PEDIATRIC DIABETES, vol.21, no.7, pp.1176-1182, 2020 (SCI-Expanded)
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(IPK)) that leads to diabetes in the second decade of life, in addition to multiple endocrine dysfunction and nervous system involvement. 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 detectDNAJC3defect 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 DNAJC3defect 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.