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A de novo CACNA1D missense mutation in a patient with congenital hyperinsulinism, primary hyperaldosteronism and hypotonia.
Channels ( IF 3.3 ) Pub Date : 2020-05-04 , DOI: 10.1080/19336950.2020.1761171
María Carmen De Mingo Alemany 1 , Luis Mifsud Grau 2 , Francisca Moreno Macián 1 , Belén Ferrer Lorente 1 , Sara León Cariñena 1
Affiliation  

Congenital hyperinsulinemic hypoglycemia is the most frequent cause of persistent and recurrent hypoglycemia in the first years of life and in many patients rare genetic variants can be identified. Recently a case of congenital hyperinsulinemic hypoglycemia and a severe neurodevelopmental syndrome due to a mutation in the voltage-gated Cav1.3 Ca2+ channel CACNA1D gene has been reported which required long-term treatment with diazoxide. This suggested CACNA1D variants as a potential cause for this condition.Here we support this observation by presenting the case of a female child with congential hyperinsulinemic hypoglycemia and primary hyperaldosteronism, aortic insufficiency, pronounced developmental delay, muscle hypotonia, and facial dysmorphias but without seizures. Sequencing of the exome of the child and its parents identified a novel de novo CACNA1D missense mutation p.L271 H, replacing a highly conserved residue in a functionally relevant region of the voltage-gated Cav1.3 Ca2+ channel. The patient was treated with diazoxide and nifedipine with adequate control of glucose metabolism and blood pressure, and with improvement in muscle tone.Our findings further confirm the pathogenic role of CACNA1D for congentital hyperinsulinemic hypoglycemia and primary aldosteronism. Moreover, we provide evidence that the dihydropyridine Ca2+ channel blocker nifedipine, although not considered a first-line treatment for congenital hyperinsulinism, may be beneficial to control blood pressure and neurological symptoms in patients with CACNA1D mutations.

中文翻译:

先天性高胰岛素血症,原发性醛固酮过多症和肌张力低下的患者的从头CACNA1D错义突变。

先天性高胰岛素性低血糖症是生命最初几年持续性和反复性低血糖症的最常见原因,在许多患者中,可以发现罕见的遗传变异。近来,由于电压门控的Cav1.3 Ca2 +通道CACNA1D基因突变引起的先天性高胰岛素低血糖和严重的神经发育综合征的病例已有报道,需要长期用二氮嗪治疗。这暗示了CACNA1D变异可能是这种情况的潜在原因。在此,我们通过提供一个患有持续性高胰岛素低血糖和原发性醛固酮过多症,主动脉瓣功能不全,明显的发育迟缓,肌肉张力低下和面部畸形但无癫痫发作的女童来支持这一观察。对该儿童及其父母的外显子组进行测序,发现了一个新的从头开始的CACNA1D错义突变p.L271 H,取代了电压门控Cav1.3 Ca2 +通道功能相关区域中的高度保守残基。该患者接受了二氮嗪和硝苯地平的治疗,可适当控制葡萄糖的代谢和血压,并改善肌张力。我们的发现进一步证实了CACNA1D对结膜性高胰岛素血症性低血糖和原发性醛固酮增多症的致病作用。此外,我们提供的证据表明,二氢吡啶类Ca2 +通道阻滞剂硝苯地平虽然不被认为是先天性高胰岛素血症的一线治疗方法,但对于控制CACNA1D突变患者的血压和神经系统症状可能是有益的。替换电压门控Cav1.3 Ca2 +通道功能相关区域中的高度保守的残基。该患者接受了二氮嗪和硝苯地平的治疗,可适当控制葡萄糖的代谢和血压,并改善肌张力。我们的发现进一步证实了CACNA1D对结膜性高胰岛素血症性低血糖和原发性醛固酮增多症的致病作用。此外,我们提供的证据表明,二氢吡啶类Ca2 +通道阻滞剂硝苯地平虽然不被认为是先天性高胰岛素血症的一线治疗方法,但对于控制CACNA1D突变患者的血压和神经系统症状可能是有益的。替换电压门控Cav1.3 Ca2 +通道功能相关区域中的高度保守残基。该患者接受了二氮嗪和硝苯地平的治疗,可适当控制葡萄糖的代谢和血压,并改善肌张力。我们的发现进一步证实了CACNA1D对结膜性高胰岛素血症性低血糖和原发性醛固酮增多症的致病作用。此外,我们提供的证据表明,二氢吡啶类Ca2 +通道阻滞剂硝苯地平虽然不被认为是先天性高胰岛素血症的一线治疗方法,但对于控制CACNA1D突变患者的血压和神经系统症状可能是有益的。该患者接受了二氮嗪和硝苯地平的治疗,可适当控制葡萄糖的代谢和血压,并改善肌张力。我们的发现进一步证实了CACNA1D对结膜性高胰岛素血症性低血糖和原发性醛固酮增多症的致病作用。此外,我们提供的证据表明,二氢吡啶类Ca2 +通道阻滞剂硝苯地平虽然不被认为是先天性高胰岛素血症的一线治疗方法,但对于控制CACNA1D突变患者的血压和神经系统症状可能是有益的。该患者接受了二氮嗪和硝苯地平的治疗,可适当控制葡萄糖的代谢和血压,并改善肌张力。我们的发现进一步证实了CACNA1D对结膜性高胰岛素血症性低血糖和原发性醛固酮增多症的致病作用。此外,我们提供的证据表明,二氢吡啶类Ca2 +通道阻滞剂硝苯地平虽然不被认为是先天性高胰岛素血症的一线治疗方法,但对于控制CACNA1D突变患者的血压和神经系统症状可能是有益的。
更新日期:2020-05-04
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