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.
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.
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.
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.
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.
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.
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.
Q U E S T I O N S
8

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.
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.
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.
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.
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.
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.
WO R K S C I T E D
1. American Liver Foundation. (2015, January 14). Alagille Syndrome. Retrieved November 26, 2015, from
http://www.liverfoundation.org/abouttheliver/info/alagille/
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 http://www.sci-news.com/biology/article00891.html
3. Emw. (2009, December 15). Protein NOTCH2 PDB 2004 [Digital image]. Retrieved November 24, 2015, from
https://commons.wikimedia.org/wiki/File:Protein_NOTCH2_PDB_2oo4.png
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
https://www.youtube.com/watch?v=MSvCYVZiePk
6. Yale Medical Cell Biology, & Yale University. (n.d.). Portal Triad [Portal triad labels]. Retrieved November 27, 2015, from
http://medcell.med.yale.edu/systems_cell_biology/liver_and_pancreas_lab.php
7. King, D. G., & Southern Illinois University School of Medicine. (2010, September 9). Organization of liver lobules. Retrieved
November 27, 2015, from http://www.siumed.edu/~dking2/erg/liver.htm
15

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 http://ghr.nlm.nih.gov/condition/alagille-syndrome
9. Mayo Clinic Staff, & Derani, J., MD (Producers). (2015, October 8). Tetralogy of Fallot [Video file]. Retrieved November 27, 2015, from
http://www.mayoclinic.org/diseases-conditions/tetralogy-of-fallot/basics/definition/con-20043262
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 http://www.liver.ca/liver-disease/types/
alagille-syndrome.aspx
12.Neel, M. (2013, March 7). Xanthoma [Photograph of patient's knee showing multiple xanthoma tuberosum]. Retrieved November 27,
2015, from https://commons.wikimedia.org/wiki/File:Xanthoma.jpg
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://
phil.cdc.gov/Phil/details.asp
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 http://radiopaedia.org/articles/butterfly-vertebra
16

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
http://radiopaedia.org/articles/lumbosacral-transitional-vertebra
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 http://www.niddk.nih.gov/health-information/health-topics/kidney-disease/renal-tubular-acidosis-
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 http://eds.b.ebscohost.com/eds/detail/detail?vid=24&sid=25c7ceb6-
d7ea-4584-bfc9-bab5cceb1e57%40sessionmgr120&hid=112&bdata=JnNpdGU9ZWRzLWxpdmUmc2NvcGU9c2l0ZQ%3d
%3d#db=edb&AN=60263842&anchor=GoToAllQVI
17

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
https://www.youtube.com/watch?v=1kmU2CgXnyA
20.World Medical School (Producer). (2012, July 28). Renal Tubular Acidosis - USMLE step 2 review [Video file]. Retrieved
November 27, 2015, from https://www.youtube.com/watch?v=wr9v3C3eQHE
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
http://www.alagille.org/pdf/AGS_2011_Renal_Involvement_in_AGS_Dr_Lin.pdf
22.Admin. (2015, August 8). Kidney disease [Digital image]. Retrieved November 27, 2015, from
http://wikybrew.com/kidney-disease/
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 http://www.medscape.com/viewarticle/410658_2
24.Pitchal, F., Sample, I., & Cobris. (2011, October 12). Liver transplant [Digital image]. Retrieved November 27, 2015, from
http://www.theguardian.com/science/2011/oct/12/skin-liver-cells-inherited-disease
18

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 https://commons.wikimedia.org/wiki/File:Caproic_acid_acsv.svg
26.Calvero, & ChemDraw. (2007, January). Caprylic acid [Chemical structure of caprylic acid, aka octanoic acid.]. Retrieved
November 27, 2015, from https://commons.wikimedia.org/wiki/File:Caprylic_acid.svg
27.Calvero, & ChemDraw. (2007, March). Decanoic acid acsv [Chemical structure of decanoic acid.]. Retrieved November 27,
2015, from https://commons.wikimedia.org/wiki/File:Decanoic_acid_acsv.svg
28.Calvero, & ChemDraw. (2006, December). Lauric acid [Chemical structure of lauric acid.]. Retrieved November 27, 2015, from
https://commons.wikimedia.org/wiki/File:Lauric_acid.svg
29.American Heart Association. (2015, October 26). Tetralogy of Fallot. Retrieved November 27, 2015, from http://www.heart.org/
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://
www.achaheart.org/resources/for-patients/health-information/tetralogy-of-fallot.aspx
19

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 http://reference.medscape.com/article/926678-treatment
32.United States National Library of Medicine, & MedlinePlus. (2015, May 15). Cholestyramine resin: MedlinePlus drug
information. Retrieved November 27, 2015, from https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682672.html
33.Cardiac Health. (2015). Congenital heart tof [Digital image]. Retrieved November 28, 2015, from
http://www.cardiachealth.org/cardiac-healthcare-providers/surgical-anatomy/defects-with-a-right-to-left-shunt/tof
34.Clayton, M., Lonnemann, E., & Walker, W. (n.d.). Cyanosis [Digital image]. Retrieved November 28, 2015, from http://
www.physio-pedia.com/Tetrology_of_Fallot
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 http://www.genecards.org/cgi-bin/carddisp.pl?gene=JAG1
36.Genetic and Rare Diseases Information Center (GARD), & National Institutes of Health (NIH). (2015, November 27).
Chromosome 20 trisomy. Retrieved November 30, 2015, from https://rarediseases.info.nih.gov/gard/5332/chromosome-20-
trisomy/resources/1
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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 .