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FUN2: 11-12:00
Scribe: Ashley Holladay
Thursday, November 20, 2008
Proof: Teresa Kilborn
Dr. Faye- Patterson
Pathology
Page 1 of 4
Genetics, Metabolic Disease
Introduction- Don’t use stuff from her power point without her permission.
Why showing things to do with children?- Parents will bring their children to the doctor when they might not be as likely to
go to the doctor (dentist or optometrist) themselves. You may be more likely to see children with these disorders.
Parents will more than likely know that the children have these disorders, but you may be one of the first persons to see
these children (ophthalmic issues)- pressure on the back of the eyeball- different causes than an adult.
I. Osteogenesesis Imperfecta (OI) [S57]
a. Formation of imperfect bone- group of disorders of autosomal dominance.
b. Osteopenia- insufficient bone- X-rays are pale
c. Osteoporosis- tendency to fracture. Both of these things lead to skeletal deformity.
d. Autosomal dominant- 1 gene doesn’t work so you make half the amount of collagen that you need.
i. Collagen is connective tissue. Collagen Type I is used in bone formation- component of osteoid- what
osteocytes elaborate around. Then they ossify/ calcify.
ii. These people’s bone is not able to ossify/ calcify as well.
e. Other places where collagen is used.
f. This is a disease with 100% penetrance- meaning you can see it all of the time.
II. OI Type I- most common [S58,S59]
a. Excessive bone fragility with 90% penetrance ( 90% of the time fractures will be present)
b. Since collagen is also in connective tissue they may bruise easily, may be short in stature.
c. Kyphoscoliosis-bent twisted spine
d. Joint hypermobility because ligaments not formed appropriately
e. Deafness because inner ear bones not formed (ossicles)
f. Ocular features- sclera has collagen type I- if it is deficient you can’t make it and you can see the blue colored
choroid through the sclera- 100% penetrance
g. Subtypes of OI- D- subtype
i. Opalescent/ improperly formed dentin- teeth have opalescent/ translucent quality- they break more easily.
The teeth are a blue/ color. They may have short roots and be porous.
ii. [S69] Picture of blue sclera and OI
iii. Most of these are OI type I- tends to occur later in life. Children with OI Type I have increased fragility of
bone and one of the main causes of non-accidental trauma. Look for and exclude when looking at child
abuse. Multiple fractures of varying age. Bones don’t all break at the same time in the same way.
h. [S61] Lethal Type- makes no collagen- results in multiple fractures during movement during fetal life. They
have no bone in their skull. The brain is blottable- if you push on one side- you can feel the fluid on the other in
OI type 2 baby.
i. Their ribs break in utero, cannot expand chest and lungs cannot develop. Die because they don’t get
adequate lung growth to support them when they come out.
ii. Neumothorax- tried to ventilate baby against pressure and air trapped against lung and chest wall- dark
spot in chest x ray.
i. [S63] Cartilage makes scaffolding. At growing points in your bones, they all start from cartilage base. The
cartilage proliferates and the osteocytes populate the scaffolding and start elaborating osteoid to calcify. The
cartilage cell cannot live if the environment is calcified. Osteoblasts have developed a way to live by stringing
along like a “daisy chain” that they can pass nutrients down and live in a calcified environment. If you don’t
make the bony trabecullae like you are supposed to- you cannot support yourself- and you get fracturespatients with OI type I. ( happens in any tissue that tries to form bone)
i. Skull direct transition from fibroblasts to osteoblasts (there is not a cartilage interface)- no skull in type 2.
III. [S64] Ehlers-Danlose Syndrome- multiple type of inheritance pattern- most autosomal dominant (couple recessive)defects of collagen- all share extreme joint hypermobility and extreme joint dystensibility- stretchibility.
a. Hyperflexible
b. Bow-legged- pressure on legs would make the bones bow out because of the flexibility of the knee joints
IV. Marfan Syndrome [S65, S66, S67,S68]- connective tissue disorder
a. Probably is underestimated – like TCS underdiagnosed
b. There is a defect in the formation of fibrilin- precursor molecule scaffolding for the formation of elastin fibers.
They are basically missing elastic fibers.
i. Few key things in the body that have elastic- Aorta- big arteries and vessels- large amount of elastic
tissues. Elasticity allows you to put force on something and not have it stretch out completely and be able
to come back.
ii. Elastic is what holds your lenses in your eyeballs- zonulas.- how your lens changes shape.
1. Patients with Marfans syndrome have ectopic lenses- lose the position of their lenses.
FUN2: 11-12:00
Scribe: Ashley Holladay
Thursday, November 20, 2008
Proof: Teresa Kilborn
Dr. Faye- Patterson
Pathology
Page 2 of 4
iii. They are tall, dolicocephaly (head looks like it has been in a shoe box, prominent eyebrows), Connective
tissue around the brain the spinal cord also does not have elastic- dural ectasia- puts pressure on your
nerves.
iv. Bladder incontinence, ADD, long lower body segments, long fingers, flexible
v. Extra long arms, arachnodactyly- spider jointed, pectus excavatum- sternum goes in, disproportional length
of legs and arms in comparison to rest of body, tooth crowding is a problem
vi. [S69] OCULAR-Ectopia lenses- usually bilateral- dislocated lentis- usually supertemperal
1. Detatched retina because globe not formed correctly
vii. If you are deficient in this elastic fiber- aortic root as it comes out of your heart doesn’t have any other
support. Patients with Marfan’s have aortic valve incompentence and are at risk for aortic valve rupturebig cause of death.
1. [S70] Aneurysm in the arorta of a Marfan patient
viii. [S71] Nearsightednesses also a problem
V. Autosomal Recessive [S73, S74]
a. Everything that was true for autosomal dominant will now not be true for autosomal recessive (in a sense).
b. In dominant- need one copy of gene, in recessive- need two copies
c. Because it is so bad there is little variance from one person to another.
d. It is almost completely penetrant.
e. If there are 2 bad copies- chances are, there are going to be problems and you are going to be able to tell it.
f. It doesn’t matter if you are male or female.
g. The parents are usually carriers and are not affected. Every time the genes the genes get together there is a
1:4 chance that there will be a bad outcome.
h. These affect enzymes.
i. You will not see a lot of these. They tend to be lethal. They will occur primarily in children
i. There are a couple that will allow you to live- sickle cell anemia, Ehlers-Danlos
ii. One of the exceptions is Gaucher’s disease- 3 forms- not uniformly bad and lethal
VI. LSDs [S75,S76,S77]
a. Big group of autosomal recessive disorders (metabolic disorders) is lysosomal storage disorders.
i. Lysosomes are cell organelles responsible for recycling cell material. They are responsible for
metabolizing- taking a substrate and turning into product or breaking down a product that they no longer
need. (autophage- self digesting)
ii. If they have an enzyme problem in their ability to break down something- result in a pile up right before
where that enzyme deficiency is.
iii. Most of the LSDs are due to acid hydrolases- chops OH groups off in an acid environment.
1. Anything that has to make that enzyme could also be effected- may make an enzyme- but not very
efficient.
a. Something like Gaucher could have an enzyme deficiency but not be lethal because you are
still getting a little bit out of it.
2. It can affect any cell that has these lysosomes in them- a whole lot of cells. Depending on where the
deficiency is- groupings of disorders where the symptoms affect the nerves or macrophages or other
cells.
3. Lysosomes are in neurons (brain, peripheral nerves) and macrophages (spleen, liver, LN, bone
marrow)
4. If you don’t have hydrolase- get a pile up- like constipation- the lysosome is constipated. You cannot
make a functional enzyme. It can be a defect of any part of the production of the protein.
VII. LSDs affecting the CNS and macrophages- Tay Sachs, Niemann- Pick, Gaucher [S78]
a. Purple- neuronal
b. Blue- marcrophage
c. Tay Sachs- almost entirely neuronal
d. Niemann-Pick- neuronal and macrophages involved
e. Gauchers- mostly macrophages
f. All of them are referred to as LSDs
g. Inability to break things down in neuron- swell up- not functional
h. Macrophage- living in liver, spleen, BM. Get a lot of macrophages not able to process material. Keep
proliferating macrophages and they are becoming distended. Bone marrow is becoming replaced with these
stuffed cells and you don’t have room to make other cell lines that you need to be making.
i. There is a high carrier rate for Tay Sachs and Neimann-Pick and one form of Gaucher in Eastern European
Jews. Most of these defects are screened for in these effected nationalities.
j. It depends on where you practice and what your population base is.
FUN2: 11-12:00
Scribe: Ashley Holladay
Thursday, November 20, 2008
Proof: Teresa Kilborn
Dr. Faye- Patterson
Pathology
Page 3 of 4
k. The majority of Gaucher is not found in Eastern European Jews- it is a widespread ezymopathy.
l. Don’t need to know metabolites- just understand why they have these problems. [S79]
m. [S81,S82] Onset for Tay Sachs- 3-6 months
i. Enzyme problem almost always effect neurons
ii. As infant large turnover of brain cells
iii. Cellular components have to be metabolized
iv. If you have an enzyme deficiency- neuronal problems
v. There is an enzyme with an alpha and a beta subunit and an activator. A deficiency in any of these will
cause a problem. In Tay Sachs the deficiency is in the alpha subunit.
vi. [S83] Diagnosed- get neurons from biopsy of the GI tract
1. The neurons are swollen with the piled up material
n. [S84] Cherry red spots- seen in Tay Sachs and Neimann-Pick
i. Neurons swell
ii. Retina full of neuronal cell. When the neurons are swollen do not transmit light appropriately and the red
reflex from the choroid behind it is not coming through- so you have a blanching of your retina. The red is
from the ophthalmic artery haloed by all of these stuffed neurons.
o. [S85,S86,S87,S88] Neimann-Pick is also a neuro-degenerative disorder. There are some in peripheral blood
(affects monocytes and macrophages)- can make diagnosis of how cells look in the peripheral blood.
VIII. Other LSD- glycogen breakdown [S89,S90]
a. Glycogen is the animal starch. It is the sugar that goes to the liver and turned into glycogen
b. 3 sites where glycogen important: liver, skeletal muscle, heart.
c. All of these muscles depend on the breakdown of glycogen. There are defects that affect the breakdown of
glycogen that should release glucose and sugar for you.
d. Defect at the first bread point- completely hypoglycemic once you are born.
i. In utero, mother’s blood sugar keeps you sustained.
ii. Once born, seizures, lethal- Type 1
e. Type 5- muscles cannot metabolize glycogen- cramps when exercising but not increase in lactate.
f. Mucopolysaccharides- connective tissue molecule (not collagen, not structural)- goop around structural. You
need it to hold the collagen and the fibroblast together. If you have an inability to metabolize this- coarse facies.
g. Metabolism has to take place in the macrophages in the connective tissues.
h. Face gets really big.
i. This metabolite is prevalent in your cornea- corneal crowding- mucopolysaccharidoses type 1.
j. [S91,S92,S93,S94,S95,S96] 2 types of mucopolysaccharidosesi. Type 1- Autosomal Recessive- Hurler’s
ii. Type 2- X-linked Recessive- women pass it to their sons (Recessive disorder on the X chromosome. If you
are a female- you have another chromosome to take care of things. If you are a male- it is the only one
you have. Those patients don’t have corneal clouding. Hunter’s Syndrome
iii. Way to remember- men are hunters- need to be able to see to hunt- don’t have corneal clouding.
k. [S93,S94]Connective tissue disorder- malformed head, don’t grow well, limb contracture
i. Just because some people might exhibit some of these characteristics doesn’t necessarily mean that they
have the disease.- just something that points to it and something to look for.
IX. [S102] Even though a person can have a normal number of chromosomes and no defects in their chromosomes, the
chromosomes you get from your mother are different from those you get from your father. They will look the same
with Giemsa banding, but they do not function the same.
a. As an embryo
i. Make sure you have red cells to keep you going.
ii. Make sure you have germ cells- make sure there is going to be a next generation. Something you do very
early.
iii. Imprinted material from both parents. Everything else with exception of future ova or sperm are functionally
dependent on appearance. But the germ cells that are made as an embryo. Each person erases the
imprinting from their parents and imprints their own germ cells- make their own unique stamp. Each
parents imprinted to make embryo, embryo inherits those unique genes and makes own imprint.
iv. Imprinting is something that we do to our genetic material that we tend to pass own.
v. [S103] Females imprint areas differently than males. Embryo’s sex determines this.
vi. Imprinting results in a shutting off of whatever that information was going to be- make it inactive.
vii. [S104] For normal function- if the father’s information has not been imprinted, it is what is being used, what
is functional. This is balanced and turned on from the mother.
viii. Abnormalities/ imbalance in imprinting- responsible for a lot of tumors.
b. Don’t need to understand details- need to understand that it occurs
FUN2: 11-12:00
Scribe: Ashley Holladay
Thursday, November 20, 2008
Proof: Teresa Kilborn
Dr. Faye- Patterson
Pathology
Page 4 of 4
c. [S105] Once you imprint the material, it stays there. All of the offspring, will have this material. Happens at the
very beginning of development.
d. [S107] This process of imprinting became known because there were 2 types of mental deficiency patients that
had chromosomal analysis that showed they were missing a small piece of chromosome 15. It looked like the
same area on the long arm of chromosome 15 ( a small deletion)
e. They discovered that when that portion of material was missing from the father’s chromosome, it was one
disease, but if it was missing from the mother’s chromosome, it was a different disease.
f. [S109 S110] If lost the dad’s- Prader- Willi Syndrome
i. Kid won’t stop eating, obese, retarded, hypogonadism, fair skinned
ii. Can affect males or females
iii. Due to loss of the paternal gene (the active one). The mom’s is shut off. So the kid keeps eating. That is
the phenotype.
g. [S111,S112,S113,S114] Angelman’s syndrome- thin, growth deficient, absence of speech, jerky movements
i. Happy Puppet syndrome
ii. These patients were missing the mother’s chromosome 15 segment (the active one). The father’s is shut
off.
h. Imprinting shuts things off. You need a balance from mom and dad to be fully functional.
X. [S115-S119] Fragile X syndrome- second most common cause of mental retardation in males.
a. Fragile X defined by culturing cells and putting in folate deficient material and the end of the chromosome fell
off- it is in a place that is prone to breaking.
b. If a mother is not affected but passes the gene to the next generation, every time the gene goes through a
female, a portion of the gene is amplified. There is a maximum copy of the trinucleotide that can line up. A
female can amplify the gene. A female has a son who has a female who will also be a transmitter if not affected
and retarded.
XI. Huntingdon’s disease- Neurodegenerative disease
a. Gets amplified when it passes through males
b. Father might not be affected but amplifies the gene as it passes it through his germ line.
c. The more copies there are, the more likely you are to have it.
d. It is a copy number problem.
e. There is a maximum number of copies that can be tolerated before breakage so how does this even continue?breaks off and the whole cycle starts again.
[End 52:18]