Aminoacyl-tRNA synthetase deficiencies in search of common themes

Sabine A Fuchs; Imre F Schene; Gautam Kok; Jurriaan M Jansen; Peter G J Nikkels; Koen L I van Gassen; Suzanne W J Terheggen-Lagro; Saskia N van der Crabben; Sanne E Hoeks; Laetitia E M Niers; Nicole I Wolf; Maaike C de Vries; David A Koolen; Roderick H J Houwen; Margot F Mulder; Peter M van Hasselt

doi:10.1038/s41436-018-0048-y

Aminoacyl-tRNA synthetase deficiencies in search of common themes

Sabine A Fuchs, Imre F Schene, Gautam Kok, Jurriaan M Jansen, Peter G J Nikkels, Koen L I van Gassen, Suzanne W J Terheggen-Lagro, Saskia N van der Crabben, Sanne E Hoeks, Laetitia E M Niers, Nicole I Wolf, Maaike C de Vries, David A Koolen, Roderick H J Houwen, Margot F Mulder, Peter M van Hasselt

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

PURPOSE: Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care.

METHODS: Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital.

RESULTS: In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy.

CONCLUSION: We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.

Original language	English
Pages (from-to)	319-330
Number of pages	12
Journal	Genetics in Medicine
Volume	21
Issue number	2
DOIs	https://doi.org/10.1038/s41436-018-0048-y
Publication status	Published - 1 Feb 2019

Keywords

Amino Acyl-tRNA Synthetases/deficiency
Central Nervous System Diseases/enzymology
Child
Failure to Thrive/enzymology
Feeding and Eating Disorders/enzymology
Female
Genes, Recessive
Genetic Diseases, Inborn/enzymology
Growth Disorders/enzymology
Humans
Liver Diseases/enzymology
Male
Phenotype
Clinical phenotype
Cytosolic translation
Aminoacyl-tRNA synthetase deficiency

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10.1038/s41436-018-0048-y

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Fuchs, S. A., Schene, I. F., Kok, G., Jansen, J. M., Nikkels, P. G. J., van Gassen, K. L. I., Terheggen-Lagro, S. W. J., van der Crabben, S. N., Hoeks, S. E., Niers, L. E. M., Wolf, N. I., de Vries, M. C., Koolen, D. A., Houwen, R. H. J., Mulder, M. F., & van Hasselt, P. M. (2019). Aminoacyl-tRNA synthetase deficiencies in search of common themes. Genetics in Medicine, 21(2), 319-330. https://doi.org/10.1038/s41436-018-0048-y

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abstract = "PURPOSE: Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care.METHODS: Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital.RESULTS: In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy.CONCLUSION: We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.",

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author = "Fuchs, {Sabine A} and Schene, {Imre F} and Gautam Kok and Jansen, {Jurriaan M} and Nikkels, {Peter G J} and {van Gassen}, {Koen L I} and Terheggen-Lagro, {Suzanne W J} and {van der Crabben}, {Saskia N} and Hoeks, {Sanne E} and Niers, {Laetitia E M} and Wolf, {Nicole I} and {de Vries}, {Maaike C} and Koolen, {David A} and Houwen, {Roderick H J} and Mulder, {Margot F} and {van Hasselt}, {Peter M}",

year = "2019",

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doi = "10.1038/s41436-018-0048-y",

language = "English",

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Fuchs, SA, Schene, IF, Kok, G, Jansen, JM, Nikkels, PGJ, van Gassen, KLI, Terheggen-Lagro, SWJ, van der Crabben, SN, Hoeks, SE, Niers, LEM, Wolf, NI, de Vries, MC, Koolen, DA, Houwen, RHJ, Mulder, MF & van Hasselt, PM 2019, 'Aminoacyl-tRNA synthetase deficiencies in search of common themes', Genetics in Medicine, vol. 21, no. 2, pp. 319-330. https://doi.org/10.1038/s41436-018-0048-y

TY - JOUR

T1 - Aminoacyl-tRNA synthetase deficiencies in search of common themes

AU - Fuchs, Sabine A

AU - Schene, Imre F

AU - Kok, Gautam

AU - Jansen, Jurriaan M

AU - Nikkels, Peter G J

AU - van Gassen, Koen L I

AU - Terheggen-Lagro, Suzanne W J

AU - van der Crabben, Saskia N

AU - Hoeks, Sanne E

AU - Niers, Laetitia E M

AU - Wolf, Nicole I

AU - de Vries, Maaike C

AU - Koolen, David A

AU - Houwen, Roderick H J

AU - Mulder, Margot F

AU - van Hasselt, Peter M

PY - 2019/2/1

Y1 - 2019/2/1

N2 - PURPOSE: Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care.METHODS: Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital.RESULTS: In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy.CONCLUSION: We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.

AB - PURPOSE: Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care.METHODS: Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital.RESULTS: In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy.CONCLUSION: We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.

KW - Amino Acyl-tRNA Synthetases/deficiency

KW - Central Nervous System Diseases/enzymology

KW - Child

KW - Failure to Thrive/enzymology

KW - Feeding and Eating Disorders/enzymology

KW - Female

KW - Genes, Recessive

KW - Genetic Diseases, Inborn/enzymology

KW - Growth Disorders/enzymology

KW - Humans

KW - Liver Diseases/enzymology

KW - Male

KW - Phenotype

KW - Clinical phenotype

KW - Cytosolic translation

KW - Aminoacyl-tRNA synthetase deficiency

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U2 - 10.1038/s41436-018-0048-y

DO - 10.1038/s41436-018-0048-y

M3 - Article

C2 - 29875423

SN - 1098-3600

VL - 21

SP - 319

EP - 330

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 2

ER -

Aminoacyl-tRNA synthetase deficiencies in search of common themes

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Keywords

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