Genomics and Modification of Pain

We have capitalized on inherited erythromelalgia (IEM) as a well-characterized genetic model of chronic pain, and studied IEM patients carrying Nav1.7 mutations which affect channel activation and often produce hyperexcitability of DRG neurons. Whole exome sequencing was used to discover multiple gene variants that might contribute to neuronal excitability and that might serve as modifiers of sensory neuron firing, and identified the Kv7.2 channel as a contributor to differences in pain profiles between individuals.]]>
Patients with newly diagnosed familial inheritance of an unknown acquired pain syndrome will be enrolled in this study. Also patients with early onset of symptoms (in the first two decades of life) will be included. We will accept samples for analysis based on the clinical presentation of the disease and on the description of the disease. Eligibility will also be determined by the treating physician and one of the investigators. Other etiologies of known acquired pain syndromes, such as systemic lupus or Fabry disease, will be excluded from this study.]]>
Erythromelalgia is the first known inherited painful neuropathy to be examined at a molecular level. Interestingly, primary erythromelalgia is also the first known human disease that involves the Nav1.7 sodium channel. Until recently, the pathogenesis of this disease was unknown. Hypotheses encompassing vascular shunting, neuropathic etiologies, microvascular etiologies, and inflammatory etiologies have all been suggested. Two mutations in SCN9A, the gene for the human Nav1.7 sodium channel, were reported in primary erythromelalgia, and were shown by our team to cause a hyperpolarizing shift in activation and slow deactivation. Subsequently, in 2004, a large American kindred was found to have individuals in multiple generations suffering from primary erythromelalgia. A single amino acid substitution was identified in the Nav1.7 channel. All affected family members carried this mutation, while it was absent in unaffected family members and in the alleles from an ethnically matched control group. More than ten mutations in the Nav1.7 channel from patients with inherited erythromelalgia have been reported to date, and penetrance appears to be 100% for inherited erythromelalgia mutations. Our team has also demonstrated that Nav1.7 mutations in PEPD, which impair slow-inactivation of the channel, produce hyperexcitability of DRG neurons. More recently, we have shown that another group of Nav1.7 mutation and variants, which produce different changes in channel function, are associated with small fiber neuropathy and no other apparent cause, a disorder that produces significant pain and autonomic dysfunction in a large number of adult patients. This study was the first to demonstrate that an alteration in sodium channel function may be associated with a known hereditary pain syndrome. Moreover, additional mutations (either in the sodium channel or other ion channels) are expected to be identified in families with inherited erythromelalgia, and possibly in sporadic cases of erythromelalgia, where no other underlying disease is implicated, or in other families with inherited neuropathic pain.]]>