Compound heterozygous variants of the NARS2 gene in siblings with refractory seizures: two case report and literature review
BackgroundBiallelic variants in NARS2 that encodes the mitochondrial asparaginyl-tRNA synthetase are associated with a wide spectrum of clinical phenotypes. Herein, we report on two siblings carrying the same compound heterozygous missense variants in NARS2, to improve the understanding of the pheno...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Pediatrics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fped.2025.1571426/full |
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| author | Heyan Wu Min Zhou Xiaoting Ye Huabao Chen Hongxin Lin Li Wang Xing Nie Lidan Zhang |
| author_facet | Heyan Wu Min Zhou Xiaoting Ye Huabao Chen Hongxin Lin Li Wang Xing Nie Lidan Zhang |
| author_sort | Heyan Wu |
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| description | BackgroundBiallelic variants in NARS2 that encodes the mitochondrial asparaginyl-tRNA synthetase are associated with a wide spectrum of clinical phenotypes. Herein, we report on two siblings carrying the same compound heterozygous missense variants in NARS2, to improve the understanding of the phenotypic heterogeneity of NARS2 variants.Case presentationThe two probands, a 3-year-old female (Patient 1) and a 16-month-old male (Patient 2), were clinically suspected of Combined oxidative phosphorylation deficiency 24 (COXPD24). Both presented with neurological manifestations, including refractory epilepsy, developmental delay and motor developmental regression, within the first year of life, accompanied by symmetrical brain lesions identified on magnetic resonance imaging (MRI). To elucidate the underlying genetic etiology, whole-exome sequencing (WES) was performed, followed by Sanger sequencing validation in the patients and their non-consanguineous parents. Genetic analysis revealed that both probands harbored identical compound heterozygous variants in the NARS2 gene: c.1253G>A (p.Arg418His) and c.1163C>T (p.Thr388Met). Notably, the c.1163C>T (p.Thr388Met) variant in NARS2 represents a novel finding, further expanding the genetic spectrum associated with this disorder.ConclusionsOur findings expand the mutational spectrum of NARS2 and highlight the associated phenotypic heterogeneity, underscoring the critical role of NARS2 in epilepsy and neurodevelopmental processes. For pediatric patients with refractory epilepsy, early genetic testing is essential to improve diagnostic accuracy, refine prognostic stratification, and guide personalized treatment strategies. Additionally, mitochondrial drug cocktail therapy may be beneficial for epilepsy caused by NARS2 mutations. |
| format | Article |
| id | doaj-art-c5fae857aeaa411bbc23981aec2ddc88 |
| institution | OA Journals |
| issn | 2296-2360 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pediatrics |
| spelling | doaj-art-c5fae857aeaa411bbc23981aec2ddc882025-08-20T02:08:23ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602025-04-011310.3389/fped.2025.15714261571426Compound heterozygous variants of the NARS2 gene in siblings with refractory seizures: two case report and literature reviewHeyan Wu0Min Zhou1Xiaoting Ye2Huabao Chen3Hongxin Lin4Li Wang5Xing Nie6Lidan Zhang7Pediatric Intensive Care Unit, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaDepartment of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaPediatric Intensive Care Unit, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaPediatric Intensive Care Unit, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaPediatric Intensive Care Unit, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaPediatric Intensive Care Unit, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaPediatric Intensive Care Unit, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaPediatric Intensive Care Unit, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaBackgroundBiallelic variants in NARS2 that encodes the mitochondrial asparaginyl-tRNA synthetase are associated with a wide spectrum of clinical phenotypes. Herein, we report on two siblings carrying the same compound heterozygous missense variants in NARS2, to improve the understanding of the phenotypic heterogeneity of NARS2 variants.Case presentationThe two probands, a 3-year-old female (Patient 1) and a 16-month-old male (Patient 2), were clinically suspected of Combined oxidative phosphorylation deficiency 24 (COXPD24). Both presented with neurological manifestations, including refractory epilepsy, developmental delay and motor developmental regression, within the first year of life, accompanied by symmetrical brain lesions identified on magnetic resonance imaging (MRI). To elucidate the underlying genetic etiology, whole-exome sequencing (WES) was performed, followed by Sanger sequencing validation in the patients and their non-consanguineous parents. Genetic analysis revealed that both probands harbored identical compound heterozygous variants in the NARS2 gene: c.1253G>A (p.Arg418His) and c.1163C>T (p.Thr388Met). Notably, the c.1163C>T (p.Thr388Met) variant in NARS2 represents a novel finding, further expanding the genetic spectrum associated with this disorder.ConclusionsOur findings expand the mutational spectrum of NARS2 and highlight the associated phenotypic heterogeneity, underscoring the critical role of NARS2 in epilepsy and neurodevelopmental processes. For pediatric patients with refractory epilepsy, early genetic testing is essential to improve diagnostic accuracy, refine prognostic stratification, and guide personalized treatment strategies. Additionally, mitochondrial drug cocktail therapy may be beneficial for epilepsy caused by NARS2 mutations.https://www.frontiersin.org/articles/10.3389/fped.2025.1571426/fullcombined oxidative phosphorylation deficiency 24 (COXPD24)NARS2refractory epilepsybiallelic variantspediatricmitochondrial drug cocktail therapy |
| spellingShingle | Heyan Wu Min Zhou Xiaoting Ye Huabao Chen Hongxin Lin Li Wang Xing Nie Lidan Zhang Compound heterozygous variants of the NARS2 gene in siblings with refractory seizures: two case report and literature review Frontiers in Pediatrics combined oxidative phosphorylation deficiency 24 (COXPD24) NARS2 refractory epilepsy biallelic variants pediatric mitochondrial drug cocktail therapy |
| title | Compound heterozygous variants of the NARS2 gene in siblings with refractory seizures: two case report and literature review |
| title_full | Compound heterozygous variants of the NARS2 gene in siblings with refractory seizures: two case report and literature review |
| title_fullStr | Compound heterozygous variants of the NARS2 gene in siblings with refractory seizures: two case report and literature review |
| title_full_unstemmed | Compound heterozygous variants of the NARS2 gene in siblings with refractory seizures: two case report and literature review |
| title_short | Compound heterozygous variants of the NARS2 gene in siblings with refractory seizures: two case report and literature review |
| title_sort | compound heterozygous variants of the nars2 gene in siblings with refractory seizures two case report and literature review |
| topic | combined oxidative phosphorylation deficiency 24 (COXPD24) NARS2 refractory epilepsy biallelic variants pediatric mitochondrial drug cocktail therapy |
| url | https://www.frontiersin.org/articles/10.3389/fped.2025.1571426/full |
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