NovelSCN9AMutations Underlying Extreme Pain Phenotypes: Unexpected Electrophysiological and Clinical Phenotype Correlations

Abstract

The importance of Na V 1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced Na V 1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype-phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of Na V 1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies.

Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a

“…Dynamic clamp experiments in small DRG neurons suggest that total loss of Nav1.7 should increase current threshold for single action potentials by about 40%, together with a marked decrease in ability to produce repetitive impulse activity50. Two mutations (W1775R and L1831X) have been identified in CIP patients that retain Na V 1.7 function, but cause a voltage-dependent depolarizing shift in channel activation, similar to Pn3a51. This suggests that a high level of, but not complete, inhibition is sufficient to cause analgesia.…”

Small‐fiber neuropathy: Expanding the clinical pain universe

“…The A1632E variant has been found in a patient with a mixed phenotype of IEM and PEPD, and causes a mixed physiological change in channel function, of hyperpolarized activation and impaired fast inactivation of the channel, which are typically associated with IEM and PEPD, respectively . The heterozygous L245V variant that was found in a large family with IEM did not affect channel activation, but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady‐state slow inactivation, which is more characteristic for PEPD . Overall at the structural level, most IEM variants tend to be located within the domains I and II of the protein, while PEPD variants are commonly located in the domains III and IV.…”

“…258 The heterozygous L245V variant that was found in a large family with IEM did not affect channel activation, but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, which is more characteristic for PEPD. 259 Overall at the structural level, most IEM variants tend to be located within the domains I and II of the protein, while PEPD variants are commonly located in the domains III and IV. The structural dichotomy, while not present in every case, parallels the biophysical effects of the two types of variants.…”

Prolonged Sinus Pauses Revealing A Paroxysmal Extreme Pain Disorder: Is It A Frequent Situation? A Case Report

“…These attacks can escalate to seizures, hypertonia, respiratory arrest, and even asystolic cardiac arrest [6]. Tonic attacks might be confused with epilepsy; however, findings of electroencephalography are normal [10]. Important stimuli are physical factors: defecation or eating but strong emotion can also be a trigger.…”

“…Pretreatment with cyclooxygenase 1 and 2 inhibitors could be beneficial in the absence of any contraindications. [10] Multimodal analgesia should be administered to minimize the precipitation of symptoms caused by pain.…”