Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group.
diabetes mellitus
growth retardation
hyperinsulinemic hypoglycemia
hypothyroidism
neurodegeneration
sensorineural deafness
Journal
Pediatric diabetes
ISSN: 1399-5448
Titre abrégé: Pediatr Diabetes
Pays: Denmark
ID NLM: 100939345
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
22
04
2020
revised:
11
07
2020
accepted:
24
07
2020
pubmed:
2
8
2020
medline:
19
11
2021
entrez:
2
8
2020
Statut:
ppublish
Résumé
A number of inborn errors of metabolism caused by abnormal protein trafficking that lead to endoplasmic reticulum storage diseases (ERSD) have been defined in the last two decades. One such disorder involves biallelic mutations in the gene encoding endoplasmic reticulum resident co-chaperone DNAJC3 (P58 The aim of this study was to define the natural history of this new form of diabetes, especially the course of abnormalities related to glucose metabolism. Whole-exome and Sanger sequencing was used to detect DNAJC3 defect in two patients. Detailed analysis of their clinical history as well as biochemical, neurological and radiological studies were carried out to deduce natural history of neurological and endocrine phenotype. DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss. Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin. Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life. Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration.
Sections du résumé
BACKGROUND
A number of inborn errors of metabolism caused by abnormal protein trafficking that lead to endoplasmic reticulum storage diseases (ERSD) have been defined in the last two decades. One such disorder involves biallelic mutations in the gene encoding endoplasmic reticulum resident co-chaperone DNAJC3 (P58
OBJECTIVE
The aim of this study was to define the natural history of this new form of diabetes, especially the course of abnormalities related to glucose metabolism.
METHODS
Whole-exome and Sanger sequencing was used to detect DNAJC3 defect in two patients. Detailed analysis of their clinical history as well as biochemical, neurological and radiological studies were carried out to deduce natural history of neurological and endocrine phenotype.
RESULTS
DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss. Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin. Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life.
CONCLUSION
Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration.
Substances chimiques
DNAJC3 protein, human
0
HSP40 Heat-Shock Proteins
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1176-1182Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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