A de novo CACNA1D missense mutation in a patient with congenital hyperinsulinism, primary hyperaldosteronism and hypotonia
Open Access
- 1 January 2020
- journal article
- research article
- Published by Taylor & Francis Ltd in Channels
- Vol. 14 (1), 175-180
- https://doi.org/10.1080/19336950.2020.1761171
Abstract
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.Keywords
Funding Information
- received for this work
This publication has 18 references indexed in Scilit:
- Diagnosis and management of hyperinsulinaemic hypoglycaemiaBest Practice & Research Clinical Endocrinology & Metabolism, 2018
- The third case report a patient with primary aldosteronism, seizures, and neurologic abnormalities (PASNA) syndrome de novo variant mutations in the CACNA1D geneZhurnal nevrologii i psikhiatrii im. S.S. Korsakova, 2018
- Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channelsChannels, 2018
- New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsyHuman Molecular Genetics, 2017
- A CACNA1D mutation in a patient with persistent hyperinsulinaemic hypoglycaemia, heart defects, and severe hypotoniaPediatric Diabetes, 2017
- Cav1.3 (CACNA1D) L‐type Ca2+ channel dysfunction in CNS disordersJournal Of Physiology-London, 2016
- The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic PotentialPharmacological Reviews, 2015
- The Diagnosis and Management of Hyperinsulinaemic HypoglycaemiaJournal of Clinical Research in Pediatric Endocrinology, 2015
- Persistent hyperinsulinaemic hypoglycaemia in infancySeminars in Pediatric Surgery, 2014
- Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronismNature Genetics, 2013