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

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research.

• MeSH
• Child MeSH
• Adult MeSH
• Phenotype * MeSH
• Histones * genetics   MeSH
• Humans MeSH
• Intellectual Disability genetics   pathology   MeSH
• Adolescent MeSH
• Neurodegenerative Diseases genetics   pathology   MeSH
• Neurodevelopmental Disorders genetics   pathology   MeSH
• Child, Preschool MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to proteins (referred to as O-GlcNAcylation) is a modification that is crucial for vertebrate development. O-GlcNAcylation is catalyzed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). Missense variants of OGT have recently been shown to segregate with an X-linked syndromic form of intellectual disability, OGT-linked congenital disorder of glycosylation (OGT-CDG). Although the existence of OGT-CDG suggests that O-GlcNAcylation is crucial for neurodevelopment and/or cognitive function, the underlying pathophysiologic mechanisms remain unknown. Here we report a mouse line that carries a catalytically impaired OGT-CDG variant. These mice show altered O-GlcNAc homeostasis with decreased global O-GlcNAcylation and reduced levels of OGT and OGA in the brain. Phenotypic characterization of the mice revealed lower body weight associated with reduced body fat mass, short stature and microcephaly. This mouse model will serve as an important tool to study genotype-phenotype correlations in OGT-CDG in vivo and for the development of possible treatment avenues for this disorder.

• MeSH
• beta-N-Acetylhexosaminidases metabolism   MeSH
• Phenotype MeSH
• Glycosylation MeSH
• Intellectual Disability * genetics   MeSH
• Disease Models, Animal * MeSH
• Brain pathology   metabolism   MeSH
• Mice MeSH
• N-Acetylglucosaminyltransferases * metabolism   genetics   deficiency   MeSH
• Neurodevelopmental Disorders pathology   genetics   enzymology   MeSH
• Body Weight MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

• MeSH
• Diagnosis, Differential MeSH
• Child MeSH
• Humans MeSH
• Musculoskeletal Diseases * diagnosis   classification   pathology   MeSH
• Neurodevelopmental Disorders diagnosis   pathology   MeSH
• Vestibular Diseases * etiology   therapy   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Review MeSH

Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.

• MeSH
• Chromatin chemistry   immunology   MeSH
• Child MeSH
• Host Cell Factor C1 genetics   immunology   MeSH
• Heterozygote MeSH
• Histones genetics   immunology   MeSH
• Infant MeSH
• Humans MeSH
• Mutation, Missense * MeSH
• Adolescent MeSH
• Loss of Function Mutation * MeSH
• Tumor Suppressor Proteins deficiency   genetics   immunology   MeSH
• Neurodevelopmental Disorders genetics   immunology   pathology   MeSH
• Child, Preschool MeSH
• Proteasome Endopeptidase Complex genetics   immunology   MeSH
• BRCA1 Protein genetics   immunology   MeSH
• Gene Expression Regulation MeSH
• Chromatin Assembly and Disassembly genetics   immunology   MeSH
• Family MeSH
• T-Lymphocytes immunology   pathology   MeSH
• Ubiquitin Thiolesterase deficiency   genetics   immunology   MeSH
• Ubiquitin genetics   immunology   MeSH
• Ubiquitination MeSH
• Ubiquitin-Protein Ligases genetics   immunology   MeSH
• Germ-Line Mutation * MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

INTRODUCTION: Biallelic variants in the SLC1A4 gene have been so far identified as a very rare cause of neurodevelopmental disorders with or without epilepsy and almost exclusively described in the Ashkenazi-Jewish population. PATIENTS AND METHODS: Here we present Czech patient with microcephaly, severe global developmental delay and intractable seizures whose condition remained undiagnosed despite access to clinical experience and standard diagnostic methods including examination with an epilepsy targeted NGS gene panel. RESULTS: Whole exome sequencing revealed a novel variant NM_003038.4:c.1370G > A p.(Arg457Gln) of the SLC1A4 gene in a homozygous state in the patient, and afterwards Sanger sequencing in both parents confirmed the biallelic origin of the variant. A variant in the same codon, but with a different amino acid exchange, was described previously in a patient that had a very similar phenotype, however, without epilepsy. CONCLUSION: Our data suggest that the SLC1A4 gene should be considered in the diagnosis of patients with severe, early onset neurodevelopmental impairment with epilepsy and encourage the analysis of SLC1A4 gene variants via targeted NGS gene panel or whole exome sequencing.

• MeSH
• Child MeSH
• Homozygote MeSH
• Humans MeSH
• Microcephaly genetics   pathology   MeSH
• Mutation MeSH
• Neurodevelopmental Disorders genetics   pathology   MeSH
• Amino Acid Transport System ASC genetics   MeSH
• Seizures genetics   pathology   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

• Keywords
• hyperaktivita,
• MeSH
• Autistic Disorder diagnosis   MeSH
• Central Nervous System growth & development   MeSH
• Diagnosis, Differential MeSH
• Child MeSH
• Humans MeSH
• Central Nervous System Diseases classification   congenital   MeSH
• Brain Diseases diagnostic imaging   diagnosis   classification   pathology   MeSH
• Neurodevelopmental Disorders * diagnosis   classification   pathology   MeSH
• Neurulation MeSH
• Autism Spectrum Disorder diagnosis   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Review MeSH

BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. FINDINGS: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. INTERPRETATION: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies. FUNDING: Netherlands Organisation for Health Research and Development, and the Sherman Foundation.

• MeSH
• Biomarkers analysis   MeSH
• Child MeSH
• Adult MeSH
• Mental Disorders etiology   pathology   MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• International Agencies MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation MeSH
• Follow-Up Studies MeSH
• Muscular Diseases etiology   pathology   MeSH
• Neurodevelopmental Disorders etiology   pathology   MeSH
• Child, Preschool MeSH
• Monocarboxylic Acid Transporters deficiency   genetics   MeSH
• Prognosis MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Symporters deficiency   genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH

Náš výzkum se zaměří na poruchy autistického spektra (PAS) a vývojovou dysfázii (VD), dvě diagnostické kategorie ze skupiny neurovývojových poruch. Podle Mezinárodní klasifikace nemocí, 10. revize sdílejí PAS a VD některé podobnosti v jazykových a řečových deficitech, ale liší se v sociálním deficitu, jenž je zejména doménou PAS. Neurozobrazovací metody stimulovaly výzkum u PAS i VD, nicméně výsledky zůstávají rozporné. Jen několik studií zkoumalo vztah neuroanatomických nálezů k psychopatologii neurovývojových poruch. Cílem našeho projektu je výzkum neuroanatomického substrátu obou jednotek u školních dětí ve věku 6 – 12 let za užití traktografie (studie dlouhých i regionálních krátkých mozkových spojení) a dalších parametrů získaných pomocí diffusion tensor imaging. Dále náš projekt prozkoumá vztah mezi neurálním substrátem a psychopatologií se zřetelem na psychopatologické podobnosti a rozdíly mezi PAS a VD.; Our research will focus on autism spectrum disorders (ASD) and developmental dysphasia (DD), two diagnostic categories from the group of neurodevelopmental disorders. According to the International Classification of Diseases, 10th ed., ASD and DD share some similarities in language and speech deficits but differ in social deficit, which is predominantly the domain of ASD. Neuroimaging has driven the research in both ASD and DD; however, the results have been inconsistent. Few studies have examined the relationship between neuroanatomical findings and the psychopathology of neurodevelopmental disorders. The aim of our project is to study the neuroanatomical substrate of both conditions in school children aged 6 – 12 years using tractography (long-range as well as regional short-range brain connections) and other diffusion tensor – derived parameters. Furthermore, our project will explore the relationship between neural substrate and psychopathology with regard to the psychopathological similarities and dissimilarities of the ASD and DD.

• MeSH
• Aphasia diagnostic imaging   pathology   MeSH
• Child MeSH
• Humans MeSH
• Neurodevelopmental Disorders diagnostic imaging   pathology   MeSH
• Autism Spectrum Disorder diagnostic imaging   pathology   MeSH
• Diffusion Tensor Imaging methods   MeSH
• Check Tag
• Child MeSH
• Humans MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• neurologie
• psychiatrie
• pediatrie
• NML Publication type
• závěrečné zprávy o řešení grantu AZV MZ ČR

• MeSH
• Chromosome Disorders classification   pathology   MeSH
• Circadian Rhythm MeSH
• Child MeSH
• Epileptic Syndromes classification   pathology   MeSH
• Attention Deficit Disorder with Hyperactivity pathology   MeSH
• Humans MeSH
• Melatonin physiology   MeSH
• Neurodevelopmental Disorders classification   pathology   MeSH
• Polysomnography MeSH
• Sleep Wake Disorders * epidemiology   etiology   classification   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH