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