Seronegative Neuromyotonia and Congenital Hyperinsulinism with Mutation of the Inwardly Rectifying Potassium Channel (KCNJ11) (P05.183)

Abstract

Objective: We present a man with congenital hyperinsulinism due to mutation of the inwardly rectifying potassium channel (Kir6.2) and neuromyotonia. Background Patients with activating mutations in the KCNJ11 gene can have neonatal diabetes mellitus and associated DEND syndrome (developmental delay, epilepsy and hypotonia). Inactivating mutations of this ATP-sensitive potassium channel lead to congenital hyperinsulism due to insulin oversecretion from pancreatic beta-cells. Down-regulation of Kir6.2 expression in myometrium may contribute to enhanced uterine contractility with onset of labor. Neuromyotonia is a disorder of peripheral nerve hyperexcitability characterized by myokymia, muscle cramps and stiffness, usually due to autoantibodies against neuronal voltage-gated potassium channels (VGKC) or rare VGKC mutations. Design/Methods: The patient is of European descent and was born uneventfully to a family without neurologic or endocrine problems. He was hypoglycemic at birth and was eventually diagnosed with hyperinsulinism. He underwent a subtotal pancreatectomy at two months after unsuccessful medication trials and developed diabetes mellitus at 12. Around age 13, he noted muscle spasms and twitching, with difficulty relaxing his muscles after exertion and falls due to stiffness. He had no percussion or grip myotonia, muscle rippling or myokymia at rest. With hyperextension of his legs he demonstrated grouped fasciculations of the quadriceps. Results: Needle EMG captured increased neuromyotonic discharges. Antibodies against VGKC were negative. PCR and sequence analysis showed that he was heterozygous for an alanine to threonine mutation at codon 213 (p. Ala213Thr). Conclusions: Our patient has co-occurrence of congenital hyperinsulism and seronegative neuromyotonia in the setting of a known inactivating mutation in the Kir6.2 channel (KCNJ11). Inactivation of this channel decreases potassium flow into the cell and resting membrane potential. This channel is known to be expressed in the CNS; its distribution in the PNS is unknown. We speculate that KCNJ11 mutation is causally related to our patient9s peripheral nerve hyperexcitability. Disclosure: Dr. Thyerlei has nothing to disclose. Dr. Oakley has received personal compensation for activities with Neurovista as a consultant. Dr. Jayadev received personal compensation from About.com/New York Times for medical review. . . . . . . Dr. Jayadev has received personal compensation in an editorial capacity for About.com and The New York Times. Dr. Weiss has received personal compensation for activities with Walgreens, CSL Behring and Talecris Biotherapeutics as a consultant and/or speaker.