Annual Meeting Abstracts: View

  • (Abst. 3.210), 2014
  • KCNQ2-DEFICIENCY: CLINICAL SPECTRUM OF EPILEPSY, ENCEPHALOPATHY, AND RESPONSE TO EZOGABINE
  • Authors: Kristen Park, John Millichap and Edward Cooper
  • Content:

    Rationale: Variations in KCNQ2 were recently appreciated to underlie a spectrum of epilepsy from benign to severe. Current understanding is nonetheless limited. De novo KCNQ2 mutations have been found in about 60 published cases of neonatal-onset epileptic encephalopathy. Only a few of these mutations have been studied in vitro, but strongly suppressed channel activity, suggesting that phenotype severity reflects the degree of "KCNQ2-deficiency". Since ezogabine can increase KCNQ2 channel function, its use in severe KCNQ2 variants could be beneficial. However, previous use of ezogabine in infants and children is very limited. Methods: Clinical features of KCNQ2-deficiency cases were collected retrospectively by physician survey following diagnosis by neurologists from 11 institutions. Results: Twenty-three (11 female) patients with KCNQ2-deficiency were studied. The diagnosis was suspected by the physician prior to genetic testing in 8. There was a family history of seizures in 8 (47.8%). The mean seizure onset age was 1.76 days. The initial seizure types were focal (n=9), tonic (n=6), myoclonic (n=4), mixed focal and generalized (n=1), generalized tonic-clonic (n=1), and epileptic spasms (n=1). An initial EEG was obtained within the first week of life in 20/23 patients; 11 showed suppression-burst, 11 showed dysmaturity and/or focal findings, and 1 was normal. Brain MRI was normal in 16/23 patients; abnormalities varied and included diffuse atrophy, periventricular increased white matter signal, and thin corpus callosum. The age at last follow-up ranged from 28 days to 7 years. In 15 patients, other seizure types appeared in infancy; the most common was epileptic spasms (n=8). By the time of last follow up, seizures had resolved in 14/23 patients. Only 3/11 patients over the age of 2 years continued to have seizures. Development at last follow up was severely abnormal in 15/23, moderately abnormal in 5/23, and mildly abnormal in 3/23. Eleven patients were treated with ezogabine. Side effects included urinary retention, chromaturia, and somnolence. Patients were also monitored for skin and retinal discoloration but these were not observed. Four patients began treatment under 6 months old, and 3 of those reported improvement in seizures and development while one had no clinical change. One additional patient treated at age 3 years had subjective improvement in seizures and development, 1 patient had improved alertness and EEG background activity, and 1 patient had improvement in development only. Conclusions: This series represents the spectrum of KCNQ2-deficiency and adds to the number of reported cases. Ezogabine appeared well tolerated. Owing to limited developmental metrics, the clearest benefit was against refractory seizures and when started under 6 months old. Testing whether early treatment may both reduce seizures and improve long-term outcome requires rapid turnaround testing of suspected neonatal cases. The wide severity spectrum complicates evaluation of such interventions; therefore, continued study of genotype-phenotype relationships is highly valuable.