Approach to diagnosing a pediatric patient with severe insulin resistance in low- or middle-income countries

Diabetes mellitus (DM) in children is most often caused by impaired insulin secretion (type 1 DM). In some children, the underlying mechanism for DM is increased insulin resistance, which can have different underlying causes. While the majority of these children require insulin dosages less than 2.0 U/kg/day to achieve normoglycemia, higher insulin requirements indicate severe insulin resistance. Considering the therapeutic challenges in patients with severe insulin resistance, early diagnosis of the underlying cause is essential in order to consider targeted therapies and to prevent diabetic complications. Although rare, several disorders can attribute to severe insulin resistance in pediatric patients. Most of these disorders are diagnosed through advanced diagnostic tests, which are not commonly available in low- or middle-income countries. Based on a case of DM with severe insulin resistance in a Surinamese adolescent who was later confirmed to have autosomal recessive congenital generalized lipodystrophy, type 1 (Berardinelli–Seip syndrome), we provide a systematic approach to the differential diagnosis and work-up. We show that a thorough review of medical history and physical examination generally provide sufficient information to diagnose a child with insulin-resistant DM correctly, and, therefore, our approach is especially applicable to low- or middle-income countries

Understanding Behavior in Phelan-McDermid Syndrome

BackgroundPhelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is a rare genetic disorder characterized by developmental delay, hypotonia and severely delayed speech. Behavioral difficulties are often reported in PMS, although knowledge of behavioral profiles and the interpretation of reported behavior remains limited. Understanding the meaning of behavior requires considering the context as well as other domains of functioning, for example the individual's level of cognitive, social and emotional development. Combining structured direct in-person neurodevelopmental assessments with contextual assessments to enable meaningful interpretations of reported behavior on functional dimensions across multiple units of analysis, as proposed by the RDoc framework, is essential. MethodsIn this article we present a structured multidisciplinary method of assessment through direct in-person neurodevelopmental assessments and assessment of contextual factors. Our study sample includes data of 33 children with an average age of 6.2 years (range 1.1 to 15.7) with PMS, obtained through individual in-person assessments in combination with parent informed questionnaires. We assessed developmental age using the Bayley-III, adaptive behavior was assessed with the Vineland screener, social-emotional development with the ESSEON-R and behavior by using the CBCL. ResultsOur results show a great deal of variability in phenotypic presentation with regard to behavior, symptom expression and symptom severity in individuals with PMS. The data on behavior is interpreted in the context of the individual's level of cognitive, adaptive development and the (genetic) context. Behavioral data showed high levels of withdrawn behavior and attention problems. More than half of the children showed borderline or clinical symptoms related to Autism Spectrum Disorder (ASD). ConclusionsThe interpretation of the meaning of certain behavior in PMS is often based on questionnaires and descriptions without taking the specific context of development into account. Combining questionnaires with direct in-person assessments measuring different domains of functioning should be considered a more accurate method to interpret the meaning of findings in order to understand behavior in rare genetic disorders associated with developmental delay such as PMS. Direct in-person assessment provides valuable and specific information relevant to understanding individual behavior and inform treatment as well as increase knowledge of the neurodevelopmental phenotype in individuals with PMS. More specific application of the proposed frameworks on behavior in PMS is desirable in making useful interpretations

Copy number variation in a hospital-based cohort of children with epilepsy

Objective: To evaluate the diagnostic yield of microarray analysis in a hospital-based cohort of children with seizures and to identify novel candidate genes and susceptibility loci for epilepsy. Methods: Of all children who presented with their first seizure in the University Medical Center Groningen (January 2000 through May 2013) (n = 1,368), we included 226 (17%) children who underwent microarray analysis before June 2014. All 226 children had a definite diagnosis of epilepsy. All their copy number variants (CNVs) on chromosomes 1-22 and X that contain protein-coding genes and have a prevalence of <1% in healthy controls were evaluated for their pathogenicity. Results: Children selected for microarray analysis more often had developmental problems (82% vs. 25%, p < 0.001), facial dysmorphisms (49% vs. 8%, p < 0.001), or behavioral problems (41% vs. 13%, p < 0.001) than children who were not selected. We found known clinically relevant CNVs for epilepsy in 24 of the 226 children (11%). Seventeen of these 24 children had been diagnosed with symptomatic focal epilepsy not otherwise specified (71%) and five with West syndrome (21%). Of these 24 children, many had developmental problems (100%), behavioral problems (54%) or facial dysmorphisms (46%). We further identified five novel CNVs comprising four potential candidate genes for epilepsy:MYT1L, UNC5D, SCN4B,andNRXN3. Significance: The 11% yield in our hospital-based cohort underscores the importance of microarray analysis in diagnostic evaluation of children with epilepsy

Imaging of Clival Hypoplasia in CHARGE Syndrome and Hypothesis for Development:A Case-Control Study

BACKGROUND AND PURPOSE: We present the largest case series to date on basiocciput abnormalities in CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities and/or deafness). We aimed to show that basiocciput abnormalities are common and may aid in diagnosis. We furthermore explored whether clivus size correlates with the type of chromodomain-helicase-DNA binding protein 7 gene (CHD7) mutation, which causes CHARGE syndrome, and with clinical criteria according to Blake et al and Verloes. MATERIALS AND METHODS: We retrospectively analyzed the clivus of 23 patients with CHARGE syndrome with CHD7 mutations on MR imaging or CT. We recorded the size of the clivus, the Welcher angle, basilar invagination, and Chiari I malformations. We compared the clival size and Welcher angle of patients with CHARGE syndrome with those of 72 age-matched controls. Additionally, we tested for correlations between clivus size and mutation type or clinical criteria. RESULTS: Eighty-seven percent of the patients with CHARGE syndrome had an abnormal clivus; 61% had a clivus >2.5 SD smaller than that of age-matched controls. An abnormally large Welcher angle was observed in 35%. Basiocciput hypoplasia was found in 70%, and basilar invagination, in 29%. None of the patients had a Chiari I malformation. At the group level, patients with CHARGE syndrome had a smaller clivus and larger Welcher angle than controls. No significant correlation between clivus size and mutation type or clinical criteria was found. CONCLUSIONS: Most patients with CHARGE syndrome have an abnormal clivus. This suggests that clivus abnormalities may be used as an additional diagnostic tool. Our results provide evidence that CHD7, which is expressed in the presomitic mesoderm during somitogenesis, plays an important role in the formation of the clivus

Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome

Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2–33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.</p

Should every child with epilepsy undergo screening for psychiatric comorbidities?

Purpose: We aimed to build a classification system that uses resting-state (no visible scalp epileptic activity) EEG-based directed functional connectivity values to assign a patient to one of three classes: left TLE (LTLE), right TLE (RTLE) or healthy control. Methods: Twenty LTLE, 20 RTLE and 35 healthy controls underwent resting-state high-density EEG. For each subject, sixty 1-sec epochs free of artifacts or interictal spikes were selected. The source activity was obtained for 82 regions of interest using an individual head model and distributed linear inverse solution. The summed outflow and whole-brain directed functional connectivity were estimated in the theta, alpha and beta frequency bands using Granger-causal modeling. A Random Forest classifier (an ensemble of decision tree classifiers) was then used to assign the subject to one of three classes. The mean classification accuracy was computed with a leave-one-out procedure. We selected a maximum of six connectivity values for classification, using a greedy forward selection algorithm. Finally, three classifiers were built: ‘Control vs. LTLE’, ‘Control vs. RTLE’ and ‘LTLE vs. RTLE’. In the final classification system, a new subject is assigned to the class that was most voted by these three classifiers. Results: The ‘Control vs. RTLE’ classifier achieved an accuracy of 78.2% (sensitivity: 80.0%, specificity 77.2%), ‘Control vs. LTLE’ an accuracy of 83.6% (sensitivity 85.0%, specificity 82.9%) and ‘LTLE vs. RTLE’ an accuracy of 85.0% (sensitivity 85.0%, specificity 85.0%). Combining these classifiers into one system yielded that 16, 15 and 27 subjects were correctly classified as being, respectively, RTLE, LTLE and control. Conclusion: The high accuracy achieved demonstrates the potential of resting-state EEG-based directed functional connectivity for the diagnosis and lateralization of TLE. This could constitute a new clinical biomarker for surgical candidates and earlier in the course of the disease

Changes in empowerment and anxiety of patients and parents during genetic counselling for epilepsy

Genetic testing and counselling are increasingly important in epilepsy care, aiming at finding a diagnosis, understanding aetiology and improving treatment and outcome. The psychological impact of genetic counselling from patients' or parents & rsquo; perspectives is, however, unknown. We studied the counseleereported outcome of genetic counselling before and after genetic testing for epilepsy by evaluating empowerment - a key outcome goal of counselling reflecting cognitive, decisional and behavioural control, emotional regulation and hope - and anxiety. We asked patients or their parents (for those (c) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

The Results of CHD7 Analysis in Clinically Well-Characterized Patients with Kallmann Syndrome

Item does not contain fulltextCONTEXT: Kallmann syndrome (KS) and CHARGE syndrome are rare heritable disorders in which anosmia and hypogonadotropic hypogonadism co-occur. KS is genetically heterogeneous, and there are at least eight genes involved in its pathogenesis, whereas CHARGE syndrome is caused by autosomal dominant mutations in only one gene, the CHD7 gene. Two independent studies showed that CHD7 mutations can also be found in a minority of KS patients. OBJECTIVE: We aimed to investigate whether CHD7 mutations can give rise to isolated KS or whether additional features of CHARGE syndrome always occur. DESIGN: We performed CHD7 analysis in a cohort of 36 clinically well-characterized Dutch patients with KS but without mutations in KAL1 and with known status for the KS genes with incomplete penetrance, FGFR1, PROK2, PROKR2, and FGF8. RESULTS: We identified three heterozygous CHD7 mutations. The CHD7-positive patients were carefully reexamined and were all found to have additional features of CHARGE syndrome. CONCLUSION: The yield of CHD7 analysis in patients with isolated KS seems very low but increases when additional CHARGE features are present. Therefore, we recommend performing CHD7 analysis in KS patients who have at least two additional CHARGE features or semicircular canal anomalies. Identifying a CHD7 mutation has important clinical implications for the surveillance and genetic counseling of patients

Practical guidelines for interpreting copy number gains detected by high-resolution array in routine diagnostics

The correct interpretation of copy number gains in patients with developmental delay and multiple congenital anomalies is hampered by the large number of copy number variations (CNVs) encountered in healthy individuals. The variable phenotype associated with copy number gains makes interpretation even more difficult. Literature shows that inheritence, size and presence in healthy individuals are commonly used to decide whether a certain copy number gain is pathogenic, but no general consensus has been established. We aimed to develop guidelines for interpreting gains detected by array analysis using array CGH data of 300 patients analysed with the 105K Agilent oligo array in a diagnostic setting. We evaluated the guidelines in a second, independent, cohort of 300 patients. In the first 300 patients 797 gains of four or more adjacent oligonucleotides were observed. Of these, 45.4% were de novo and 54.6% were familial. In total, 94.8% of all de novo gains and 87.1% of all familial gains were concluded to be benign CNVs. Clinically relevant gains ranged from 288 to 7912 kb in size, and were significantly larger than benign gains and gains of unknown clinical relevance (P<0.001). Our study showed that a threshold of 200 kb is acceptable in a clinical setting, whereas heritability does not exclude a pathogenic nature of a gain. Evaluation of the guidelines in the second cohort of 300 patients revealed that the interpretation guidelines were clear, easy to follow and efficient

Affective Man-Machine Interface: Unveiling human emotions through biosignals

As is known for centuries, humans exhibit an electrical profile. This profile is altered through various psychological and physiological processes, which can be measured through biosignals; e.g., electromyography (EMG) and electrodermal activity (EDA). These biosignals can reveal our emotions and, as such, can serve as an advanced man-machine interface (MMI) for empathic consumer products. However, such a MMI requires the correct classification of biosignals to emotion classes. This chapter starts with an introduction on biosignals for emotion detection. Next, a state-of-the-art review is presented on automatic emotion classification. Moreover, guidelines are presented for affective MMI. Subsequently, a research is presented that explores the use of EDA and three facial EMG signals to determine neutral, positive, negative, and mixed emotions, using recordings of 21 people. A range of techniques is tested, which resulted in a generic framework for automated emotion classification with up to 61.31% correct classification of the four emotion classes, without the need of personal profiles. Among various other directives for future research, the results emphasize the need for parallel processing of multiple biosignals