A L A G I L L E S Y N D R O M EJ AC K S O N D AV 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

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

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JAG1 (>70%)

NOTCH2 (<30%)

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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

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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 SH E PAT I C C O N S I D E R A T I O N S

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T E T R A L O G Y O F FA L L O TC 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

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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

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Butterfly vertebrae

Normal vertebrae (thoracic section)

Image Credit16Posterior embryotoxon

Xanthomatosis (tuberosum)

RTA (Type II)

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T R E AT M E N T

• Hepatic allograft (usually orthotopic)

• MCFAs

• Lipid-soluble vitamins

• Cholestyramine (Rx)

• SBE prophylaxis

• Antihistaminic agents (for pruritus)

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Q U E S T I O N S

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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

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

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?

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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.

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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?

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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.

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WO R K S C I T E D15.Muzio, B. D., MD. (2015, July 18). Lumbosacral transitional vertebra: Sacralisation of L5 [Assimilation of L5 to the sacrum is

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31.Scheimann, A., MD, MBA, & Baldassano, R., MD. (2013, December 5). Alagille syndrome treatment & management. Retrieved

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34.Clayton, M., Lonnemann, E., & Walker, W. (n.d.). Cyanosis [Digital image]. Retrieved November 28, 2015, from http://

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trisomy/resources/1

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