Bridging the gaps: recent advances in diagnosis, care, and outcomes in congenital hyperinsulinism.

PURPOSE OF REVIEW: To highlight advances in congenital hyperinsulinism (HI), including newly described molecular mechanisms of disease, novel therapeutic interventions, and improved understanding of long-term outcomes. RECENT FINDINGS: Important advances have been made elucidating the molecular mechanisms responsible for HI. Non-coding variants in HK1 have been found to cause aberrant hexokinase expression. Inactivating mutations in SLC25A36 have been identified in children with features of the hyperinsulinism hyperammonemia syndrome. Low-level mosaic mutations in known HI genes have been detected in cases of 'genetic testing negative' HI. Identification and localization of focal HI lesions remains a priority, since focal HI can be cured with surgery. Use of 68 Ga-NODAGA-exendin-4 PET has been proposed to localize focal lesions. Additional studies are needed before this technique replaces 18 F-DOPA PET as standard of care. Treatment options for children with diffuse HI remain limited. The long-acting somatostatin analog, lanreotide, was shown to significantly improve glycemic control in a large series of children with HI. New therapies are under development, with promising preliminary results. Long-term quality of life and neurodevelopmental outcomes remain suboptimal. SUMMARY: Advanced genetic and epigenomic analytic techniques have uncovered novel molecular mechanisms of HI. Development of new drugs holds promise to improve long-term outcomes for individuals with HI.

Incidence and risk factors for hypoglycemia during maintenance chemotherapy in pediatric acute lymphoblastic leukemia.

BACKGROUND: Fasting hypoglycemia is a recognized occurrence among pediatric patients with acute lymphoblastic leukemia (ALL) during maintenance therapy. Existing publications describing this finding are limited to small studies and case reports. Our objective was to determine the incidence of hypoglycemia during maintenance chemotherapy and to investigate the association of age, as well as other potential risk factors, with this outcome in pediatric patients with ALL. PROCEDURE: This retrospective cohort study included individuals 1 to 21 years of age with ALL treated with antimetabolite-containing maintenance chemotherapy at a large children's hospital between January 2011 and December 2014. The primary endpoint was time to first documented episode of hypoglycemia during maintenance therapy, defined as single measurement of plasma glucose <60 mg/dL. Cox regression was used to evaluate the association with age and identify other potential risk factors. RESULTS: We identified 126 eligible patients, of whom 63% were documented as White, non-Hispanic, 28% as non-White, non-Hispanic, and 9% as Hispanic. Twenty-eight children (22%) had documented hypoglycemia during maintenance therapy. Younger age at the start of maintenance and hepatotoxicity documented during chemotherapy prior to maintenance initiation were associated with hypoglycemia (adjusted HR age = 0.88; 95% CI, 0.78-0.99; adjusted HR prior hepatotoxicity = 3.50; 95% CI, 1.47-8.36). CONCLUSIONS: Nearly one quarter of children in our cohort had hypoglycemia documented during maintenance chemotherapy. Younger age at maintenance initiation and hepatotoxicity during chemotherapy prior to maintenance initiation emerged as risk factors. These findings highlight the importance of counseling about the risk of, and monitoring for, hypoglycemia, particularly in young children.

Congenital hyperinsulinism disorders: Genetic and clinical characteristics.

Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Delays in diagnosis and initiation of appropriate treatment contribute to a high risk of neurocognitive impairment. HI represents a heterogeneous group of disorders characterized by dysregulated insulin secretion by the pancreatic beta cells, which in utero, may result in somatic overgrowth. There are at least nine known monogenic forms of HI as well as several syndromic forms. Molecular diagnosis allows for prediction of responsiveness to medical treatment and likelihood of surgically-curable focal hyperinsulinism. Timely genetic mutation analysis has thus become standard of care. However, despite significant advances in our understanding of the molecular basis of this disorder, the number of patients without an identified genetic diagnosis remains high, suggesting that there are likely additional genetic loci that have yet to be discovered.

Psychiatric Risk Assessment from the Clinician's Perspective: Lessons for the Future.

Accurate prediction of risk-states in Serious Mental Illnesses (SMIs) is critical for reducing their massive societal burden. Risk-state assessments are notably inaccurate. Recent innovations, including widely available and inexpensive mobile technologies for ambulatory "biobehavioral" data, can reshape risk assessment. To help understand and accelerate clinician involvement, we surveyed 90 multi-disciplinary clinicians serving SMI populations in various settings to evaluate how risk assessment is conducted and can improve. Clinicians reported considerable variability in conducting risk assessment, and few clinicians explicated their procedures beyond tying it to broader mental status examinations or interviews. Very few clinicians endorsed using currently-available standardized risk measures, and most reported low confidence in their utility. Clinicians also reported spending approximately half the time conducting individual risk assessments than optimally needed. When asked about improvement, virtually no clinicians acknowledged biobehavioral, objective technologies, or ambulatory recording. Overall, clinicians seemed unaware of meaningful ways to improve risk assessment.

Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome.

Context: Kabuki syndrome (KS) is associated with congenital hyperinsulinism (HI). Objective: To characterize the clinical and molecular features of HI in children with KS. Design: Retrospective cohort study of children with KS and HI evaluated between 1998 and 2023. Setting: The Congenital Hyperinsulinism Center of the Children's Hospital of Philadelphia. Patients: Thirty-three children with KS and HI. Main Outcome Measures: HI presentation, treatment, course, and genotype. Results: Hypoglycemia was recognized on the first day of life in 25 children (76%). Median age at HI diagnosis was 1.8 months (interquartile range [IQR], 0.6-6.1 months). Median age at KS diagnosis was 5 months (IQR, 2-14 months). Diagnosis of HI preceded KS diagnosis in 20 children (61%). Twenty-four children (73%) had a pathogenic variant in KMT2D, 5 children (15%) had a pathogenic variant in KDM6A, and 4 children (12%) had a clinical diagnosis of KS. Diazoxide trial was conducted in 25 children, 92% of whom were responsive. HI treatment was discontinued in 46% of the cohort at median age 2.8 years (IQR, 1.3-5.7 years). Conclusion: Hypoglycemia was recognized at birth in most children with KS and HI, but HI diagnosis was often delayed. HI was effectively managed with diazoxide in most children. In contrast to prior reports, the frequency of variants in KMT2D and KDM6A were similar to their overall prevalence in individuals with KS. Children diagnosed with KS should undergo evaluation for HI, and, because KS features may not be recognized in infancy, KMT2D and KDM6A should be included in the genetic evaluation of HI.

Undiagnosed hypoglycaemia disorders in children detected when hypoglycaemia occurs in the setting of illness: a retrospective study.

OBJECTIVE: Whether hypoglycaemia incidentally detected during intercurrent illness in children requires an endocrine workup remains controversial. This study aimed to determine the yield of conducting a diagnostic evaluation in this setting and to compare clinical and biochemical features between patients ultimately diagnosed with a hypoglycaemic disorder and those who were not. DESIGN: Single-center, retrospective review of children referred to endocrinology between January 2013 and December 2018 for evaluation of hypoglycaemia (defined as plasma glucose<3.9 mmol/L (<70 mg/dL)) in the setting of acute illness. RESULTS: 145 patients met eligibility criteria. A hypoglycaemia disorder was identified in 12 patients (8% of the cohort, 17% of those who underwent a diagnostic fast). There were no cases in which diagnosis was established in the absence of a diagnostic fast. Characteristics associated with identifying an underlying disorder included younger age (1.03 years (IQR: 0.05-1.54) vs 2.18 years [IQR: 1.29-3.99], p<0.001), higher bicarbonate level (22±5.5 mmol/L vs 16±3.6 mmol/L, p<0.001), lower frequency of elevated plasma or urine ketones (25% vs 92%, p=0.004) and lower frequency of other documented medical problems (17% vs 50%, p=0.03). CONCLUSIONS: The yield of diagnostic evaluation among children with incidental detection of hypoglycaemia in the setting of illness is not insignificant. We thus recommend that all children with hypoglycaemia in the setting of illness undergo guided diagnostic evaluation. Younger age and absence of ketosis and acidosis at presentation may serve as useful predictors for establishing a diagnosis. Future studies are needed to confirm these findings.

Using Automated Speech Processing for Repeated Measurements in a Clinical Setting of the Behavioral Variability in the Stroop Task.

The Stroop interference task is indispensable to current neuropsychological practice. Despite this, it is limited in its potential for repeated administration, its sensitivity and its demands on professionals and their clients. We evaluated a digital Stroop deployed using a smart device. Spoken responses were timed using automated speech recognition. Participants included adult nonpatients (N = 113; k = 5 sessions over 5 days) and patients with psychiatric diagnoses (N = 85; k = 3-4 sessions per week over 4 weeks). Traditional interference (difference in response time between color incongruent words vs. color neutral words; M = 0.121 s) and facilitation (neutral vs. color congruent words; M = 0.085 s) effects were robust and temporally stable over testing sessions (ICCs 0.50-0.86). The performance showed little relation to clinical symptoms for a two-week window for either nonpatients or patients but was related to self-reported concentration at the time of testing for both groups. Performance was also related to treatment outcomes in patients. The duration of response word utterances was longer in patients than in nonpatients. Measures of intra-individual variability showed promise for understanding clinical state and treatment outcome but were less temporally stable than measures based solely on average response time latency. This framework of remote assessment using speech processing technology enables the fine-grained longitudinal charting of cognition and verbal behavior. However, at present, there is a problematic lower limit to the absolute size of the effects that can be examined when using voice in such a brief 'out-of-the-laboratory condition' given the temporal resolution of the speech-to-text detection system (in this case, 10 ms). This resolution will limit the parsing of meaningful effect sizes.

Mosaic GLUD1 Mutations Associated with Hyperinsulinism Hyperammonemia Syndrome.

INTRODUCTION: The hyperinsulinemia-hyperammonemia syndrome (HIHA) is the second most common cause of congenital hyperinsulinism and is caused by activating heterozygous missense mutations in GLUD1. In the majority of HIHA cases, the GLUD1 mutation is found to be de novo. We have identified 3 patients in whom clinical evaluation was suggestive of HIHA but with negative mutation analysis in peripheral blood DNA for GLUD1 as well as other known HI genes. METHODS: We performed next-generation sequencing (NGS) on peripheral blood DNA from two children with clinical features of HIHA in order to look for mosaic mutations in GLUD1. Pancreas tissue was also available in one of these cases for NGS. In addition, NGS was performed on peripheral blood DNA from a woman with a history of HI in infancy whose child had HIHA due to a presumed de novo GLUD1 mutation. RESULTS: Mosaic GLUD1 mutations were identified in these 3 cases at percent mosaicism ranging from 2.7% to 10.4% in peripheral blood. In one case with pancreas tissue available, the mosaic GLUD1 mutation was present at 17.9% and 28.9% in different sections of the pancreas. Two unique GLUD1 mutations were identified in these cases, both of which have been previously reported (c.1493c>t/p.Ser445Leu and c.820c>t/p.Arg221Cys). CONCLUSION: The results suggest that low-level mosaic mutations in known HI genes may be the underlying molecular mechanism in some children with HI who have negative genetic testing in peripheral blood DNA.

Characterizing the neurological phenotype of the hyperinsulinism hyperammonemia syndrome.

BACKGROUND: Hyperinsulinism hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1, encoding glutamate dehydrogenase (GDH). Atypical absence seizures and neuropsychological disorders occur at high rates in this form of hyperinsulinism. Dysregulated central nervous system (CNS) glutamate balance, due to GDH overactivity in the brain, has been hypothesized to play a role. This study aimed to describe the neurologic phenotype in HI/HA syndrome and investigate CNS glutamate levels using glutamate weighted chemical exchange saturation transfer magnetic resonance imaging (GluCEST MRI). In this cross-sectional study, 12 subjects with HI/HA syndrome had plasma ammonia measurement, self- or parent-completed neurocognitive assessments, electroencephalogram (EEG), and GluCEST MRI at 7 T performed. GluCEST MRI measures were compared to a historic reference population of 10 healthy adults. RESULTS: Subjects were five males and seven females with median age of 25.5 years. Seventy-five percent of subjects reported a history of neurodevelopmental problems and 42% had neurocognitive assessment scores outside the normal range. Fifty percent had interictal EEG findings of generalized, irregular spike and wave discharges. Higher variability in hippocampal GluCEST asymmetry (p = 0.002), and in peak hippocampal GluCEST values (p = 0.008), was observed in HI/HA subjects (n = 9 with interpretable MRI) compared to the healthy reference population (n = 10). CONCLUSIONS: The high prevalence of abnormal neurocognitive assessment scores and interictal EEG findings observed highlights the importance of longitudinal neuropsychological assessment for individuals with HI/HA syndrome. Our findings demonstrate the potential application of GluCEST to investigate persistent knowledge gaps in the mechanisms underlying the unique neurophenotype of this disorder.

Case Report: Two Distinct Focal Congenital Hyperinsulinism Lesions Resulting From Separate Genetic Events.

Focal hyperinsulinism (HI) comprises nearly 50% of all surgically treated HI cases and is cured if the focal lesion can be completely resected. Pre-operative localization of the lesion is thus critical. Few cases of hyperinsulinism with multiple focal lesions have been reported, and assessment of the molecular mechanisms driving this rare occurrence has been limited. We present two cases of multifocal HI, each resulting from two independent, pancreatic focal lesions. 18Fluoro-dihydroxyphenylalanine positron emission tomography/computed tomography detected both lesions preoperatively in one patient, whereas identification of the second lesion was an incidental finding during surgical exploration in the other. Complete resection of the focal lesions resulted in cure of the HI in both cases. In each patient, genetic testing of the individual focal lesions revealed different regions of loss of heterozygosity for the maternal 11p15 allele, confirming that each lesion arose from independent somatic events in the setting of a paternally inherited germline ABCC8 mutation. These cases highlight the importance of a multidisciplinary and personalized approach to the management of infants with HI.

A Dynamic Method, Analysis, and Model of Short-Term Memory for Serial Order with Clinical Applications.

This study examined the robustness of a traditional memory task when moved out of controlled traditional settings. A letter recall task was designed to be self-administered via a smart-device which assessed recall by participants' writing their responses on the device. This enabled collection of both the letter recalled and the timing of this recall such that the temporal dynamics could be examined. Participants were patients with mental illness (n=71) and healthy volunteers (n=103). Temporal dynamics were examined using a new mechanism that measured memory retrieval time precisely. Data were analyzed for accuracy, time and their relationships. The classic memory phenomena and associated effects were replicated. In terms of temporal dynamics, this is the first demonstration of primacy and recency effects in time domain variables, as well as phonological similarity effects as evident by the inverted U-shaped curves in time. The speed of short-term memory processes affects accuracy, error types and timing. The robustness of these memory effects and new approach to temporal dynamics suggest this framework may be suitable for clinical applications, notably for the long-term monitoring of cognition in patients with mental illness.

Applying speech technologies to assess verbal memory in patients with serious mental illness.

Verbal memory deficits are some of the most profound neurocognitive deficits associated with schizophrenia and serious mental illness in general. As yet, their measurement in clinical settings is limited to traditional tests that allow for limited administrations and require substantial resources to deploy and score. Therefore, we developed a digital ambulatory verbal memory test with automated scoring, and repeated self-administration via smart devices. One hundred and four adults participated, comprising 25 patients with serious mental illness and 79 healthy volunteers. The study design was successful with high quality speech recordings produced to 92% of prompts (Patients: 86%, Healthy: 96%). The story recalls were both transcribed and scored by humans, and scores generated using natural language processing on transcriptions were comparable to human ratings (R = 0.83, within the range of human-to-human correlations of R = 0.73-0.89). A fully automated approach that scored transcripts generated by automatic speech recognition produced comparable and accurate scores (R = 0.82), with very high correlation to scores derived from human transcripts (R = 0.99). This study demonstrates the viability of leveraging speech technologies to facilitate the frequent assessment of verbal memory for clinical monitoring purposes in psychiatry.

Moving psychological assessment out of the controlled laboratory setting: Practical challenges.

Behavioral assessment using smart devices affords novel methods, notably remote self-administration by the individuals themselves. However, this new approach requires navigating complex legal and technical terrain. Given the limited empirical data that currently exists, we provide and discuss anecdotes of the methodological, technical, legal, and cultural issues associated with an implementation in both U.S. and European settings of a mobile software application for regular psychological monitoring purposes. The tasks required participants to listen, watch, speak, and touch to interact with the smart device, thus assessing cognition, motor skill, and language. Four major findings merit mention: First, moving assessment out of the hands of a trained investigator necessitates excellent usability engineering, such that the tool is easily usable by the participant and the resulting data relevant to the investigator. Second, remote assessment requires that the data are transferred safely back to the investigator, and that risk of compromising participant confidentiality is minimized. Third, frequent data collection over long periods of time is associated with a possibility that participants may choose to withdraw consent for participation thus requiring data retraction. Fourth, data collection and analysis across international borders creates new challenges and new opportunities because of important cultural and language issues that may inform the underlying behavioral constructs of interest. In conclusion, the new technological frameworks provide unprecedented opportunities for remote self-administered behavioral assessments but will be most productive in multidisciplinary teams to ensure the highest level of user satisfaction and data quality, and to guarantee the highest level of data protection. (PsycINFO Database Record (c) 2019 APA, all rights reserved).