PR1-163
Management of Pain in a Child with a Rare SCN9A Mutation Characterized by Alternating Insensitivity to Pain and Paroxysmal Bouts of Extreme Pain
Rabito M, Hays S, Morgan T, Mignemi M, Franklin A
Vanderbilt Children's Hospital, Nashville, TN, USA
The patient is a 4-year-old female with longstanding poorly controlled pain who presented for re-fixation of a right Monteggia fracture with bilateral upper extremity spica casting. Since age 3 months she had an unusual appearance of her hands and feet progressing to intermittent painful erythema consistent with erythromelalgia. At times she seemed indifferent to painful stimuli; at other times she appeared to have episodes of extreme pain without apparent inciting factors. She also had longstanding self-injurious behavior, particularly biting her hands. Her pain and behavior were refractory to gabapentin. The pediatric pain service was consulted for assistance with perioperative analgesia.
Before surgery, genetic testing indicated an I234T mutation in the SCN9A gene encoding the α-subunit of the Nav1.7 neuronal voltage-gated sodium channel found in nociceptors throughout the nervous system, mutations in which are associated with pain indifference and/or paroxysmal extreme pain disorder (1). Congenital insensitivity to pain is a rare condition rendering patients incapable of perceiving pain: approximately 20 cases have been reported. Loss-of-function SCN9A mutations produce a dysfunctional α-subunit that impairs nociception. Paroxysmal extreme pain disorder is another rare condition characterized by erythema, warmth, and bouts of severe pain throughout the body typically lasting seconds to minutes: approximately 80 cases have been reported. Gain-of-function SCN9A mutations produce aberrant α-subunits causing Nav1.7 channels to close incompletely when deactivated, enhancing nociception (2). Concomitant congenital insensitivity to pain and paroxysmal extreme pain disorder has not been described.
From the patient’s geneticist, it was learned that the I234T mutation had been mapped to the active site of carbamazepine on the α-subunit of the Nav1.7 neuronal voltage-gated sodium channel, and that carbamazepine restores normal function in neuronal preparations with the I234T mutation (3, 4, 5). The patient was begun on carbamazepine 65 mg (~5 mg/kg) PO BID; given poor sleep, she was also begun on nortriptyline 5 mg (~0.5 mg/kg) PO QHS. The following morning, the mother reported that the patient had slept well for one of the first times in her life. In clinic 2 months later the patient continued to do well with little apparent pain and improved sleep. Carbamazepine was increased to 100 mg (~7.5 mg/kg) PO BID, and nortriptyline was continued. She continues to do well on this regimen.
References:
1. Ahn HS et al. A new Nav1.7 sodium channel mutation I234T in a child with severe pain. Eur J Pain 2010 Oct;14(9):944-50.
2. SCN9A gene: sodium voltage-gated channel alpha subunit 9. Retrieved from https://ghr.nlm.nih.gov/gene/SCN9A.
3. Yang Y et al. Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Nav1.7 mutation I234T. Br J Pharmacol 2017 Jun 28; [Epub ahead of print].
4. Meijer IA et al. An atypical case of SCN9A mutation presenting with global motor delay and a severe pain disorder. Muscle Nerve 2014 Jan;49(1):134-8.
5. Fischer TZ et al. A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia. Ann Neurol 2009 Jun;65(6):733-41.
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