1. Medical Genetics
Part III

2. Autosomal Recessive Dz’s
Sickle Cell Disease
Genetics and Cell Level:
Point mutation in Beta-globin
chain
Glutamic acid to Valine
Don’t forget about hemoglobin C which can also add to HbS and cause Sickle cell dz
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
Don’t forget about hemoglobin C which can also add to HbS and cause Sickle cell dz

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
Don’t forget about hemoglobin C which can also add to HbS and cause Sickle cell dz

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 Increases levels of fetal hemoglobin (HbF) 4. Decreases levels of HbS 5. 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 sickle cell 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 Lane Lane Lane 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)

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 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
decr a-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)
decr a-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.
This was on my Step 1 so it is important!

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

51. END PART III (NEXT >>>>>>>>>Gene Therapy)