Trigger 3: Treatments and Diagnosis of Gordon's syndrome

Question 1

patients with Gordon are suggested to…

Answer 1

have a low salt diet or take thiazide diuretics

Question 2

surveillance includes..

Answer 2

routine electrolyte and BP measurement

Question 3

Treatments aim to

Answer 3

keep BP low and electrolytes balanced

Question 4

preventative

Answer 4

low salt diet

Question 5

name 4 potential treatments for GS

Answer 5

1) Thiazide diuretics
2) Loop diuretics
3) SPAK inhibitors
4) WNK inhibitors

Question 6

Thiazide diuretics: name two

Answer 6

chlorothalidone and metolazone

Question 7

Thiazide diuretics basic mechanism

Answer 7

• antagonist of the NCC Na/Cl transporter

- prevents the 10% sodium reabsorption which usually occurs in the DCT- preventing water absorption and lowering BP

Question 8

Thiazide diuretics increase renal excretion of

Answer 8

sodium, potassium and hydrogen ion (metabolic alkalosis)

Question 9

TDs decrease renal excretion of

Answer 9

Calcium

Question 10

How to TDs work on a molecular basis

Answer 10

TDs compete for the chloride binding site on the Na/Cl cotransporter- inhibiting its ability to transport ions

Question 11

Why do TDs decrease the renal excretion of calcium?

Answer 11

Inhibition of Na/Cl cotransporters lowers intracellular NA, which in turns results in lowering of intracellular calcium mediated by Na/Ca exchange expression basolateral membrane
- this facilitates the diffusion of calcium through calcium ion channels expressed on the lumen membrane

Question 12

limitations of TDs

Answer 12

patients with WNK4 mutations respond better than those with WNK1 mutations
- cant take if urinanry problem, serve kidney or liver disease, addison disease

Question 13

Loop diuretics

Answer 13

Inhibits NKCC2 symporters (LoH)

• reducing osmotic force to drive reabsorption of water in the collecting duct
• can cause hypokalaemia

Question 14

Name two treatments in development

Answer 14

SPAK inhibitors and WNK inhibitors

Question 15

SPAK inhibitors

Answer 15

SPAK kinases up regulate chloride influx through phosphorylation of NCC and NKCC2. In SPAK-knockout mice are hypotensive.

Question 16

why could SPAK inhibitors be beneficial

Answer 16

• would inhibit Cl- influx through both NCC and NKCC2

- wold avoid the side effect of hypokalaemia caused by T and L diuretics

Question 17

WNK inhibitors are

Answer 17

in clinical trials

Question 18

WNK inhibitors

Answer 18

would work by inhibiting the whole WNK-OSR-1/SPAK NCC cascade- reducing activation of NACL cotransporters, decreasing uptake of water and reducing BP.

Question 19

what is the proband

Answer 19

• a particular subject being studied or reported on.
• on pedigrees, the proband is noted with a square (male) or circle (female) shaded accordingly.
• the proband is the first affected family member who seeks medical attention for a genetic disorder

Question 20

key diagnostic features (6)

Answer 20

• hyperkalemia
• normal GFR
• hypertension
• metabolic acidosis
• hyperchloremia
• suppressed plasma renin levels
• low aldosterone

Question 21

genetic diagnosis

Answer 21

identification of heterozygous pathogenic variants.

Question 22

identification of heterozygous pathogenic variants… in which genes

Answer 22

CUL3, WNK1 or WNK4 or balletic pathogenic variants in KLHL3

Question 23

formal diagnostic criteria for PHAII

Answer 23

none published

Question 24

PHAII clinical feature manifest generally

Answer 24

in adolescence or adulthood

Question 25

Hypertension...

Answer 25

>140/90

Question 26

metabolic acidosis

Answer 26

serum conc of bicarbonate ranging from 14-24mmol/l

Question 27

Hyperchloremia

Answer 27

serum conc of chloride ranging from 105 to 117 mol/L

Question 28

most PHAII cases are attributed to which pathogenic varianat

Answer 28

KLHL3 (41/86

Question 29

individuals with heterozygous CUL3 pathogenic variant tend to have ..

Answer 29

more severe hyperkalemia and metabolic acidosis, earlier development of hypertension and greater likelihood of growth impairment

Question 30

clinical manifestations tend to be milder in individuals with with heterozygous..

Answer 30

WNK1 or WNK4 pathogenic variants

Question 31

Biallelic

Answer 31

mutations in both alleles (not necessarily the same mutation)

Question 32

Individuals with balletic KLHL3 pathogenic variants

Answer 32

have more severe phenotypes than individuals with heterozygous pathogen variants in KLHL3

Question 33

Thiazide diuretics target

Answer 33

NCC cotransporters

Question 34

lopp diuretics target

Answer 34

NKCC1/2 cotransporters

Question 35

Gitelman syndrome caused by mutation in which cotransporter

Answer 35

NCC

Question 36

PHAII mutations on KLHL3 occur at

Answer 36

R528H

Question 37

PHAII mutations on CUL3 at

Answer 37

exon 9 deletion

Question 38

PHAII mutations on Wnk4 at

Answer 38

D561A