USMLE STEP I Review Week 2: Genetics

1. Steven Katz, MSIV USMLE STEP I Review Week 2: Genetics

2. Genetics Terms • Basic Terms (Review) • Gene: A hereditary unit consisting of a sequence of DNA that occupies a specific location on a chromosome and determines a particular characteristic in an organism. • Trait: A distinguishing feature, a genetically determined characteristic or condition. • Allele: Versions of a gene • Genotype: Genetic makeup, distinguished from the physical appearance. (G for genetic and genotype) • Phenotype: The observable physical or biochemical characteristics as determined by both genetic makeup and environment

3. Genetics Terms (cont.) • High Yield Terms: • Classical Dominance: Dominant allele is expressed if present • Incomplete Penetrance: Not all individuals with a mutant genotype display the phenotype (many genetics dz’s but good example is NF1) • Variable Expression: Nature and severity of phenotype changes between individuals • Co-dominance: Neither of two alleles is dominant (e.g. blood types) • Anticipation: Severity of disease worsens or age of onset is earlier in succeeding generations (e.g. Huntington’s Dz)

4. Genetics Terms (cont.) • High Yield Terms (cont.) • Loss of heterozygosity: When a tumor suppressor gene is mutated or deleted, the complimentary allele must be lost before a cancer develops. Not true with oncogenes! • Dominant negative mutation: a non-functioning protein also prevents a normal protein from functioning appropriately (e.gMarfan’s syndrome) • Heteroplasmy: Both NL and mutmtDNA results in variable expression in mitochondrial inherited dz’s • Uniparentaldisomy: offspring receives 2 copies of a chromosome from 1 parent and none from the other

5. Imprinting • Definition: At a single locus, only one allele is active, the other is inactive; can also occur as a result of uniparentaldisomy • Phenotype depends on origin of mutation  paternal v. maternal • Both syndromes due to inactivation or deletion of genes on chromosome 15 • Prader-Willi: Deletion of normally active PATERNAL allele • Mental retardation, obesity, hypogonadism, hypotonia • Angelman’s syndrome (aka “Happy Puppet Syndrome”): Deletion of normally active MATERNAL allele • Mental retardation, seizures, ataxia, innapropriate laughter

6. Modes of Inheritance • Autosomal Dominant: Affects both males and females in all generations. Presents clinically after puberty and FH is essential for diagnosis. • Examples: Achondroplasia, Huntington’s dz, Neurofibromatosis types 1 & 2, and many many more!

7. Modes of Inheritance • Autosomal Recessive: only offspring of 2 carrier parents can be affected. Usually only seen in one generation, usually due to enzyme deficiencies. • Commonly more severe than dominant disorders, presents in childhood • Examples: Albinism, Cystic Fibrosis, PKU, Wilson’s dz, and many more!

8. Modes of Inheritance • X-linked recessive: only sons of heterozygous mothers can be affected, no father to son transmission. • Examples: Fragile X, Lesch-Nyhan, Hemophilia A and B • Females may rarely be affected due to random inactivation of X chrom (e.g. Lyonization)

9. Modes of Inheritance • X-linked dominant: Transmitted through both parents, males and females can be affected, but all females of affected fathers are affected. • Example- • Hypophosphatemic rickets: increased phosphate wasting at proximal tubule

10. Modes of Inheritance • Mitochondrial: Transmission ONLY through the mother. All offspring of affected mothers are affected. • Variable expression due to heteroplasmy

11. Autosomal Dominant Dz’s • Achondroplasia • Genetics and Cell Level: • Defect in Fibroblast Growth Factor receptor 3 • Causes abnormal cartilage development • Phenotypic Traits: • Dwarfism: short limbs, head and neck nl size • Misc info: • Associated with advance paternal age • AD so if one parent affected then 50% of children affected • Homozygotes die either before or shortly after birth

12. Autosomal Dominant Dz’s • APKD (adult polycystic kidney dz) • Genetics and Cell Level: • 90% due to mut in APKD1 on chromosome 16 • Phenotypic Traits: • Bilateral enlargement of kidney due to multiple cysts • Clinical Presentation: b/l flank pain, hematuria, HTN, progressive renal failure • Usually presents in adulthood (hence the name!) • Misc info: • Associated with polycystic liver dz, berry aneurysms, MVP

13. APKD

14. Autosomal Dominant Dz’s • Familial AdenomatousPolyposis • Genetics and Cell Level: • Deletion on chromosome 5q21-22 (APC gene) • Phenotypic Traits: • Colon covered with polyps after puberty that progress to cancer if not resected • Clinical Presentation: anemia, melena, changes in bowel habits • Misc info: • Will need colonoscopies early and often

15. FAPCC

16. Autosomal Dominant Dz’s • Familial hypercholesterolemia (HLP type 2A) • Genetics and Cell Level: • Defective or absent LDL receptor • Heterozygotes (1:500) ~ 300 mg/dl • Homozygotes (very rare) ~ 700+ mg/dl • Phenotypic Traits: • Xanthelasma palpebrarum, tendon xanthomas (classically on the Achilles tendon), severe atherosclerotic dz, MI may develop early

17. Familial Hypercholesterolemia

18. Autosomal Dominant Dz’s • Huntington’s Disease • Genetics and Cell Level: • Gene located on Chromosome 4, trinucleotide repeat disorder (CAG)n • Decreased levels of GABA and Ach in the brain • Clinical Presentation: depression, progressive dementia, choreiform movements, caudate atrophy • Usually presents between the ages of 20 to 50 • Misc info: • Age of onset is variable but typically the more repeats you have the earlier the onset of the disease • Watch out for ethical issues!

19. Autosomal Dominant Dz’s • Marfan’s Syndrome • Genetics and Cell Level: • Mutation in the fibrillin gene (Chrom 15) • Phenotypic Traits: • Connective tissue disorder affecting skeleton, heart, and eyes • Clinical Presentation: tall with long extremities, pectusexcavatum, hyperextensive joints, and long tapering fingers and toes • Misc info: • Cystic medial necrosis of the aorta leads to aortic incompetence and dissecting aortic aneurysms • Floppy mitral valve • Subluxation of lenses

20. Marfan’s Syndrome

21. Autosomal Dominant Dz’s • Multiple Endocrine Neoplasia (MEN)

22. Autosomal Dominant Dz’s • Neurofibromatosis 1 (NF1/von Recklinghausen’s dz) • Genetics and Cell Level: • Mutation on chromosome 17q11 (long arm of 17) • Clinical Presentation: café-au-lait spots, neural tumors, Lisch nodules (pigmented iris hamartomas) • Misc info: • Increased incidence of pheochromocytomas, susceptibility to tumors, and skeletal disorders

23. NF1

24. Autosomal Dominant Dz’s • Neurofibromatosis 2 (NF2) • Genetics and Cell Level: • Mutation on chromosome 22q12 • Clinical Presentation: bilateral acoustic neuromas on CN8, juvenile cataracts • Tumors may cause tinnitus, HA, hearing loss, balance problems, vertigo, etc.

25. Autosomal Dominant Dz’s • Tuberous Sclerosis • Genetics and Cell Level: • Incomplete penetrance, 2/3 of new cases arise from spontaneous mutations • Clinical Presentation: facial lesions (adenoma sebaceum), hypopigmented “ash leaf spots”, cortical and retinal hamartomas, seizures, mental retardation, renal cysts and angiomyolipomas, cardiac rhabdomyomas, increased incidence of astrocytomas • Misc: • Needless to say presentation is VERY variable

26. Tuberous Sclerosis:“Ash Leaf Spot”

27. Autosomal Dominant Dz’s • Von Hippel-Lindau disease • Genetics and Cell Level: • Deletion of VHL gene (tumor suppressor) on chromosome 3, results in expression of HIF and activation of angiogenic growth factors • Phenotypic Traits: • Hemangioblastomas of retina/cerebellum/medulla • About ½ of affected develop multiple b/l renal cell carcinomas and other tumors • Clinical Presentation: miscellaneous can be discomfort from growing tumors or blindness 2/2 tumors in retina

28. Autosomal Recessive Dz’s • a1-antitrypsin deficiency • Genetics and Cell Level: • Serine protease inhibitor important for elastase • Clinical Presentation: COPD and cirrhosis in early adulthood • Misc: • Important when presented with pt who has COPD sx’s and has only smoked for a few years • PiMM: 100% (normal) • PiMS: 80% of normal serum level of A1AT • PiSS: 60% of normal serum level of A1AT • PiMZ: 60% of normal serum level of A1AT • PiSZ: 40% of normal serum level of A1AT • PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency) • PiZ is caused by a glutamate to lysine mutation at position 342 • PiS is caused by a glutamate to valine mutation at position 264

29. Autosomal Recessive Dz’s • Cystic Fibrosis: this one is important • Genetics and Cell Level: • CFTR gene mutation on chrom 7 DF508 classically (loss of phenylalanine) • Defective Cl channel • Clinical Presentation: secretion of abnl thick mucus into lungs, pancreas, and liver • Pulm infections (P. aeruginosa and S. aureus) • Chronic bronchitis, bronchiectasis, pancreatic insufficiency, male infertility (absence of vas deferens)

30. Autosomal Recessive Dz’s • Cystic Fibrosis (cont.) • Diagnosis: • increased concentration of Cl in sweat test • Treatment: • N-acetylcysteine to loosen mucus plugs • Misc: • If presented with . . . THINK CF! • newborn with meconium ileus or failure to thrive • Fat soluble vitamin deficiency • Pancreatic insufficiency

31. Autosomal Recessive Dz’s • PKU • Genetics and Cell Level: • Defect in phenylalanine hydroxylase which converts Phe to Tyr • Clinical Presentation: Mental retardation, seizures, albinism, “musty odor” to urine and sweat • Misc: • Very treatable diet low in Phe and high in Tyr • Newborn screening is Mandatory!

32. Autosomal Recessive Dz’s • Sickle Cell Disease • Genetics and Cell Level: • Point mutation in Beta-globin chain • Glutamic acid to Valine • Clinical Presentation: • Heterozygotes usually clinically silent but added protection to malaria • Homozygotes: symptoms are complications of sickled RBC  must be vaccinated against S. pneumo before loss of spleen • Hyposplenism, vaso-occlusive crises, many other complications including priaism, stroke, etc. • Misc: Parvovirus B19 can cause aplastic crisis • Treatment: Hydroxyurea, Folic acid, pain control for vaso-occlusive crises

33. 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) • Clinical Presentation • Mental retardation ranges from mild to severe • Also autism, elongated face, large or protruding ears, flat feet, macroorchidism, and low muscle tone • Fragile X = eXtra-large testes, jaw, and ears • Misc: Presentation is variable but si/sx fall into six classic categories • Intelligence and learning • Physical • Social and emotional • Speech and language • Sensory • Disorders commonly associated or sharing features with Fragile X

34. X-Linked Recessive Dz’s • Hemophilia A • Genetics and Cell Level: • Loss of Factor VIII • 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

35. 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

36. 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

37. G6PD

38. 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

39. Gower’s maneuver

40. 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 • Misc: dx is similar to Duchenne’s

41. 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, 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

42. 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

43. Down Syndrome

44. 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 • Misc: Death usually within one year of age

45. 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 (anyone see a theme??) • Misc: Death usually within 1 year of birth

46. Nondisjunction

47. 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.

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

49. 22q11 deletion syndromes • Variable presentation includes • Cleft palate • Abnormal facies • Thymic aplasia which leads to T-cell deficienies • Cardiac defects • Hypocalcemia 2/2 parathyroid aplasia • CATCH-22

50. 22q11 deletion syndromes • Aberrant development of 3rd and 4th branchial pouches • DiGeorge Syndrome: • Thymic, parathyroid (hypocalcemia), and cardiac defects • Cardiac defects include Tetralogy of Fallot, VSD, and perisistent truncus arteriosus • Velocardiofacial syndrome: • Palate, facial, and cardiac defects