Genetic disorders of sodium transport




1. What is the difference between mendelian (or monogenic) forms of hypertension and essential hypertension?


Essential hypertension has a multifactorial etiology, including demographic and environmental (dietary) factors, and genetic predisposition, which results from multiple gene–gene and gene–environment interactions. Large genome-wide association studies among various populations mapped many gene loci for essential hypertension; however these loci have been predicted to have a very small effect on individual blood pressure variation, often estimated to be less than 2%. In contrast, Mendelian (or monogenic) forms of hypertension have a large effect on blood pressure level, with identifiable and often effectively treatable causes. The most common mechanism involves activation of the mineralocorticoid pathway, leading to increased kidney sodium reabsorption and volume expansion. Up to 20% of cases with resistant hypertension have either aldosterone-producing adrenal adenomas (APA) or bilateral adrenal hyperplasia. Based on recent DNA sequencing studies from adrenal adenoma tissues, ∼50% of APA cases are caused by somatic mutations in genes controlling adrenal zona glomerulosa cell proliferation and aldosterone production. APA is the most common form of secondary hypertension, estimated to affect up to ∼10% of patients with hypertension. Nevertheless, most monogenic forms of hypertension are exceedingly rare and estimated to be less than 2% of newly diagnosed hypertension. They result from mutations in a single gene and are mostly inherited in a Mendelian pattern. Since the early 1990s, more than 20 genes have been implicated in the etiology of Mendelian hypertension ( Table 72.1 ). Similarly, many Mendelian genes have been identified that lower blood pressure ( Table 72.2 ), with renal salt wasting being the main mechanism.



Table 72.1.

Monogenic Syndromes of Hypertension

















































































SYNDROME MAIN FEATURES TREATMENT LOCUS INHERITANCE DISEASE GENE
Liddle syndrome


  • Salt-sensitive



  • Hypokalemia and metabolic alkalosis



  • Renin and aldosterone suppressed

ENaC inhibitors 16p12 AD ENaC (Epithelial Na+ channel)
Glucocorticoid-remediable aldosteronism (GRA)


  • Salt-sensitive



  • Hypokalemia and metabolic alkalosis



  • Renin suppressed



  • Aldosterone normal or elevated



  • “Unusual” urine steroid metabolites

Corticosteroid therapy 8q24 AD CYP11B1/CYP11B2
(chimeric gene)
Apparent mineralocorticoid excess (AME)


  • Salt-sensitive



  • Hypokalemia and metabolic alkalosis



  • Renin and aldosterone suppressed



  • Nephrocalcinosis can be seen



  • Elevated urinary cortisol-to-cortisone ratio

Spironolactone and ENaC inhibitors 16q22 AR 11 β -HSD 2
Mineralocorticoid receptor (MR) activating mutation


  • Salt-sensitive



  • Hypokalemia and metabolic alkalosis



  • Renin and aldosterone suppressed



  • Exacerbated in pregnancy



  • Spironolactone acts as agonist

ENaC inhibitors 4q31 AD NR3C2
Aldosterone-producing adrenal adenomas (APA)


  • Salt-sensitive



  • Hypokalemia and metabolic alkalosis



  • Renin suppressed



  • Aldosterone elevated



  • Imaging can show adrenal adenoma

Spironolactone or eplerenone adenomectomy 11q24 3p21 1p13 Xq28 De novo/AD de novo
De novo
De novo
KCNJ5 CACNA1D ATP1A1ATP2B3
Congenital adrenal hyperplasia (CAH)


  • Salt-sensitive



  • Hypokalemia and metabolic alkalosis



  • Renin and aldosterone suppressed



  • ACTH elevated



  • Mineralocorticoids (e.g., DOC) elevated



  • Glucocorticoid deficiency and abnormal sex hormones

Corticosteroid therapy 10q248q24 AR
AR
17 α-hydroxylase 11 β-hydroxylase
Pseudohypoaldosteronism
type 2 (PHA 2)



  • Salt-sensitive



  • Hyperkalemia and metabolic acidosis



  • Renin suppressed



  • Aldosterone normal



  • Hypercalciuria can be seen

Thiazide diuretics 12p13 17q215q312q36 AD
AD
AR/
de novo
WNK1
WNK4
Kelch-like3 Cullin3
Pheochromocytoma


  • Labile hypertension



  • Orthostatic hypotension



  • Renin and aldosterone elevated



  • Hypokalemia can be seen



  • Elevated metanephrines




  • Alphablocker



  • Surgery

10q11
17q11
3p25
1p36
1q23
11q23
12q13
etc.
AD/
de novo
de novo
Ret
NF1
VHL
SDHB
SDHC
SDHD
KMT2D
etc.
Hypertension-brachydactyly syndrome


  • Not salt-sensitive



  • Renin and aldosterone suppressed



  • Baroreceptor dysfunction



  • Orthostatic hypertension



  • Short stature



  • Brachydactyly type E

Multidrug therapy 12p12 AD PDE3A
Hypertension, hypomagnesemia, and hypercholesterolemia; mitochondrial


  • Hypomagnesemia



  • Hyperlipidemia



  • Incomplete penetrance

Multidrug therapy mDNA Maternal tRNAIle

AD, Autosomal-dominant; AR, autosomal-recessive; ATP1A1, Na+/K+ ATPase α-1 subunit; ATP2B3, ATPase, Ca++ transporting, plasma membrane3; 11 β HSD, 11β-hydroxysteroid dehydrogynase 2; CACNA1D, calcium channel, voltage-dependent, L type, α-1D subunit; DOC, Deoxycorticosterone; KCNJ5, K+ inwardly-rectifying channel, subfamily J, member 5; KMT2D, Histone-lysine N-methyltransferase 2D; mDNA, mitochondrial DNA; NF1, neurofibromatosis 1; PDE3A, phosphodiesterase 3A; Ret, rearranged during transfection; SDHB/C/D, succinate dehydrogenase subunit B, C or D; PDE3A, phosphodiesterase 3A; tRNAIle, tRNA Isoleucin; Ret, rearranged during transfection; VHL, von Hippel-Lindau; WNK1, With-No-Lysine(K) 1.


Table 72.2.

Monogenic Syndromes of Renal Salt-Wasting Lowering Blood Pressure







































SYNDROME INHERITANCE MAIN FEATURES TREATMENT LOCUS DISEASE GENE
Bartter syndrome (TAL)
Type 1
Type 2
Type 3
Type 4
Type 4b
Type 5
AR
AR
AR
AR
AR
AD



  • Hypokalemia and metabolic alkalosis



  • Renin and Aldosterone elevated



  • Nephrocalcinosis (types 1 and 2)



  • Neonatal manifestation (types 1, 2, 4, and 4b)



  • Deafness (types 4 and 4b)



  • Hypercalciuria



  • Renal failure (rare)




  • Increase salt intake



  • Potassium supplementation



  • NSAIDs



  • K+-sparing diuretic

15q21
11q24
1p36
1p32
1p36
3q13
SLC12A1 (NKCC2)
KCNJ1 (ROMK)
CLCNKB
BSND (Barttin)
CLCNKB/CLCNKA
CASR
Gitelman syndrome (DCT) AR


  • Hypokalemia and metabolic alkalosis



  • Renin and Aldosterone elevated



  • Hypomagnesemia



  • Hypocalciuria



  • Increased bone density



  • Chondrocalcinosis (rare)




  • Increase salt intake



  • Potassium supplementation



  • Magnesium supplementation



  • K+-sparing diuretic



  • NSAIDs

16q13 SLC12A3 (NCCT)
EAST syndrome
(DCT, CNT, and CD)
AR


  • Hypokalemia and metabolic alkalosis



  • Renin and Aldosterone elevated



  • Hypomagnesemia



  • Hypocalciuria



  • Seizures



  • Hearing loss




  • Increase salt intake



  • Potassium supplementation



  • Magnesium supplementation



  • K-sparing diuretics

1q23 KCNJ10
Pseudohypo-aldosteronism
Type 1 (PHA I)
(CD)
AD
AR
AR
AR



  • Hyperkalemia and metabolic acidosis



  • Renin elevated



  • Failure to thrive



  • Resistance to steroid treatment




  • Saline infusion



  • Bicarbonate supplementation



  • Dialysis

4q31
12p13
16p13
16p13
NR3C2
SCNN1A
SCNN1B
SCNN1G

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Jul 23, 2019 | Posted by in NEPHROLOGY | Comments Off on Genetic disorders of sodium transport
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