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• W3094058242 abstract "Since publication of our previous paper on aminoacyl-tRNA synthetase (ARS) deficiencies,1.Fuchs S.A. Schene I.F. Kok G. et al.Aminoacyl-tRNA synthetase deficiencies in search of common themes.1:CAS:528:DC%2BC1cXht1Cgt7fK10.1038/s41436-018-0048-yGenet Med. 2019; 21: 319-330Google Scholar the number of recognized patients suffering from these diseases has steadily increased, putatively through progressively genetic diagnostic testing, aided by recognition of the clinical phenotype. To further improve disease recognition, counseling, prognostic prediction, and potential treatment development and evaluation, further understanding of the disease mechanism, genotypes, and clinical phenotypes remains crucial. Shen et al. provide interesting additional clinical information on QARS deficiency,2.Shen YW, Zou LP. A possible natural model for excitation/inhibition imbalance in epilepsy. Genet Med (in press).Google Scholar one of these ARS deficiencies. They show that serum protein levels were consistently decreased in their three patients with QARS deficiency, while albumin was only slightly and inconsistently decreased, which they attribute to the relatively low glutamine content of albumin (3.3%). Hypoalbuminemia is common to multiple ARS deficiencies,1.Fuchs S.A. Schene I.F. Kok G. et al.Aminoacyl-tRNA synthetase deficiencies in search of common themes.1:CAS:528:DC%2BC1cXht1Cgt7fK10.1038/s41436-018-0048-yGenet Med. 2019; 21: 319-330Google Scholar including IARS, LARS, MARS, and possibly KARS. However, the abundance of the corresponding amino acids varies (isoleucine: 1.5%, leucine: 10.5%, methionine: 1.1% methionine, and lysine: 9.9%). Therefore, a more general mechanism seems more plausible. Of the QARS deficient patients we previously described,1.Fuchs S.A. Schene I.F. Kok G. et al.Aminoacyl-tRNA synthetase deficiencies in search of common themes.1:CAS:528:DC%2BC1cXht1Cgt7fK10.1038/s41436-018-0048-yGenet Med. 2019; 21: 319-330Google Scholar,3.Salvarinova R. Ye C.X. Rossi A. et al.Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities.1:CAS:528:DC%2BC2cXhvF2gsLbE10.1007/s10048-014-0432-yNeurogenetics. 2015; 16: 145-149Google Scholar the first1.Fuchs S.A. Schene I.F. Kok G. et al.Aminoacyl-tRNA synthetase deficiencies in search of common themes.1:CAS:528:DC%2BC1cXht1Cgt7fK10.1038/s41436-018-0048-yGenet Med. 2019; 21: 319-330Google Scholar displayed normal serum albumin concentrations at ages 1.5 years (40 g/l, normal values: 35–50 g/l), and 3 years (43 g/l), but decreased concentrations at age 5.5 years (28 g/l). The second patient3.Salvarinova R. Ye C.X. Rossi A. et al.Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities.1:CAS:528:DC%2BC2cXhvF2gsLbE10.1007/s10048-014-0432-yNeurogenetics. 2015; 16: 145-149Google Scholar also displayed mostly normal concentrations except at age 12 years (31 g/l, normal values: 34–42 g/l). Total plasma protein concentration was only measured once in both patients and was normal (63 g/l, normal 60–80 g/l) at age 1.5 years in the first patient1.Fuchs S.A. Schene I.F. Kok G. et al.Aminoacyl-tRNA synthetase deficiencies in search of common themes.1:CAS:528:DC%2BC1cXht1Cgt7fK10.1038/s41436-018-0048-yGenet Med. 2019; 21: 319-330Google Scholar and decreased (54 g/l, normal 60–80 g/l) at age 13 years in the second.3.Salvarinova R. Ye C.X. Rossi A. et al.Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities.1:CAS:528:DC%2BC2cXhvF2gsLbE10.1007/s10048-014-0432-yNeurogenetics. 2015; 16: 145-149Google Scholar In this second patient, serum prealbumin concentrations were normal, and marginally reduced once (185 g/l, normal 186–335 g/l) at age 9 years. When looking at our other ARS deficient patients,1.Fuchs S.A. Schene I.F. Kok G. et al.Aminoacyl-tRNA synthetase deficiencies in search of common themes.1:CAS:528:DC%2BC1cXht1Cgt7fK10.1038/s41436-018-0048-yGenet Med. 2019; 21: 319-330Google Scholar IARS deficient patient 1 also had low plasma protein levels (33 and 34 g/l at age 1 month and 2.5 months, respectively), but IARS deficient patient 2 had normal levels (80 g/l) at age 4 years and so did KARS deficient patient 4 (64 g/l) at age 1 year. Plasma protein concentration was not determined in our LARS deficient patients. Collectively, these data suggest that both plasma albumin and protein concentrations may be decreased in ARS deficiencies, putatively through a common mechanism shared among the ARS deficiencies involving either insufficient protein synthesis, mistranslation, and/or increased peptide/protein degradation. Affected proteins may depend on the specific amino acid corresponding to the ARS deficiency. Since QARS deficiency is a predominantly neurological disease, Shen et al. sought to extend the hypothesis of decreased protein synthesis to the central nervous system.2.Shen YW, Zou LP. A possible natural model for excitation/inhibition imbalance in epilepsy. Genet Med (in press).Google Scholar However, they did not find decreased protein levels in cerebrospinal fluid (CSF). Similarly, our QARS deficient patients1.Fuchs S.A. Schene I.F. Kok G. et al.Aminoacyl-tRNA synthetase deficiencies in search of common themes.1:CAS:528:DC%2BC1cXht1Cgt7fK10.1038/s41436-018-0048-yGenet Med. 2019; 21: 319-330Google Scholar,3.Salvarinova R. Ye C.X. Rossi A. et al.Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities.1:CAS:528:DC%2BC2cXhvF2gsLbE10.1007/s10048-014-0432-yNeurogenetics. 2015; 16: 145-149Google Scholar did not have decreased CSF protein levels (0.36 g/l, normal range 0–0.40, and 0.36 g/l, normal values 0.10–0.35 g/l, respectively), nor did our KARS deficient patient (0.31 g/l) and our IARS deficient patient (0.75 g/l; but this sample was contaminated with >80,000 erythrocytes and >400 leukocytes). Shen et al. then propose an interesting hypothesis of excitotoxicity induced by increased glutamate/glutamine ratios due to QARS deficiency.2.Shen YW, Zou LP. A possible natural model for excitation/inhibition imbalance in epilepsy. Genet Med (in press).Google Scholar Indeed, severe neurological symptoms have been associated with increased glutamate/glutamine ratios in several inborn errors of metabolism.4.Rumping L. Vringer E. Houwen R.H.J. Hasselt P.M. Jans J.J.M. Verhoeven‐Duif N.M. Inborn errors of enzymes in glutamate metabolism.1:CAS:528:DC%2BB3cXktlCgsLs%3D10.1002/jimd.12180J Inherit Metab Dis. 2020; 43: 200-215Google Scholar However, CSF amino acid analysis in our reported QARS patients1.Fuchs S.A. Schene I.F. Kok G. et al.Aminoacyl-tRNA synthetase deficiencies in search of common themes.1:CAS:528:DC%2BC1cXht1Cgt7fK10.1038/s41436-018-0048-yGenet Med. 2019; 21: 319-330Google Scholar,3.Salvarinova R. Ye C.X. Rossi A. et al.Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities.1:CAS:528:DC%2BC2cXhvF2gsLbE10.1007/s10048-014-0432-yNeurogenetics. 2015; 16: 145-149Google Scholar revealed normal glutamate (3 µmol/l, normal range 0–7.8 µmol/l and <8.5 µmol/l, normal range: <8.5 µmol/l, respectively) and nearly normal glutamine concentrations (488 µmol/l, normal range 363–785 µmol/l and 688 µmol/l, normal range 260–684 µmol/l, respectively). The first patient1.Fuchs S.A. Schene I.F. Kok G. et al.Aminoacyl-tRNA synthetase deficiencies in search of common themes.1:CAS:528:DC%2BC1cXht1Cgt7fK10.1038/s41436-018-0048-yGenet Med. 2019; 21: 319-330Google Scholar also had slightly decreased taurine concentrations (2 µmol/l, normal range 4–13 µmol/l) and the second3.Salvarinova R. Ye C.X. Rossi A. et al.Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities.1:CAS:528:DC%2BC2cXhvF2gsLbE10.1007/s10048-014-0432-yNeurogenetics. 2015; 16: 145-149Google Scholar marginally decreased serine concentrations (24.4 µmol/l, normal 25–56 µmol/l). Although the proposed disease mechanism would be QARS specific, the underlying mechanistic hypothesis would suggest alterations in the corresponding amino acids in CSF of other ARS deficiencies. However, CSF amino acids were also normal in our KARS deficient patient. As a global central nervous system fluid, CSF may not reflect local concentrations of amino acids in the brain. We performed brain magnetic resonance (MR) spectroscopy in the white matter of our QARS patient,1.Fuchs S.A. Schene I.F. Kok G. et al.Aminoacyl-tRNA synthetase deficiencies in search of common themes.1:CAS:528:DC%2BC1cXht1Cgt7fK10.1038/s41436-018-0048-yGenet Med. 2019; 21: 319-330Google Scholar which revealed low N-acetyl aspartic acid peaks compatible with white matter disease, and prominent glutamate/glutamine peaks. Unfortunately, these 3-Tesla MRI scans do not allow distinction between glutamate and glutamine. Further studies with more advanced spectroscopy in different brain areas may provide further insight in this hypothesis. Similarly, as also mentioned by Shen et al.,2.Shen YW, Zou LP. A possible natural model for excitation/inhibition imbalance in epilepsy. Genet Med (in press).Google Scholar the response to treatments affecting the glutamate/glutamine balance (like glutamine supplementation) and/or excitotoxicity (like memantine, which antagonizes the interaction between glutamate and the NMDA receptor and pyridoxine, which is required for the conversion of glutamate to GABA) may provide further support for this hypothesis and guide therapeutic strategies. Nevertheless, since neurological symptoms are shared among many cytosolic, combined cytosolic and mitochondrial, and mitochondrial ARS deficiencies, a more common translational deficiency or mitochondrial dysfunction may also contribute to the neurological phenotype. When interpreting genetic variations, their potential pathogenicity, associated clinical phenotype. and response to specific treatments, their precise genetic location is crucial. This is the reason we dedicated Fig. 5 of our previous article1.Fuchs S.A. Schene I.F. Kok G. et al.Aminoacyl-tRNA synthetase deficiencies in search of common themes.1:CAS:528:DC%2BC1cXht1Cgt7fK10.1038/s41436-018-0048-yGenet Med. 2019; 21: 319-330Google Scholar to the genetic locations of all reported ARS variants. We have updated this figure (Supplemental Fig. 1) with novel pathogenic variants,5.Datta A. Ferguson A. Simonson C. et al.Case report: QARS deficiency and favorable outcome following treatment of seizures with ketogenic diet.10.1177/0883073816685508J Child Neurol. 2017; 32: 403-407Google Scholar, 6.Kodera H. Osaka H. Iai M. et al.Mutations in the glutaminyl-tRNA synthetase gene cause early-onset epileptic encephalopathy.1:CAS:528:DC%2BC2MXjsVags78%3D10.1038/jhg.2014.103J Hum Genet. 2015; 60: 97-101Google Scholar, 7.Johannesen K.M. Mitter D. Janowski R. et al.Defining and expanding the phenotype of QARS -associated developmental epileptic encephalopathy.10.1212/NXG.0000000000000373Neurol Genet. 2019; 5: e373Google Scholar, 8.Alabdullatif M.A. Al Dhaibani M.A. Khassawneh M.Y. El-Hattab A.W. Chromosomal microarray in a highly consanguineous population: diagnostic yield, utility of regions of homozygosity, and novel mutations.1:CAS:528:DC%2BC2sXkslKmsbs%3D10.1111/cge.12872Clin Genet. 2017; 91: 616-622Google Scholar, 9.Leshinsky-Silver E. Ling J. Wu J. et al.Severe growth deficiency, microcephaly, intellectual disability, and characteristic facial features are due to a homozygous QARS mutation.10.1007/s10048-017-0516-6Neurogenetics. 2017; 18: 141-146Google Scholar, 10.Kuperberg M. Lev D. Blumkin L. et al.Utility of whole exome sequencing for fenetic diagnosis of previously undiagnosed pediatric neurology patients.10.1177/0883073816664836J Child Neurol. 2016; 31: 1534-1539Google Scholar and hope this genetic information, the additional clinical features, and deduced mechanistic hypotheses will aid other researchers and clinicians to improve understanding of ARS deficiencies and care for this expanding group of patients. The authors declare no conflicts of interest. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Download .pdf (.19 MB) Help with pdf files Supplementary data" @default.
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• W3094058242 title "Response to Shen and Zou" @default.
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