Previously, we reviewed
biological evidence that
mercury could induce autoimmunity and coronary arterial wall relaxation as observed in
Kawasaki syndrome (KS) through its effects on calcium signaling, and that
inositol 1,4,5-triphosphate 3-kinase C (ITPKC) susceptibility in KS would predispose patients to
mercury by increasing Ca(2+) release. Hg(2+) sensitizes
inositol 1,4,5-triphosphate (IP3) receptors at low doses, which release Ca(2+) from intracellular stores in the sarcoplasmic reticulum, resulting in delayed, repetitive
calcium influx. ITPKC prevents IP3 from triggering IP3 receptors to release
calcium by converting IP3 to
inositol 1,3,4,5-tetrakisphosphate. Defective IP3 phosphorylation resulting from reduced genetic expressions of ITPKC in KS would promote IP3, which increases Ca(2+) release. Hg(2+) increases
catecholamine levels through the inhibition of
S-adenosylmethionine and subsequently
catechol-O-methyltransferase (COMT), while a single nucleotide polymorphism of the COMT gene (rs769224) was recently found to be significantly associated with the development of coronary artery lesions in KS. Accumulation of
norepinephrine or
epinephrine would potentiate Hg(2+)-induced
calcium influx by increasing IP3 production and increasing the permeability of cardiac sarcolemma to Ca(2+).
Norepinephrine and
epinephrine also promote the secretion of
atrial natriuretic peptide, a potent
vasodilator that suppresses the release of
vasoconstrictors. Elevated
catecholamine levels can induce
hypertension and
tachycardia, while increased arterial pressure and a rapid heart rate would promote arterial vasodilation and subsequent fatal
thromboses, particularly in tandem. Genetic risk factors may explain why only a susceptible subset of children develops KS although
mercury exposure from methylmercury in fish or
thimerosal in pediatric
vaccines is nearly ubiquitous. During the infantile
acrodynia epidemic, only 1 in 500 children developed
acrodynia whereas
mercury exposure was very common due to the use of teething powders. This hypothesis mirrors the leading theory for KS in which a widespread
infection only induces KS in susceptible children.
Acrodynia can mimic the clinical picture of KS, leading to its inclusion in the differential diagnosis for KS.
Catecholamine levels are often elevated in
acrodynia and may also play a role in KS. We conclude that KS may be the acute febrile form of
acrodynia.