Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in <i>GLS</i>

Kuilenburg, André B. P.; Tarailo‐Graovac, Maja; Richmond, Phillip A.; Drögemöller, Britt I.; Pouladi, Mahmoud A.; Leen, René; Brand-Arzamendi, Koroboshka; Dobritzsch, Doreen; Dolzhenko, Egor; Eberle, Michael A.; Hayward, Bruce E.; Jones, Meaghan J.; Karbassi, Farhad; Kobor, Michæl S.; Koster, Janet; Kumari, Daman; Li, Meng; MacIsaac, Julia L.; McDonald, Cassandra; Meijer, Judith; Nguyen, Charlotte; Rajan‐Babu, Indhu‐Shree; Scherer, Stephen W.; Sim, Bernice; Trost, Brett; Tseng, Lillian; Turkenburg, Marjolein; Vugt, Joke J.F.A. van; Veldink, Jan H.; Walia, Jagdeep S.; Wang, Youdong; Weeghel, Michel van; Wright, Galen E.B.; Xu, Xiaohong; Yuen, Ryan K. C.; Zhang, Jinqiu; Ross, Colin J.D.; Wasserman, Wyeth W.; Geraghty, Michael T.; Santra, Saikat; Wanders, Ronald J. A.; Wen, Xiao‐Yan; Waterham, Hans R.; Usdin, Karen; Karnebeek, Clara van

doi:10.1056/nejmoa1806627

Cited by 72 publications

(74 citation statements)

References 28 publications

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“…Awareness of this phenotypic spectrum is needed for recognition and diagnosis of these patients. 22,24,25 Glutamate and glutamine concentrations are most aberrant in defects of the two enzymes directly interconverting these amino acids: GLS and GS. Interestingly, in GLS hyperactivity, glutamate and glutamine levels are normal in plasma and CSF, while both are deviant when analysed using brain MRS and in urine in line with tissue specific expression of GLS.…”

Section: Discussionmentioning

confidence: 99%

“…Glutamate plasma levels were unaltered. 25 Congenital glutamine synthetase deficiency, caused by bi-allelic mutations is the GLUL gene, has been described in four unrelated children. All the patients suffered from seizures which developed either after birth or within few months of life.…”

Section: Disorders Of Glutamine-glutamate Interconversionmentioning

confidence: 99%

“…Three other unrelated patients with GLS deficiency, as a consequence of tandem repeat expansion in GLS, presented with early‐onset delay in overall development, progressive ataxia and elevated glutamine plasma levels. Glutamate plasma levels were unaltered …”

Section: Introductionmentioning

confidence: 99%

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Inborn errors of enzymes in glutamate metabolism

Rumping

Vringer

Houwen

et al. 2019

J of Inher Metab Disea

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Glutamate is involved in a variety of metabolic pathways. We reviewed the literature on genetic defects of enzymes that directly metabolise glutamate, leading to inborn errors of glutamate metabolism. Seventeen genetic defects of glutamate metabolising enzymes have been reported, of which three were only recently identified. These 17 defects affect the inter‐conversion of glutamine and glutamate, amino acid metabolism, ammonia detoxification, and glutathione metabolism. We provide an overview of the clinical and biochemical phenotypes of these rare defects in an effort to ease their recognition. By categorising these by biochemical pathway, we aim to create insight into the contributing role of deviant glutamate and glutamine levels to the pathophysiology. For those disorders involving the inter‐conversion of glutamine and glutamate, these deviant levels are postulated to play a pivotal pathophysiologic role. For the other IEM however—with the exception of urea cycle defects—abnormal glutamate and glutamine concentrations were rarely reported. To create insight into the clinical consequences of disturbed glutamate metabolism—rather than individual glutamate and glutamine levels—the prevalence of phenotypic abnormalities within the 17 IEM was compared to their prevalence within all Mendelian disorders and subsequently all disorders with metabolic abnormalities notated in the Human Phenotype Ontology (HPO) database. For this, a hierarchical database of all phenotypic abnormalities of the 17 defects in glutamate metabolism based on HPO was created. A neurologic phenotypic spectrum of developmental delay, ataxia, seizures, and hypotonia are common in the inborn errors of enzymes in glutamate metabolism. Additionally, ophthalmologic and skin abnormalities are often present, suggesting that disturbed glutamate homeostasis affects tissues of ectodermal origin: brain, eye, and skin. Reporting glutamate and glutamine concentrations in patients with inborn errors of glutamate metabolism would provide additional insight into the pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Section: Disorders Of Glutamine-glutamate Interconversionmentioning

confidence: 99%

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Inborn errors of enzymes in glutamate metabolism

Rumping

Vringer

Houwen

et al. 2019

J of Inher Metab Disea

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“…Whole genome sequencing (WGS) enables complete coverage of the genome and has higher sensitivity than WES for certain coding variants, indels, chromosomal rearrangements, and copy number variants . WGS may also detect short tandem repeat (STR) expansions in IEM, such as the recently described expansion of a GCA‐repeat in GLS , resulting in glutaminase deficiency . However, interpretation is often hindered by difficulty in prioritization of the vast numbers of variants detected and our incomplete understanding of the noncoding sequence, and so the diagnostic yield is only modestly increased to just over 40% by WGS .…”

Section: Introductionmentioning

confidence: 99%

The diagnosis of inborn errors of metabolism by an integrative “multi‐omics” approach: A perspective encompassing genomics, transcriptomics, and proteomics

Stenton

Kremer

Kopajtich

et al. 2019

J of Inher Metab Disea

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Given the rapidly decreasing cost and increasing speed and accessibility of massively parallel technologies, the integration of comprehensive genomic, transcriptomic, and proteomic data into a “multi‐omics” diagnostic pipeline is within reach. Even though genomic analysis has the capability to reveal all possible perturbations in our genetic code, analysis typically reaches a diagnosis in just 35% of cases, with a diagnostic gap arising due to limitations in prioritization and interpretation of detected variants. Here we review the utility of complementing genetic data with transcriptomic data and give a perspective for the introduction of proteomics into the diagnostic pipeline. Together these methodologies enable comprehensive capture of the functional consequence of variants, unobtainable by the analysis of each methodology in isolation. This facilitates functional annotation and reprioritization of candidate genes and variants—a promising approach to shed light on the underlying molecular cause of a patient's disease, increasing diagnostic rate, and allowing actionability in clinical practice.

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“…Methodological advances in bioinformatics in the last two years have made the simultaneous testing for all known REs through whole genome sequencing (WGS) feasible [2] . Additionally, multiple novel REs have been discovered in neurological disorders using WGS in the last two years alone, including in epilepsy [3] and ataxia [4][5][6]. Indeed, there is a growing recognition of the importance of REs and potential contribution to unsolved neurogenetic disease [7].…”

Section: Introductionmentioning

confidence: 99%

Rapid diagnosis of SCA36 in a three-generation family using short-read whole genome sequencing data

Rafehi

Szmulewicz

Pope

et al. 2019

Preprint

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Background: Spinocerebellar ataxias (SCA) are often caused by expansions of short tandem repeats (STRs). Recent methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible. Objectives: To determine the genetic basis of ataxia in a large, multigenerational Australian pedigree, with autosomal dominant inheritance and possible anticipation. Methods and Results: WGS was performed on three affected relatives. The sequence data was screened for known pathogenic REs using three repeat expansion detection tools: exSTRa, ExpansionHunter and GangSTR. This screen provided a clear and rapid diagnosis (<5 days from receiving the sequencing data) of SCA36, a very rare form of ataxia which is caused by an intronic hexanucleotide GGCCTG RE in NOP56. Conclusions:We have demonstrated that diagnosis of rare ataxias caused by REs is highly feasible and cost effective with WGS. We propose a change in current clinical practice, such that WGS be implemented as the frontline, cost effective methodology for molecular testing of individuals with a clinical diagnosis of ataxia.

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Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS

Cited by 72 publications

References 28 publications

Inborn errors of enzymes in glutamate metabolism

Inborn errors of enzymes in glutamate metabolism

The diagnosis of inborn errors of metabolism by an integrative “multi‐omics” approach: A perspective encompassing genomics, transcriptomics, and proteomics

Rapid diagnosis of SCA36 in a three-generation family using short-read whole genome sequencing data

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