Two Siblings With Valproate-Related Hyperammonemia and Novel Mutations in Glutamine Synthetase (GLUL) Treated With
Jennifer Bennett1, Christy Gilkes1, Karin Klassen1
1Department of Medical Genetics and Pediatrics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Abstract:
This case report describes 2 siblings with myoclonic epilepsy who had novel mutations in the glutamine synthetase (GLUL) gene: c.316C>T, p.(Arg106*) and c.42G>C, p.(Lys14Asn). Valproic acid improved seizure control, but was associated with hyperammonemic encephalopathy. Addition of carglumic acid reduced ammonia levels but drug coverage was declined. We therefore designed a protocol to measure the reduction in plasma ammonia in response to carglumic acid therapy. After the first dose of carglumic acid, Patient 1 showed a reduction in plasma ammonia levels within 3 hours, from 114 umol/L to 68 umol/L (reference 12-47 umol/L), and Patient 2 from 108 umol/L to 80 umol/L, which was sustained over a 2 week period. Overall, there was a strong negative correlation between plasma ammonia levels and carglumic acid levels (r = -0.86, p = 0.0013), and recurrence of hyperammonemic encephalopathy was not observed while the patients were taking carglumic acid.
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