PSMD11 loss-of-function variants correlate with a neurobehavioral phenotype, obesity, and increased interferon response.

Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1, PSMC1, PSMC3, or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy. PSMD11 loss-of-function variants caused early-onset syndromic intellectual disability and neurodevelopmental delay with recurrent obesity in 10 unrelated children. Our findings demonstrate that the cognitive impairment observed in these individuals could be recapitulated in Drosophila melanogaster with depletion of the PMSD11 ortholog Rpn6, which compromised reversal learning. Our investigations in subject samples further revealed that PSMD11 loss of function resulted in impaired 26S proteasome assembly and the acquisition of a persistent type I interferon (IFN) gene signature, mediated by the integrated stress response (ISR) protein kinase R (PKR). In summary, these data identify PSMD11 as an additional member of the growing family of genes associated with neurodevelopmental proteasomopathies and provide insights into proteasomal biology in human health.

[Weigth Loss in a Neonate- A Case of Hypoaldosteronism].

The Neonatal weight loss is a common problem which most physicians who take care of newborns should recognise. The most common reason is insufficient dietary intake. However the reason can also be an underlying disease. Aldosterone insufficiency in neonates is a rare disease and if not treated correctly can be life threatening. It presents with serious electrolytes abnormalities and metabolic acidosis. It is therefore important to distinguish between serious and benign causes of weight loss in neonates.

[Graves' disease in children and adolescents in Iceland].

INTRODUCTION: Graves' disease is an autoimmune disease in which autoantibodies cause an increase in the production of thyroid hormones, and is the most common cause of thyrotoxicosis in children. Symptoms in children are often more obscure than in adults. The aim of the study is to assess the incidence of Graves' disease in children and adolescents in Iceland over the span of two decades (2001-2021), and furthermore to investigate if the incidence rate has increased, as well as to describe treatment options and disease recurrence. MATERIAL/METHODS: This retrospective descriptive study included all children diagnosed with Graves' disease in the years 2001-2021 in Iceland. Information was obtained from the Directorate of Health's drug database and from ICD-10 diagnoses at Landspítali - The National University Hospital. RESULTS: In total, 57 children and adolescents were diagnosed with Graves', the overall incidence rate was 3.5/100,000 person-years. Gender ratio was 1:2.7 (male : female) and the mean age at diagnosis was 13.6 for boys and 13.9 years for girls. Of those 12 individuals currently receiving drug therapy (21.8%), four patients have had disease relapse. Thirteen patients reached an euthyroid state with medication (23.7%), 25 received treatment with radioactive iodine (45.5%) and 5 underwent surgery (9.1%). Boys were more likely to relapse. Disease recurrence was 31.8%. CONCLUSION: The incidence of Graves' disease did not increase during the study period. The disease was more common in girls, although the gender ratio was lower than expected. Antithyroid drugs were the first choice in treatment and radioactive iodine was the most common permanent treatment option. Disease recurrence was common. A possible relationship between the duration of the original drug therapy and disease recurrence should be investigated.

Effect of screening for type 1 diabetes on early metabolic control: the DiPiS study.

AIMS/HYPOTHESIS: It has been shown that children previously enrolled in follow-up studies have better glycaemic control during the early period after diabetes diagnosis. The aim of this study was to analyse glycaemic control over a longer period, past the period of partial remission, after diagnosis in children followed before diagnosis in the Swedish Diabetes Prediction in Skåne (DiPiS) study compared with children of equal age not enrolled in pre-diabetes follow-up, receiving equivalent diabetes care. METHODS: HbA1c from diagnosis and for the following 5 years, as well as differences in insulin dosage, BMI, pump use, partial remission according to insulin dose-adjusted HbA1c and baseline demographics were compared between children who were enrolled in follow-up and had received information on diabetes risk (n = 51) and children not enrolled in follow-up (n = 78). RESULTS: The group followed before diagnosis had a higher proportion of first-degree relatives (FDRs) with diabetes (28% vs 5.6%; p = 0.001) and a higher proportion of participants with mothers born in Sweden (100% vs 89%; p = 0.02). No significant differences in total daily insulin dose, pump use or other baseline sociodemographic factors were detected between the groups. Median HbA1c at diagnosis and at 1, 2, 3, 4 and 5 years after diabetes diagnosis was significantly lower in children followed before diagnosis (all p < 0.05), and was not related to FDR status. CONCLUSIONS/INTERPRETATION: Compared with controls not previously enrolled in follow-up, our study shows that children enrolled in longitudinal follow-up before the diagnosis of diabetes have better glycaemic control, measured by HbA1c, up to 5 years after diagnosis and during the initial period of partial remission. Improved glycaemic control in the initial years of living with type 1 diabetes could affect long-term outcome and complications and might also improve study enrolment in future longitudinal studies.

Safety and efficacy of autoantigen-specific therapy with 2 doses of alum-formulated glutamate decarboxylase in children with multiple islet autoantibodies and risk for type 1 diabetes: A randomized clinical trial.

OBJECTIVE: Treatments have failed to delay or stop the autoimmune process, preceding onset of type 1 diabetes. We investigated if autoantigen-specific treatment with alum-formulated glutamate decarboxylase (GAD-Alum) was safe and affected progression to type 1 diabetes in children with islet autoimmunity. METHODS: In an investigator-initiated, double-blind, placebo-controlled clinical trial, non-diabetic children aged 4 to 17.9 years with autoantibodies to glutamate decarboxylase (GADA) and at least one of insulinoma-associated protein 2, insulin or zinc-transporter 8, were randomized, stratified by 2 or ≥3 islet autoantibodies, to 2 injections of 20 µg GAD-Alum or placebo, 30 days apart. Main outcome was safety, investigated by adverse events, hematology, chemistry, thyroid and celiac autoimmunity and titers of islet autoantibodies, and efficacy, investigated by cumulative incidence of diabetes onset over 5-year follow-up. Secondary variables: change in first-phase insulin release (FPIR) after intravenous glucose tolerance tests, fasting, 120 minutes and Area under the curve (AUC) C-peptide and p-glucose after oral glucose tolerance tests and HbA1c. RESULTS: Fifty children (median age: 5.2) were assigned 1:1 to GAD-Alum or placebo, all receiving full treatment and included in the analyses. GAD-Alum did not affect any safety parameter, while GADA titers increased (P = .001). Time to clinical diagnosis was not affected by treatment (hazard ratio, HR = 0.77, P = .574) in the full population or in the separate stratum groups. Treatment did not affect any of the secondary variables. CONCLUSIONS: GAD-Alum as a subcutaneous prime and boost injection was safe in prediabetic young children but did not affect progression to type 1 diabetes. The safety of GAD-Alum should prove useful in future prevention studies.

Analgesic antipyretic use among young children in the TEDDY study: no association with islet autoimmunity.

BACKGROUND: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. METHODS: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. RESULTS: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). CONCLUSIONS: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.

Glucose tolerance and beta-cell function in islet autoantibody-positive children recruited to a secondary prevention study.

AIMS: Children with type 1 diabetes (T1D) risk and islet autoantibodies are recruited to a secondary prevention study. The aims were to determine metabolic control in relation to human leukocyte antigen (HLA) genetic risk and islet autoantibodies in prepubertal children. METHODS: In 47 healthy children with GADA and at least one additional islet autoantibody, intravenous glucose tolerance test (IvGTT) and oral glucose tolerance test (OGTT) were performed 8-65 d apart. Hemoglobin A1c, plasma glucose as well as serum insulin and C-peptide were determined at fasting and during IvGTT and OGTT. RESULTS: All children aged median 5.1 (4.0-9.2) yr had autoantibodies to two to six of the beta-cell antigens GAD65, insulin, IA-2, and the three amino acid position 325 variants of the ZnT8 transporter. In total, 20/47 children showed impaired glucose metabolism. Decreased (≤ 30 µU/mL insulin) first-phase insulin response (FPIR) was found in 14/20 children while 11/20 had impaired glucose tolerance in the OGTT. Five children had both impaired glucose tolerance and FPIR ≤ 30 µU/mL insulin. Number and levels of autoantibodies were not associated with glucose metabolism, except for an increased frequency (p = 0.03) and level (p = 0.01) of ZnT8QA in children with impaired glucose metabolism. Among the children with impaired glucose metabolism, 13/20 had HLA-DQ2/8, compared to 9/27 of the children with normal glucose metabolism (p = 0.03). CONCLUSION: Secondary prevention studies in children with islet autoantibodies are complicated by variability in baseline glucose metabolism. Evaluation of metabolic control with both IvGTT and OGTT is critical and should be taken into account before randomization. All currently available autoantibody tests should be analyzed, including ZnT8QA.

Prevalence of Thyroid Peroxidase and Thyroglobulin Autoantibodies in the Swedish Population.

Autoimmune thyroid disease (AITD) may be detected prior to clinical symptoms through the presence of autoantibodies against thyroid peroxidase (TPOab), thyroglobulin (TGab), or both.The present study aimed to develop a novel radiobinding assay (RBA) for TPOab and to determine the prevalence of TPOab and TGab in the Swedish population.Patient samples from 27 newly diagnosed Graves' disease patients in longitudinal follow-up and 124 AITD autoantibody-positive children in prospective follow-up for increased risk of type 1 diabetes were included to validate the novel RBA for TPO. The results of RBA were compared with those obtained by commercial radioimmunoassay (RIA) and electrochemiluminescence (ECL). Furthermore, 476 serum samples from adult blood donors and 297 from 13-year-old school children were analyzed for the presence of TPOab and TGab.Receiver operating characteristics analysis for the novel TPOab resulted in an area under curve (AUC) value of 0.82 (p<0.0001), a sensitivity of 77.8%, and a specificity of 91.9% in adult blood donors, and an AUC value of 0.70 (p<0.0001), a sensitivity of 53.2% and a specificity of 95.3% in the 13-year-old school children, respectively. TPOab levels in RBA correlated with both ECL (r=0.8950, p<0.0001) and RIA (r=0.9295, p<0.0001). The prevalence of TPOab and TGab was 6.3% and 7.6% in adult blood donors and 2.9 and 3.7% in 13-year-old school children.In conclusion, a novel RBA for the determination of TPOab was developed and validated with current methodologies. This study also reports an increasing prevalence of thyroid autoantibodies from adolescence to adulthood.

Prevalence of diabetes and presence of autoantibodies against zinc transporter 8 and glutamic decarboxylase at diagnosis and at follow up of Graves' disease.

PURPOSE: The aim of this work was to investigate, in patients with newly diagnosed Graves' disease (GD), the frequency of islet autoantibodies including autoantibodies against Zink transporter 8 (ZnT8A), as well as to investigate the relation between thyroid autoantibodies, islet autoantibodies and diabetes both before GD diagnosis and at follow-up. METHODS: Blood samples from 278 patients with newly diagnosed GD were analyzed for autoantibodies against glutamic acid decarboxylase (GADA), insulinoma-associated protein-2 (IA2-A), three variants of zinc transporter 8 (ZnT8A), thyroid peroxidase (TPOA) and the TSH receptor (TRAb). Information on other autoimmune diseases, as well as development of diabetes during follow up was gathered from patient's medical journal. RESULTS: At GD diagnosis, 13.7% were positive for islet autoantibodies, with the majority being positive for GADA (8.7%) and ZnT8A (7.6%). TPOA were found positive in 71% and TRAb in 83%. No association was found between islet autoantibodies and thyroid autoantibodies or diabetes diagnosis during follow up. Positive association was found between islet autoantibodies and all forms of diabetes, diagnosed both before and after GD (OR: 2.5, CI: 1.1-6.8, p = 0.03) but not to other autoimmune diseases at GD diagnosis. CONCLUSIONS: The incidence of GADA and ZnT8A in patients with GD is high and might indicate wide range endocrine autoimmunity, as well as risk for non-autoimmune diabetes rather than exclusively mark beta cell autoimmunity and type 1 diabetes.

Childhood thyroid autoimmunity and relation to islet autoantibodies in children at risk for type 1 diabetes in the diabetes prediction in skåne (DiPiS) study.

BACKGROUND: The aim was to determine prevalence and age at seroconversion of thyroid autoimmunity in relation to islet autoantibodies, gender and HLA-DQ genotypes in children with increased risk for type 1 diabetes followed from birth. METHODS: In 10-year-old children (n = 1874), blood samples were analysed for autoantibodies against thyroid peroxidase (TPOAb), thyroglobulin (TGAb), glutamic acid decarboxylase 65 (GADA), Zink transporter 8 (ZnT8R/W/QA), insulinoma-associated protein-2 (IA-2A), insulin (IAA) and HLA-DQ genotypes. Prospectively collected samples from 2 years of age were next analysed for TPOAb, and TGAb and, finally, in confirming samples at 11-16 years of age along with TSH and FT4. Frequencies were tested with Chi-square or Fischer's exact tests, autoantibody levels with Wilcoxon and correlations between autoantibody levels with Spearman's rank correlation test. RESULTS: The prevalence of thyroid autoimmunity was 6.9%, overrepresented in girls (p < .001) also having higher TPOAb levels at 10 years (p = .049). TPOAb was associated with GADA (p = .002), ZnT8R/W/QA (p = .001) and IA-2A (p = .001) while TGAb were associated with ZnT8R/W/QA (p = .021). In boys only, TPOAb were associated with GADA (p = .002), IA-2A (p = .001), ZnT8R/W/QA (p = .001) and IAA (p = .009), and TGAb with GADA (p = .013), IA-2A (p = .005) and ZnT8R/W/QA (p = .003). Levels of IA-2A correlated to both TPOAb (p = .021) and to TGAb (p = .011). In boys only, levels of GADA and TGAb correlated (p = .009 as did levels of IA-2A and TPOAb (p = .013). The frequency and levels of thyroid autoantibodies increased with age. At follow-up, 22.3% had abnormal thyroid function or were treated with thyroxine. CONCLUSIONS: Thyroid autoimmunity and high TPOAb levels were more common in girls. In contrast, in boys only, there was a strong association with as well as correlation between levels of thyroid and islet autoantibodies. It is concluded that while girls may develop autoimmune thyroid disease (AITD) independent of islet autoantibodies, the risk for thyroid disease in boys may be linked to concomitant islet autoimmunity.

Are Perinatal Events Risk Factors for Childhood Thyroid Autoimmunity?

BACKGROUND: Environmental and genetic factors possibly trigger thyroid autoimmunity. Studies on perinatal risk factors for childhood thyroid autoimmunity are sparse. OBJECTIVES: The aim was to investigate if perinatal factors, family history of autoimmune diseases, and HLA-DQ genotypes contribute to thyroid autoimmunity in the Diabetes Prediction in Skåne (DiPiS) study. METHODS: Samples from 1,874 ten-year-old children were analyzed for autoantibodies to thyroid peroxidase (TPOAb), thyroglobulin (TGAb), and HLA-DQ genotypes. Information on perinatal events and family history of autoimmunity was gathered prospectively in questionnaires. RESULTS: Thyroid autoimmunity was found in 6.9% of the children (TPOAb 4.4%, TGAb 5.8%, both autoantibodies 3.3%) and was overrepresented in girls. Prematurity was positively related to TGAb (OR: 2.4, p = 0.003, pc = 0.021). Autoimmune diseases in the family increased the risk of thyroid autoimmunity: TPOAb (OR: 2.2, p = 0.012), any autoantibody (OR: 1.7, p = 0.04), and both autoantibodies (OR: 2.2, p = 0.024). A first-degree relative (FDR) with thyroid disease increased the risk for TPOAb (OR: 2.4, p = 0.03) and both autoantibodies (OR: 2.6, p = 0.03), a FDR or sibling with celiac disease increased the risk for both autoantibodies (OR: 3.7, p = 0.03, and OR: 4.8, p = 0.003), a FDR or sibling with diabetes increased the risk for thyroid autoantibody (OR: 3.0, p = 0.01, and OR: 5.4, p = 0.032), and a father with rheumatic disease increased the risk for TPOAb (OR: 15.2, p = 0.017), TGAb (OR: 11.3, p = 0.029), any autoantibody (OR: 9.6, p = 0.038), and both autoantibodies (OR: 20, p = 0.01). CONCLUSIONS: Thyroid autoimmunity was found in 6.9% of the 10-year-old children who were being followed for their risk of type 1 diabetes. No relation to perinatal factors was found, with the exception of a possible association between prematurity and TGAb. Family history of autoimmune diseases increased the risk of thyroid autoimmunity.

Thyroid and Islet Autoantibodies Predict Autoimmune Thyroid Disease at Type 1 Diabetes Diagnosis.

Context: Screening of autoimmune thyroid disease in children with type 1 diabetes is important but varies between clinics. Objective: To determine the predictive value of thyroid autoantibodies, thyroid function, islet autoantibodies, and HLA-DQ at diagnosis of type 1 diabetes for autoimmune thyroid disease during follow-up. Setting: Forty-three Swedish pediatric endocrinology units. Design, Patients, and Main Outcome Measures: At diagnosis of type 1 diabetes, autoantibodies against thyroid peroxidase (TPOAb), thyroglobulin (TGAb), glutamic acid decarboxylase (GADA), insulin, insulinoma-associated protein-2, and 3 variants of zinc transporter 8 (ZnT8W/R/QA) HLA-DQA1-B1 genotypes and thyroid function were analyzed in 2433 children. After 5.1 to 9.5 years, information on thyroxine treatment was gathered from the Swedish National Board of Health and Welfare's Prescribed Drug Register. Results: Thyroxine was prescribed to 6% of patients. In patients <5 years of age, female sex [hazard ratio (HR) = 4.60; P = 0.008] and GADA (HR = 5.80; P = 0.02) were predictors. In patients 5 to 10 years old, TPOAb (HR = 20.56; P < 0.0001), TGAb (HR = 3.40; P = 0.006), and thyroid-stimulating hormone (TSH) (HR = 3.64; P < 0.001) were predictors, whereas in 10 to 15 year olds, TPOAb (HR = 17.00; P < 0.001) and TSH (HR = 4.11; P < 0.001) predicted thyroxine prescription. Conclusion: In addition to TPOAb and TSH, GADA at diagnosis of type 1 diabetes is important for the prediction of autoimmune thyroid disease in children <5 years of age.