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Alagille Syndrome – A Brief Overview

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Slides from an Apple Keynote presentation given by Jackson David Reynolds on December 1, 2015 at the University of North Georgia, Gainesville campus for Dr. Jeanelle Morgan, PhD’s Genetics course.

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Alagille Syndrome – A Brief Overview

  1. 1. A L A G I L L E S Y N D R O M E J AC K S O N DAV I D R E Y N O L D S U N I V E R S I T Y O F N O RT H G E O R G I A
  2. 2. B A S I C S • Autosomal dominant • Jagged 1/notch 2 • 1 in ~100,000 live births • Multi-system presentation • Chief focuses: • Hepatic • Cardiac • Dz stabilization in late childhood Image Credit2 Image Credit3 JAG1 (>70%) NOTCH2 (<30%) Reference1,5,8,11,19,35 2
  3. 3. S A M E M U TAT I O N ; D I F F E R E N T R E S U LT S 3 Reference4
  4. 4. P O R TA L T R I A D PAT H O L O G I C A L R A M I F I C AT I O N S H E PAT I C C O N S I D E R A T I O N S Image Credit134 Reference1,5,7,8,11,19 Image Credit6
  5. 5. Image Credit33 Reference1,8,9,10,16,18,19,29,30 T E T R A L O G Y O F FA L L O T C A R D I A C C O N S I D E R A T I O N S 1. VSD 2. RVOT obstruction (usually PS) 3. RVH 4. Overriding aorta Image Credit34 5
  6. 6. R E N A L , D E R M AT O L O G I C , O R T H O P E D I C , & O P H T H A L M O L O G I C PAT H O L O G I E S O T H E R S Y S T E M I C C O N S I D E R A T I O N S Reference1,8,,11,16,17,18,19 6 Image Credit12 Image Credit14,15 Butterfly vertebrae Normal vertebrae (thoracic section) Image Credit16 Posterior embryotoxon Xanthomatosis (tuberosum) RTA (Type II) Image Credit23,22
  7. 7. T R E AT M E N T • Hepatic allograft (usually orthotopic) • MCFAs • Lipid-soluble vitamins • Cholestyramine (Rx) • SBE prophylaxis • Antihistaminic agents (for pruritus) Image Credit25,26,27,28 Image Credit24Reference1,5,8,11,19,31 7
  8. 8. Q U E S T I O N S 8
  9. 9. Q U E S T I O N 1 Q. The JAG1 and NOTCH2 gene products interact with one another in a wild-type individual. JAG1 functions as one of five ligands to which the transmembrane proteins in the notch signaling pathway (including NOTCH2) can selectively bind. Proteins in the notch family participate in intracellular cell signaling cascades which secondarily serve to regulate the biochemistry (and potentially, the proliferative behavior) between physically proximate cells. Despite the interaction of JAG1 and NOTCH2 gene products, these two proteins (as seen in SLIDE 2) are very different, with the JAG1 product possessing a markedly lesser degree of higher-level structure than is the case for the NOTCH2 protein product. Taking all this into consideration, what is a likely explanation for the fact that an independent mutation in either gene results in virtually identical pathological presentations across any given sample of varied individuals? 9 Reference1,5,8,11,19,35
  10. 10. Q U E S T I O N 1 A. Both gene products are quite different, to be sure, but because they are ultimately both critically involved in the same cell-signaling pathway(s), the effects of a mutation in either gene are, in general, likely to engender similar (and in this case, virtually identical) effects on the system regulated by the cascade. 10 Reference1,5,8,11,19,35
  11. 11. Q U E S T I O N 2 Q. Non-mosaic trisomy of chromosome 20 is rare in humans and generally results in the death and spontaneous abortion of such a trisomy 20 fetus prior to the completion of the first trimester of pregnancy. Mosaic trisomy 20, however, in which only a portion of an individual’s cells are trisomic for chromosome 20, usually results in a viable fetus and a phenotypically normal individual. Considering that the locus of the JAG1 gene is on the p arm of chromosome 20, what might be the potential ramifications of a JAG1 mutation in an individual with a mosaic trisomy 20? 11 Reference19,36
  12. 12. Q U E S T I O N 2 A. Assuming that the mutant JAG1 gene on each copy of chromosome 20 is transcribed at least part of the time in the trisomic cells, the dosage effect of double the mutant JAG1 gene product in the body during embryonic development would likely result in a far more severe symptomatic presentation of the multiple pathologies characteristic of Alagille syndrome in a wild type (disomic) individual, if such a fetus could be brought to term at all.* *NOTE: This question is an interesting one, but the provided answer is largely speculative. To date, I have come across no literature in which a mosaic trisomy 20 individual with a JAG1 (or, for that matter, NOTCH2) mutation is discussed. 12 Reference8,19,36
  13. 13. Q U E S T I O N 3 Q. The chief pathology of Alagille syndrome is congenital and progressive stenosis of the hepatic bile ducts, resulting in chronic hyperbilirubinemia, xanthomatosis from systemic lipid buildup, potential hepatic cirrhosis, and a host of other nefarious liver-derived pathologies. Considering that individuals with Alagille syndrome also frequently suffer serious cardiac issues, with Teratology of Fallot among these being especially common and notable, what might be the potential cardiac implications of the chronic hyperlipidemia caused by the poor hepatic function characteristic of the disease? 13 Reference1,5,7,8,11,16,17,18,19
  14. 14. Q U E S T I O N 3 A. Given the well established link between hyperlipidemia (especially hypertriglyceridemia and hypercholesterolemia) and the development of coronary artery disease, especially when the former is the physiological status quo for an extended period of time, it seems reasonable to assume that individuals with Alagille syndrome may well be at a higher risk to suffer compounded cardiac pathologies later in life, as an already weakened heart is forced to cope with the problems which arise from stenotic and atherosclerotic coronary arteries, myocardial infarction being chief among them. 14
  15. 15. WO R K S C I T E D 1. American Liver Foundation. (2015, January 14). Alagille Syndrome. Retrieved November 26, 2015, from 2. Prostak, S. (2013, February 20). Structure of the jagged 1 protein and the location of the JAG1 gene on the short arm of chromosome 20 [Digital image]. Retrieved November 26, 2015, from 3. Emw. (2009, December 15). Protein NOTCH2 PDB 2004 [Digital image]. Retrieved November 24, 2015, from 4. Kamath, B. M., Bason, L., Piccoli, D. A., Krantz, I. D., & Spinner, N. B. (2003). Consequences of JAG1 mutations [Abstract]. Journal of Medical Genetics, 112(2), 163-170. doi:10.1136 5. The Children's Hospital of Philadelphia (Producer). (2010). Alagille syndrome overview - the children's hospital of Philadelphia [Video file]. United States of America: The Children's Hospital of Philadelphia. Retrieved November 26, 2015, from 6. Yale Medical Cell Biology, & Yale University. (n.d.). Portal Triad [Portal triad labels]. Retrieved November 27, 2015, from 7. King, D. G., & Southern Illinois University School of Medicine. (2010, September 9). Organization of liver lobules. Retrieved November 27, 2015, from 15
  16. 16. WO R K S C I T E D 8. Genetics Home Reference, & United States National Library of Medicine. (2015, November 23). Alagille syndrome. Retrieved November 27, 2015, from 9. Mayo Clinic Staff, & Derani, J., MD (Producers). (2015, October 8). Tetralogy of Fallot [Video file]. Retrieved November 27, 2015, from 10.Sims, S. L., RN, PhD. (1994). Alterations of cardiovascular function in children. In K. L. McCance RN, PhD & S. E. Huether RN, PhD (Authors) & S. Schrefer (Ed.), Pathophysiology: The biological basis of disease in adults and children (2nd ed., pp. 1105-1107). St. Louis, MO: Mosby-Year Book. 11.Canadian Liver Foundation. (2015). Alagille syndrome. Retrieved November 27, 2015, from alagille-syndrome.aspx 12.Neel, M. (2013, March 7). Xanthoma [Photograph of patient's knee showing multiple xanthoma tuberosum]. Retrieved November 27, 2015, from 13.Hudson, & Centers for Disease Control and Prevention Public Health Image Library (PHIL). (1967). 5604 [This 6 week old female presented with symptoms of jaundice, which was proven to be due to hypothyrodism.]. Retrieved November 27, 2015, from http:// 14.Byrne, A., & Goel, A., MBBS, DNB. (2010, January 13). Case 1 [Butterfly vertebra in a 2 year old boy with VATER syndrome who also has a tracheoesophageal fistula.]. Retrieved November 27, 2015, from 16
  17. 17. WO R K S C I T E D 15.Muzio, B. D., MD. (2015, July 18). Lumbosacral transitional vertebra: Sacralisation of L5 [Assimilation of L5 to the sacrum is more common than lumbarisation of S1, occurring in ~17% of the population.]. Retrieved November 27, 2015, from 16.Turnpenny, P. D., & Ellard, S. (2012). Alagille syndrome: Pathogenesis, diagnosis and management. European Journal of Human Genetics, 23(3), 251-257. doi:10.1038/ejhg.2011.181 17.DuBose Jr., T., MD, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), & Wake Forest University Baptist Medical Center. (2010, September). Renal Tubular Acidosis. Retrieved November 27, 2015, from rta/Pages/facts.aspx 18.Bonegio, R. B., Beck, L. H., Kahlon, R. K., Weining, L., & Salant, D. J. (2011). The fate of notch-deficient nephrogenic progenitor cells during metanephric kidney development. (International Society of Nephrology, Ed.). Kidney International, 79(10), 1099-1112. Retrieved November 27, 2015, from d7ea-4584-bfc9-bab5cceb1e57%40sessionmgr120&hid=112&bdata=JnNpdGU9ZWRzLWxpdmUmc2NvcGU9c2l0ZQ%3d %3d#db=edb&AN=60263842&anchor=GoToAllQVI 17
  18. 18. WO R K S C I T E D 19.Membership Examination of the Royal College of Paediatrics and Child Health (MRCPCH) Revision (Producer), & Soto, C., MRCPCH (Writer). (2015, April 20). Alagille syndrome [Video file]. Retrieved November 25, 2015, from 20.World Medical School (Producer). (2012, July 28). Renal Tubular Acidosis - USMLE step 2 review [Video file]. Retrieved November 27, 2015, from 21.Lin, H. C., MD. (2011, June 25). Renal Involvement in alagille syndrome. Lecture presented at 5th International Symposium on Alagille Syndrome in Hilton Orrington, Evanston, Chicago, Illinois. Retrieved November 27, 2015, from 22.Admin. (2015, August 8). Kidney disease [Digital image]. Retrieved November 27, 2015, from 23.Kurtzman, N. A., Southern Medical Journal, Corgan, & Morris. (2009). Figure 1 [Potential cellular mechanisms of proximal (type 2) renal tubular acidosis.]. Retrieved November 27, 2015, from 24.Pitchal, F., Sample, I., & Cobris. (2011, October 12). Liver transplant [Digital image]. Retrieved November 27, 2015, from 18
  19. 19. WO R K S C I T E D 25.Calvero, & ChemDraw. (2007, March). Caproic acid acsv [Chemical structure of caproic acid.]. Retrieved November 27, 2015, from 26.Calvero, & ChemDraw. (2007, January). Caprylic acid [Chemical structure of caprylic acid, aka octanoic acid.]. Retrieved November 27, 2015, from 27.Calvero, & ChemDraw. (2007, March). Decanoic acid acsv [Chemical structure of decanoic acid.]. Retrieved November 27, 2015, from 28.Calvero, & ChemDraw. (2006, December). Lauric acid [Chemical structure of lauric acid.]. Retrieved November 27, 2015, from 29.American Heart Association. (2015, October 26). Tetralogy of Fallot. Retrieved November 27, 2015, from HEARTORG/Conditions/CongenitalHeartDefects/AboutCongenitalHeartDefects/Tetralogy-of- Fallot_UCM_307038_Article.jsp# 30.Ammash, N., MD, & Adult Congenital Heart Association. (n.d.). Tetralogy of Fallot. Retrieved November 27, 2015, from http:// 19
  20. 20. WO R K S C I T E D 31.Scheimann, A., MD, MBA, & Baldassano, R., MD. (2013, December 5). Alagille syndrome treatment & management. Retrieved November 27, 2015, from 32.United States National Library of Medicine, & MedlinePlus. (2015, May 15). Cholestyramine resin: MedlinePlus drug information. Retrieved November 27, 2015, from 33.Cardiac Health. (2015). Congenital heart tof [Digital image]. Retrieved November 28, 2015, from 34.Clayton, M., Lonnemann, E., & Walker, W. (n.d.). Cyanosis [Digital image]. Retrieved November 28, 2015, from http:// 35.Gene Cards Human Gene Database, LifeMap Sciences, Inc., BioTime, Inc., & Weizmann Institute of Science. (2015). JAG1 gene (protein coding). Retrieved November 28, 2015, from 36.Genetic and Rare Diseases Information Center (GARD), & National Institutes of Health (NIH). (2015, November 27). Chromosome 20 trisomy. Retrieved November 30, 2015, from trisomy/resources/1 20
  21. 21. J A C K S O N D AV I D R E Y N O L D S 2 0 1 5 P U B L I S H E D U N D E R A C R E A T I V E C O M M O N S L I C E N S E . R E U S E A L L O W E D W I T H A T T R I B U T I O N .