Physiology Correlations for Mendelian Forms of Hypertension

Question 1

Describe the presentation of AME (Syndrome of Apparent Mineralocorticoid excess)

Answer 1

• Low birth weight
• Failure to thrive
• Severe hypertension in early childhood
• Extensive organ damage
• Renal failure

Question 2

In AME, what happens with plasma renin and aldosterone levels?

Answer 2

Low plasma renin activity

Low plasma aldosterone levels

Question 3

What gene defect is seen in AME?

Answer 3

11-ß-HSD2 gene

Question 4

What is the function of 11-ß HSD2?

How does its function aid in diagnosis of AME?

Answer 4

Converts cortisol to cortisone

Meausre urine cortisol to cortisone ratio - in most patients with a defective enzyme, the urinary free cortisone levels are very low or undetectable

Question 5

What type of inheritance is associated with AME?

Answer 5

Autosomal recessive

Question 6

Liddle syndrome is also known as ____________

Answer 6

Pseudoaldosteronism

Question 7

What characteristics are associated with pseudoaldosteronism?

Answer 7

• Hypertension - young onset, severe
• Hypokalemia
• Metabolic Alkalosis

Question 8

What RAA system components have low levels and activity in pseudoaldosteronism (Liddle syndrome)

Answer 8

Low plasma renin activity

Low plasma aldosterone AND urinary aldosterone

Question 9

What genes can be sequenced to confirm the diagnosis of Pseudoaldosteronism

Answer 9

SCNN1G

SCNN1B

Question 10

Liddle syndrome is associated with a _____ __ ______mutation in the renal _____ channel

Answer 10

gain of function; ENaC

Question 11

Mutations in LIddle Syndrome lead to increased absorption of _______ leading to hypertension

Answer 11

sodium

Question 12

Where does aldosterone act and what function does it serve?

Answer 12

• Acts in principal cells of late distal tubule and collecting duct
• Increases Na⁺ reabsorption , increases K⁺ secretion

Question 13

Cortisol and aldosterone can bind to the mineralcorticoid receptor with equal affinity but aldosterone is the primary effector. Why is this?

Answer 13

Cortisol is quickly converted to cortisone upon entering into the cell

Question 14

What medication is used to reduce endogenous cortisol production (decrease sodium channel activity) in AME?

Answer 14

Amiloride

Triamterene

Question 15

What medications block the mineral corticoid receptor in AME?

Answer 15

Spironolactone

Eplerenone

Question 16

Other therapies for AME treatment?

Answer 16

Potassium repletion

Dexamethasone for ACTH suppression

Question 17

How does Bartter syndrome present?

Answer 17

• Early childhood
• Growth and mental retardation
• Polyuria and Polydipsia
• Hypercalciuria

Question 18

How does Gitelman syndrome present?

Answer 18

• Adolescence/Adulthood
• Cramping of arms and legs
• Fatigue
• Hypomagnesemia
• Polyuria and nocturia

Question 19

What are the clinical findings in Bartter syndrome?

Answer 19

Hypokalemia

Hyperreninemia

Hyperaldosteronism

Metabolic Alkalosis

Question 20

What pattern of inheritance is associated with Gitelman syndrome?

Answer 20

Autosomal recessive

Question 21

Which portion of the renal tubule has the following characteristics…

Reabsorbs 25% of filtered Na+

Impermeable to water

Drives reabsorption of sodium, potassium, magnesium, and calcium

Answer 21

Thick ascending loop of Henle

Question 22

What part of the renal tubule is succeptible to thiazide diuretics?

Answer 22

Early distal tubule

Question 23

What genes are mutated in Bartter syndrome?

Answer 23

Genes that encode proteins in the ascending part of Henle’s loop:

BSND, CLCNKA, CLCNKB, KCHJ1, SLC12A1

Question 24

What genes are mutated in Gitelman Syndrome?

Answer 24

Mutations in SLC12A3 or less commonly CLCNKB

Question 25

In Bartter syndrome, tubular defect mimics chronic _____ _______ injestion

Answer 25

loop diuretic

Question 26

In Gitelman syndrome, tubular defect mimics ______ _______ ingestion

Answer 26

thiazide diuretic

Question 27

Which disease (Bartter syndrome or Gitelman syndrome) has a worse prognosis?

Answer 27

Bartter syndrome (life expectancy is reduced in severe cases)