Department of Pediatric Endocrinology, Genetic and Metabolism, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
J Diabetes Res. 2018 Sep 16;2018:2802540. doi: 10.1155/2018/2802540. eCollection 2018.
To characterize the genotype and phenotype of Chinese patients with congenital hyperinsulinism (CHI) caused by activating mutations in , the gene that encodes mitochondrial enzyme glutamate dehydrogenase (GDH).
The clinical data of glutamate dehydrogenase hyperinsulinism (GDH-HI) patients were reviewed, and gene mutations were confirmed by whole exome sequencing (WES) and Sanger DNA sequencing.
Twenty-six patients with GDH-HI heterozygous missense mutations were identified from 240 patients diagnosed as congenital hyperinsulinism over past 15 years. The median age at onset was 8 months (range: 1 day of life to 3 years). Seizure disorder was common in our cohort of patients (23/26). Four patients had normal serum ammonia levels; the median serum concentration was 101 mol/L (range: 37-190 mol/L). Hypoglycemic symptoms could be triggered by fasting or protein meals in all patients while blood glucose could be well controlled in all patients with diazoxide. Dosage of diazoxide could be reduced by protein restriction. Attempts to lower ammonia levels failed with different therapies such as protein restriction, benzoate, or N-carbamoyl glutamate. In follow-up, 15 of 26 patients had normal intelligence. Eleven patients developed epilepsy at the age of 6 months to 11 years. De novo mutations in were found in 24 cases, and dominant inheritance was observed in the other two; all were heterozygous. A total of 35% (9/26) patients carried c.1493C>T (p.S445L) mutation.
Phenotypic heterogeneity of GDH-HI patients was observed within the Chinese cohort in the present study. The fact that most patients had a p. S445L mutation implies that this site could be a hotspot in Chinese patients. A high frequency of GDH-HI with normal ammonia has been reported in this study. Hence, mutational analysis may be an important method to differential diagnosis of GDH-HI from other diazoxide-responsive CHI in Chinese patients.
研究编码线粒体酶谷氨酸脱氢酶（GDH）的 基因突变导致的中国人先天性高胰岛素血症（CHI）患者的基因型和表型特征。
回顾谷氨酸脱氢酶高胰岛素血症（GDH-HI）患者的临床资料，通过全外显子组测序（WES）和 Sanger DNA 测序确认基因突变。
在过去 15 年诊断为先天性高胰岛素血症的 240 例患者中，鉴定出 26 例 GDH-HI 杂合错义突变患者。发病年龄中位数为 8 个月（范围：生后 1 天至 3 岁）。在本研究队列中，癫痫发作较为常见（23/26）。4 例患者血清氨水平正常；血清浓度中位数为 101μmol/L（范围：37-190μmol/L）。所有患者禁食或高蛋白饮食均可诱发低血糖症状，所有患者均能通过二氮嗪良好地控制血糖。限制蛋白质摄入可减少二氮嗪的剂量。不同的治疗方法，如限制蛋白质摄入、苯甲酸钠或 N-氨甲酰谷氨酸，均未能降低血氨水平。随访中，26 例患者中有 15 例智力正常。11 例患者在 6 个月至 11 岁时出现癫痫。24 例患者中发现 新发突变，另外 2 例为显性遗传，均为杂合子。35%（9/26）的患者携带 c.1493C>T（p.S445L）突变。
本研究中，中国人群中观察到 GDH-HI 患者的表型异质性。大多数患者存在 p.S445L 突变，提示该位点可能是中国患者的热点。本研究报道了 GDH-HI 患者常伴有正常血氨的高频度，因此， 基因突变分析可能是中国患者与其他对二氮嗪反应性 CHI 进行 GDH-HI 鉴别诊断的重要方法。
