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MEDG 419 > Alagille Syndrome > Flashcards

Alagille Syndrome Flashcards

1
Q

What is Alagille Syndrome (ALGS)?

A

Complex multisystem disorder involving liver, heart, eyes, face and skeleton.

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2
Q

What are the main features of Alagille Syndrome (ALGS)?

A

cholestasis (due to bile duct paucity), congenital cardiac defects (pulmonary stenosis or Tetraology of Fallot), eye defects (posterior embryotoxon), vertebral defects (butterfly vertebrae), facial features (triangular face, deep set eyes, pointed chin)

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3
Q

What is the frequency of ALGS?

A

Fairly rare: one study estimates 1:70,000, another 1:30,000-50,000 live births
Likely underestimated

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4
Q

What is the genetic causation for ALGS?

A

• JAG1 (ligand) pathogenic variants in 89% of individuals with ALGS
• NOTCH2 (receptor) pathogenic variants found in 1-2% of individuals
• 30-50% of cases are inherited, rest are de novo.
– Autosomal dominant inheritance pattern, Haploinsufficiency is part of disease mechanism
– High penetrance but variable expressivity

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5
Q

What is Tetralogy of Fallot?

A

Pulmonary Infundibular Stenosis
Overriding aorta
Ventricular septal defect (VST)
Right ventricular hypertrophy

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6
Q

How does the heart tube form?

A

The heart tube is formed by adding cells from specific proliferation zones at the end of the tube.

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7
Q

How do cardiac chambers form?

A

After the tube is formed, the chambers proliferate on the outer curvature more than inner curvature to cause ballooning of chambers.

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8
Q

What does cardiac septation do?

A

divides the heart into the four chambers and divides the

outflow tract into the base of the aorta and pulmonary artery

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9
Q

What are the two parts of ventricular separation?

A

muscular and membranous
The muscular septum grows up from the apex on the heart between the left and right ventricles.
– Membranous septum comes from the AVC (atrioventricular canal) cardiac cushions.

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10
Q

Where does atrial station start?

A

starts from the dorsal mesenchyme

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11
Q

Outflow tract septation

A

partially arises from OFT cardiac cushions.

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12
Q

What is required to position the arteries properly and isolate the systemic and pulmonary blood flow?

A

Anticlockwise rotation of the OFT

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13
Q

What are the two atrioventricular valves?

A

mitral valve and tricuspid valve

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14
Q

What are the two semilunar valves in the outflow tract?

A

aortic valve and pulmonary valve

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15
Q

Heart valve formation (general progression)

A
  1. Heart looping
  2. Endothelial-to-mesenchymal transition (EMT),
  3. Valve remodelling in the cardiac cushions
  4. Adult AV valve results
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16
Q

What are cardiac cushions?

A

Swellings formed when myocardium in the AVC and OFT synthesize cardiac jelly (extra cellular matrix) in response to BMP signaling

17
Q

Valve formation is similar to what other tissue formation?

A

chondrogenesis, aka cartilage formation

18
Q

Valve formation

A
  1. Cardiac cushions form when myocardium in the AVC and OFT synthesizes cardiac jelly in response to BMP signalling
  2. Endocardial Cells undergo EMT and migrate to cardiac jelly to populate the cushions
  3. In the OFT, NCCs migrate to distal portion of the cardiac cushions
  4. Cells in cushions proliferate
  5. Cells are remodelled to form valve leaflets and portions of the separation
  6. Cushions become compacted and the ECM becomes highly organized into three zones
19
Q

How do cardiac cushions form?

A

Myocardium in the AVC and OFT synthesize cardiac jelly (extra cellular matrix) in response to BMP signaling.

20
Q

What regulates myocardium in the AVC and OFT to synthesize cardiac jelly?

A

BMP signalling

21
Q

Valve formation (summarized)

A
  1. Cardiac cushions form
  2. Endocardial Cells undergo EMT and migrate to cardiac jelly
  3. In the OFT, NCCs migrate to distal portion of the cardiac cushions
  4. Proliferation of cells in cushions remodel to forms valve leaflets and parts of septation
  5. Cushions compact and the ECM is organized
22
Q

What are the 3 zones the ECM is organized to when the cardiac cushions compact?

A

atrialis/ventricularis (elastin)
spongiosa (proteoglycans)
fibrosa (collagens)

23
Q

How do we know that Notch is important?

A
  1. Notch ligands and receptors are expressed in the developing valves.
  2. Gain and loss of function experiments demonstrate that Notch is required for EMT
  3. Notch cooperates with BMP and TGFβ in this process
  4. Notch signaling is also required for chamber formation.
24
Q

How do gain and loss of function experiments demonstrate that Notch is required for EMT?

A
  1. Notch intracellular domain (NICD) is a constitutively active or dominant positive
    • NICD expression in ventricular endocardium can induce mesoderm (EMT) phenotype in presence of BMP
  2. Loss of RBPJ (CSL,CBF1) causes failure to form mesenchyme in valve regions.
  3. Loss of Notch or expression of dominant-negative MAML (endothelial specific) blocks cellularization of AVC cushions
25
Q

HOW DOES HEART DEVELOPMENT RELATE TO TOF?

A

Errors in endocardial cushion formation and heart development can lead to impaired or poorly developed trabeculae. This can result in the incorrect formation of the OFT septa and valves which can cause symptoms of TOF

26
Q

TOF consists of 4 heart abnormalities…

A

A: Pulmonary Infundibular Stenosis
B: Overriding aorta
C: ventricular septal defect (VSD)
D: Right ventricular hypertrophy

27
Q

Heart formation overview?

A
  1. Heart tube proliferation
  2. Cardiac chambers septation
  3. Valve formation
28
Q

Summary:
• Heart valves form in the ___ and ___
• ___ are required to control blood flow
• Cardiac cushions are initiated by synthesis of ___ ___
• Cells undergo ___ from ___ to populate the cardiac cushions
• ___ signaling is critical for valve formation

A
  • Heart valves form in the AVC and OFT
  • Valves are required to control blood flow
  • Cardiac cushions are initiated by synthesis of cardiac jelly
  • Cells undergo EMT from endocardium is to populate the cardiac cushions
  • Notch signaling is critical for valve formation

MEDG 419 (26 decks)

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