An atypical case of SCN9A mutation presenting with global motor delay and a severe pain disorder

Abstract

This is a case of global motor delay and erythromelalgia associated with SCN9A. The motor delay may be attributed to the extreme pain episodes or to a developmental perturbation of proprioceptive inputs.

Small‐fiber neuropathy: Expanding the clinical pain universe

“…178,191 This left shift of activation enhances excitability, intuitively explaining the pain phenotype. 177,192,193 The phenotype, however, can be complex and variable, 188,[194][195][196][197][198][199] even within families carrying the same variant. 170 The I234T-variant, which causes IEM-like pain phenotype, exhibits a complex phenotype that includes automutilation 199,200 and bilateral congenital corneal anesthesia.…”

“…177,192,193 The phenotype, however, can be complex and variable, 188,[194][195][196][197][198][199] even within families carrying the same variant. 170 The I234T-variant, which causes IEM-like pain phenotype, exhibits a complex phenotype that includes automutilation 199,200 and bilateral congenital corneal anesthesia. 201 These findings, which suggest both gain of function and loss of function at the clinical level for patients carrying this variant, are explained by the unusually large hyperpolarization of activation of the mutant channel, which produces a massive depolarization in the resting potential of some dorsal root ganglion (DRG) neurons, thus silencing them.…”

Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Nav1.7 mutation I234T

“…Episodes of severe pain, associated with sweating and erythema of the lower limbs and hands, lasting 30–60 s, recurred multiple times per hour. In response to treatment with carbamazepine, at a therapeutic dose (30 mg·kg −1 ) with adequate blood levels, the episodes became less frequent and less intense (Meijer et al ., ). This case represents the third mutation of IEM for which patients respond to treatment with carbamazepine and has provided the opportunity to test our approach using structural modelling and in vitro pharmacological analysis.…”

“…A trial of carbamazepine in this patient was terminated because of side effects (Ahn et al ., ). A second patient of French‐Canadian ancestry carrying the same mutation, also with a history of severe intermittent pain, was subsequently reported (Meijer et al ., ) (Kim et al ., ). Episodes of severe pain, associated with sweating and erythema of the lower limbs and hands, lasting 30–60 s, recurred multiple times per hour.…”

“…Here, we followed up a report of pain relief by carbamazepine in a patient with severe pain due to the Na v 1.7 mutation I234T (Meijer et al ., ). This patient reported warmth‐induced pain attacks, similar to the vast majority of IEM patients carrying Na v 1.7 mutations.…”