Analysis of genotypes and clinical phenotypes in two children with convulsions as the first symptom of hypoglycemia_Journal of Epilepsy

Authors：

YIN Xiaojing ^1,2 ,  GAO Li ¹ , LI Yan ¹ , CAO Ruiming ¹ , YANG Liu ¹ , FAN Hongye ¹ , QI Hui ¹ , ZHANG Jun ¹ , FENG Jie ¹ , LI Junlong ¹

1. Department of neurology, General Hospital of Henan Province, Zhengzhou 450000, China;
2. Graduate Division of Xinxiang Medical University, Xinxiang 453003, China;

Corresponding author：

GAO Li, Email: 1879872583@qq.com

Keywords：

Convulsions; Glucopenia; Family; Genotype; Gene analysis

DOI：

10.7507/2096-0247.20180020

Video：

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ObjectiveTo recognize the convulsion caused by hypoglycemia, and to analyze its genotype and clinical phenotype, so as to deepen the understanding of hyperinsulinemia.MethodFull exon detection were performed on 2 children with hypoglycemia and convulsions, who had been treated with antiepileptic drugs for 1 year in pediatric neurology department, Henan Provincial People’s Hospital in 2012 and 2014 respectively, but with poor curative effect.ResultABCC8 gene mutations were found in a child. The mutations located in Chromosome 11, with the nucleic acid changes of c.4607C>T (exon38) and the amino acid change of p.A1536V, rs745918247. The inheritancemode of ABCC8 gene could be autosomal dominant or autosomal recessive inheritance. Both of the parents were wild type on this genelocus. The gene mutation is associated with type 1 familial hyperinsulinemic hypoglycemia/nesidioblastosis. The other child was carrying GLUD1 gene mutation, witch is located in chromosome 10, with the nucleic acid changes of c.1498G>A (exon12) and the amino acid change of p.A500T. The inheritance mode of GLUD1 gene is autosomal dominant andthe child’s parents were both wild type. This gene mutationis associated with type 6 familial hyperinsulinemic hypoglycemia/nesidioblastosis. The 2 mutations have not been reported, which are new mutations.ConclusionMutations in these 2 gene loci may be the underlying cause of hypoglycemic convulsions, and are the best explanation for the poor convulsionscontrol of antiepileptic drugs.

Citation： YIN Xiaojing, GAO Li, LI Yan, CAO Ruiming, YANG Liu, FAN Hongye, QI Hui, ZHANG Jun, FENG Jie, LI Junlong. Analysis of genotypes and clinical phenotypes in two children with convulsions as the first symptom of hypoglycemia. Journal of Epilepsy, 2018, 4(2): 94-97. doi: 10.7507/2096-0247.20180020 Copy

1.	Senniappan S, Shanti B, James C, et al. Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management. J Inherit Metab Dis, 2012, 35(4): 589-601.
2.	Frigerio F, Karaca M, De Roo M, et al. Deletion of glutamate dehydrogenase 1(GLUD1) in the central nervous system affects glutamate handling without altering synaptic tranmission.JNeurochem, 2012, 123(3): 342-348.
3.	Aynsley-Green A, Hussain K, Hall J, et al. Practical management of hyperinsulinism ininfancy. Arch Dis Child Fetal Neonatal Ed, 2000, 82(2): F98-F107.
4.	Hussain K, Blankenstein O, De Lonlay P, et al. Hyperinsulinaemic hypoglycaemia: biochemical basis and theimportance of maintaining normoglycaemia during management. Arch Dis Child, 2007, 92(7): 568-570.
5.	Collins JE, Leonard JV. Hyperinsulinism in asphyxiated andsmall for dates infants with hypoglycaemia. Lancet, 1984, 2(8398): 311-313.
6.	Munns CF, Batch JA. Hyperinsulinism and Beckwith-Wiedemannsyndrome. Arch Dis Child Fetal Neonatal Ed, 2001, 84(1): F67-F69.
7.	Böhles H, Sewell AA, Gebhardt B, et al. Hyperinsulinemic hypoglycemia-leading symptom in a patient with congenital disorders ofglycosylation 1a (phosphomannomutase deficiency). J InheritMetab Dis, 2001, 24(8): 858-862.
8.	桑艳梅, 张亚楠, 刘敏, 等.先天性高胰岛素血症四例 ABCC8 基因突变分析. 中华胰腺病杂志, 2013, 13(6): 407-409.
9.	康丽丽, 刘建红, 李晓莺. ABCC8 突变致药物治疗无效的新生儿高胰岛素血症一例. 中国新生儿杂志, 2016, 31(1): 62-63.
10.	桑艳梅, 倪桂臣, 刘桂琴, 等. 三例谷氨酸脱氢酶型先天性高胰岛素血症患儿的 GLUDl 基因突变分析. 中华医学遗传杂志, 2010, 27(5): 493-496.
11.	Kapoor RR, Flanagan SE, Fulton P, et al. Hyperinsulinism-hyperammonaemia syndrome: novelmutations in the GLUD1 gene and genotype-phenotypecorrelations. EurJEndocrinol, 2009, 161(5): 731-735.
12.	Nakano K, Kobayashi K, Okano Y, et al. Intractable absence seizures inHyperinsulinism-HyperammonemiaSyndrome.Pediatr Neurol, 2012, 47(2): 119-122.
13.	徐子迪, 桑艳梅. ATP 敏感性钾离子通道型先天性高胰岛素血症的遗传发病机制及诊疗进展. 中华实用儿科临床杂志, 2016, 31(8): 628-630.
14.	桑艳梅, 胡姝雯, 刘敏, 等. ABCC8 基因突变致 ATP 敏感性钾通道型先天性高胰岛素血症一例家系分析. 中华内分泌代谢杂志, 2012, 28(1): 51-53.
15.	Stanley CA, Fang J, Kutyna K, et al. Molecular basis and characterization of thehyperinsulinism/hyperammonemia syndrome.predominance of mutations in exons 11 and 12of the glutamate dehydrogenase gene. Diabetes, 2000, 49(4): 667-673.
16.	Kapoor RR, Flanagan SF, James CT, et al. Hyperinsulinaemic hypoglycaemia and diabetes mellitusdue to dominant ABCC8/KCNJ11 mutations. Diabetologia, 2011, 54(10): 2575-2583.

1. Senniappan S, Shanti B, James C, et al. Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management. J Inherit Metab Dis, 2012, 35(4): 589-601.
2. Frigerio F, Karaca M, De Roo M, et al. Deletion of glutamate dehydrogenase 1(GLUD1) in the central nervous system affects glutamate handling without altering synaptic tranmission.JNeurochem, 2012, 123(3): 342-348.
3. Aynsley-Green A, Hussain K, Hall J, et al. Practical management of hyperinsulinism ininfancy. Arch Dis Child Fetal Neonatal Ed, 2000, 82(2): F98-F107.
4. Hussain K, Blankenstein O, De Lonlay P, et al. Hyperinsulinaemic hypoglycaemia: biochemical basis and theimportance of maintaining normoglycaemia during management. Arch Dis Child, 2007, 92(7): 568-570.
5. Collins JE, Leonard JV. Hyperinsulinism in asphyxiated andsmall for dates infants with hypoglycaemia. Lancet, 1984, 2(8398): 311-313.
6. Munns CF, Batch JA. Hyperinsulinism and Beckwith-Wiedemannsyndrome. Arch Dis Child Fetal Neonatal Ed, 2001, 84(1): F67-F69.
7. Böhles H, Sewell AA, Gebhardt B, et al. Hyperinsulinemic hypoglycemia-leading symptom in a patient with congenital disorders ofglycosylation 1a (phosphomannomutase deficiency). J InheritMetab Dis, 2001, 24(8): 858-862.
8. 桑艳梅, 张亚楠, 刘敏, 等.先天性高胰岛素血症四例 ABCC8 基因突变分析. 中华胰腺病杂志, 2013, 13(6): 407-409.
9. 康丽丽, 刘建红, 李晓莺. ABCC8 突变致药物治疗无效的新生儿高胰岛素血症一例. 中国新生儿杂志, 2016, 31(1): 62-63.
10. 桑艳梅, 倪桂臣, 刘桂琴, 等. 三例谷氨酸脱氢酶型先天性高胰岛素血症患儿的 GLUDl 基因突变分析. 中华医学遗传杂志, 2010, 27(5): 493-496.
11. Kapoor RR, Flanagan SE, Fulton P, et al. Hyperinsulinism-hyperammonaemia syndrome: novelmutations in the GLUD1 gene and genotype-phenotypecorrelations. EurJEndocrinol, 2009, 161(5): 731-735.
12. Nakano K, Kobayashi K, Okano Y, et al. Intractable absence seizures inHyperinsulinism-HyperammonemiaSyndrome.Pediatr Neurol, 2012, 47(2): 119-122.
13. 徐子迪, 桑艳梅. ATP 敏感性钾离子通道型先天性高胰岛素血症的遗传发病机制及诊疗进展. 中华实用儿科临床杂志, 2016, 31(8): 628-630.
14. 桑艳梅, 胡姝雯, 刘敏, 等. ABCC8 基因突变致 ATP 敏感性钾通道型先天性高胰岛素血症一例家系分析. 中华内分泌代谢杂志, 2012, 28(1): 51-53.
15. Stanley CA, Fang J, Kutyna K, et al. Molecular basis and characterization of thehyperinsulinism/hyperammonemia syndrome.predominance of mutations in exons 11 and 12of the glutamate dehydrogenase gene. Diabetes, 2000, 49(4): 667-673.
16. Kapoor RR, Flanagan SF, James CT, et al. Hyperinsulinaemic hypoglycaemia and diabetes mellitusdue to dominant ABCC8/KCNJ11 mutations. Diabetologia, 2011, 54(10): 2575-2583.

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