Medical Genetics

1. Part III Medical Genetics

2. Autosomal Recessive Dz’s • Sickle Cell Disease • Genetics and Cell Level: • Point mutation in Beta-globin chain Glutamic acid to Valine Africans are most commonly affected

3. Autosomal Recessive Dz’s • Sickle Cell Disease • Clinical Presentation: • Heterozygotes usually clinically silent but added protection to malaria • requires > 90% HbS to sickle in systemic vasculature exception is in the renal papilla where oxygen tension is low enough to induce sickling but sometimes renal papillary necrosis

4. Autosomal Recessive Dz’s • Sickle Cell Disease • Clinical Presentation: • Homozygotes • Presents with sickle cell vaso-occlusive crises • Chest pain , bone pain • Fever, stroke • Abdominal pain • gallstones • Dactylitis  • painful swelling of the hands and feet

5. Question • Patients with the diagnosis of sickle cell anemia make a specific type of hemoglobin known as HgbS. This mutation results in the sickling of their red blood cells when exposed to inciting factors such as hypoxic conditions. Patients are often treated with hydroxyurea,

6. Which of the following has direct effects on their hemoglobin physiology ? 1. Increases oxygen carrying capacity of Hb. 2. Decreases oxygen carrying capacity of Hb. 3. Increases levels of fetal hemoglobin (HbF) 4. Decreases levels of HbS5. Decreases levels of fetal hemoglobin (HbF)

7. Question • A 7-year-old girl with a history of painful crises and impaired growth presents for evaluation of sicklecell disease. You perform hemoglobin gel electrophoresis, and diagnose her with homozygous sickle cell disease. Which of the gel electrophoresis lanes in the image is hers?         • 1. Lane 2 2. Lane 3 3. Lane 4 4. Lane 6 5. Lane 7

8. Question • A 17-year-old African-American male presents to his family physician after noticing red-tinged urine the week before, when he was suffering from a cold. The patient states that he had experienced that before. His father is with him and says that this happens to him on occasion as well. What is the most likely diagnosis for this patient? 1. Acute cystitis 2. Acute interstitial nephritis 3. Sickle cell trait 4. Acute glomerulonephritis 5. Hemophilia

9. X-Linked Recessive Dz’s • Fragile X (most common inherited form of retardation) • Genetics and Cell Level: • Expansion of CGG on chrom X (FMR1 gene), full mutation is > 200 repeats • Associated with chromosomal breakage (hence the name) http://www.yourgenesyourhealth.org/fragx/cause.htm

10. X-Linked Recessive Dz’s • Fragile X Clinical Presentation • Large Head • Large Ears • Large Testicles (Macroorchidism) • Mental Retardation • Testing: PCR, Southern Blot, Cytogenetic analysis

11. Question • A 4-year-old boy presents to his pediatrician for severe developmental delay. On exam he is noted to have macroorchidism, large protruding ears, a large jaw, and a long thin face. Suspicious of what the diagnosis may be, the pediatrician orders a PCR and DNA sequencing. The results reveal an expansion of 250 repeats of CGG.

12. What is the diagnosis of the boy? 1. Huntington's disease 2. Fragile X syndrome 3. Freidrich ataxia 4. Myotonic dystrophy type 1 5. Spinal and bulbar muscular atrophy

13. X-Linked Recessive Dz’s • Hemophilia A • Genetics and Cell Level: • Loss of Factor VIII • Increased PTT but normal PT and bleeding time

14. X-Linked Recessive Dz’s • Hemophilia A • Clinical Presentation: Increased PTT but normal PT and bleeding time • Bleeding can occur into many sites most common are joints, brain, muscles, and GI tract • Treatment is with Factor VIII • If dz is caused by low levels of Factor VIII and not loss then desmopressin can be used.

15. X-Linked Recessive Dz’s • Hemophilia B aka Christmas Dz • Genetics and Cell Level: • Loss of Factor IX • Clinical Presentation: Increased PTT but normal PT and bleeding time • Bleeding can occur into many sites most common are joints, brain, muscles, and GI tract • REVIEW THE CLOTTING CASCADE

16. X-Linked Recessive Dz’s • Hemophilia C aka Rosenthal Syndrome • Genetics and Cell Level: • Loss of Factor XI • Ashkenazi Jews • Clinical Presentation: Increased PTT but normal PT and bleeding time • Bleeding does not occur in joints!!! • Occurs while doing surgery • REVIEW THE CLOTTING CASCADE

17. X-Linked Recessive Dz’s • G6PD (aka Favism) • Genetics and Cell Level:

18. X-Linked Recessive Dz’s • G6PD (aka Favism) • Genetics and Cell Level: • Defect in glucose 6-phosphate dehydrogenase • Clinical Presentation: • Prolonged neonatal jaundice can be complicated by kernicterus • Acute hemolytic anemia in the presence of simple infection, fava beans, or rxn with certain medicines (antibiotics, antipyretics, and antimalarials) • Misc: Look for Heinz bodies on peripheral smear in active process

19. X-Linked Recessive Dz’s • G6PD (aka Favism) • Genetics and Cell Level:

20. Muscular Dystrophies • Duchenne’s • Genetics and Cell Level: • Frame shift mutation in dystrophin gene (DMD) leads to deletion and accelerated muscle breakdown. • Dystrophin anchors muscle fibers, primarily skeletal and cardiac muscles • Clinical Presentation: Dx by increased CPK and muscle biopsy, onset before age 5 • Weakness begins in pelvic girdle and progresses superiorly • Pseudohypertrophy of calf muscles 2/2 fibrofatty replacement of muscle • Misc: Look for use of Gower’s maneuver

21. Gower’s maneuver

22. Muscular Dystrophies • Duchenne’s

23. Muscular Dystrophies • Becker’s • Genetics and Cell Level: • Defect in dystrophin gene, less severe than Duchenne’s defect • Clinical Presentation: • Progressive muscle weakness, onset later than Duchenne’s • Note: Both Duchenes and Becker’s are associated with Heart Condition called Dilated Cardiomyopathy .

25. Reciprocal Translocation in germinal cells can give rise to deletions, amplifications The presence of this translocation is a highly sensitive test for CML, since 95% of people with CML have this abnormality.

27. Robertsonian Translocation In humans, generally occurs in the five acrocentric chromosome pairs, namely 13, 14, 15, 21 and 22

28. Robertsonian Translocation

29. Downs Mosiac

31. Autosomal Trisomies • Down Syndrome (Trisomy 21) (cont.) • 95% of cases due to meiotic nondisjunction of homologous chromosomes • Associated with advanced maternal age • 1:1500 at maternal age 20-24 • 1: 210 at maternal age 35-39 • 1: 25 at maternal age >45 • 4% of cases due to Robertsonian translocation • Long arm of chrom 21 is attached to another chromosome and is kept diploid during gametogenesis • 1% of cases due to Down mosaicism

32. Autosomal Trisomies • Down Syndrome (Trisomy 21) • Most common chromosomal disorder and most common cause of congenital mental retardation • Diagnosis done by triple screen • decra-fetoprotein, decr estriol, incr. b-hCG • Quad screen is above plus inhibin A (incr is +) • U/S shows increased nuchal translucency • Clinical Presentation: • Mental retardation, flat facies, prominent epicanthal folds, simian crease, duodenal atresia, congenital heart dz (septum primum type ASD), hypotonia • Misc: increased risk of ALL and Alzheimer's dz

33. Down Syndrome

35. Autosomal Trisomies • Edward’s Syndrome (Trisomy 18) • Edward’s = Eighteen • Most common trisomy in live birth after Down syndrome (1:8000) • Clinical Presentation: • Severe mental retardation, rocker-bottom feet, micrognathia, low-set ears, clenched hands, prominent occiput, congenital heart dz (ASD & VSD) • decra-fetoprotein, decr estriol, decr b-hCG • Inhibin is also decr • Misc: Death usually within one year of age

37. Autosomal Trisomies • Patau’s Syndrome (Trisomy 13) • Incidence is 1:15000 • Clinical Presentation: • Severe mental retardation, rocker-bottom feet, microphthalmia, microcephaly, cleft lip/Palate, holoProsencephaly, Polydactyly, congenital heart dz (ASD & VSD) (anyone see a theme??) • Misc: Death usually within 1 year of birth

39. Sex chromosomal Trisomies

40. Klinefelter syndrome Are males having one copy of extra X chromosome 47 XXY genotype Lower IQ Tall Stature Poor muscle Tone Gynecomastia Small Testis (infertility)

41. Triple X Syndrome (47 XXX) • Appear like normal females • Not diagnosed clinically • Diagnosed accidentally • Lyonization 47 XYY Syndrome • These guys are not superman • But they are tall • Have high achne level • Normal intelligence • Not aggressive as previously thought

42. Trisomy would feel left out without its partner! Generally, if a chromosomal mutations occurs during meiosis, one half of the gametes will have monosomy and the other half will have trisomy

43. Turner’s Syndrome • Females born with loss of 1 X chromosome • Genotype is 45 XO • Occurs due to non dysjunction

44. Turner’s Syndrome • Features includes short stature, short broad neck, and a broad chest. • Intelligence does not seem to be affected • It is NOT linked maternal age. • Cardiac abnormalities coarctation of aorta & Bicuspid aortic valve • Women with Turner's syndrome can live relatively normal lives, though they are unable to bear children.

45. Turner’s Syndrome • Develop Osteoporosis? • No Ovaries (dysgenic Ovaries, hence estrogen deficiency • Hearing Loss • Horseshoe shaped Kidney • Lymphedema of feet

46. Cri-du-Chat syndrome • Genetics and Cell Level: • Congenital microdeletion of short arm of chromosome 5 (46 XX or XY, 5p-) • Clinical Presentation: • Microcephaly, moderate to severe mental retardation, epicanthal folds, cardiac abnormalities • Misc: Cri-du-chat is French for cry of the cat. The disease is named this way as the children affected make a high pitched mewing/crying sound.

47. Cri du Chat Cry of the Cat individuals sound like cats crying. Why? The larynx of the child is improperly developed.

48. Williams syndrome • Genetics and Cell Level: • Congenital microdeletion of long arm of chromosome 7 (46 XX or XY, 7q-) which includes the elastin gene

49. Williams syndrome • Clinical Presentation: • Distinctive “elfin” facies • mental retardation • well-developed verbal skills • cheerful disposition, extreme friendliness with strangers • cardiovascular problems