Erythermalgia: molecular basis for an inherited pain syndrome.
ABSTRACT Inherited erythermalgia (also termed erythromelalgia) is characterized by severe pain in the limbs in response to mild thermal stimuli or exercise. Its molecular basis has, until recently, been enigmatic. Studies of families with autosomal dominant erythermalgia have now demonstrated mutations in sodium channel Na(v)1.7, which is selectively expressed within nociceptive dorsal root ganglion and sympathetic ganglion neurons. Shifts in activation and deactivation, and enhanced responses to small stimuli in mutant channels, decrease the threshold for single impulses and high-frequency trains of impulses in pain-sensing neurons. Erythermalgia, the first inherited painful neuropathy to be understood at a molecular level, is a model disease that could hold lessons for other painful conditions and for the development of rational, mechanism-based treatments for pain.
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ABSTRACT: Most patients who undergo surgery or experience a traumatic injury suffer from acute pain that subsides once tissues heal. Nevertheless, the pain remains in 15-30% of patients, sometimes for life, and this chronic post-surgical pain (CPSP) can result in suffering, depression, anxiety, sleep disturbance, physical incapacitation, and an economic burden. The incorporation of genetic knowledge is expected to lead to the development of more effective means to prevent and manage CPSP using tools of personalized pain medicine. The purpose of this review article is to provide an update on the current state of CPSP genetics and its future potential. The large variability in CPSP amongst patients undergoing similar surgery suggests that individual factors are significant contributors to CPSP, raising the possibility that CPSP is influenced by genetic determinants. Heritability estimates suggest that about half of the variance in CPSP levels is attributable to genetic variation. These estimates suggest that identifying the genetic underpinnings of CPSP may lead to significant improvements in treatment. Analyzing patients' DNA sequences, blood and salivary pain biomarkers, as well as their analgesic responses to medications will facilitate developing insights into CPSP pathophysiology and inform predictive algorithms to determine a patient's likelihood of developing CPSP even prior to surgery. These algorithms could facilitate effective treatment regimens that will protect against the transition to chronicity in traumatically injured patients or those scheduled for surgery and lead to better therapy for patients who have already developed CPSP. Pharmacogenomic technologies and strategies provide an opportunity to expand our knowledge in CPSP treatment that may manifest in a personalized approach to diagnosis, prevention, and therapy. Capitalizing on this genomic knowledge will necessitate the analysis of many tens of thousands of study patients. This will require an international coordinated effort to which anesthesiologists and surgeons can contribute substantially.Canadian Journal of Anaesthesia 12/2014; 62(3). DOI:10.1007/s12630-014-0287-6 · 2.50 Impact Factor
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ABSTRACT: Mutations in genes encoding voltage-gated sodium channels have emerged as the most clinically relevant genes associated with epilepsy, cardiac conduction defects, skeletal muscle channelopathies and peripheral pain disorders. Geneticists in partnership with neurologists and cardiologists are often asked to comment on the clinical significance of specific mutations. We have reviewed the evidence relating to genotype phenotype associations among the best known voltage-gated sodium channel related disorders. Comparing over 1300 sodium channel mutations in central and peripheral nervous system, heart and muscle, we have identified many similarities in the genetic and clinical characteristics across the voltage-gated sodium channel family. There is evidence, that the level of impairment a specific mutation causes can be anticipated by the underlying physico-chemical property change of that mutation. Across missense mutations those with higher Grantham scores are associated with more severe phenotypes and truncating mutations underlie the most severe phenotypes. Missense mutations are clustered in specific areas and are associated with distinct phenotypes according to their position in the protein. Inherited mutations tend to be less severe than de novo mutations which are usually associated with greater physico-chemical difference. These findings should lead to a better understanding of the clinical significance of specific voltage-gated sodium channel mutations, aiding geneticists and physicians in the interpretation of genetic variants and counselling individuals and their families.Journal of Medical Genetics 08/2014; 51(10). DOI:10.1136/jmedgenet-2014-102608 · 5.64 Impact Factor
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ABSTRACT: Neurological channelopathies are attributed to aberrant ion channelsaffectingCNS, PNS, cardiac and skeletal muscles.To maintain thehomeostasis of excitable tissues; functional ion channels are necessary to rely electrical signalswhereas any malfunctioning serves as an intrinsic factor todevelop neurological channelopathies.Molecular basis of these disease arestudiedbased on genetic and biophysical approaches, e.g. loci positional cloning whereas pathogenesis and bio-behavioralanalysis revealed the dependency ongenetic mutations and inter-current triggering factors.Although, electrophysiological studies revealed the possible mechanisms of diseases but analytical study of ion channels remained unsettled and therefore underlying mechanism in channelopathies is necessary for better clinical application. Herein, we demonstrated (i) structural and functional role of various ion channels(Na+, K+, Ca2+,Cl-), (ii) pathophysiology involved in the onset of their associated channelopathies and (iii) comparative sequence and phylogenetic analysis of diversified sodium, potassium, calcium and chloride ion channel subtypes.Journal of Membrane Biology 07/2014; 247(11). DOI:10.1007/s00232-014-9716-2 · 2.17 Impact Factor