Download Genetic Metabolic Diseases I

CLASS: 11:00 – 12:00
DATE: November 10, 2010
PROFESSOR: Faye-Peterson
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VII.
GENETIC METABOLIC DISEASES I
Scribe: Adam Baird
Proof:
Page 1 of 6
GENETIC DISORDERS [S1]
a.
OBJECTIVES: BE ABLE TO DESCRIBE… [S2]
a. These are things that will be covered.
GENETIC DISORDERS: BASIC CONCEPTS [S3]
a. Genetic disorders are present at conception.
1. Congenital means “present at birth”. However, it depends on when you look for a disorder. If you are
looking at a population of stillborn fetuses, the incidence of those babies having genetic disorders is
infinitely higher (about 20x higher) than a baby who goes to the Neonatal Intensive Care Unit (NICU).
So, the population that you look at will determine the incidence of a genetic disorder.
2. Most of the descriptions of genetic disorders have been made on living patients. Pathologists, then,
must determine what is “normal” development (completion of proper developmental milestones) or
“abnormal” development (incompletion of proper developmental milestones). If the baby is
“abnormal”, the question must be asked: Was it due to a genetic disorder?
b. Prenatal testing has become available to detect genetic disorders. There are many sophisticated methods for
this type of testing too.
1. Amniocentesis – The embryo and fetus sits in the fluid bath. Fluid is pulled out of the developing
womb; cells are collected, grown, and analyzed. Most of the time, it is a karyotype (46 X-Y or 46 X-X
chromosomes) with banding of the chromosomes. Those cells are now available for higher caliber
testing; enzymatic abilities can be tested, individuals or large populations can be screened for
genetic disorders, etc.
2. Chorionic Villous Sampling – Chorionic villous refers to the tissue that makes up the placental tree
that keeps life alive through gestation. It is an organ – an interface between the mother and child. A
chorionic villous sample can be collected before there is enough fluid to be collected (so there is less
waiting involved).
3. Postnatal Testing – Women who are pregnant are essentially housing a parasite – a parasite that is
not only “sucking the life out of them” but is also sending cells from the placenta into their circulation.
Most of the time, there isn’t any harm as a result though. Peripheral blood can be drawn from the
pregnant woman. This blood can then be analyzed and checked for genetic disorders.
GENETIC DISORDERS: BASIC CONCEPTS [S4]
a. Incident of genetic disorders depends on population evaluated and most are polygenetic.
1. Most genetic disorders are not one gene dependent; many genetic disorders involve interactions with
multiple genes. (There is more than one gene that causes autism, for example.)
2. So, there is a family of mechanisms that could be a result of a variety of genetic abnormalities.
b. Most structural abnormalities (physical structure or form of organs in the body) are due to genetic
abnormalities, but so is the susceptibility to allergies (like penicillin, for example), infections, etc.
c. There is a lot of evidence that Freud was right. As it turns out, intrauterine life is quite informative to what can
be expected later (cardiovascular disease, for example).
d. Genetic disorders appear to have one common starting point are actually from multiple genes and intrauterine
and extrauterine environment.
MANY MEANS FOR DETECTING GENETIC DISORDERS… [S5]
a. First picture referenced: This is the stage that we do chorionic villous sampling. A “snip” of this stuff is
collected, grown, and analyzed.
1. Notice the amniotic fluid accumulation
2. Notice the bag of water is very thin. It gets bigger though, and as it does, it will stick onto the surface
of the placenta. That bag of water, after birth, has a couple of liters of fluid in it.
3. At 18 weeks, there is enough fluid to suck some out (amniocentesis) without damaging or
threatening the baby. The baby continues to grow because of the placenta.
AMNIOCENTESIS PERFORMED AT ~18 WEEKS OF GESTATION [S6]
a. Here is a diagram showing amniocentesis.
INTRAUTERINE ENVIRONMENT [S7]
a. There are many genetic disorders, like cardiovascular disease, hypertension diabetes, chronic renal disease,
etc. – all of which have been linked to a bad intrauterine environment. (The mother does not supply the
placental bed with adequate oxygen or blood flow, harming the baby by making it “bump off” glomeruli in the
kidney, which can never be recovered.)
b. The father donates the sperm, which supplies the nuclear material. The mother donates the cytoplasm. The
cytoplasm of that egg is what supplies the cellular development, including mitochondria, for example. The
CLASS: 11:00 – 12:00
Scribe: Adam Baird
DATE: November 10, 2010
Proof:
PROFESSOR: Faye-Peterson
GENETIC METABOLIC DISEASES I
Page 2 of 6
mitochondria also have DNA. Disorders of mitochondrial DNA include neurodegenerative disorders (which
will not be covered in today’s lecture).
VIII.
OBJECTIVES: BE ABLE TO DESCRIBE… [S8]
IX.
MORPHOLOGIC DEFECTS: CATEGORIES REFLECT MECHANISMS [S9]
a. We’ll start with some definitions.
1. Malformation – An embryo is on a normal development process, but something interrupts the
progression. In general, a malformation is a remnant of a normal process that just didn’t get finished.
It is an intrinsic abnormality of the primordium. Something is wrong with the tissue and it doesn’t form
correctly.
i. Example: Palate. During development, the baby doesn’t have fused palettes. So if the
baby is interrupted from forming un-fused palate, it is born with a fused palatal cleft. (It
doesn’t form and then go away. It just never forms.)
ii. Another example: Neural tube defects.
2. Deformation – A defect due to mechanical, external force.
i. Example: Oligohydramnios sequence (shown in the pictures) results from abnormalities
in the position of the baby (the limbs are flexed, the face is smashed, etc.). There is
insufficient fluid around the baby for it to move in, so the baby is immobile, so the baby
can’t develop correctly. The tissue hasn’t formed correctly, so it’s difficult to straighten
the limbs anyway. The baby can’t be “just made better”.
X.
DEFORMATIONS CAN COEXIST WITH ISOLATED MALFORMATIONS [S10]
a. Malformations and deformations can coexist too.
1. Example: Extralobar sequestration. Lungs develop off the primitive esophagus (gut, endodermal
tube). They branch out and then divide. The only place that there is a common opening is the mouth.
And if that budding process is altered and there is another lobe on the lung, a malformation results.
So, the process of lung growth is normal and the process of budding is normal too, but the addition
of a new lobe on the lung is abnormal. This is called extralobar sequestration (a sequesterd part of
tissue that “wants to be a lung”, but is not connected to the main airway). As it grows, the lung tissue
produces a little fluid on its own, but there isn’t an exit pathway for it, so the mass continues to grow,
producing a deformation (smashing the heart and the thoracic activity).
XI.
DYSPLASIA [S11]
1. Dysplasia – “Dis” meaning “abnormal”, “plasia” meaning “proliferation”. Dysplasia, then, is due to an
intrinsic abnormality of tissue (in contrast to intrinsic abnormality of a primordium or region) – and
there are multiple kinds of tissue (vascular, neural, etc.). In dysplasia, a component of tissue is
abnormal. Therefore, if it is a tissue that is present at multiple sites in the body, it affects many
organs or even the whole body. It’s rare for it to be isolated to a single organ.
i. Example: Tubersclerosis complex (TSC) is a tumor-suppressor gene abnormality.
Tumor-suppressor genes control proliferation.
ii. Example: Osteogenesis imperfecta is a tissue abnormality of bone production
(osteopenia, under-ossification of bone, etc.). In this case, it is lethal.
b.
c.
XII.
DISRUPTION [S12]
a. Disruption – Development is initially normal, until something happens (usually extrinsic) to disrupt the
process.
1. Example: Vascular disruption. We have to have blood supply to the body. But if a main blood vessel
is cut off, anything that is dependent on that blood vessel can’t grow. This is a vascular disruption
shown here. The gut stops growing and is plugged close. Anything proximal to it has retrograde
plugging (distention).
2. Example: External disruption (see next slide).
XIII.
AMNIOTIC DISRUPTION SEQUENCE [S13]
a. This is the amniotic sac. It can break open, resulting in tiny strands of amnion floating around. The fetus can
get entangled in these tiny amnion strands, resulting in possible amputations. The tiny strands of amnion can
also be swallowed, resulting in facial clefting.
b. Note: Syndromes tend to be symmetric, equally affecting everything. Disruptions tend to be asymmetric,
affecting areas “by chance”. An asymmetric jaw, for example, would be caused by a disruption.
XIV.
NO TITLE [S14]
1. Anomaly – An anomaly refers to anything abnormal. It can be a major anomaly (affecting health and
longevity, for example) or it can be a minor anomaly (affecting physical appearance or structure, like
CLASS: 11:00 – 12:00
Scribe: Adam Baird
DATE: November 10, 2010
Proof:
PROFESSOR: Faye-Peterson
GENETIC METABOLIC DISEASES I
Page 3 of 6
eyebrows, for example). A minor anomaly might be a clue that there may be a major anomaly
though.
b. Agenesis – Agenesis means the absence of the primordium or the complete failure of development of
necessary tissue. Agenesis of the kidney, for example, cannot support life.
c. Hypoplasia – Hypoplasia is undergrowth of a structure due to insufficient cell proliferation and/or induction of
growth, like lung hypoplasia, for example. Malformations and deformations can be present at the same time.
XV.
NO TITLE [S15]
a. Here are some major terms. Pay attention to these.
b. These definitions will help you to understand new information in the future.
c. If you evaluate a syndrome, for example, you will know to look for a specific collection of things that is caused
by a chromosomal abnormality.
1. Sequence – Pattern of multiple anomalies derived from a single known or presumed prior anomaly or
mechanical factor. You can start with an initial sequence and potentially predict what may occur.
2. Syndrome – Multiple anomalies that may be pathogenically related. Even if the cause is known,
however, not everything about it can be explained.
a. Example: It’s known that Down Syndrome is caused by trisomy-21, but it’s not know what it is
on the 21st chromosome that actually causes it. We don’t know how it’s all fit together.
3. Association – Multiple structural abnormalities that are connected in a seemingly unknown way. They
occur together non-randomly. Associations are collections of abnormalities that occur during the first
four weeks of development.
XVI.
OLIGOHYDRAMNIO SEQUENCE [S16]
a. Without adequate amniotic fluid, the baby cannot move and grow.
b. Lung development is dependent upon the ability to breath in amniotic fluid. Why? There is a specific amount
of influx pressure that is required for lung growth stimulation. If there is insufficient amniotic fluid, then, the
lungs will not grow properly.
c. Additionally, the baby will have a smashed face, increased suborbital creases, flattened ears, and the limbs
cannot be distended. This is an example of sequence.
XVII. VACTERL(S) ASSOCIATION [S17]
a. VACTERL(S) stands for:
1. Vertebral
2. Anal Atresia
3. Cardia Defect
4. Tracheo-Esophageal Fistula
5. Renal Anomaly - Could be a complete absence of the kidney. The adrenal gland, then, tries to act
like the kidney, forming a pyramid shaped structure. Kidney output is important during development
too, as urine is a key component in the last half of gestation for amniotic volume fluid. If the kidneys
are absent, urine will be absent, affecting amniotic fluid volume, potentially stunting the development
of the lungs, etc.
6. Limb
b. Only three of these associations indicates VACTERL(S) Association. It is possible, then, for you to see
patients with VACTERL(S) association.
XVIII. RENAL ANOMALIES: MCRD, AGENESIS, COMBINATIONS [S18]
XIX.
OBJECTIVES: BE ABLE TO DESCRIBE… [S19]
XX.
DOWN SYNDROME PHENOTYPE (TRI-21) [S20]
a. They have ocular problems, inability to see, etc.
b. Very characteristic cranial-facial features.
XXI.
DOWN SYNDROME [S21]
a. An extra copy of chromosome 21 causes a vast majority of Down syndrome cases. Instead of 46 XY, for
example, Down syndrome patients are 47 XY+21.
b. Features:
1. Up-slanting palpebral fissures
a. Note: It is not called an anti-mongoloid slant.)
2. Epicanthal fold
a. Not an abnormality, but when paired with up-slanting palpebral fissures and mid-facial
hypoplasia, it is a clue that a patient might have Down syndrome.
3. Clinodactyly
a. In turning of the middle finger, due to a hypoplastic, under-grown middle finger.
b. Seen in 80% of Down syndrome patients.
CLASS: 11:00 – 12:00
Scribe: Adam Baird
DATE: November 10, 2010
Proof:
PROFESSOR: Faye-Peterson
GENETIC METABOLIC DISEASES I
Page 4 of 6
4. Sandal toe abnormality
a. As if they were wearing flip-flops in utero, because they have an increased space between
their toes.
5. Abnormal ear formations
XXII. DOWN SYNDROME: DENTAL AND OCULAR FEATURES [S22]
a. Because of some of the features, patients with Down syndrome will be prone to sinus infections, recurrent
upper respiratory tract infections, etc.
b. Down syndrome patients will be myopic (nearsighted).
c. Down syndrome patients will have hypoplastic teeth (interfering with dentin, enamel, bone, etc.), swallowing
difficulties (due to hypotonia), a short palate, and a protruding tongue. Some books will say they have “big,
wrinkled tongues”. This isn’t true. Their tongues protrude, yes, but only because they don’t have the muscle
to pull it back in.
d. Down syndrome patients will have areas of pigmentation abnormality in the iris, specifically in a bilateral and
sprinkled distribution.
e. Down syndrome patients will also have peripheral hypoplasia of the iris.
f. They may also have lens opacities, refractive error, nystagmus, strabismus, lacrimal duct blockage, and
cataracts.
XXIII. BRUSHFIELD’S SPOTS [S23]
a. Here are Brushfield’s spots.
b. Yellow spots that are slightly elevated on the iris (creating a “speckled” look).
c. Parents will call them “stars” in the eyes.
XXIV. DOWN SYNDROME FEATURES [S24]
a. Here is an image out of the book.
b. GI peristalsis is abnormal, leading to dilated colons (mega colons).
c. Because of laxity in muscle tone, they can have a hernia around the umbilical area.
d. Down syndrome patients will also have congenital heart disease. About 40% of Down syndrome patients
have it. So, you have to assume that they have it until you have proven it otherwise. Of that 40%, another
40% have complete atrioventricular canal (which will be talked about later).
e. Down syndrome babies need to be on antibiotics.
f. They have an increased risk of leukemia.
g. They might be small (under grown).
h. Extra note: During an ultrasound of the baby, look for nucleuscency, indicated by dark area under the skin on
the back of the neck due to a failure of a lymphatic cistern in the body. The lymphatic system is connected to
the vascular system in the neck. Failure of this connection during development means that there is a
distention in the neck because there is too much fluid. If the dark area on the back of the neck greater than
5mm, it’s an indication of nucoluscency, which is a risk for Down syndrome. (This can also be called a
nuclehydroma.)
i. Some Down syndrome babies will have abnormal posterior hairline because their skin was stretched out in
utero.
XXV. VIEW “DOWN” ORIFICE OF COMMON AV VALVE IN CAVL [S25]
a. Notice the anterior and the posterior sections.
b. We’re looking at the AV valve.
c. If everything is normal, the atriums and the ventricles don’t communicate. There should be four chambers.
d. In development, the heart is one single bag though (without chambers), so it has to divide at some point. A
central mass that the chambers can attach to is needed for the divisions to occur. This is called an
endocardial cushion. Patients with Down syndrome don’t form the endocardial cushion though, so they don’t
have the normal divisions and the normal four chambers in the heart. Every systole, blood circulates
improperly.
e. A complete AV canal is a persistence of a normal state in development. It’s a malformation.
f. The blood doesn’t circulate properly.
g. This is why they need antibiotic therapy.
h. This includes any manipulation around the eye or mouth where there might be bleeding. Why? Because their
valves aren’t normal, there are holes where there shouldn’t be, and there is abnormal turbulence in the heart
circulation as a result. There is fibrin buildup too.
XXVI. SEQUELAE [S26]
a. Endocarditis and thromboembolic phenomena due to vegetations.
XXVII. EDWARD SYNDROME [S27]
CLASS: 11:00 – 12:00
Scribe: Adam Baird
DATE: November 10, 2010
Proof:
PROFESSOR: Faye-Peterson
GENETIC METABOLIC DISEASES I
Page 5 of 6
a. You probably won’t see an Edward syndrome baby. Why? To have a fully copy of chromosome 18 is
essentially lethal.
XXVIII. TRISOMY 18 [S28]
a. A vast majority of trisomy babies with lethal abnormalities are typically mosaics. You may see someone who
is a trisomy 18 mosiac, for example. But out of 20 cells in the culture, maybe 5 of them will have an extra 18
chromosome, yet the rest are okay.
b. A typical feature for trisomy 18: two finer overlap on the hand.
c. You may see a patient who has undergone a repair for an omphalocele though. What is an omphalocele?
d. During development of the GI tract, during the 8 – 10 weeks, the gut migrates into the umbilical cord
(because there isn’t enough room in the abdomen). A problem occurs when the gut remains in there though –
it is a true malformation. When this happens, it’s called an omphalocele.
XXIX. PATAU SYNDROME [S29]
a. Trisomy 13
b. You will likely never see Patau syndrome, because patients rarely live a few hours or day past birth.
c. It is a highly lethal abnormality.
d. Most sever retardation.
e. Most sever craniofacial and CNS malformations and MR.
XXX. PATAU SYNDROME [S30]
a. This is a baby with full trisomy 13.
b. Notice the clefts in the labial folds.
c. Notice the palatal cleft.
d. Notice that the eyes are too close together.
e. They may have polydactyly.
f. They may have an umbilical hernia.
XXXI. PATAU SYNDROME [S31]
a. Instead of two hemispheres of the brain, there is only one common chamber (like a big bag, for example).
This is called alobar holoprosencephaly.
b. Due to abnormal brain formation, there is abnormal skull, skin, and scalp formation too. There may be scalp
defects.
XXXII. TURNER SYNDROME [S32]
a. Is 95% lethal in utero (still born babies)
b. Phenotypic female missing X chromosome
c. The patients who survive are, for the most part, mosaics. (They will be 45 X, 46 XX.) Depending on how
many cells are missing an X chromosome determines the severity of the syndrome (like mental retardation
severity, for example).
XXXIII. TURNER SYNDROME “MONOSOMY X” [S33]
a. Some features:
1. Coarctation of aorta
2. Abnormal carrying angle in the arms
3. Broad chests
4. Big ears
5. Webbing of neck – They have the same problem (which never gets better) as the nuclehydroma. So,
the nucleluscency is a harbinger for trisomy 21, 18, and 13. It is also a harbinger for Monosomy X
too. Monosomy X has a high incidence of spontaneous abortion.
6. Picture: Still born baby who was floating around after death in amniotic cavity, which is why the skin
is peeling off. This is what a Monosomy X fetus usually looks like.
XXXIV. TURNER SYNDROME: 45, X PHENOTYPE [S34}
a. If a baby could survive, it might have a stretched neck, an abnormal posterior hairline, large, forward-pushing
ears, a wide space between the eyes, a wide space between the nipples, coarctation of the aorta, etc.
b. Here is what a baby may look like. The reasons for this phenotype (webbed neck, widely spaced eyes, broad
chest, etc.)? Because of the cistern issue, which is not specific to Monosomy X, but it is a distinguishing
characteristic of it.
XXXV. JUGULOLYMPHATIC OBSTRUCTION SEQUENCE [S35]
XXXVI. KLINEFELT SYNDROME [S36]
a. Too many chromosomes….
b. These patients may have a shortened longevity.
c. May have ocular and dental problems.
d. May have diminished mental capacity or mildly retarded.
CLASS: 11:00 – 12:00
DATE: November 10, 2010
PROFESSOR: Faye-Peterson
e. May be very tall.
f. [End 50:22 mins]
GENETIC METABOLIC DISEASES I
Scribe: Adam Baird
Proof:
Page 6 of 6