Compound heterozygous variants of the NARS2 gene in siblings with developmental delay, epilepsy, and neonatal diabetes syndrome
Compound heterozygous variants of the NARS2 gene in siblings with developmental delay, epilepsy, and neonatal diabetes syndrome
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DOI：
10.1002/ajmg.a.62873
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发表时间：
2022-06-15
影响因子：
2
通讯作者：
Inukai, Takeshi
中科院分区：
文献类型：
--
作者：
Yagasaki, Hideaki;Sano, Fumikazu;Inukai, Takeshi
新生儿糖尿病（NDM）伴发育迟缓和癫痫被分类为发育迟缓、癫痫和新生儿糖尿病（DEND）综合征。大多数DEND综合征是由于K-ATP通道的严重破坏性变体，很少有报道与DEND相关的基因。我们在这里报告两个日本同胞谁被临床诊断为DEND综合征，其中NARS 2复合杂合子变异检测。患者1是一名3岁女孩，在3个月大时出现糖尿病酮症酸中毒。患者2是一名1岁男孩，患有严重高血糖症，并在3天大时开始胰岛素治疗。在第一次发作后，他们都表现出严重的发育迟缓，听力损失和难治性癫痫伴进行性脑萎缩。全外显子组测序显示两名患者中存在复合杂合NARS 2 p.R159C和p.L217V变体以及GATA 4 p.P407Q变体。他们接受了维生素B1、左旋肉碱和辅酶Q10的线粒体支持治疗。患者2在6个月大时停止胰岛素治疗。这是第一个报告的NDM中检测到的NARS 2基因编码的线粒体蛋白的变体。新生儿糖尿病伴神经源性症状的患者应考虑进行包括线粒体基因在内的遗传分析。
Neonatal diabetes mellitus (NDM) with developmental delay and epilepsy is classified as developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. The majority of DEND syndrome are due to severely damaging variants of K-ATP channels, and few mitochondria-related genes have been reported. We report here two Japanese siblings who were clinically diagnosed with DEND syndrome in whom NARS2 compound heterozygous variants were detected. Patient 1 was a 3-year-old girl and presented with diabetes ketoacidosis at 3 months old. Patient 2 was a 1-year-old boy who presented with severe hyperglycemia and started insulin therapy at 3 days old. After the first episodes, they both presented with severe developmental delay, hearing loss and treatment-resistant epilepsy accompanied by progressive brain atrophy. Whole-exome sequencing revealed compound heterozygous NARS2 p.R159C and p.L217V variants, and the GATA4 p.P407Q variant in both patients. They were treated by mitochondrial supportive therapy of vitamin B1, L-carnitine, and coenzyme Q10. Patient 2 was withdrawn from insulin therapy at 6 months old. This is the first report of NDM in which variants of the NARS2 gene coding mitochondrial protein were detected. Genetic analysis including mitochondrial genes should be considered in patients with neonatal onset diabetes associated with neurogenic symptoms.