PURPOSE: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND. METHODS: We describe 19 patients with congenital CACNA1G-variants, including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants, including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity. RESULTS: We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics and an increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity. CONCLUSION: This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia.

• MeSH
• Child MeSH
• Phenotype * MeSH
• Genetic Association Studies MeSH
• Heterozygote MeSH
• Infant MeSH
• Humans MeSH
• Mutation, Missense * genetics   MeSH
• Adolescent MeSH
• Neurodevelopmental Disorders * genetics   pathology   MeSH
• Child, Preschool MeSH
• Calcium Channels, T-Type * genetics   metabolism   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Bipolar disorder (BD) is a complex and heterogeneous psychiatric disorder. It has been suggested that neurodevelopmental factors contribute to the etiology of BD, but a specific neurodevelopmental phenotype (NDP) of the disorder has not been identified. Our objective was to define and characterize an NDP in BD and validate its associations with clinical outcomes, polygenic risk scores, and treatment responses. METHODS: We analyzed the FondaMental Advanced Centers of Expertise for Bipolar Disorders cohort of 4468 patients with BD, a validation cohort of 101 patients with BD, and 2 independent replication datasets of 274 and 89 patients with BD. Using factor analyses, we identified a set of criteria for defining NDP. Next, we developed a scoring system for NDP load and assessed its association with prognosis, neurological soft signs, polygenic risk scores for neurodevelopmental disorders, and responses to treatment using multiple regressions, adjusted for age and gender with bootstrap replications. RESULTS: Our study established an NDP in BD consisting of 9 clinical features: advanced paternal age, advanced maternal age, childhood maltreatment, attention-deficit/hyperactivity disorder, early onset of BD, early onset of substance use disorders, early onset of anxiety disorders, early onset of eating disorders, and specific learning disorders. Patients with higher NDP load showed a worse prognosis and increased neurological soft signs. Notably, these individuals exhibited a poorer response to lithium treatment. Furthermore, a significant positive correlation was observed between NDP load and polygenic risk score for attention-deficit/hyperactivity disorder, suggesting potential overlapping genetic factors or pathophysiological mechanisms between BD and attention-deficit/hyperactivity disorder. CONCLUSIONS: The proposed NDP constitutes a promising clinical tool for patient stratification in BD.

• MeSH
• Bipolar Disorder * genetics   MeSH
• Adult MeSH
• Phenotype * MeSH
• Attention Deficit Disorder with Hyperactivity genetics   MeSH
• Cohort Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Multifactorial Inheritance genetics   MeSH
• Neurodevelopmental Disorders genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rRNA processing. CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of "ribosomopathies."

• MeSH
• Child MeSH
• Genes, Dominant MeSH
• Phenotype MeSH
• Genes, Recessive MeSH
• Nuclear Proteins * genetics   MeSH
• Infant MeSH
• Humans MeSH
• Intellectual Disability genetics   pathology   MeSH
• Adolescent MeSH
• Brain pathology   MeSH
• Mutation MeSH
• Brain Diseases * genetics   pathology   MeSH
• Neurodevelopmental Disorders * genetics   MeSH
• Child, Preschool MeSH
• Developmental Disabilities * genetics   pathology   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Eozinofilní ezofagitida je chronické zánětlivé, imunologicky podmíněné onemocnění, charakterizované patologickou infiltrací sliznice jícnu eozinofilními granulocyty. Na vzniku nemoci se podílí genetická predispozice a faktory vnějšího prostředí. Stanovení správné diagnózy se u dětí opírá o klinické příznaky dysfunkce jícnu, zvracení, neprospívání a typický histologický nález. Velmi častou komorbiditou jsou alergická onemocnění. Cílem léčby je odstranit klinické příznaky onemocnění, potlačit infiltraci jícnu eozinofilními granulocyty a zabránit komplikacím, zejména přestavbě stěny (remodelace) a zúžení jícnu. U dětí je nezbytné zajistit správný růst a vývoj. Léčba je komplexní a zahrnuje empirickou eliminační dietu nebo kombinovanou farmakoterapii inhibitorem protonové pumpy nebo topickým kortikosteroidem (budesonid jako suspenze nebo rozpustná tableta). U nejtěžších případů je indikována celková farmakoterapie prednisonem a biologická léčba (dupilumabem). Kazuistika u chlapce ukazuje na úskalí diagnostiky eozinofilní ezofagitidy v kojeneckém věku a na nutnost mezioborové spolupráce nejen při stanovení správné diagnózy a zahájení adekvátní komplexní léčby za nezbytné spolupráce rodičů nemocného dítěte, ale i při dispenzární péči a včasném rozpoznání recidivy onemocnění.

Eosinophilic esophagitis is a chronic inflammatory immune-mediated disease characterized by pathological eosinophilic infiltration of the esophageal wall. Genetic predisposition and environmental factors contribute to the development of this illnes. Establishing the correct diagnosis in children is based on clinical symptoms of esophageal dysfunction, vomiting, failure to thrive and typical histological findings. Allergic diseases are very common comorbidities. The treatment aims to remove the clinical symptoms of the disease, suppress the infiltration of the esophagus by eosinophilic granulocytes, and prevent complications, especially the remodeling of the esophagus wall with its subsequent narrowing. Ensuring proper children's growth and development is essential. Treatment of eosinophilic esophagitis is comprehensive and includes empiric elimination diet, or pharmacotherapy with proton pump inhibitors, or topical corticosteroids. In the most severe cases, systemic pharmacotherapy with prednisone and biological treatment is indicated dupilumab. The presented case report illustrates the difficulties in diagnosing in infancy and the necessity of an interdisciplinary approach (pediatrician-gastroenterologist-allergist) not only in establishing the correct diagnosis and starting adequate treatment necessitating the cooperation of the chilďs parents but also in long-term care and early recognition of the possible disease recurrence.

In a recent Cell article, Baluapuri et al.1 show that loss of the Integrator (INT) complex activates the integrated stress response via double-stranded RNA from incomplete pre-mRNAs, revealing a link to INT-related neurodevelopmental diseases and potential therapeutic targets.

• MeSH
• RNA, Double-Stranded metabolism   genetics   MeSH
• Stress, Physiological * MeSH
• Humans MeSH
• Neurodevelopmental Disorders * genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Kazuistika se zaměřuje na kognitivně-behaviorálně vedenou terapii obsedantně-kompulzivní symptomatologie u chlapce s autismem a dalšími neurovývojovými poruchami v komorbiditě. Popisuje složitý klinický obraz poruchy a dlouhodobě vedenou terapii.

The case report focuses on Cognitive Behavioural Guided Therapy of obsessive­compulsive symptomatology in a boy with autism and other neurodevelopmental disorders in comorbidity. It describes the complex clinical picture of the disorder and long­term therapy.

• MeSH
• Antidepressive Agents administration & dosage   therapeutic use   MeSH
• Behavior Therapy methods   MeSH
• Child MeSH
• Cognitive Behavioral Therapy methods   MeSH
• Humans MeSH
• Neurodevelopmental Disorders diagnosis   MeSH
• Obsessive-Compulsive Disorder * diagnosis   psychology   therapy   MeSH
• Autism Spectrum Disorder diagnosis   psychology   therapy   MeSH
• Family Relations MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

The human genome contains approximately 20,000 protein-coding genes, of which more than 15,000 (3/4) are expressed, among others, in the central nervous system. Variants that damage the function of these genes (called pathogenic variants) can lead to various forms of neurodevelopmental disorders (NDD), including speech and language disorders. These can occur alone or in various combinations. In this review article, we provide information on the possibilities, limits and importance of genetic testing in patients with NDD.

• MeSH
• Genetic Variation MeSH
• Genetic Diseases, Inborn diagnosis   genetics   MeSH
• Genetic Testing methods   MeSH
• Humans MeSH
• Abnormalities, Multiple diagnosis   genetics   MeSH
• Mutation MeSH
• Neurodevelopmental Disorders * diagnosis   etiology   genetics   MeSH
• Language Development Disorders diagnosis   etiology   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

OBJECTIVES: Regular physical activity (PA) and reduced sedentary behaviour (SB) have been associated with positive health outcomes, but many older adults do not comply with the current recommendations. Sensor-triggered ecological momentary assessment (EMA) studies allow capturing real-time data during or immediately after PA or SB, which can yield important insights into these behaviours. Despite the promising potential of sensor-triggered EMA, this methodology is still in its infancy. Addressing methodological challenges in sensor-triggered EMA studies is essential for improving protocol adherence and enhancing validity. Therefore, this study aimed to examine (1) the patterns in sensor-triggered EMA protocol adherence (eg, compliance rates), (2) the impact of specific settings (eg, event duration) on the number of prompted surveys, and (3) participants' experiences with engaging in a sensor-triggered EMA study. DESIGN: Two longitudinal, sensor-triggered EMA studies-one focused on PA and the other on SB-were conducted using similar methodologies from February to October 2022. Participants' steps were monitored for seven days using a Fitbit activity tracker, which automatically prompted an EMA survey through the HealthReact smartphone application when specified (in)activity thresholds were reached. After the monitoring period, qualitative interviews were conducted. Data from both studies were merged. SETTING: The studies were conducted among community-dwelling Belgian older adults. PARTICIPANTS: The participants had a median age of 72 years, with 54.17% being females. The PA study included 88 participants (four dropped out), while the SB study included 76 participants (seven dropped out). PRIMARY AND SECONDARY OUTCOME MEASURES: Descriptive methods and generalised logistic mixed models were employed to analyse EMA adherence patterns. Simulations were conducted to assess the impact of particular settings on the number of prompted EMA surveys. Additionally, qualitative interview data were transcribed verbatim and thematically analysed using NVivo. RESULTS: Participants responded to 81.22% and 79.10% of the EMA surveys in the PA and SB study, respectively. The confirmation rate, defined as the percentage of EMA surveys in which participants confirmed the detected behaviour, was 94.16% for PA and 72.40% for SB. Logistic mixed models revealed that with each additional day in the study, the odds of responding to the EMA survey increased significantly by 1.59 times (OR=1.59, 95% CI: 1.36 to 1.86, p<0.01) in the SB study. This effect was not observed in the PA study. Furthermore, time in the study did not significantly impact the odds of participants confirming to be sedentary (OR=0.97, 95% CI: 0.92 to 1.02, p=0.28). However, it significantly influenced the odds of confirming PA (OR: 0.81, 95% CI: 0.68 to 0.97, p=0.02), with the likelihood of confirming decreasing by 19% with each additional day in the study. Furthermore, a one-minute increase in latency (ie, time between last syncing and starting the EMA survey) in the PA study decreased the odds of the participant confirming to be physically active by 20% (OR: 0.80, 95% CI: 0.72 to 0.89, p<0.01). Simulations of the specific EMA settings revealed that reducing the event duration and shorter minimum time intervals between prompts increased the number of EMA surveys. Overall, most participants found smartphone usage to be feasible and rated the HealthReact app as user-friendly. However, some reported issues, such as not hearing the notification, receiving prompts at an inappropriate time and encountering technical issues. While the majority reported that their behaviour remained unchanged due to study participation, some noted an increased awareness of their habits and felt more motivated to engage in PA. CONCLUSIONS: This study demonstrates the potential of sensor-triggered EMA to capture real-time data on PA and SB among older adults, showing strong adherence potential with compliance rates of approximately 80%. The SB study had lower confirmation rates than the PA study, due to technical issues and discrepancies between self-perception and device-based measurements. Practical recommendations were provided for future studies, including improvements in survey timing, technical reliability and strategies to reduce latency.

• MeSH
• Exercise * MeSH
• Fitness Trackers MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Ecological Momentary Assessment * MeSH
• Independent Living * MeSH
• Sedentary Behavior * MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Belgium MeSH

Mutations in CACNA1C, the gene encoding Cav1.2 voltage-gated calcium channels, are associated with a spectrum of disorders, including Timothy syndrome and other neurodevelopmental and cardiac conditions. In this study, we report a child with a de novo heterozygous missense variant (c.1973T > C; L658P) in CACNA1C, presenting with refractory epilepsy, global developmental delay, hypotonia, and multiple systemic abnormalities, but without overt cardiac dysfunction. Electrophysiological analysis of the recombinant Cav1.2 L658P variant revealed profound gating alterations, most notably a significant hyperpolarizing shift in the voltage dependence of activation and inactivation. Additionally, molecular modeling suggested that the L658P mutation disrupts interactions within the IIS5 transmembrane segment, reducing the energy barrier for state transitions and facilitating channel opening at more negative voltages. These findings establish L658P as a pathogenic CACNA1C variant primarily associated with severe neurological dysfunction and expands the phenotypic spectrum of CACNA1C-related disorders.

• MeSH
• Child MeSH
• Ion Channel Gating * MeSH
• Humans MeSH
• Mutation, Missense genetics   MeSH
• Models, Molecular MeSH
• Neurodevelopmental Disorders * genetics   MeSH
• Child, Preschool MeSH
• Amino Acid Sequence MeSH
• Calcium Channels, L-Type * genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

Tranzientní hypogamaglobulinemie je poměrně častá primární protilátková imunodeficience kojenců a batolat se širokým klinickým obrazem. Patofyziologickým podkladem je opožděný nástup tvorby vlastních imunoglobulinů, rezultující v přechodný pokles sérové koncentrace IgG u kojence. THI většinou spontánně odezní ve věku 2 až 6 let. V laboratoři dominuje snížená sérová koncentrace IgG (ev. i IgA a IgM) při normálním zastoupení B-lymfocytů. V diferenciální diagnostice zvažujeme i jiné imunodeficience. Velmi důležitá je mezioborová spolupráce.

Transient hypogammaglobulinemia is a relatively common primary antibody immunodeficiency in infants and toddlers with a wide clinical picture. The pathophysiologi­cal basis is a delayed onset of the production of own immunoglobulins, resulting in a temporary decrease in serum IgG concentration in the infant. THI usually resolves spontaneously between the ages of 2 and 6 years. In the laboratory, a reduced serum IgG concentration (possibly also IgA and IgM) dominates with a normal representation of B-lymphocytes. In the differential diagnosis, we also consider other immunodeficiencies. Interdisciplinary cooperation is very important.

• Keywords
• THI, etiopathogenesis, clinical evaluation, differential diagnosis, treatment, THI, etiopatogeneze, klinické hodnocení, diferenciální diagnostika, léčba,
• MeSH
• Hypersensitivity etiology   immunology   MeSH
• Anti-Bacterial Agents therapeutic use   MeSH
• Common Variable Immunodeficiency * diagnosis   epidemiology   therapy   MeSH
• Dermatitis etiology   immunology   MeSH
• Diagnosis, Differential MeSH
• Child * MeSH
• Immunologic Tests MeSH
• Respiratory Tract Infections etiology   immunology   MeSH
• Immunoglobulins, Intravenous therapeutic use   MeSH
• Humans MeSH
• Check Tag
• Child * MeSH
• Humans MeSH