FUN2: 10:00-11:00Scribe: Teresa Kilborn

Thursday, November 20, 2008Proof: Ashley Holladay

Dr. Ona Faye-PetersenGenetic DisordersPage1 of 6

  1. Genetic Disorders [S1]: Focus will be on babies and adults. Will not be asked to identify a lesion (microscopic photograph) by histology. She wants us to be able to take what we learn here and think through to a reasonable answer. No a and b or all of the above answers from her at least.
  2. Genetic Disorders: The Basics [S2]
  3. Traditionally, defined genetic disorders affect 10% of the population
  4. But in reality they really affect about 50% or higher if you take into account the fact that we all have DNA and within our DNA is stored material that makes it possible for us to contract a particular disorder or develop a diseased state
  5. 1-2% of the population has an autosomal dominant disorder.
  6. Keep in mind that you may never see one of these, but you probably will.
  7. You won’t be diagnosing people with these disorders but you will be treating them.
  8. 1% doesn’t reflect the number of people seeking medical attention, just how many there are.
  9. Also depends on how far back you go. Any inherited disorder starts in the zygote. All of the risk factors are there from the start, although environmental factors do play a role as to whether you develop the disease.
  10. Over half (60%) of all conceptions result in spontaneous abortion- late period.
  11. There is a natural sorting process that starts very early. If you look at previable fetus, those that if they were born could not sustain life themselves, it is already 35%. If you look at all hospitalized newborns and infants about 20% have a genetic disorder.
  12. [ S3]Descriptions of disorders have been made on infants that are viable, toddlers, adolescents, and young adults.
  13. On a side note: She went through everything that she is presenting to us with Dr. Waites, and he selected the topics. Her goal is to teach us everything for us to know to become an informed practicing optometrist or dentist and for us to be able to take new information and to process it and to continue to learn and educate ourselves throughout our careers.
  14. Prenatal testing
  15. Amniocentisis-Takecells from the amniotic fluid, done at around 18 weeks.
  16. Chorionic villi sampling- can be done early around 6 or 8 weeks. Taking a tiny bit of the placental tissue from around the developing baby
  17. Maternal blood sampling- any time during pregnancy there are little cells of the fetus in the mother’s circulation, not a lot, they obtain access to the maternal blood circulation. You can isolate them and test them. That aspect of fetus cells being in the maternal blood is “fetal trafficking”.
  18. Of the three tests, the first two are done here, fetal trafficking is not done at UAB.
  19. [S4] Most, but not all of structural abnormalities are due to genetic abnormalities.
  20. Most of the time you see something missing or something malformed, it is due to a genetic disorder.
  21. This does not include abnormalities of missing fingers or toes, those are processes called disruptions, they happen very early in development due to the breakage of the bag of water so the little limbs go outside of the bag and the bag remnants are floating around and actually strangulate and cause amputations.
  22. With the exceptions of those and things that happen to you in your environment the majority of structural anomalies are mainly due to genetic abnormalities.
  23. Individual susceptibility to infections, allergies, unexpected reactions to drugs are all genetically determined
  24. There is evidence that adverse connections during intrauterine life have a major role in determining one’s long term and immediate risks for developing disorders as in chronic cardiovascular disease, kidney disease, hyertension and diabetes.
  25. Picture of uterus with embryo inside, developmental bag, and placenta [S5]
  26. Chorionic villi sampling takes little bits of tissue from placenta and analyses them.
  27. Somewhere before term rupture of bag of water can happen and the amnion which is the bag can actually can get loose ends and that can cause disruptions-disruption abnormalities.
  28. On right is term baby, uterus, and placenta. This gives idea of relative idea of size of you, the house you are living in, and the placenta that has to support you later.
  29. Amniocentesis[S6]- performed at 18 weeks, that means there is enough fluid in this bag, it is separate from the surface of the placenta itself. It literally has to expand and apply itself like a transparent balloon so it is applied to the surface of the placenta where the blood vessels. There is a time in which you are too small and your bag is too small for anyone to go needling anything. But by 18-20 weeks, you have expanded your bag so that the other side is to the uterine wall. You are now floating in enough fluid and it is safe to try to suck some of it out. Amniotic cells are taken out, grown on a plate, and analyzed for various things such as chromosomal abnormalities, functional abnormalities of enzymes, and many others.
  30. Intrauterine environment[S7]-
  31. All of these diseases with asterisks are disorders that you have an unfavorable intrauterine life (placenta doesn’t grow big enough to support you etc.) these can make you vulnerable for chronic disorders later on.
  32. There is a big source of DNA in you, the nucleus, but the mitochondria also has DNA (circular DNA). There isa family of disorders that may be brought about due to defects in that mitochondrial DNA, but we are not to discuss them. Mitochondrial DNA disorders are degenerative disorders. They affect the CNS and your ability to walk, talk, etc. in particular the loss of neuronal (brain) function.
  33. Objectives [S8]
  34. Having too much DNA or having abnormal DNA- neither are good
  35. Basic premises of inheritance: dominant, recessive, x-linked recessive
  36. Major disorders with high frequencies
  37. Less common disorders that have either ocular or dental findings that may turn up on boards.
  38. Anueploidy [S9]
  39. Means abnormal number of chromosomes
  40. Trisomies have to do with chromosomes 1-22. We have 23 chromosomes, but the last is our XX and XY, sex chromosomes or gonadal chromosomes. In general, trisomies are having an extra one of those 22 first chromosomes.
  41. Down syndrome[S10]-
  42. Most important trisomy
  43. Full extra copy of chromosome 21
  44. The features of the syndromes are important because you know someone has the syndrome because of these characteristic phenotypic features. The features make someone with the syndrome look more like other people with the syndrome than their own parents.
  45. Features:
  46. Upslanting palpebral fissures-sometimes referred to as anti-mongoloid slants but politically incorrect
  47. Epicanthal fold- extra fold on the inner campus of their eye
  48. Single palmar crease instead of two creases- used to be referred to as semian creases, usually bilateral, but sometimes just one
  49. Clinodactyly- in turning of the little, 5th finger, because there is missing portion of the middle bone, so distal fornix is stuck on the strut of the first on and it curves in. if you have clinodactyly does that mean that you have down syndrome? No. Does every person with Down Syndrome have clinodactyly? No, but a good percentage, 75% do.
  50. Sandal toe abnormality- big space between the hallux, or big toe and the second one. Looks like they’ve been wearing thongs during development.
  51. Abnormal posterior hair line
  52. Abnormally shaped and positioned ears- low set- lower than a line drawn from your lateral campus and back, usually posteriorly positioned as well
  53. [S11] If you look at their karyotype, there is a whole extra chromosome on number 21.
  54. [S12] 95% of patients with Down Syndrome are mentally retarded and that is one of the major characteristics. Most of them have a full extra copy of chromosome 21, however some have a portion of chromosome 21 stuck on another chromosome, that would be called a translocation.
  55. Less than 30 % of all conceptions that have Down syndrome actually make it to be born. It is not good to have extra stuff
  56. Babies tend to be short and small and are hypotonic.
  57. If you see a patient that has a midfacial hyperplasia, upslanting palpebral fissures, and a tongue that hangs out that is because they have a tongue that is hypotonic. They have generalized low muscle tone. They cannot keep their tongue intheir mouth. It is not because their tongue is too big (macroglossia). They have a normal sized tongue.
  58. They are not able to pass things normally with their GI tract so they have to thicken their feds to give them something to grab on to push through their GI tract. They tend to have continued low weigh. They don’t thrive.
  59. They are also predisposed to infections particularly because their mid-face is underdeveloped so they get a lot upper respiratory tract infections and inner ear infections.
  60. They have a predisposition to getting Alzheimer’s. They have small heads, a nuchal hygroma (a swelling at the back of their necks from fluid accumulation during development), and a flat occipital (back of their head).
  61. [S13] Picture with things crossed out that aren’t true.
  62. Still born fetus with trisomy 21- huge neck, edema, its called hydrops, as in extra fluid in the fetus. Having this disorder is generally lethal- remember less than 30% even get to become your patients. If they manage to make it to birth they still tend to have some residual fluid in the back of their neck that gives them abnormal hair line.
  63. They tend to have megacolon. They can’t push things through that well so they don’t have good peristalsis.
  64. They are also at risk for having atresia or closing off of their duodenum.
  65. [S14] The most important thing for us to remember is that 40% of Down syndrome babies have congenital heart disease and 40% of those have this particular abnormalities called complete atrioventricular canal defect.
  66. Normally you have a 4 chambered heart- 2 atria and 2 ventricles are separated from each other and a very well developed connection our right atrium and ventricle and between our left atrium and ventricle. In complete atrioventricular canal defect, the atrioventricular valves, the tricuspid and mitral, are not separate, they are one big hole because they do not develop appropriately. Instead of having a normal situation with separation and conduction system between atria and ventricles, blood goes from ventricle to ventricle, both directions and to the atria. This is not good because this means that your heart is inefficient and you are mixing oxygenated blood and deoxygenated blood. You are unable to get enough oxygen to your tissues, you are unable to grow.
  67. Picture on left is looking down with the two atria removed. It is a big ovoid and you can see in to the right ventricle and in to the left ventricle. The leaflets of the valve are crossing over.
  68. If you are treating a patient with this disorder, particularly if treating in the mouth, you need to make sure that they get antibiotics before they come to your office because these valves that are very abnormal are flopping around very uncontrollable and causing turbulence. Turbulence causes fibrin disposition. Fibrin is lots of protein that bacteria make homes on and they are called vegetations. Vegetations will flip off, travel through body particularly to head, spleen, kidneys, anywhere. Bacteria is showered throughout your system and clots are thrown into vessels which everything distal to the clot to become ischemic. When you have a patient with this make sure they are on antibiotics.Thromboembolic- means thrombus as in coagulation in the blood space and embolic means thrown somewhere else.
  69. [S16] They can also have very hypoplastic teeth. They tend to have a lot of periodontal disease. They have swallowing difficulties, so we have to suck their mouths more (they have a hypotonic problem). Hypoplasia of the frontal sinuses. Many have middle ear fluid because of their malplacement. From an ocular standpoint, brushfield spots (watch from this on boards) are little small white spots on the periphery of the iris. White spots are milder forms of true hypoplasia of the iris. They can have lens opacities. They myopic and tend to need glasses very early on. Nystagmus, strabismus, and lacrimal duct blockage.
  70. Down Syndrome is one of 3 or 4 different syndromes, one of the most important because it is not lethal. There is a lot more babies born with trisomy 21 than 13 or 18 which are lethal.
  71. Turner’s Syndrome [S17,18]
  72. Gonosomal abnormality, missing a sex chromosome
  73. Female, 45 X
  74. Broad webbed neck, low set ears, big large posteriorly positioned ears, large space between eyes, tend to have shield chest (broad and flat with nibbles laterally positioned)
  75. Over 95% of 45 X are spontaneously aborted, If you see something with this then it is more than likely that she is not a pure 45 X, she is probably a mosaic with a complement somewhere.
  76. If she is sterile will depend on if her ovaries and eggs are 46 XX even though parts of her are 45 X, parts of her will have a normal complement. It is not uniform that these women are mentally retarded and/or sterile. However, if you have to pick one of these answers that would be the answer that you pick. What is on a test is not necessary what you see in life. This is not new information, but it is probably not going to be in your text books in that way.
  77. Characteristics:
  78. They tend to not grow very well.
  79. Infertile
  80. Mildly mentally retarded
  81. Craniofacial hypertelorism- too wide of a space
  82. Inner canthal folds
  83. Cutis laxa- extra skin on the back of the neck (as in the trisomy 21 baby) has to do with poor connection of the lymphatic sack to the central venous system. The lymph fluid needs to be returned to the intravascular volume and failure of that connection to happen results in what is referred to as a nuchal hygroma, it will look like the kid has a bubble on the back on their head. If that fluid somehow reabsorbed, then they will still end up with that loose skin, wide neck, and abnormal hair line (like trisomy 21).
  84. [S19]One of the problems when you are developing if you have all of this extra fluid (hydrops) you can’t move very well. That gives rise to odd carrying angle. They are not able to move their arms as freely as fetuses and it stiffens them and causes huge swelling on the dorsum of their hands and fingers so their nails get an embedded look to them- hypoplastic or embedded nails.
  85. High risk for a particular type of cardiovascular defect called coarctation of the aorta. Coarctation means narrowing, like stenosis, but they never call it a stenosis. It is essentially a narrowing of the distal aorta that interferes with blood reaching the lower part of your body. The typical baby with Turner’s will have big pulses in the arms but very little in the legs.
  86. These patients need to be on antibiotic therapy.
  87. [S20] Here is a baby that did not get aborted. Shows characteristic phenotype- lymphodema.
  88. [S21] Here is that lymphatic sac that does connect to the central venous system near the internal jugular like it is suppose to and so fluid backs up everywhere and it also interferes with cardiovascular development and the migration and development of the chest. Virtually everything is due to this so called jugulolymphatic obstruction.
  89. Klinefelter’s syndrome [S22]
  90. Gonozomal abnormality
  91. Extra copy of a chromosome, 47 XXY
  92. Phenotypic male, but not normal
  93. Long and thin
  94. Under development of secondary sex characteristics
  95. Mildly retarded with limited social skills
  96. 1 in 500 males
  97. Lesser % of these is going to have mosacism. They will have normal complement of 46 XY. The amount of this extra stuff may have something to do with how severely retarded, tall, or underdevelopment of secondary sex characteristics.
  98. Basic premises of autosomal dominant, recessive, and x- linked disorders [S23]
  99. Autosomal dominantdisorders[S24]
  100. Means you only have to have one copy of the gene to have the disorder
  101. Doesn’t matter what your sex is
  102. If you carry the gene you have a 50% chance of passing it on
  103. Usually one of your parents is affected.
  104. The only way for you to have it if neither of your parents do is for you to be a mutation or for one of your parents to have a mutation in their germ-line meaning that some of their ova or sperm would have that mutation and some of them would not. If you have an autosomal disorder and have a sibling with it as well, but neither parent has it, then that means that one of your parents have an affected germ-line.
  105. Clinical characteristics[S25]:
  106. Penetrance and expressivity:
  107. penetrance, in genetics, means the ability to look at someone and tell what disorder they have, there is a phenotypic expression of the disorder. Some disorders have 100% penetrance. The ones that don’t are still dominant disorders, just your ability to detect them by phenotypic reason is either 100% or not.
  108. Expressivity means that there are a collection of abnormalities that are associated with that autosomal dominant disorder and you may have all of them or just a couple.