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Original Investigation
December 21, 2018

Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy

Author Affiliations
  • 1Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
  • 2Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
  • 3Department of Pediatrics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
  • 4Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany
  • 5Department of Neuropediatrics, Development and Rehabilitation, Children's Hospital of Eastern Switzerland, St Gallen, Switzerland
  • 6Center for Molecular Medicine, Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, the Netherlands
  • 7Oncode Institute, Utrecht, the Netherlands
  • 8Expertise Centre for Structural Biology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
  • 9Department of Radiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
  • 10Division for Children and Adolescents, Evangelical Hospital Oberhausen, Oberhausen, Germany
  • 11Department of Child Neurology, University Children's Hospital, Zurich, Switzerland
  • 12Department of Pediatric Intensive Care and Neonatology, Children's Hospital of Eastern Switzerland, St Gallen, Switzerland
  • 13Swiss Newborn Screening Laboratory and Children`s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
JAMA Neurol. Published online December 21, 2018. doi:10.1001/jamaneurol.2018.2941
Key Points

Question  What is the consequence of glutaminase deficiency?

Findings  This study of 2 families with 4 affected children used exome sequencing followed by functional analysis to show that biallelic loss-of-function pathogenic variants in the glutaminase gene GLS lead to early neonatal refractory seizures, respiratory failure, structural brain abnormalities and cerebral edema, and death within weeks after birth.

Meaning  Based on these results, it is hypothesized that glutaminase deficiency disturbs glutamine-glutamate homeostasis and leads to neonatal lethal epileptic encephalopathy and respiratory insufficiency; this emphasizes its importance for respiratory regulation, neurotransmission, and survival.


Importance  The identification and understanding of the monogenic causes of neurodevelopmental disorders are of high importance for personalized treatment and genetic counseling.

Objective  To identify and characterize novel genes for a specific neurodevelopmental disorder characterized by refractory seizures, respiratory failure, brain abnormalities, and death in the neonatal period; describe the outcome of glutaminase deficiency in humans; and understand the underlying pathological mechanisms.

Design, Setting, and Participants  We performed exome sequencing of cases of neurodevelopmental disorders without a clear genetic diagnosis, followed by genetic and bioinformatic evaluation of candidate variants and genes. Establishing pathogenicity of the variants was achieved by measuring metabolites in dried blood spots by a hydrophilic interaction liquid chromatography method coupled with tandem mass spectrometry. The participants are 2 families with a total of 4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts, respiratory insufficiency, simplified gyral structures, diffuse volume loss of the brain, and cerebral edema. Data analysis occurred from October 2017 to June 2018.

Main Outcomes and Measures  Early neonatal epileptic encephalopathy with glutaminase deficiency and lethal outcome.

Results  A total of 4 infants from 2 unrelated families, each of whom died less than 40 days after birth, were included. We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family. The GLS gene encodes glutaminase (Enzyme Commission, which plays a major role in the conversion of glutamine into glutamate, the main excitatory neurotransmitter of the central nervous system. All 3 variants probably lead to a loss of function and thus glutaminase deficiency. Indeed, glutamine was increased in affected children (available z scores, 3.2 and 11.7). We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system.

Conclusions and Relevance  We identified a novel autosomal recessive neurometabolic disorder of loss of function of glutaminase that leads to lethal early neonatal encephalopathy. This inborn error of metabolism underlines the importance of GLS for appropriate glutamine homeostasis and respiratory regulation, signal transduction, and survival.