De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction.

Permanent neonatal diabetes mellitus (PNDM) is caused by reduced ß-cell number or impaired ß-cell function. Understanding of the genetic basis of this disorder highlights fundamental ß-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for ß-cells and highlight EIF2B1's fundamental role within this pathway.

Paediatric non-alcoholic fatty liver disease: a practical overview for non-specialists.

Non-alcoholic fatty liver disease (NAFLD) is the most common paediatric liver disease with a prevalence of almost 10%; therefore, the majority of affected patients are under the care of general practitioners and non-specialists. The condition is caused by central obesity with insulin resistance with additional factors influencing inflammatory activity (steatohepatitis). Ongoing inflammation leads to fibrosis and end-stage liver disease, though this will usually occur after children have transitioned into adult care. However, their main morbidity and mortality is from type 2 diabetes and complications of atherosclerosis. The minority of children undergo biopsy but currently there is no other method to accurately assess the stage of disease. Management is focused at weight loss through a combination of diet and exercise. Here, we present a current review of paediatric NAFLD aimed at non-specialists, with practice points for implementation.