Mendelian Forms of Hypertension - Liang

Question 1

Syndrome of Apparant Mineralocorticoid Excess (AME)

When does it present?

Answer 1

Can be suspected at birth, due to low birth weight and FTT.

Very apparant by early childhood - severe HTN

Question 2

Syndrome of Apparant Mineralocorticoid Excess (AME)

What ion balance issues are present? Why?

Answer 2

• Hypokalemia
• Metabolic alkalosis

Overactivation of ENaC leads to increased potassium and hydrogen secretion.

Question 3

Syndrome of Apparant Mineralocorticoid Excess (AME)

What hormone disturbances are there?

Answer 3

• Low plasma renin activity
• Low plasma aldosterone levels

Question 4

Syndrome of Apparant Mineralocorticoid Excess (AME)

How can AME be differentiated from Primary Aldosteronism?

Answer 4

• AME has low plasma aldosterone levels
• PA has high plasma aldosterone levels

Question 5

Syndrome of Apparant Mineralocorticoid Excess (AME)

How can AME be diagnosed from lab findings?

What gene can be sequenced to confirm the diagnosis?

Answer 5

Lab: Measure urine cortisol to cortisone ratio. Most pts with AME will have very low or undetectable free cortisone levels.

Genetics: Gene sequencing of the 11ß-HSD2 gene

Question 6

Syndrome of Apparant Mineralocorticoid Excess (AME)

How is AME inherited?

Answer 6

Autosomal recessive

• Often from consanguinous relationship
• Affected sibs more common than affected family members from previous generations

Question 7

Syndrome of Apparant Mineralocorticoid Excess (AME)

Why does a defect in 11ß-HSD2 lead to AME? Describe the pathogenesis.

Answer 7

11ß-HSD2 converts cortisol to cortisone. Without functional 11ß-HSD2, an excess of cortisol is present. Like aldosterone, cortisol upregulates the ENaC channel among other things, leading to increased sodium reabsorption and thus water reabsorption as well.

Question 8

Liddle Syndrome

What is its other name?

When does it present?

Answer 8

Pseudoaldosteronism

“Young onset”, severe

Question 9

Liddle Syndrome

What ion balance disturbances are there? Why?

Answer 9

• Hypokalemia
• Metabolic alkalosis

Overactivation of ENaC leads to increased potassium and hydrogen secretion.

Question 10

Liddle Syndrome

What hormone distrubances are there?

Answer 10

• Low plasma renin activity
• Low plasma and urinary aldosterone

Question 11

Liddle Syndrome

A mutation in what protein(s) causes this disease?

What type of mutation is this?

Gene sequencing of what gene(s) will confirm the diagnosis?

Answer 11

ENaC (renal epithelium Na⁺ channel), gamma or beta subunit

Gain-of-Function mutation!

SCNN1G and SCNN1B

Question 12

Liddle Syndrome

Describe the pathogenesis.

Answer 12

Gain of function in ENaC leads to constituitive overactivation (Wiki says ENaC is normally already constituitively active). Increased reabsorption of sodium via ENaC leads to HTN.

Question 13

Where is the ENaC channel located? Be specific.

What hormone upregulates ENaC?

What hormone inhibits ENaC?

Answer 13

Apical membrane of the prinicpal cells, which make up the the walls of the late distal tubule and cortical collecting duct.

Upregulated by aldosterone

Inhibited by ANP

Question 14

Name two drugs that can treat AME by decreasing ENaC channel activity.

Answer 14

1. Amiloride
2. Triamterene

Question 15

Name two drugs that can treat AME by blocking the mineralocorticoid receptor.

Answer 15

1. Spironolactone
2. Eplerenone

Question 16

Aside from mineralocorticoid blockers and ENaC blockers, what are two other treatments for AME?

Answer 16

1. Potassium repletion
2. Dexamethasone for ACTH suppression

Question 17

Name two treatments for Liddle Syndrome

Answer 17

Agents that inhibit ENaC activity (also used in treating AME):

1. Amiloride
2. Triamterene

Question 18

Is the prognosis of AME or Liddle Syndrome typically better? Why?

Answer 18

Liddle syndrome has good prognosis with treatment. But without treatment, CV and reval complications occur secondary to severe HTN.

AME** typically has a worse prognosis** due to advanced progression of disease by the time it is diagnosed.

Question 19

Gitelman and Bartter Syndromes

What hormone distrubances are seen?

Answer 19

• Hyperreninemia
• Hyperaldosteronism

Question 20

Gitelman and Bartter Syndromes

How are these syndromes inherited?

Answer 20

Both are autosomal recessive

• Often due to consanguinous relationship. Siblings more likely to be affected than family members of previous generations.

Question 21

Gitelman and Bartter Syndromes

When in life do these syndromes present?

Answer 21

Gitelman: Adolescence or Adulthood

Bartter: Early Childhood

Question 22

Gitelman and Bartter Syndromes

What prominent symptoms and clinical findings are found in these syndromes?

Answer 22

Gitelman:

• Arm & leg cramping
• Fatigue
• Hypomagnesemia
• Polyuria & nocturia

Bartter:

• Growth and mental retardation
• Polyuria & polydipsia (increased thirst)
• Hypercalciuria

Question 23

Gitelman & Bartter Syndromes

What ion balance disturbances are seen?

Answer 23

• Hypokalemia
• Metabolic alkalosis

(As you may have noticed, these findings are universal across ALL of these Mendelian HTN diseases.)

Question 24

Gitelman & Bartter Syndromes

The tubular defects in these syndromes mimic the effects of chronic diuretic ingestion. What type of diuretic is mimicked in each?

Answer 24

Gitelman: chronic thiazide diuretic ingestion

**Bartter: **chronic loop diuretic ingestion

Question 25

Gitelman & Bartter Syndromes

Mutations in what genes cause each of these syndromes?

Answer 25

Gitelman: Mutations in SLC12A3 (less commonly CLCNKB) gene, the thiazide-sensitive Na-Cl cotransporter

Bartter: Mutations in genes that encode proteins in the **ascending loop of Henle, **including:

• BSND
• CLCNKA
• CLCNKB,
• KCHJ1
• SLC12A1

Question 26

Gitelman & Bartter** Syndromes**

Which has a better prognosis?

Answer 26

Gitelman Syndrome has better prognosis (with proper treatment)