A CACNA1D mutation in a patient with persistent hyperinsulinaemic hypoglycaemia, heart defects, and severe hypotonia
| Autor: | Flanagan, SE, Vairo, F, Johnson, MB, Caswell, R, Laver, TW, Lango Allen, H, Hussain, K, Ellard, S |
|---|---|
| Přispěvatelé: | Flanagan, SE [0000-0002-8670-6340], Apollo - University of Cambridge Repository |
| Rok vydání: | 2017 |
| Předmět: |
Heart Defects
Congenital Calcium Channels L-Type Developmental Disabilities Aortic Valve Insufficiency DNA Mutational Analysis Infant Newborn Case Report hyperinsulinism Neuromuscular Diseases Hypoglycemia Fetal Macrosomia CACNA1D Amino Acid Substitution Mutation Humans Muscle Hypotonia calcium channel Female exome sequencing hypoglycaemia |
| Zdroj: | Pediatric Diabetes |
| Popis: | Congenital hyperinsulinaemic hypoglycaemia (HH) can occur in isolation or it may present as part of a wider syndrome. For approximately 40%-50% of individuals with this condition, sequence analysis of the known HH genes identifies a causative mutation. Identifying the underlying genetic aetiology in the remaining cases is important as a genetic diagnosis will inform on recurrence risk, may guide medical management and will provide valuable insights into β-cell physiology. We sequenced the exome of a child with persistent diazoxide-responsive HH, mild aortic insufficiency, severe hypotonia, and developmental delay as well as the unaffected parents. This analysis identified a de novo mutation, p.G403D, in the proband's CACNA1D gene. CACNA1D encodes the main L-type voltage-gated calcium channel in the pancreatic β-cell, a key component of the insulin secretion pathway. The p.G403D mutation had been reported previously as an activating mutation in an individual with primary hyper-aldosteronism, neuromuscular abnormalities, and transient hypoglycaemia. Sequence analysis of the CACNA1D gene in 60 further cases with HH did not identify a pathogenic mutation. Identification of an activating CACNA1D mutation in a second patient with congenital HH confirms the aetiological role of CACNA1D mutations in this disorder. A genetic diagnosis is important as treatment with a calcium channel blocker may be an option for the medical management of this patient. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|