Erythromelalgia - Pathophysiology

Pathophysiology

N.B. This section pertains solely to primary erythromelalgia as the secondary form is too poorly understood.

There are 10 known mutations in the voltage-gated sodium channel α-subunit Na_V1.7 encoding gene, SCN9A. This channel is expressed primarily in nociceptors of the dorsal root ganglion and the sympathetic ganglion neurons. Nine of these mutations have received further study and they have all shown to result in similar biophysical alterations, Table 1. As can be seen from table 1, the primary effect of erythromelalgia mutations is Na_V1.7 channels that activate at more hyperpolarized potentials. Na_V1.7 channels act largely as threshold sensors and initiate action potentials. Consequently, this shift in their activation profile results in channels that open closer to the resting membrane potential. In many mutations, this shift of activation is accompanied by shifts in the voltage sensitivity of fast and/or slow inactivation, often in the depolarized direction. This results in channels that are open for a longer of period of time, producing larger and more prolonged changes in membrane potential.

Some of these mutant channels have been expressed in dorsal root ganglion (DRG) or sympathetic neurons. In DRG neurons expressing the F1449V mutation, a lower threshold is required for action potential creation (93.1 ± 12.0 pA) than those expressing wild-type channels (124.1 ± 7.4 pA). Furthermore, while DRG neurons expressing wild-type channels only respond with a few action potentials, those expressing F1449V channels respond with a high-frequency train of action potentials. There is a similar effect in DRG neurons expressing the L858H and A863P mutants. Here, there is also a notable change in resting membrane potential, being depolarized by 4-7 mV versus wild-type channel expressing cells. The situation is different, however, in sympathetic neurons expressing the L858H mutation. While L858H expressing sympathetic ganglion are depolarized ~5mV relative to wild-type expressing neurons, their threshold for action potential initian is notably higher. Furthermore, while current injection of 40pA for 950ms provokes an average of 6 action potentials in sympathetic neurons expressing wild-type channels this stimulation evokes only approximately 2 action potentials with reduced overshoots in sympathetic neurons expressing L858H mutant channels. Further investigation has demonstrated that the differences in response between DRG and sympathetic neurons is due to expression of Na_V1.8 in the former. Consequently, expression of Na_V1.8 channels in sympathetic neurons also expressing L858H mutant Na_V1.7 results in neurons with a depolarized resting membrane potential that nevertheless have a normal action potential threshold and overshoot.

An effective, though not recommended, treatment for erythromelalgia symptoms is cooling of the affected area. Activation of wild-type channels is unaffected by cooling. L858F mutant channels, however, are activated at more depolarized potentials when cooled than at normal body temperature. At 16°C the activation V_½ of the mutant channel is only 4.6mV more hyperpolarized that wild-type versus 9.6mV more hyperpolarized at 35°C. Fast inactivation is affected in a similar manner in both wild-type and L858F mutant channel and is, thus, unlikely to contribute to symptom resolution due to cooling. While such cooling is unlikely to affect neuronal cell bodies, axons and termini express Na_V1.7 and are present in the skin.