Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants.

The BiP co-chaperone DNAJC3 protects cells during ER stress. In mice, the deficiency of DNAJC3 leads to beta-cell apoptosis and the gradual onset of hyperglycemia. In humans, biallelic DNAJC3 variants cause a multisystem disease, including early-onset diabetes mellitus. Recently, hyperinsulinemic hypoglycemia (HH) has been recognized as part of this syndrome. This report presents a case study of an individual with HH caused by DNAJC3 variants and provides an overview of the metabolic phenotype of individuals with HH and DNAJC3 variants. The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence. Additionally, glycemia and insulin release were analyzed in young DNACJ3 knockout (K.O.) mice, which are equivalent to human infants. In the youngest experimentally accessible age group of 4-week-old mice, the in vivo glycemic phenotype was already dominated by a reduced total insulin secretion capacity. However, on a cellular level, the degree of insulin release of DNAJC3 K.O. islets was higher during periods of increased synthetic activity (high-glucose stimulation). We propose that calcium leakage from the ER into the cytosol, due to disrupted DNAJC3-controlled gating of the Sec61 channel, is the most likely mechanism for HH. This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis. Clinicians should screen for HH in DNAJC3 deficiency and consider DNAJC3 variants in the differential diagnosis of congenital hyperinsulinism.

Delayed-Onset Transient Hyperinsulinism in Infants with Very Low and Extremely Low Birth Weights: A Cohort Study.

We describe 16 infants born preterm with birth weights <1500 g and transient hyperinsulinism. The onset of hyperinsulinism was delayed and often coincident with clinical stabilization. We hypothesize that postnatal stress caused by prematurity and associated problems may contribute to development of delayed-onset transient hyperinsulinism.

Interleukin-7 and soluble Interleukin-7 receptor levels in type 1 diabetes - Impact of IL7RA polymorphisms, HLA risk genotypes and clinical features.

High soluble IL-7 receptor (sIL-7R) serum levels and associated single nucleotide polymorphisms in the IL7RA gene were found in autoimmune diseases including type 1 diabetes. Further determinants on sIL-7R and IL-7 availability as well as changes during type 1 diabetes disease course remain elusive. Here we performed multiparameter analysis to identify influential genetic and disease-associated factors on sIL-7R and IL-7 serum levels during type 1 diabetes disease course (239 children) and in healthy controls (101 children). We found higher sIL-7R serum concentrations at type 1 diabetes onset and decreasing levels during therapy whereas IL-7 was only higher in long term patients as compared to controls. Multiple linear regression analyses revealed several factors, including IL7RA SNP rs6897932 and HLA risk haplotypes, influencing sIL-7R levels but not IL-7, which was solely associated with the sIL-7R. This study revealed unexpected complexity in the regulation of the sIL-7R but not for IL-7.

Interleukin-7-dependent nonclassical monocytes and CD40 expression are affected in children with type 1 diabetes.

The important role of IL-7 in the generation of self-reactive T-cells in autoimmune diseases is well established. Recent studies on autoimmunity-associated genetic polymorphisms indicated that differential IL-7 receptor (IL-7R) expression of monocytes may play a role in the underlying pathogenesis. The relevance of IL-7-mediated monocyte functions in type 1 diabetes remains elusive. In the present study, we characterized monocyte phenotype and IL-7-mediated effects in children with type 1 diabetes and healthy controls with multicolor flow cytometry and t-distributed Stochastic Neighbor-Embedded (t-SNE)-analyses. IL-7R expression of monocytes rapidly increased in vitro and was boosted through LPS. In the presence of IL-7, we detected lower monocyte IL-7R expression in type 1 diabetes patients as compared to healthy controls. This difference was most evident for the subset of nonclassical monocytes, which increased after IL-7 stimulation. t-SNE analyses revealed IL-7-dependent differences in monocyte subset distribution and expression of activation and maturation markers (i.e., HLA-DR, CD80, CD86, CD40). Notably, monocyte CD40 expression increased considerably by IL-7 and CD40/IL-7R co-expression differed between patients and controls. This study shows the unique effects of IL-7 on monocyte phenotype and functions. Lower IL-7R expression on IL-7-induced CD40high monocytes and impaired IL-7 response characterize monocytes from patients with type 1 diabetes.

Reliability and Observer Dependence of Signs of Neonatal Hypoglycemia.

OBJECTIVES: To evaluate, using video documentation, the sensitivity, specificity, and interobserver reliability of visualizable signs of neonatal hypoglycemia at different glucose concentrations in neonates. STUDY DESIGN: In a prospective cohort study of 145 neonates with and without risk factors for hypoglycemia, 430 videos were recorded before blood glucose measurements and analyzed by 10 blinded investigators of different professions. The primary outcome measures were sensitivity and specificity for clinical detection of hypoglycemia. RESULTS: The overall sensitivity to detect low blood glucose (<55 mg/dL [<3.1 mmol/L]) based on signs was 30%, and the specificity was 82%. Significantly more investigators suspected hypoglycemia while viewing videos of infants with blood glucose levels of 46-54 mg/dL (2.6-3.0 mmol/L) and 30-45 mg/dL (1.7-2.5 mmol/L) compared with ≥55 mg/dL (≥3.1 mmol/L) (29 ± 3% and 31 ± 4% vs 18 ± 1%; P = .001; P = .007). After 48 hours of life, significantly more investigators suspected hypoglycemia in videos of infants with blood glucose levels of ≤45 mg/dL (≤2.5 mmol/L) compared with blood glucose levels of >45 mg/dL (>2.5 mmol/L) (28.9 ± 8.1% vs 10.9 ± 1.8%; P = .007). For blood glucose levels 30-45 mg/dL (1.7-2.5 mmol/L), sensitivity varied widely between investigators, ranging from 5% to 62%. Three hypoglycemic episodes <30 mg/dL (<1.7 mmol/L) were only partially recognized. CONCLUSIONS: Clinical observation of signs is neither sensitive nor specific to detect neonatal hypoglycemia, and there are large interobserver differences. Thus, guidelines on neonatal hypoglycemia should reconsider whether distinguishing between asymptomatic and symptomatic hypoglycemia provides useful information for the management of neonatal hypoglycemia, because it may pose a risk for systematic under-recognition and undertreatment, leading to an increased risk for neurodevelopmental impairment. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00021500 www.drks.de/drks_web/setLocale_EN.do.

Clinical presentation and long-term outcome of patients with KCNJ11/ABCC8 variants: Neonatal diabetes or MODY in the DPV registry from Germany and Austria.

OBJECTIVE: To describe clinical presentation/longterm outcomes of patients with ABCC8/KCNJ11 variants in a large cohort of patients with diabetes. RESEARCH DESIGN AND METHODS: We analyzed patients in the Diabetes Prospective Follow-up (DPV) registry with diabetes and pathogenic variants in the ABCC8/KCNJ11 genes. For patients with available data at three specific time-points-classification as K+ -channel variant, 2-year follow-up and most recent visit-the longitudinal course was evaluated in addition to the cross-sectional examination. RESULTS: We identified 93 cases with ABCC8 (n = 54)/KCNJ11 (n = 39) variants, 63 of them with neonatal diabetes. For 22 patients, follow-up data were available. Of these, 19 were treated with insulin at diagnosis, and the majority of patients was switched to sulfonylurea thereafter. However, insulin was still administered in six patients at the most recent visit. Patients were in good metabolic control with a median (IQR) A1c level of 6.0% (5.5-6.7), that is, 42.1 (36.6-49.7) mmol/mol after 2 years and 6.7% (6.0-8.0), that is, 49.7 (42.1-63.9) mmol/mol at the most recent visit. Five patients were temporarily without medication for a median (IQR) time of 4.0 (3.5-4.4) years, while two other patients continue to be off medication at the last follow-up. CONCLUSIONS: ABCC8/KCNJ11 variants should be suspected in children diagnosed with diabetes below the age of 6 months, as a high percentage can be switched from insulin to oral antidiabetic drugs. Thirty patients with diabetes due to pathogenic variants of ABCC8 or KCNJ11 were diagnosed beyond the neonatal period. Patients maintain good metabolic control even after a diabetes duration of up to 11 years.

Anxiety, depression, and quality of life in parents of children with congenital hyperinsulinism.

This study aimed to assess mental health, family burden, and quality of life (PQoL) in parents of children with persistent congenital hyperinsulinism (CHI). Forty-eight individual CHI parents (75% female) completed self-reported questionnaires and screening tools for anxiety (GAD-7), depression (PHQ-8), PQoL (ULQIE), and family burden (FaBeL). Additional data on sociodemographics, social support, and child- and disease-related data were recorded. 29.8% of parents showed major depressive symptoms and 38.3% had a probable general anxiety disorder, including 20.8% who had both. The family burden was moderate and assessment of PQoL yielded average scores. Neurological impairment in an affected child (p = .002 and p < .001, respectively) and lower working hours (p = .001 and p = .012, respectively) were the strongest predictors of worse GAD-7 and PHQ-8 scores. Furthermore, lower working hours (p = .012) and comorbidities in the affected child (p = .007) were significantly associated with lower PQoL. Mothers had worse GAD-7 scores (p = .006) and lower PQoL (p = .035) than fathers. Indication of sleep disturbance was associated with worse PHQ-8 scores (p = .003), higher family burden (p = .039), and reduced PQoL (p = .003). A higher number of caretakers besides parents was associated with decreased family burden (p = .019), improved PQoL (p < .001), and lower scores for anxiety (p = .016) and depressive (p = .021) symptoms.    Conclusion: Symptoms of depression and anxiety are alarmingly prevalent in parents of children with CHI. Psychological screening of parents should be initiated to ensure early identification of psychological strains and psychosocial support should be offered as needed. A good support network and regular work activities can improve parental mental health and well-being. What is Known: • Psychosocial strains and reduced quality of life are common in parents of chronically ill children. What is New: • In this first study evaluating mental health, family burden, and quality of life in parents of children with congenital hyperinsulinism (CHI), symptoms of depression and anxiety were alarmingly prevalent. • Parents of children with CHI should receive regular psychological screening and psychosocial support should be offered as needed. A good support network and regular work activities can improve parental mental health and well-being.

Hyperinsulinemic Hypoglycemia Associated with a CaV1.2 Variant with Mixed Gain- and Loss-of-Function Effects.

The voltage-dependent L-type calcium channel isoform CaV1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the CaV1.2 α1-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified CaV1.2L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism.

CD5-expressing CD8+ T-cell subsets differ between children with type 1 diabetes and controls.

Different lymphocyte subsets are involved in autoimmune pathogenesis of type 1 diabetes (T1D). Previous studies suggested a role of CD5-expressing T and B cells including rare unconventional lymphocytes with combined T- and B-cell features [dual expressing (DE) cells]. We performed algorithm-supported multiparameter flow cytometry and quantitative PCR to investigate immune cell subsets and DE cells in children with T1D (n = 20) and matched controls (n = 20). Comparisons of conventional immune cells detected increased proportions of CD3+ T cells in T1D patients, whereas CD19+ B-cell proportions were comparable to controls. Self-organizing maps for flow cytometry analyses (FlowSOM) showed highly similar CD5-expressing B-cell subsets and no differences for DE cells were detected between the study groups by flow cytometry or specific quantitative PCR. Notably, differences in CD8+ T cells were indicated by FlowSOM and similarity-based t-distributed stochastic neighbor embedding (tSNE) analyses. Study group comparisons confirmed significantly reduced CD8+ T-cell proportions with moderate or low CD5 expression in T1D patients. Finally, in vitro experiments showed stable CD5 expression differences of CD8+ T cells after T-cell activation, cytokine stimulation and culture. We observed differences of T-cell coreceptor CD5 expression in T1D patients with potential relevance for immune regulation of CD8+ T-cell activation.

Clinical management and knowledge of neonatal hypoglycaemia in Germany: A national survey of midwives and nurses.

AIM: Despite being a common metabolic condition, the detection and care of neonatal hypoglycaemia in Germany largely depends on the infant's health-care provider, rather than a national protocol. Therefore, this study aimed to evaluate midwives' and nurses' knowledge and management of neonatal hypoglycaemia and to determine the need for national guidelines. METHODS: An anonymous online survey was developed and completed by 127 perinatal nurses and midwives. Descriptive statistics, Mann-Whitney-U, χ2 and Fisher's exact tests were used to summarise and analyse the results. RESULTS: In total, 82% of respondents indicated using guidelines but routine blood glucose screening for neonates at risk for hypoglycaemia was rarely reported (44%). A blood glucose concentration of 2.5 mmol/L (45 mg/dL) was considered the treatment threshold by 52% of the respondents. However, the responses to clinical scenarios showed distinct differences regarding the management of neonatal hypoglycaemia. Finally, 49% of respondents reported insufficient knowledge regarding neonatal hypoglycaemia and 77% indicated that they would advocate the implication of enhanced national guidelines. CONCLUSIONS: There is considerable variation in knowledge about the prevention, screening and management of neonatal hypoglycaemia among nurses and midwives in Germany. Enhanced guidelines and education of health-care professionals are urgently needed to provide the best possible care to all hypoglycaemic newborns.

Comparative meta-analysis of Kabuki syndrome with and without hyperinsulinaemic hypoglycaemia.

BACKGROUND AND OBJECTIVE: Kabuki syndrome (KS), caused by pathogenic variants in KMT2D or KDM6A, is associated with hyperinsulinaemic hypoglycaemia (HH) in 0.3%-4% of patients. We characterized the clinical, biochemical and molecular data of children with KS and HH compared to children with KS without HH in a multicentre meta-analysis. METHODS: Data of seven new and 17 already published children with KS and HH were compared to 373 recently published KS patients without HH regarding molecular and clinical characteristics. RESULTS: Seven new patients were identified with seven different pathogenic variants in KDM6A (n = 4) or KMT2D (n = 3). All presented with HH on the first day of life and were responsive to diazoxide. KS was diagnosed between 9 months and 14 years of age. In the meta-analysis, 24 KS patients with HH had a significantly higher frequency of variants in KDM6A compared to 373 KS patients without HH (50% vs 11.5%, P < .001), and KDM6A-KS was more likely to be associated with HH than KMT2D-KS (21.8% vs. 3.5%, P < .001). Sex distribution and other phenotypic features did not differ between KS with and without HH. CONCLUSION: The higher incidence of HH in KDM6A-KS compared to KMT2D-KS indicates that KDM6A loss of function variants predispose more specifically to beta cell dysfunction compared to KMT2D variants. As difficulties to assign syndromic characteristics to KS in early infancy often lead to delayed diagnosis, genetic testing for KS should be considered in children with HH, especially in the presence of other extrapancreatic/syndromic features.

Autoimmunity risk- and protection-associated IL7RA genetic variants differentially affect soluble and membrane IL-7Rα expression.

Interleukin-7 receptor α-chain (IL7RA) haplotypes are associated with susceptibility to autoimmune diseases including type 1 diabetes (T1D). Previous studies found lower soluble IL-7Rα (sIL-7Rα) serum levels of the protection-associated IL7RA haplotype assumed to reduce IL-7 availability for self-reactive T cells. Also, a risk-associated IL7RA haplotype is accompanied by lower sIL-7Rα serum concentrations but no underlying mechanisms have been described and the causative polymorphism remains unknown. Here, we characterized functional implications of the nonsynonymous rs1494558 (Thr66Ile), which tags the protection-associated IL7RA haplotype, in HEK293T cells and serum samples of T1D patients with different haplotype carriers. Influence of risk- and protection-associated haplotypes on IL-7Rα was analyzed. The risk-associated Ile66 variant affected gel mobility and impaired secretion of the sIL-7Rα as well as expression of the membrane-associated (m)IL-7Rα in HEK293T cells. Serum sIL-7Rα analyses confirmed differential gel mobility of the Ile66 variant and found decreased sIL-7Rα serum levels of T1D patients carrying the Ile66-tagged haplotype. Differences in glycosylation were not causative for differential mobility but enhanced the effects on impaired secretion. Comparison of protection- and risk-associated haplotypes in a cell line-based in vitro model identified dominant effects of the protective haplotype tagged by rs6897932 (Ile244) on mIL-7Rα expression, whereas the risk haplotype mainly affected the sIL-7Rα. This study identified novel functional effects of the Ile66 IL7RA variant and characterized features of autoimmunity risk- and protection-associated haplotypes. The findings add to our understanding of how these haplotypes regulate sIL-7Rα and mIL-7Rα expression in T cells causing differential susceptibility to autoimmune diseases.

Animation and interactivity facilitate acquisition of pediatric life support skills: a randomized controlled trial using virtual patients versus video instruction.

BACKGROUND: Several promising studies suggest a positive impact of interactive and media-enriched e-learning resources such as virtual patients (VP) on skill acquisition in pediatric basic life support (PBLS). This study investigates which immanent VP components account for this effect. METHODS: N = 103 medical students in their 5th year were assigned to one of three groups: a video group prepared with self-instructional videos on PBLS (N = 37); an animation-enriched VP group with VP containing interactive questions (N = 35), static and animated media, and a static VP group with VP containing interactive questions and only static media (N = 31). Subsequent PBLS demonstrations were video-documented and scored for adherence to guideline-based algorithm, temporal demands (such as correct pace of rescue breaths and chest compressions), and quality of procedural steps (e.g., correct head positioning), as well as overall competency by two group-blinded, independent pediatricians. RESULTS: Groups did not differ with regard to adherence to correct algorithm (88.7 ± 10.3, 93.3 ± 6.7 and 90.3 ± 10.5, respectively). Self-instruction with animated media - through videos or animation-enriched VP - resulted in a better adherence to temporal demands, as compared with training with static VP (64.5 ± 26.3 and 50.7 ± 25.7, respectively, vs. 23.8 ± 21.0). Procedural quality by the video group was slightly inferior compared with the animation-enriched VP group (79.5 ± 12.3 vs. 82.0 ± 11.9), and distinct inferior in overall 'competent' ratings (43.2% vs. 65.7%). The static VP group performed considerably most poorly of all three groups (temporal adherence 73.2 ± 11.9 and 19.4% 'competent' ratings). CONCLUSIONS: VP can feasibly enhance PBLS skill acquisition. Thoughtful design of animations and interactivity of the VP further improves such skill acquisition, both in quality of performance and in adherence to temporal demands.

Interleukin-7 receptor α-chain haplotypes differentially affect soluble IL-7 receptor and IL-7 serum concentrations in children with type 1 diabetes.

BACKGROUND: Interleukin-7 receptor α-chain (IL7RA) haplotypes are associated with susceptibility for development of autoimmune diseases, including type 1 diabetes (T1D). A protective IL7RA haplotype which causes lower soluble IL-7R (sIL-7R) serum levels is hypothesized to restrict IL-7-availability for self-reactive T cells. Functional mechanisms affected by a risk-associated IL7RA haplotype are unknown. METHODS: We investigated the influence of IL7RA haplotypes (tagged by rs6897932T for the protective or by rs1494555G for the risk haplotype) on sIL-7R and IL-7 serum concentrations as well as disease manifestation of children with T1D (n = 259). Possible effects of differential IL-7 serum concentrations on IL-7-mediated in vitro T cell functions (i.e. IL-7R regulation and cytokine expression) were measured in a second study group of children with T1D (n = 42). RESULTS: We detected lower sIL-7R serum concentrations in children with T1D carrying protective or risk haplotypes as compared to reference haplotypes. sIL-7R levels were lowest in T1D children with the protective haplotype and lower IL-7 serum levels were exclusively detected in this study group. We found no evidence for dependency between IL-7 and sIL-7R serum concentrations and no association with T1D manifestation. Neither IL-7 nor sIL-7R serum levels were associated with mIL-7R regulation or IL-7-promoted T cell cytokine expression. CONCLUSIONS: Children with T1D carrying autoimmunity risk- or protection-associated IL7RA haplotypes had both lower sIL-7R serum concentrations as compared to the reference haplotype, but only T1D children with the protective haplotype had lower IL-7 serum levels. Our results suggest additional functional mechanisms of autoimmunity-associated IL7RA variants independent from sIL-7R mediated regulation of IL-7 availability for T cells.

Screening for non-alcoholic fatty liver disease in children and adolescents with type 1 diabetes mellitus: a cross-sectional analysis.

The liver is intensely involved in glucose metabolism and is thereby closely related to diabetes pathophysiology. Adult patients with type 1 diabetes mellitus (DM) are at an increased risk for non-alcoholic fatty liver disease (NAFLD). Here, we studied the prevalence of NAFLD in a cohort of children and adolescents with type 1 DM in a tertiary care paediatric diabetes centre in Germany. We screened 93 children and adolescents with type 1 DM using ultrasound, laboratory investigations, and liver stiffness measurements (Fibroscan® [FS] and acoustic radiation force imaging [ARFI]). Of these, 82 (88.1%) had completely normal results in all examined aspects. Only one patient (1.1%) fulfilled the criteria as potential NAFLD with ALT > twice the upper limit of normal. Ten of the 93 patients (10.8%) showed any mild abnormality in at least one examined category including ALT, conventional ultrasounds and liver stiffness measurements. However, none of these ten fulfilled the NAFLD case definition criteria. Therefore, these slightly abnormal results were judged to be unspecific or at least of unknown significance in terms of NAFLD indication. CONCLUSION: Compared to data from the general population, our results do not indicate a significantly increased prevalence of NAFLD in this cohort, and advocate against the systematic screening for NAFLD in paediatric type 1 DM. What is Known: • Non-alcoholic fatty liver disease (NAFLD) is common in adults with type 1 DM, and paediatric patients with type 1 DM in Egypt and Saudi Arabia. What is New: • Our results do not indicate a significantly increased prevalence of NAFLD in a cohort of children and adolescents with type 1 DM from Germany compared to prevalence data from the general population. • This finding advocates against the systematic screening for NAFLD in paediatric type 1 DM in western countries.

Osteonecrosis in children with acute lymphoblastic leukemia.

The morbidity and toxicity associated with current intensive treatment protocols for acute lymphoblastic leukemia in childhood become even more important as the vast majority of children can be cured and become long-term survivors. Osteonecrosis is one of the most common therapy-related and debilitating side effects of anti-leukemic treatment and can adversely affect long-term quality of life. Incidence and risk factors vary substantially between study groups and therapeutic regimens. We therefore analyzed 22 clinical trials of childhood acute lymphoblastic leukemia in terms of osteonecrosis incidence and risk factors. Adolescent age is the most significant risk factor, with patients >10 years old at the highest risk. Uncritical modification or even significant reduction of glucocorticoid dosage cannot be recommended at this stage. A novel and innovative approach to reduce osteonecrosis-associated morbidity might be systematic early screening for osteonecrosis by serial magnetic resonance images. However, discriminating patients at risk of functional impairment and debilitating progressive joint disease from asymptomatic patients still remains challenging.

Abuse of the over-the-counter antispasmodic butylscopolamine for the home synthesis of psychoactive scopolamine.

UNLABELLED: We report on two patients who ingested psychoactive scopolamine that was synthesized at home from butylscopolamine (Buscopan®), which is available as over-the-counter antispasmodic in nearly 100 countries worldwide. Patient 1 presented with severe central anticholinergic toxidrome, while patient 2 suffered from minor symptoms. An empty blister of Buscopan® was found in the patients' home, but initially was not suspected to be causative for the observed central anticholinergic symptoms, as Buscopan® is not able to pass the blood-brain barrier in its native form. Only later, the information by third parties and a Google search helped to identify homemade scopolamine derived from Buscopan® as the responsible agent in these two cases. Retrospectively, scopolamine could be detected in serum and urine of both patients, while it was absent in one control after ingestion of native Buscopan®. CONCLUSION: Over-the-counter drugs can be used to synthesize psychoactives with means that are available in every household. Such knowledge can spread via social media and internet discussion boards long before appearing in medical literature. While typical clinical presentation often enables clinicians to adequately identify and treat specific toxidromes, these sources of information need to be increasingly taken into account by medical professionals for identification of its causative agent. This potential of Buscopan® might gain importance as an easily accessible source of psychoactive scopolamine. WHAT IS KNOWN: • Substances with central anticholinergic effects are known for their hallucinogenic potential and may be used as psychoactives. What is New: • The over-the-counter antispasmodic butylscopolamine (Buscopan®) can be abused to synthesize anticholinergic, psychoactive scopolamine at home with means that are available in every household.