Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism.

OBJECTIVE: Precursors of peptide hormones undergo posttranslational modifications within the trans-Golgi network (TGN). Dysfunction of proteins involved at different steps of this process cause several complex syndromes affecting the central nervous system (CNS). We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy. METHODS: Whole exome sequencing was performed in seven individuals of six unrelated families with these features. Postmortem histopathological and HID1 expression analysis of brain tissue and pituitary gland were conducted in one patient. Functional consequences of the homozygous HID1 variant p.R433W were investigated by Seahorse XF Assay in fibroblasts of two patients. RESULTS: Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients. Postmortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly reduced expression of pituitary hormones was found in pituitary gland tissue. Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls, while the extracellular acidification rate upon stimulation with potassium chloride was significantly reduced in patient fibroblasts compared to controls. INTERPRETATION: Our findings indicate that mutations in HID1 cause an early infantile encephalopathy with hypopituitarism as the leading presentation, and expand the list of syndromic CNS diseases caused by interference of TGN function. ANN NEUROL 2021;90:149-164.

Increased Presentation of Diabetic Ketoacidosis and Changes in Age and Month of Type 1 Diabetes at Onset during the COVID-19 Pandemic in Spain.

Objective: To assess the impact of the COVID-19 pandemic and lockdown measures on the presenting characteristics (age at diagnosis, severity, monthly distribution) of newly diagnosed type 1 diabetes in Spanish children. Research Design and Methods: An ambispective observational multicenter study was conducted in nine Spanish tertiary-level hospitals between January 2015 and March 2021. Inclusion criteria: new cases of type 1 diabetes in children (0-14 years) recording age, sex, date of diagnosis, presence of diabetic ketoacidosis (DKA) at onset, and severity of DKA. Data were compared before and during the pandemic. Results: We registered 1444 new cases of type 1 diabetes in children: 1085 in the pre-pandemic period (2015-2019) and 359 during the pandemic (2020-March 2021). There was a significant increase in the group aged ≤4 years in the pandemic period (chi-squared = 10.986, df 2, p = 0.0041). In 2020-2021, cases of DKA increased significantly by 12% (95% CI: 7.2-20.4%), with a higher percentage of moderate and severe DKA, although this increase was not significant. In 2020, there was a sharp decrease in the number of cases in March, with a progressive increase from May through November, higher than in the same months of the period 2015-2019, highlighting the increase in the number of cases in June, September, and November. The first three months of 2021 showed a different trend to that observed both in the years 2015-2019 and in 2020, with a marked increase in the number of cases. Conclusions: A change in monthly distribution was described, with an increase in DKA at onset of type 1 diabetes. No differences were found in severity, although there were differences in the age distribution, with an increase in the number of cases in children under 4 years of age.