Download Genetic Disorders

CLASS: 10-11
DATE: 11-11-10
PROFESSOR: Ona Faye-Peterson
I.
II.
III.
GENETIC DISEASES
Scribe: Christine Sirna
Proof: Allison O’Brien
Page 1 of 9
LSDs: Tay Sachs [S96]
a. We are going to discuss genetic disorders including going through the lab cases
i. With the labs she is not going to go over neurofibromatosis since we already did that and not go over
trisomy 21 because we did that. She is going to concentrate on some disorders that she thinks we will see
some patients having
ii. Particularly having ocular findings
iii. The teeth are not necessarily bad in every syndrome
b. Will the test material be limited to the lab material?
i. Lab stuff covers stuff from chapters that are further along in the book
ii. Some stuff is a genetic disorder but it’s not the only time we will hear about it
iii. What she covers has enough material for an exam
iv. She is not covering all the genetic disorders that are in the textbook that are more common
v. What can she teach us? She can’t teach us how to memorize stuff but she wants to teach us how to think
of these disorders
1. So not matter what comes up with new disease we will have the tools to go through this and
determine how do we approach patients with this, what is the basic pathology here and how might
that express itself. That is what she views as her role
vi. OUR TEST WILL ONLY COVER MATERIAL SHE DISCUSSED IN CLASS FROM THE LECTURE AND
LAB
c. So we talked about some lysosomal storage disorders and we covered that these are disorders where the
lysosome cannot break down the cellular component whether it be a membrane or some part of DNA or
something
i. Thought is that the lysosome are constipated or that they are lacking something that allows them to
transport whatever material they have in them into the cytoplasm and out into the circulation so that it can
be removed in the kidney or the urine or transported into bile so that it can be excreted out of the body
1. You want to get rid of things you don’t need
2. lysosomes recycle stuff and help eliminate things
d. Tay Sachs
i. Name of disorder and usually there is a hyphen in it because Tay was the person who described the
cheery red spot he found and Sachs was a physician at Mount Siani hospital in New York who discovered
there was a high incidence of this disorder in Eastern European Jewish people
ii. She had never seen this disorder until she went to New York to train where she trained at Mount Siani
iii. It has an interest to her because it is not a weird historic thing it depends on the population
iv. Tay Sachs does occur in other people who are not Jewish like in Quebec in Canada and Cajun population
in Louisiana
1. they are slightly different enzymopathy but it’s the same disease, same gene just a different part in
that gene
v. The fact that you might not see a Tay Sachs doesn’t mean you don’t need to know about it
vi. The other part is that the pathology particularly of the retinal cheery red spot is typical of storage disorders
but can be seen in things that aren’t storage disorders and if you have a retinal artery occlusion, that would
be the branch of the ophthalmic artery, if that becomes occluded the coroid will still supply the macula so
you will still have red whereas the rest of the retina will have no blood flow and will be pale
vii. Cherry red spot is a harvenger that something is wrong
e. Goes off on story about being the only pathologist
f. Hypotonia is a feature of storage disorders because if you got nerve damage, nerve lysosomes you can’t
transmit information and you can’t flex your rnuscles
GM2 Ganglioside accumulation… [S97]
a. This is a picture of a gastrointestinal tract
b. This is Aurbach’s plexus which is in the muscle externa on the GI tract
c. For those of you who are smart you may think to yourself why would you biopsy the outside of bowel because
that would put a hole in the kid. You would be right
i. When they do these diagnosis they go in through the mucosa through the luminal side and take off a
submucosa ganglia not the one on the outside of the muscle wall but we don’t have a picture of that but it’s
the same pathology
1. You have neurons that are filled with undigested glucose, GM2 gangliosides
GM2 accumulation in retinal ganglioncells [S98]
a. GM2 is a type of ganglioside
i. the two part comes from that fact that there are 2 scialic acid resides that is all it means.
CLASS: 10-11
Scribe: Christine Sirna
DATE: 11-11-10
Proof: Allison O’Brien
PROFESSOR: Ona Faye-Peterson
GENETIC DISEASES
Page 2 of 9
b. Is a component largely in neurons, it is a component of their membranes and because of the fact that babies
brains grow rapidly there is a high turnover of CNS tissue in growing fetuses
c. If you have Tay Sach’s you have presentation at birth because you have been trying to deal with this storage
issues all through your gestation
IV.
LSDs: Niemann Pick [S99]
a. Another LSD is niemann pick disease
b. This is one and we talked about neurons and macrophages having a deficiency in this enzyme
c. It doesn’t mean the deficiency of the enzyme is not in other cells, what is means is the effect is most
pronounced in neurons and to some extent in macrophages
i. Macrophages live as monocytes in bone marrow, live as Kupffer cells in the liver, they live as macrophages
in the spleen, they live as macrophages in the lymph nodes, and inthe gut associated lymphoid tissue like
Peyers patches and ileum
ii. you can imagine they would have this storage issue going on in all thesethings
iii. However, because they are in neurons more than the other cell types they have an exhibition of usually
severe psychomotor deterioration and retinal degeneration and a retinal cherry red spot
d. Foam cells are descended lysosomes that make the cytoplasm look foamy on microscopic examination
i. They are lysosomes that are filled up
ii. It is a deficiency of sphingomyleinase
V.
Niemann Pick Disease [S100]
a. Sphingomyelinase is a part of the cell membrane
b. It has an early onset. It is rare and you will not see it
c. Principle is something you should take away
i. The principle of little lipid vacuoles, lipid meaning sphingomyelin, are unmyelinated nerves, hence the
name sphingomyelin, and because it is unmyelinated. and because it is in ganglion cells you have these
clever little lysosomes and there is some configurations on electron microscopy that you will not be
required to know.
VI.
Niemann Pick Disease [S101]
a. Because it is in ganglion cells you have these clever little lysosomes and there is some configurations on
electron microscopy that you will not be required to know.
b. Just know that there is stuffed material in the lysosomes.
VII.
LSDs: affecting liver and/or muscle Glygenoses [S102]
a. There are LSD that also predominantly exhibit manifestations in liver and muscle
i. These are thing that help break down glycogen
b. Glycogen is animal starch
i. Our sugar storage is glycogen and from glycogen you either have to make it or break it down
c. In a deficiency of enzyme in any of these steps in this complex molecule will lead to a storage disorder
d. There are many kinds of glycogen storage diseases and the ones that are most dramatic are the two we are
going to talk about or the things you will see
VIII.
LSDs: affecting liver and/or muscle glygenoses [S103]
a. This is actually a defect of the degradation of glycogen and the first one is called called VonGierke type I
i. There are probably six or more that are known that are considered standard
ii. This first one is glucose 6 phosphatase deficiency
1. What that means is that the glycogen molecules, the very first thing you have to do is to cleave a
glucose and they can’t do that
b. While in utero, the mother supplies them all the sugar they need, but once they are born and they have to rely
on their own glycogen stores, suddenly they become severely hypoglycemic and start having seizures
because they can’t do it
c. What would they have in utero?
i. In utero they have large spleen, liver and kidney enlargement because it has to do with the fact that there is
a lot of proliferation and generation of new glomeruli going on in the kidneys and you need energy to do
that
d. Death in early infancy or in childhood depending on severity of deficiency. If it is completely gone you could
imagine that it would be a problem
i. Autosomal recessive disorder means you have two copies of bad gene so you make essentially none
ii. You might make a particularly semi functional form and you might just die later
e. That is VonGierke type I
f. McArdle is the one where you don’t have sufficient muscle phosphorylase
i. Phosphorylase allows glycogen to be broken down the skeletal muscle
CLASS: 10-11
Scribe: Christine Sirna
DATE: 11-11-10
Proof: Allison O’Brien
PROFESSOR: Ona Faye-Peterson
GENETIC DISEASES
Page 3 of 9
ii. You might become incredibly fatigued but instead of having lactate build up in bloodstream you are fatigued
without lactic acidosis
g. You have muscle cramps but don’t have high lactic acidemia or myoglobin, in other words you are not
breaking down your muslce
h. People who run marathons: If you have insufficient glycogen store the in the muscle, your muscles still
require energy to keep going and you start digesting protein and muscle that you have and that causes
myoglobinuria, you pee out myoglobin
i. You have fatigue and you have inability to sustain exercise but you do not manifest lactic acidosis
IX.
LSDs: affecting liver and/or muscle Glycogenoses [S104]
a. There is a third kind which is again a rare disorder except if it happens to you and there have been cases of
Pompe disease in Birmingham and Children’s hospital see babies with this disease
b. Pediatric cardiologists treat these children with enzyme replacement so some kids do grow up and get past
the infantile stage
i. This is an acid maltase deficiency
ii. Again the stored metabolite is glycogen but there is free glycogen in cytoplasm and also some membrane
bound
c. Is this important for us to know? NO. We will not be histopathologists
d. Just understand there is a type of disorder that affects with acid maltase and this is particularly damaging in
the heart
i. The heart is a kind of mixture between smooth and skeletal muscle and it needs energy to contract
ii. So if is has glycogen and it can’t break it down, then the heart muscle will attempt to use glycogen but it
can’t and so the heart will become enlarged
iii. It will look hypertrophied but actually the cells are swollen and it is not because they have additional actin
myosin filaments in them but because they have storage component
e. You end up with severe cadiomegaly (big hearts) maybe a little liver maybe some skeletal disorder but the
majority of their problem happens to be in the heart
f. Usually the heart functions well enough in the first couple months of life and then the children deteriorate
rapidly
X.
Normal Heart v. Pompe heart [S105]
a. What does this picture show? This is normal cardiac muscle on the left which has cardiac myocytes which is
important because if the heart is going to contract you want there to be a squeeze from the bottom up
approach so the heart muscle looks histologically different from skeletal and smooth
b. In this case (right) You see big blank spaces instead of nice red cytoplasm for actin and myosin.
c. Glycogen is a carbon based molecule so when we fix tissue to make slides we send it through a series of
graded alcohols to take the water out of the cell and replace it with ethanol and then replace that water with
wax so we can cut a section of it so that you have a slide to look at
d. Works fabulously except when you have a lipid soluble component
e. What happens? The lipid soluble thing that being the glycogen is gone so now there is just these big empty
spaces so now if we wanted to look at this particular pathology we would have to use a different fixation for it
XI.
LSDs: affecting connective tissue cells, Mucopolysaccharidoses and glycosoaminoglycans [S106]
a. Third set of disorders and these are autosomal recessive for the majority and they are
mucopolysaccharidoses
b. What are mucopolysaccharidoses?
i. Components of connective tissues, they are the ground substance of connective tissue
ii. There is heparin sulfate and some other sulfates and they keep us glued together
c. They are sugars attached to molecules of complex carbohydrates and they can’t be broken down in the
ground substance
d. So if you have a disorder that affects the sugars in the ground substance and you can’t break them down
what do you think would happen to your connective tissue?
i. Tissue you swell up all over
ii. In particular you would do it in joints, skin, maybe in the formation of you face because the face although
you have a lot of muscles unless you talk like I do you don’t have hypertrophy of your jaws.
e. What that means is that the soft tissues in the face are in relatively greater proportion than skeletal muscle in
your face
f. When you have disorders that have mucopolysaccharides what happens?
i. You get thickening of the face soft tissues. That is easiest to recognize. There is nothing pulling them back
g. You have it in your arms and legs but you don’t see it as much because there are other large muscles that
keep them at bay. You don’t have that in your face.
h. Consequently a feature of mucopolysaccharidoses are course faces that means big chunky kid faces
CLASS: 10-11
Scribe: Christine Sirna
DATE: 11-11-10
Proof: Allison O’Brien
PROFESSOR: Ona Faye-Peterson
GENETIC DISEASES
Page 4 of 9
i. These glycosaoaminoglycans, this mucopolysaccharide subset, are found in all kinds of tissue, bone
cartilage, tendons, cornea, skin, joints, and tooth roots
j. If you have an accumulation of those you end up with deformities because the bone can no longer support
the weight that you have and organ dysfunction and bone dysfunction
XII.
LSDs: affecting connective tissue cells, Mucopolysaccharidoses and glycosoaminoglycans [S107]
a. The typical ones that are most common of these rare disease is mucopolysaccharidoses type 1 or Hurlers
disease
b. The metabolites, the things that aren’t digested are heparan and dermatan type sulfates. It is just component
of ground substance, it can’t be broken down, it accumulates and you get thick looking course faces and also
it is a component within the vasculature that supplies the brain, it surrounds the vessels
c. If you have a storage disorder that affects blood supply you will have mental retardation
d. You don’t get to keep the neurons because they are not being supplied. You will also have vascular
narrowing. You will also have enlarged spleen and liver
e. Again, because there is a lot of ground substance and macrophages also are still working with these
molecules. That’s where the lysosomes predominantly are
f. This is the same with corneal clouding. You are losing the translucency of the cornea
g. So the death in babies is usually with cardiac failure because they also get accumulation in the endothelium
cells and the endothelial cells are those that line vessels and they swell and that makes the lumen smaller,
which makes delivery of oxygen to the heart muscles smaller and that affects cardiac function
XIII.
LSDs: affecting connective tissue cells, Mucopolysaccharidoses and glycosoaminoglycans [S108]
a. In contrast, Hunters is an X linked recessive
i. If you are a male and inherit an X with this deficient enzyme problem you will have Hunters
b. Do these patients look any different? If I showed you a picture of Hurlers v. Hunters would you be able to tell
a difference? NO
c. How do you know it it’s a hunters or a hurlers? you would have to do a biochemical enzyme test on their
fibroblasts and macrophages
d. However, for the sake of picture, the thing that will show up on a board kind of exam is do Hunters patients
have corneal clouding?
i. Hunter’s do not have corneal clouding
ii. How do you remember that?
1. Here is her way: Men hunt (X linked recessive so it affects males) and you need to see to hunt (so
no corneal clouding)
e. Same deal with mental retardation
i. Again there is endothelium accumulation and the brain activity gets compromised and these patients are
mentally retarded
XIV.
HURLER’S MPS 1 [S109]
a. Here is a child who has hurlers
i. This is not x linked it is an Autosomal recessive
ii. Has corneal clouding
b. As you can see the head is misshapen, the body is misshapen, arm leg ratio is messed up, the kids brain is
trying to grow but the bone and the joints in face are not cooperating very well
c. Bone formation is not working well, connective tissue around bone is not working well
d. So you end up with a misshapen face, dwarfed baby, because they cannot support themselves very well
e. Have large abdomen because of spleen and liver enlargement
XV.
MUCOPOLYSACCHARIDOSIS: HURLER’S DISEASE [S110]
a. When you say can you see this at birth the answer would be unless you are brilliant you may not recognize
this
b. How would a baby with mucopolysaccharidosis particularly Hurler’s look at birth?
i. Baby looks normal but at age 2 months this is an overly chunky kid
c. You would say that is a good thing because the baby is eating well and all babies get chunky except this baby
is already falling behind milestones
i. Don’t track well with eyes, doesn’t turn to hear things
ii. There are other indications other than too much food
d. Not as though you can look and immediately know this kid has Hurler’s unless you were to do a profile of this
child and notice that the head bones are misshapen that there is connective extra stuff around here that
makes the kid look like the one we just saw
XVI.
HURLER’S DISEASE MPS I HUNTERS DISEASE MPS II [S111]
a. Over time they still have a chunky look to them
CLASS: 10-11
Scribe: Christine Sirna
DATE: 11-11-10
Proof: Allison O’Brien
PROFESSOR: Ona Faye-Peterson
GENETIC DISEASES
Page 5 of 9
b. This is the same kid at five years of age. She is definitely not smart, has coronary artery disease, has cardiac
deficiency. She is not healthy. May be happy but not healthy
c. There is nothing you could look at this picture and immediately know she has Hurler’s
d. The idea she is trying to impart is that it takes a comprehensive evaluation of patient to deliver diagnosis
e. How will you know this person has Hunters? You wouldn’t know they have hunters unless you notice they
have a prow brow and is male. Could this be a Hurler’s patient with it? Sure
f. How would you know the difference between them?
i. Check corneal clouding to differentiate between hurlers and hunters
ii. Corneal clouding means probably Hunter’s
iii. Doesn’t mean it couldn’t be something else
XVII. X LINKED RECESSIVE DISORDERS [S112]
a. Keep in mind these are storage disorder and they will be a family of abnormalities
b. There are all kinds of X linked recessive disorders not just Hunters and Hurlers
i. Duchenne muscular dystrophy, which is very common.
ii. There are several autoimmune disorders
iii. Particularly there is Fragile X syndrome
1. now the concept is you have a good and bad chromosome
2. if you have two chromosomes and it is a recessive disorder you have two bad copies and that gives
you the disease except when it’s x linked in which case you have nothing to balance it with on your Y
so if you’re male you’re out of luck
XVIII. OBJECTIVES: BE ABLE TO DESCRIBE [S113]
a. Now we are going to non mendelian genetics
b. That means it is not autosomal recessive, not autosomal dominant, not necessarily straightforward X-linked
c. This is a little different
XIX.
GENOMIC IMPRINTING [S114]
a. These are due to a process called genomic imprinting
i. It is a process that is put on top of your genome
ii. Something you do to your DNA or is done to your DNA before you even know if you will be a male or
female
iii. As an embryo you inherit imprinted material from your parents. Their chromosomes have imprinting. Moms
have imprinting, dads have imprinting so your somatic cells. The things you are aware of will have imprints
on them.
b. What that means is that even though you might have two copies of a gene one copy from one of the parents
has become inactivated, it has become methylated, so it can no longer be expressed
c. What that means is that you better have a functional copy of you will be out of luck.
d. There are disorders that exhibit non mendelian genetics. They are disorder of genomic imprinting.
e. Some of them also happen to exhibit inhibit autosomal dominant inheritance problem, some exhibit an
autosomal recessive inheritance problem but they are disorders of imprinted genome
XX.
GENOMIC IMPRINTING [S115]
a. Let’s back up. Let’s say you are an embryo and you are barely you have kind of figured out you will have
gonadal regions, you are ready to send cells there to populate and become either ovaries or testes
b. Before you send those cells to that location you decide that you have had it with parental influence and you
want to make your own statement to the world only problem is it will be your offspring that will have the
statement.
c. You got the statement your parents made but decide you don’t want to be like them. You want to make your
own stuff
d. As am embryo you erase essentially the genomic imprinting made from your parents
e. You take off the methylated group and you now free your chromosomes, free your DNA
f. If you are a male embryo you reimprint, you select your own chromosome and reimprint them again. And if
you are a female you reimprint them again
g. You have some autonomy
h. Every year she lectures these they are not the same
i. Minimal change on this but important one is last year the concept was you can’t do anything about your
imprinting. Once you get imprinted stuff you can’t change it
ii. As it turns out that is not entirely true, but for the most part it is true, you cannot change your somatic cell
imprinting
i. Even though we say you erase everything that is imprinted in germ cells that is not entirely true, apparently
you do not get to clean the slate completely. You still have to live with your parents and have some influence
CLASS: 10-11
Scribe: Christine Sirna
DATE: 11-11-10
Proof: Allison O’Brien
PROFESSOR: Ona Faye-Peterson
GENETIC DISEASES
Page 6 of 9
j. Your ability to create a completely new individual is not completely your decision. However, for your
purposes of understanding you imprint whatever you want on your own germ cells and they go forward and
represent you
k. So she said they are mostly erased whereas last year would say erased
XXI.
GENOMIC IMPRINTING [S116]
a. The embryo sex determines which chromosomes are imprinted and what the imprinting pattern is. It is unique
to you because your set of chromosomal information is unique to you. Therefore what you imprint and how
that imprinting works will be unique to your offspring.
b. Not all human chromosomes are imprinted, Only about 25% are and it’s not usually the whole chromosome,
only tiny pieces of it. Microsections of it that are imprinted.
c. Specifically it is very different from X inactivation
d. What it X inactivation?
i. Two X’s if you are a female and you only need to use one of them so randomly one becomes inactivated
e. This affects males and females and is not X inactivation.
f. This affects somatic chromosomes not your gomosomes although the X actually does also
XXII. GENOMIC IMPRINTING [S117]
a. For your understanding, it results in stable changes, in other words there is very little you can do about it
b. Once you get his imprinted stuff, your offspring that’s it they are set. You made a decision for them.
c. Parental imprinting is kept in your somatic cells for all intensive purposes and you only have the option of
flipping our your germ cells
d. Why would you want imprinting? What would that do for you?
i. Stable function of the genome required that someone becomes boss
ii. Somewhere there is a balance and effect of this imprinting
e. So It has worked in our favor that we have this
f. If you don’t have imprinting that goes appropriately you may end up with a tumor you may have an increased
risk for neoplasia for example or disease
XXIII. HUMAN EMBRYO STAGE 23 [S118]
a. This is the end of embryogenesis
b. This imprinting has already occurred that shows you how early it happens
XXIV. PICTURE [S119]
a. This is a scheme of what I just said
b. You create your chromosomes in meiosis you pass them to the germ cells, the germ cells go to make you
and you erase the imprinting and start over
XXV. PICTURE [S120]
a. How did imprinting become aware? How did we learn about this?
i. It was by accident, it happened when there were genetic analysis of patients who exhibited extremely
opposite phenotypes
1. One of them was short with little hands and feet hypogonadism and uncontrollable appetite,
hyperphasia, with severe mental retardation
2. Hypotonia was a problem for these kids
b. In contrast there was a different presentation, this is a female but it doesn’t have to be a female, called
Angelman syndrome
i. First was called prader willi and this was called angelman because angelman described it. This patient had
profound mental retardation was unable to speak but had peroxisms of laughter and very jerky motions and
this was referred to as happy puppet syndrome or angelman syndrome
XXVI. GENOMIC IMPRINTING [S121]
a. When they chromosomal analysis they discovered there were little deletions on 15 chromosome particularly
on the 15 Q region at this specific site
b. Determined there was imprint and those with Prater willI were missing genetic information the activated
prader willi site.
c. Their paternal chromosome had that microdeletion. In other words, it’s a male that got a 15 from dad but
somehow there was a microdeletion of that paternal chromosome so without that active gene the patient had
prader willi
d. In contrast, children that had a microdeletion from the chromosome 15 from their mom had Angelman’s
because the active site that was not turned off was supposed to be on mom but it was missing so that patient
exhibits Angelman
e. They are microdeletions in very similar areas of slightly different material but from subbanding they look like
the same chunk of tissue. They are not exactly the same site as we’ll see.
f. Let’s talk about genomic imprinting again
CLASS: 10-11
Scribe: Christine Sirna
DATE: 11-11-10
Proof: Allison O’Brien
PROFESSOR: Ona Faye-Peterson
GENETIC DISEASES
Page 7 of 9
i. Normal mendelian genetics you have 2 copies of equal weight, one from dad and one from mom that
determine what you have
ii. In paternal imprinting whatever genome is on the paternal chromosome is active and the one from your
mom is turned off
1. Same locus B is active on dad’s one and locus B on mom is shut down
iii. The opposite is true of maternal imprinting you inactivate the chromosome you got from your dad.
XXVII. PRADER-WILLI SYNDROME [S122]
a. There is a Q12 region that is a microdeletion.
b. I want you to note that when people talk about chromosomes they talk about the 15 and then the 15 q arm
which is the long one, and then the 1 the next 1 describes the region closest to centromere and the next 1 of
that describes the one band closest to the centromere and within that is the dot one that is a micro micro part
of that
c. The way you say this is Q one one microdeletion
d. Somewhere between the one one and the one three somewhere near the centromere is where the deletion is
XXVIII. PRADER-WILLI SYNDROME [S123]
a. Again, small stature, obesity, almond shaped eyes, blue eyes, mental retardation, and this is the phenotype
b. They have uncontrollable eating, something is wrong with they hypothalamus
c. Parents of children who have prader willi have to lock the refrigerator and lock everything in the house
XXIX. ANGELMAN SYNDROME [S124]
a. In an interstitial deletion of the maternally derived area of a very similar site and again post natal growth
deficiency.
XXX. ANGELMAN SYNDROME [S125]
a. They don’t grow well and have small stature small size, little heads, pale blue eyes, big time mental
retardation, absense of speech, laughter, this is the phenotype
XXXI. PICTURE [S126]
a. It says that prader willi gene on the maternal chromosome is inactivated on the mom’s chromosome
b. If you lose the paternal active prader willi site you have a prader willi gene but it’s turned off so you get prader
willi syndrome
c. Whatever one you are missing it means that that is the active one that is missing
d. Angleman means absences of the active UBE3A gene
XXXII. UNIPARENTAL DISOMY/ ISODISOMY [S127]
a. Another concept you will not hear at any other time but it might become useful at some point
b. Let’s say that you know that Cystic fibrosis is autosomal recessive chromosome 7
i. This is a deadly disease
ii. This means that you have a parent on each side that is a carrier and you got two bad recessive genes and
ended up with cystic fibrosis
c. What if you do genetic analysis and determine only one parent, say the mom has that one recessive gene but
has a normal one so she doesn’t have cystic fibrosis and the dad is normal
d. So you think it must be a mutation. There must be a second mutation in the gene from his dad. NO
e. What happened was you had uniparental disomy
i. Means that you started out as trisomy for chromosome 7 and you lost the dads gene
ii. So you are a 46XY normal chromosome number but you got two 7s from your mom
f. You can have uniparental disomy with autosomal recessive disorder that are still autosomal recessive but got
2 chromosomes from one parent
XXXIII. EFFECTS OF GENOMIC IMPRINTING UNIPARENTAL DISOMY [S128]
a. The effects is, these X’s are not X chromosome they are normal chromosome
b. What it is is a correction of trisomy
i. Let’s say you have the maternal chromsome 7 and you
c. If you lose one of the mom’s you’re normal if you lose the other mom’s you’re normal but If you lose the dads
you are ebinormal
XXXIV. EFFECTS OF GENOMIC IMPRINTING (CONT’D) [S129]
a. You can have prader willi if you have the microdeletion of dad site
b. You have have prader willi If you have two normal 15’s from your mom. There is no microdeletion you just
shut that thing off.
c. That is what uniparental disomy can do
i. Want a balanced set
ii. Want one from each parent and want them to be imprinted from each parent
XXXV. TRINUCLEOTIDE REPEAT DISORDERS.. HEREDITARY UNSTABLE DNA [S130]
a. The next concept is trinucleotide repeat disorder. This is non mendelian genetics.
CLASS: 10-11
Scribe: Christine Sirna
DATE: 11-11-10
Proof: Allison O’Brien
PROFESSOR: Ona Faye-Peterson
GENETIC DISEASES
Page 8 of 9
b. These are disorders that are affected by the production of germ cells in the mom or the dad during
gametogenesis
c. If you are a father and you have a particular trisomy 3 nucleotide repeat that places you at risk for huntingtons
disease, when you make sperm you amplify that trinucleotide repeat
d. There is a stable copy number that allows you to be asymptomatic to not have Huntington’s but your son or
daughter may have it because during creation of your sperm you have amplified the copy number so now it’s
unstable.
e. It is a different concept than straight Mendelian genetics
XXXVI. HEREDITARY UNSTABLE DNA [S131]
a. Fragile X is one of those repeat disorders
i. There are lots of them
b. Fragile X let’s talk about how it got named that
i. Fragile X was discovered when there were doing straight karyotyping on mentally retarded individuals
ii. They were probably looking for trisomy 21
iii. If they grew those cells in folate deficient media, what they discovered is one of the X’s fell off. It is a fragile
site. It’s not there it’s shorter on this one X
c. They traced back and discovered if they did the same thing and grew those cells in normal media they were
fine but as soon as you put those cells with the funny little X in there in media deficient folate the end fell off
d. That missing chunk is what is responsible for mental retardation in Fragile X syndrome
e. Who is at greatest risk for fragile X mental retardation? Males
i. Can have it in females but there is a certain copy number that is ok before there is genetic instability and
you lose critical material
f. Critical material can either result in a gain of function or a loss of function
g. Each trinucleotide repeat disorders is sex specific
h. You will have amplification in either the male or female side so that you get something called dosage effect
i. you may be asymptomatic but your offspring are
i. If you are a female with fragile X, almoseness you have tolerated a number of repeats so that you are not
mentally retarded. However, the ova she produced amplified fragile X site, so now if she has a male son he
will be mentally retarded. She will be a carrier female and he will be an affected male.
j. What about If she amplifies it but not enough to make it fragile X. He is ok. What is he now? Now he is a
transmitting male
i. He will not amplify it more. He won’t do anything to his X.
ii. Let’s say he donates his X to a daughter and when she makes her ova she amplified her X and now her
children got it
k. Rachel’s question:
i. Amplify means increase the copy number, trinucleotide repeat
1. Let’s say for Fragile X it’s CGG over and over let’s say you can tolerate 200 copies. By the time you
get to 250 you have genetic instability and they exhibit mental retardation. We don’t know why it
does’t get amplified in the male
2. Huntingtons disease doesn’t undergo amplification unless it passes through the male
3. If your dad has Huntington’s you will get it. If your mom doesn’t have Huntington’s you probably
won’t get it either unless your dad has it. It’s your dad’s fault if you get it.
l. What happen is dosage effect: more copy is worse symptomatology, worse symptomatology, earlier
expression, earlier phenotypic display. This is called amplification.
XXXVII. PICTURE [S132]
a. These repeat disorders exhibit dosage and anticipation and with that increased severity
b. How is it that the entire male population isn’t retarded?
i. If it’s so unstable that it breaks you lose the extra repeats so you start over. It’s like a self correctly
mechanism
c. Again these are some examples are trinucleotide repeat disorders
XXXVIII.
FRAGILE X SYNDROME [S133]
a. Fragile X is the second most common cause of mental retardation in males. Has an incidence of 1 in 550
males.
i. Again some craniofacial features: have long face and prominent jaw
b. Every person with Prader Willi, Fragile X, all suddenly have pale blue eyes
i. There is something that is going on with pigmentation of the iris but no one really know what’s going on
1.That makes it a syndrome because they resemble each other more than their parents so it is a
syndrome
CLASS: 10-11
Scribe: Christine Sirna
DATE: 11-11-10
Proof: Allison O’Brien
PROFESSOR: Ona Faye-Peterson
GENETIC DISEASES
Page 9 of 9
2. We know the cause and we know it’s a trinucleotide repeat and we know it is a decent copy
number that is tolerated but we don’t know exactly how it works
3. That is what is means to be a syndrome just like trisomy 21. We know if you have this extra copy of
21 material you have mental retardation, funny fingers, heart disease, we just don’t know why.
That is where over time you will see these things in medical literature
c. How important is it to understand if you are a male with fragile X you have an 80% chance of having mental
retardation, IQ of less than down syndrome, it’s pretty severe. 30% might be borderline because you have a
normal functioning X but but what do you know about the two X’s? one becomes inactivated
d. There is X inactivation and if you inactive your X that is a good thing gut if you are a female and you inactive
your good X you might have a tendency to be slightly mentally retarded. You can have a spectrum.
XXXIX. PICTURE [S134]
a. Here are picture of patients with Fragile X
b. Almond shaped eyes, pale blue eyes, big ears
XL. FRAGILE X SYNDROME [S135]
a. We’ve gone through all this
b. We’ve talked about phenotype, we’ve talked about carrier status, we’ve talked about amplification, we’ve
talked about anticipation so we’re at the end.
XLI.
THE END [S136]
[End 53:43 mins]