Two Siblings With Valproate-Related Hyperammonemia and Novel Mutations in Glutamine Synthetase (GLUL) Treated With Carglumic Acid

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.

Proteomic and Bioinformatic Tools to Identify Potential Hub Proteins in the Audiogenic Seizure-Prone Hamster GASH/Sal

“…The two-fold increase in basal GLUL expression levels could indicate the need for greater availability of this enzyme by the GASH/Sal, a fact that can be correlated with elevated glutamate levels, which is widely described in epilepsy [ 114 , 115 ]. On the other hand, ammonium levels also modulate the occurrence of seizures in myoclonic epilepsy and various other related conditions [ 116 , 117 ]. GLUL is directly related to the detoxification process of both compounds mentioned above, and both could be found increased during and after convulsive crises, such as those described in the GASH/Sal model.…”