Infantile Spasms as an Epileptic Feature of DEND Syndrome Associated With an Activating Mutation in the Potassium Adenosine Triphosphate (ATP) Channel, Kir6.2

Abstract

Activating mutations in the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium (KATP) channel is a cause of neonatal diabetes associated with various neurological disorders that include developmental delay, epilepsy, and neonatal diabetes (known together as DEND syndrome). This article reports a girl who developed infantile spasms and early onset diabetes mellitus at the age of 3 months and revealed DEND syndrome with a heterozygous activating mutation in Kir6.2. Infantile spasms with hypsarrhythmia on the electroencephalogram were severe and refractory to steroids. Steroids combined with oral sulfonylurea, a drug that closes the ATP-sensitive potassium channel by an independent mechanism, allowed partial and transitory control of the epilepsy. However, the child still exhibited severe encephalopathy and died of aspiration pneumonia. The role of oral sulfonylurea as an anticonvulsant in DEND syndrome associated with Kir6.2 mutation is discussed.

Infantile spasms: review of the literature and personal experience

“…There is marked cerebellar atrophy and infantile spasms [42,43]. IS can also be associated in DEND syndrome, characterized by developmental delay, epilepsy and neonatal diabetes [44]. …”

Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene

“…The fi rst patient described with a mutation at codon 166 with substitution of cysteine by phenylalanine (C166F) presented with neonatal diabetes, full DEND syndrome and dysmorphic features including prominent metopic suture, bilateral ptosis and down turned mouth, but she died from aspiration pneumonia at the age of 6 months after partial and transitory control of epilepsy with tolbutamide (0.75 mg/kg/d) combined with ACTH therapy (26,27). Afterwards, Flanagan et al (19) demonstrated the C166Y mutation (substitution of cysteine by tyrosine) in our patient, followed by another case (C166Y) described by Suzuki et al (28) of neonatal diabetes with DEND syndrome, dysmorphic facial features and arthrogryposis who has been treated exclusively with insulin.…”

Regulation of Gap Junctional Communication by Astrocytic Mitochondrial K_ATP Channels following Neurotoxin Administration in in vitro and in vivo Models

“…It has been reported that neuronal K ATP channels show an ability to adjust cell excitability [11][12][13] . Pharmacological and genetic studies have provided evidence to further support the roles of neuronal K ATP channels in the control of neuronal excitability and seizure propagation by depolarizing presynaptic neuron and subsequently by inhibiting the release of excitatory neurotransmitter, or by regulating GABA transporters [1,[14][15][16][17][18][19] . However, little is known about the roles of astrocytic sK ATP /mitoK ATP channels in epileptogenesis.…”

“…Manipulation of the K ATP channel status in various cellular types and at various intracellular locations has shown a variety of functional roles [3,[7][8][9][10] . It has been revealed that neuronal K ATP channels in the brain are involved in the control of neuronal excitability [11][12][13] and seizure propagation [1,[14][15][16][17][18][19] . The roles that glial K ATP channels play are receiving renewed attention due to improved understanding of the molecular events underpinning the physiological functions of glial cells.…”