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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 5, September/October 2017
e6
AFRICA
Discussion
Low-renin hypertension has been found to be more common in
people of black African origin.
2
Furthermore, in South Africa,
low renin was found to be associated with low aldosterone levels
in patients with resistant hypertension.
The epithelial sodium channel is the final and rate-limiting
step in sodium reabsorption. Liddle’s syndrome was described
in a family that presented with hypertension and hypokalaemia
associated with metabolic alkalosis.
3
The genetic variant was found
to be a truncating mutation of the beta-subunit of the epithelial
sodium channel. Truncation of the carboxy terminal of the beta-
subunit results in impaired internalisation of the channel with
ongoing sodium and water reabsorption, resulting in hypertension.
Aberations due to activating mutations within the carboxyl
terminal region of the epithelial sodium channel (ENaC) beta-
or alpha-subunits are known to cause Liddle’s syndrome. Such
mutations negatively affect targeting of the protein products for
endocytic degradation, which in turn leads to increased sodium
reabsorption and resultant hypertension.
4
The mechanism is
thought to be due to interference with PPPY-targeting motifs
needed for recognition by NEDD4 ubiquitin ligases.
Multiple variants in the
SCNN1B
gene have been reported,
many causing complete Liddle’s syndrome. Some mutations
affect the PY motif, others truncate the carboxy terminal. In the
case of single-nucleotide polymorphisms that do not affect the
PY motif, the full Liddle’s phenotype is not usually present.
5,6
A variant (R563Q, c.1815G
>
A) of the beta-subunit of the
epithelial sodium channel was found frequently in patients with
resistant hypertension and with low renin and aldosterone levels.
7
This variant was described to result in the full Liddle’s phenotype
during pregnancy;
8
and in black South African hypertensive
patients, the prevalence was 5.9% versus 1.7% in normotensives.
1
Unlike the c.1815G
>
A (p.R563Q) variant, which affects
a single amino acid in the protein product, the c.1709del11
(p.Ser570Tyrfs*20) deletion, seen in our patient (Fig. 1A),
causes a frame shift, resulting in complete mistranslation from
this point onwards and ultimately resulting in a premature stop
codon 20 amino acids downstream. This mutation results in loss
of the PPPY motif, impairing ENaC degradation, and resulting
in unopposed sodium and water reabsorption.
As neither parent could be tested and no siblings were found
to carry this variant, it is impossible to say whether this is a new
or inherited variant. However, both parents were hypertensive
and it is likely that one of them are/were affected. Ideally the
mother of this patient and/or any living paternal siblings should
be tested. The mild hypertension present in the older brother can
be explained on the basis of him having the metabolic syndrome
phenotype.
In patients with Liddle’s syndrome, treatment requires
inhibition of the sodium channel. There are two agents
available for this: triamterene and amiloride. In the intial
stages of hypertension, inhibition of the sodium channel
can completely reverse the clinical effects. After prolonged
uncontrolled hypertension, the vascular consequences can result
in hypertension that is more difficult to treat.
Neither amiloride nor triamterene are licenced in South
Africa, which impacts negatively on treatment. Amiloride is only
available in combination with large doses of hydrochlorothiazide
(5 mg amiloride/50 mg hydrochlorothiazide), which is not ideal
in the setting of hypokalaemia. Our patient has responded well
to this treatment, although he is not yet fully controlled and most
likely requires a higher dose of amiloride.
Amiloride 10 mg can be issued on an individualised basis
under section 21 drug use but availability is limited and extremely
expensive. Due to the frequency of described variants of the
SCNN1B
gene in South Africa, specific therapy targeting the
epithelial sodium channel should be made more widely available.
Conclusion
We have described a novel c.1709del11 (p.Ser570Tyrfs*20)
deletion in the beta-subunit of the ENaC associated with
Liddle’s syndrome in a young black African male. Due to
this frameshift mutation, the defect is likely causative of the
hypertension and therapy should be targeted at inhibition of
ENaC. Unfortunately, this is not easily achievable in our context
and treatment of such patients is therefore severely hampered in
South Africa.
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