Hyperinsulinism and hyperammonemia syndrome: Report of twelve unrelated patients
Hyperinsulinism and hyperammonemia syndrome: Report of twelve unrelated patients
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DOI：
10.1203/00006450-200109000-00010
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发表时间：
2001-09-01
影响因子：
3.6
通讯作者：
Saudubray, JM
中科院分区：
文献类型：
--
作者：
De Lonlay, P;Benelli, C;Saudubray, JM
据报道，高胰岛素血症和高氨血症综合征是导致胰腺弥漫性受累的中重度高胰岛素血症的原因。这种疾病是由GLUD1基因的功能突变引起的。导致三磷酸鸟苷对谷氨酸脱氢酶（GDH）酶的抑制作用降低。本文报道了12例高胰岛素血症和高氨血症综合征患者（男6例，女6例）。临床表型具有异质性，新生儿和婴儿发病低血糖和对药物（二氮氧化物）和饮食（亮氨酸限制饮食）治疗的不同反应性。高氨血症（90-200 mu mol/L，正常< 50 mu mol/L）是恒定的，不受口服蛋白质、限制蛋白质和亮氨酸饮食、苯甲酸钠或n-氨甲酰谷氨酸的影响。在培养的淋巴细胞中，患者的平均基础GDH活性（18.3 +/- 0.9 nmol/min/mg蛋白）与对照组（17.9 +/- 1.8 nmol/min/mg蛋白）没有差异。在所有患者淋巴细胞培养中，三磷酸鸟苷抑制GDH活性的敏感性都降低了（IC50，或抑制GDH活性50%所需的浓度）。IC50值为83 +/- 1.0 nmol/L)。ADP的变构作用在正常范围内。亮氨酸对GDH活性的激活作用因患者而异，其中4例患者对亮氨酸限制饮食的临床反应为阴性，这与敏感性显著降低有关。对11例患者进行了分子研究。杂合突变定位在GLUD1基因的天线区（4例在11外显子，2例在12外显子）和鸟苷三磷酸结合位点（2例在6外显子，2例在7外显子）。在对该基因的外显子5-13进行测序后，未在一名患者中发现突变。
Hyperinsulinism and hyperammonemia syndrome has been reported as a cause of moderately severe hyperinsulinism with diffuse involvement of the pancreas. The disorder is caused by gain of function mutations in the GLUD1 gene. resulting in a decreased inhibitory effect of guanosine triphosphate on the glutamate dehydrogenase (GDH) enzyme. Twelve unrelated patients (six males, six females) with hyperinsulinism and hyperammonemia syndrome have been investigated. The phenotypes were clinically heterogeneous, with neonatal and infancy-onset hypoglycemia and variable responsiveness to medical (diazoxide) and dietary (leucine-restricted diet) treatment. Hyperammonemia (90-200 mu mol/L, normal < 50 mu mol/L) was constant and not influenced by oral protein, by protein- and leucine-restricted diet, or by sodium benzoate or N-carbamylglutamate administration. The patients had mean basal GDH activity (18.3 +/- 0.9 nmol/min/mg protein) not different from controls (17.9 +/- 1.8 nmol/min/mg protein) in cultured lymphoblasts. The sensitivity of GDH activity to inhibition by guanosine triphosphate was reduced in all patient lymphoblast cultures (IC50, or concentrations required for 50% inhibition of GDH activity. ranging from 140 to 580 nM, compared with control IC50 value of 83 +/- 1.0 nmol/L). The allosteric effect of ADP was within the normal range. The activating effect of leucine on GDH activity varied among the patients, with a significant decrease of sensitivity that was correlated with the negative clinical response to a leucine-restricted diet in plasma glucose levels in four patients. Molecular studies were per-formed in 11 patients. Heterozygous mutations were localized in the antenna region (four patients in exon 11, two patients in exon 12) as well as in the guanosine triphosphate binding site (two patients in exon 6, two patients in exon 7) of the GLUD1 gene. No mutation has been found in one patient after sequencing the exons 5-13 of the gene.