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Erythromelalgia: Clinical Features, Effective Treatment with Carbamazepine
Abstract & Commentary
By Russell L. Chin, MD, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Chin reports no financial relationship relevant to this field of study
Synopsis: Carbamazepine is reported to be an effective symptomatic treatment for inherited erythromelalgia (IEM) due to the novel mutation of the Na(v)1.7 sodium channel, which is preferentially expressed in dorsal root ganglia.
Sources: Fischer TZ, Gilmore ES, Estacion M, et al. A novel Na(v)1.7 mutation producing carbamazepine-responsive erythromelalgia. Ann Neurol 2009;65:733-741; Han C, Dib-Hajj SD, Lin Z, et al. Early- and late-onset inherited erythromelalgia: Genotype-phenotype correlation. Brain 2009;132: 1711-1722.
Erythromelalgia (also known as erythermalgia) is a disorder characterized by intense, episodic burning pains affecting the extremities, associated with erythema. The symptoms are triggered by warmth and, less consistently, by overexertion, constrictive footwear, or vasodilating agents such as alcohol. Primary or inherited erythromelalgia (IEM) may be sporadic or inherited in an autosomal dominant manner. Secondary erythromelalgia is associated with conditions such as essential thrombocytopenia, polycythemia vera, autoimmune disorders, medications (e.g., verapamil, nifedipine, ticlopidine, bromocriptine), and mercury poisoning. The response to symptomatic medications is variable and the pain is often refractory to treatment.
IEM has been linked to mutations of the SCN9A gene which encodes the Na(v)1.7 sodium channel. This channel is preferentially expressed in nociceptive dorsal root ganglion (DRG) and sympathic ganglion neurons, and plays a critical role in the generation and conduction of action potentials. The channel produces rapidly activating and inactivating, tetrodotoxin-sensitive currents that recover slowly from fast-inactivation, allowing the channel to remain available for activation with small or slowly developing depolarizations.
Gain of function mutations of the Na(v)1.7 channel alter these physiologic responses in important ways: 1.) a hyperpolarizing shift in the voltage dependence of channel activation allows the channel to be activated by smaller than normal depolarizations; 2.) deactivation is slowed so that the channel is open longer once activated; and 3.) a slow, depolarizing stimulus generates a larger-than-normal inward sodium current in the mutant channel. The end result is increased hyperexcitability of the affected DRG neurons.
Most mutations have been linked to families with early-onset symptoms (usually before age 6). Fischer and colleagues reported a novel mutation (V400M) in such a family. The proband (whose symptoms began at age 1) and his two children reported significant pain relief with carbamazepine (CBZ), 400–800 mg/day. Cell lines were analyzed using whole-cell patch-clamp recording for changes in activation, deactivation, steady-state inactivation and response to a slow-voltage ramp. CBZ, at concentrations within the human therapeutic range, normalized the effect of the mutation on channel activation; whereas, it did not affect the tested parameters in wild-type sodium channels.
In a related article, Han and colleagues reported another novel mutation (Q10R) in a single patient with symptoms beginning in the second decade (i.e., late-onset symptoms). They found that this mutant channel caused smaller effects on channel activation and induced less hyperexcitability in DRG neurons when compared with a mutant channel associated with early-onset IEM.
IEM may be infrequently encountered, much less diagnosed, by neurologists; however, the data presented in these papers may prove useful in understanding the mechanisms behind more commonly encountered cases of secondary erythromelalgia and small fiber neuropathy. The latter is a heterogenous disorder characterized by involvement of small, myelinated A delta and unmyelinated C fibers with decreased epidermal nerve fiber densities per skin biopsy specimens. Some small fiber neuropathy variants are thought to be due to DRG involvement and may present with acute, burning pains similar to those seen in erythromelalgia, but in a multifocal, non-length-dependent pattern.
CBZ preferentially binds to sodium channels in the inactivated state, resulting in fewer of these channels being available for sodium conductance. CBZ is a recognized symptomatic treatment for painful neuropathy, such as trigeminal neuralgia. The patients with the V400M mutation had a dramatic response to CBZ and further studies on this mutation provide a better understanding of the mechanism of action of this common anti-epileptic, which is used in a variety of neuropathic pain syndromes.
1. Davis MD, Weenig RH, Genebriera J, et al. Histopathologic findings in primary erythromelalgia are nonspecific: Special studies show a decrease in small nerve fiber density. J Am Acad Dermatol 2006;55:519-522.
2. Drenth JP, Waxman SG. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J Clin Invest 2007;117:3603-3609.