Abstracts

Rationale: KCNJ10 mutations are associated with EAST or SeSAME syndrome, a recessive disorder characterized by seizures, sensorineural deafness, ataxia, mental retardation and electrolyte imbalance. We present the first report of infantile spasms associated with a heterozygous R297C variant in the KCNJ10 gene, which is predicted to be likely pathogenic. Methods: Our patient is a 7-month old girl who presented with infantile spasms. At 6 months, her mother noted subtle, involuntary movements of the shoulders. She experienced developmental stagnation and then regression, which became apparent soon after the seizures started. By the time of admission she was experiencing multiple daily clusters of up to 10-12 flexor spasms per cluster and her EEG showed hypsarrhythmia. She was born full term product of an uneventful pregnancy and delivery. Her physical examination showed hypotonia but no dysmorphic features. Her hearing test was normal and no electrolyte abnormalities were found. Her brain MRI was also normal. Additional metabolic studies, including serum lactate/pyruvate, plasma quantitative amino acids, urine organic acids, plasma ceruloplasmin levels, biotinidase enzymatic assay, carnitine profile and CSF studies including lactate and glycine were normal. Genetic analysis was sent and treatment with vigabatrin (VGB) was initiated following an unsuccessful trial of intravenous pyridoxine. Surprisingly, her spasms subsided after the third dose of VGB despite the delay in therapy initiation. She experienced a parallel improvement in her development, but the EEG continued to show hypsarrhythmia. On week 3 of therapy hypsarrhythmia was present only during sleep and on week 4 hypsarrhythmia had completely resolved. The background EEG remained slow with occasional multifocal spikes. Results: A comprehensive epilepsy panel (GeneDx) revealed a heterozygous p.Arg297Cys (R297C): c.889C>T variant in exon 2 of the KCNJ10 gene. In silico analysis predicts this variant is probably damaging to the protein structure/function. She was also heterozygous for a variant of uncertain clinical significance in the TBC1D24 gene. Conclusions: KCNJ10 gene encodes an inwardly rectifying potassium channel (Kir4.1) that is expressed in inner ear cells, renal epithelial cells, and glial cells in the central nervous system. Channelopathies involving the KCNJ10 gene have been described in infants with epilepsy. Here we report the first case of infantile spasms associated with this likely pathogenic variant in the KCNJ10 gene which may reflect an expanding clinical spectrum. This patient experienced rapid resolution of clinical spasms to vigabatrin with a more delayed EEG response. Additional testing, including parental analyses, functional analysis and whole exome sequencing are pending. 1. Sicca F1, Imbrici P, D'Adamo MC,et al. Autism with seizures and intellectual disability: possible causative role of gain-of-function of the inwardly-rectifying K+ channel Kir4.1.. Neurobiol Dis. 2011 Jul; 43(1):239-47. 2. Buono RJ, Lohoff FW, Sander T, Sperling MR, O'Connor MJ, Dlugos DJ, et al. Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility. Epilepsy Res. 2004; 58: 175?"183 Funding: none