Niemann-Pick disease, type A and B:
1) what’s the problem? (include the deficiency)
2) what inheritance? chromosome?
3) what population of people?
4) where is it expressed preferentially? why?
accumulation of sphingomyelin due to a deficiency of sphingomyelinase
Autosomal recessive, 11p15.4
Ashkenazi Jew
on the maternal chromosome due to epigenetic silencing of the paternal gene
Say we have a mutation that fails to inactivate a tissue-damaging substrate.. what is an example? what does it lead to?
A1-antitrypsin deficiency –> can’t inactivate neutrophil elastase in the lung (decreases surface area, decreases oxygenation)
this leads to EMPHYSEMA
Turner syndrome:
1) what is common among 25-50% of patients?
2) mortality comes from what? when does this happen?
3) what are the classic gross features they have?
4) What’s going on with sexual development?
5) why might 50% of people with Turner syndrome have more weight than a normal person?
Congenital heart disease (LEFT SIDED).. COARCTATION of the aorta
cardiovascular abnormalities in children with turner
short stature, nipples are farther apart than typical, shield shaped chest, WEBBING OF THE NECK, cubitus valgus
“menopause before menarche” –> they have streak ovaries (or fibrotic ovaries), and amenorrhea
50% of Turner syndrome have hypothyroidism
McArdle disease:
1) what is the deficiency
2) what kind of disease is it?
3) what is the patient presenting with?
4) when does it present? is it fatal?
Muscle Phosphorylase –> so presents in the muscle
Myopathic Glycogenoses
Painful cramps associated with strenuous exercise, along with failure to raise lactate levels.
in adulthood, no
Explain the deletions and insertions seen in gene mutations?
what are two famous deletions to know? what kind of deletion?
what’s a famous insertion to know? what kind of insertion?
if the number of base pairs involved is 3 or a multiple of it –> reading frame is intact and will only involve extra amino acids.
if not a multiple of 3 –> it’s a frameshift mutation.. not the same reading frame, you screw up the whole protein. usually results in a truncation because of a premature stop codon.
cystic fibrosis –> amino acid 508 (phenylalanine), it’s only 3 base pairs that are removed so it’s not a frameshift.
ABO O allele –> single base deletion at the ABO locus –> frameshift mutation)
Tay-Sachs –> 4 base pair insertion (so is a frameshift) in the hexosaminidase A gene.
What are Mucopolysaccharidoses (MPS)?
1) what are we deficient in?
2) where are these Mucopolysaccharides abundant in?
3) what are all of these inheritance patterns? any exceptions?
deficient enzymes degradign glycosaminoglycans
ground substance of connective tissue
all autosomal recessive except HUNTER which is X LINKED RECESSIVE
Trinucleotide repeat mutations typically cause what kind of disorder?
what are the 3 key mechanisms by which these repeats cause disease? examples of diseases pairing with each?
what’s the morphologic hallmark?
neurodegenerative
loss of function (repeats in non-coding) –> fragile X
toxic gain of function (repeats in coding) –> Huntington disease
toxic gain of function mediated by mRNA –> fragile x tremor-ataxia syndrome
all of these diseases accumulate aggregated mutant proteins (misfiled proteins) in large intranuclear inclusions
Mutation in germ cells gives rise to what?
what about in somatic cells?
inherited disease
cancer and some congenital malformations
In general, sex chromosome disorders cause what?
in general, the greater amount of X chromosomes, what happens?
say you have XXXXXY, what’s the gender?
subtle, chronic problems related to SEXUAL development and INFERTILITY
the more likelihood of mental retardation
male, doesn’t matter how many X’s there are.
How do you differentiate AR from AD? (there are 5 things)!
(All AR)
expression of the defect is more uniform in Autosomal Recessive –> everyone has a similar trait or phenotype pattern
complete penetrance common
EARLY onset!!
new mutations are RARELY detected –> usually takes several generations
many mutations involve ENZYMES (inborn errors of metabolism)
