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

Spontánne rozprávanie predstavuje základnú formu komunikácie v rámci každodenných interakcií. U pacientov s afáziou dochádza k oslabeniu rôznych aspektov spontánnej produkcie, pričom miera narušenia koreluje so závažnosťou afázie - od ľahkej cez stredne ťažkú až po ťažkú formu. Doposiaľ však chýbajú detailné poznatky o tom, v ktorých konkrétnych oblastiach spontánnej reči sa tieto rozdiely najviac prejavujú v závislosti od stupňa afázie. Cieľom štúdie je preto komplexne zhodnotiť spontánnu produkciu u pacientov s afáziou a interpretovať zistené rozdiely so zreteľom na závažnosť afázie. Spontánna produkcia je analyzovaná prostredníctvom metodiky Analýzy spontánnej reči (ASpoR), rozšírenej o hodnotenie koherencie a informatívnosti, čím sa dosiahlo komplexnejšie posúdenie schopností pacientov. Výskumnú vzorku tvorí 40 osôb s afáziou, rozdelených na pacientov s ľahkým a stredne ťažkým stupňom afázie. Podľa výsledkov existujú signifikantné rozdiely medzi týmito skupinami v parametroch produktivity (počet správne vyjadrených elementárnych textových jednotiek), chybovosti (celkový počet fonologických chýb a chýb v gramatickej zhode), koherencie (globálnej aj lokálnej) a informatívnosti (počet hlavných konceptov a index jadrového lexikónu). Na základe získaných poznatkov možno konštatovať, že komplexné hodnotenie spontánnej reči predstavuje spoľahlivý indikátor závažnosti afázie, najmä v kontexte vybraných parametrov analýzy

Spontaneous language production represents a fundamental form of communication in everyday interactions. In patients with aphasia, various aspects of spontaneous production are weakened, with the degree of impairment correlating with the severity of aphasia - ranging from mild to moderate to severe forms. However, there is still a lack of detailed knowledge regarding which specific areas of spontaneous speech are most affected depending on the degree of aphasia. The aim of this study is to comprehensively evaluate spontaneous production in patients with aphasia and to interpret the observed differences with respect to the severity of aphasia. Spontaneous production is analysed using the methodology of Spontaneous Speech Analysis (ASpoR), expanded with an assessment of coherence and informativeness, achieving a more comprehensive evaluation of the patient's abilities. The research sample consists of 40 individuals with aphasia, divided into two groups of mild and moderate aphasia. According to the results, significant differences exist between these groups in terms of productivity (the number of correctly expressed elementary text units), error rate (total number of phonological errors and grammatical agreement errors), coherence (both global and local), and informativeness (the number of main concepts and the core lexicon index). Based on the findings, it can be concluded that a comprehensive evaluation of spontaneous speech serves as a reliable indicator of aphasia severity,

• MeSH
• Aphasia * diagnosis   therapy   MeSH
• Communication Disorders MeSH
• Humans MeSH
• Speech Production Measurement methods   MeSH
• Speech Disorders MeSH
• Speech Intelligibility MeSH
• Check Tag
• Humans MeSH
• Publication type
• Clinical Study MeSH
• Research Support, Non-U.S. Gov't MeSH

INTRODUCTION: Variable expressivity is an emerging characteristic of KMT2B-related dystonia. However, it remains poorly understood whether variants reoccurring at specific sites of lysine-specific methlytransferase-2B (KMT2B) can drive intra- and interfamilial clinical heterogeneity. Our goal was to ascertain independent families with variants affecting residue Arg2565 of KMT2B. METHODS: Whole-exome/genome sequencing, multi-site recruitment, genotype-phenotype correlations, and DNA methylation episignature analysis were performed. RESULTS: We report four individuals from two families harboring the variant c.7693C > G, p.Arg2565Gly. In an additional patient, a de-novo c.7693C > T, p.Arg2565Cys variant was identified. The observed phenotypic spectrum ranged from childhood-onset dystonia (N = 2) over unspecific intellectual disability syndromes (N = 2) to undiagnosed behavioral symptoms in adulthood (N = 1). Samples bearing p.Arg2565Gly had a KMT2B-typical episignature, although the effect on methylation was less pronounced than in carriers of loss-of-function KMT2B variants. CONCLUSIONS: We established the existence of a KMT2B missense-mutation hotspot associated with varying degrees of disease severity and expression, providing information for patient counseling and elucidation of pathomechanisms.

• MeSH
• Child MeSH
• Adult MeSH
• Dystonic Disorders * genetics   MeSH
• Dystonia genetics   MeSH
• Histone-Lysine N-Methyltransferase * genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation, Missense MeSH
• Adolescent MeSH
• Young Adult MeSH
• Pedigree * MeSH
• Exome Sequencing MeSH
• Developmental Disabilities genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

Přehledová studie se věnuje tématu opožděného vývoje jazykových schopností (dále OVJ), který představuje rané opoždění v jazykovém vývoji. Toto rané opoždění může být symptomem některých neurovývojových poruch (nejčastěji poruchy autistického spektra, vývojové poruchy intelektu, vývojové poruchy jazyka a vývojové poruchy učení), nebo může v průběhu vývoje spontánně vymizet. Druhá varianta vývojové trajektorie se v komunitě českých klinických logopedů označuje jako OVJ prostý. V českém prostředí je na jedné straně upozorňováno na nadužívání tohoto termínu, na druhé straně zde postrádáme informace, které by danou kategorii jasněji ohraničily a vymezily situace, kdy můžeme označovat potíže v jazykovém vývoji tímto termínem. Tato studie proto podává přehled dosavadních poznatků, díky nimž můžeme vymezit kvalitu jazykových obtíží a věkové rozmezí, které lze k OVJ vztahovat. Dále na podkladě zahraničních výzkumů informuje o prevalenci, etiologii a diagnostice OVJ a jeho vztahu k neurovývojovým poruchám. Jsou zde popsány také konkrétní diagnostické postupy pro identifikaci OVJ v raném věku a pro odlišení OVJ prostého od OVJ doprovázejícího neurovývojové poruchy. Zvláštní prostor je v tomto směru věnován vývojové poruše jazyka v souvislosti s diagnostickými markery, které představují spolehlivý nástroj diferenciální diagnostiky, což je doloženo i řadou longitudinálních studií.

The review study focuses on the topic of language delay (LD), which represents an early delay in language development. This early delay may be a symptom of certain neurodevelopmental disorders (autism spectrum disorders, developmental intellectual disabilities, developmental language disorders, developmental learning disorders) or may spontaneously disappear during development. The second variant of the developmental trajectory is referred to in the Czech clinical speech therapy community as simple language delay. In the Czech environment, on the one hand, the overuse of this term is pointed out; on the other hand, there is a lack of information that would more clearly delimit the category and define the situations in which we can use this term to refer to difficulties in the language development. Therefore, this study provides an overview of the existing knowledge that allows us to define the quality of language difficulties and the age range that can be related to the LD. It also reports on the prevalence, aetiology and diagnosis of LD and its relationship to neurodevelopmental disorders based on international research. It also describes specific diagnostic procedures for identifying LD in early life and for distinguishing simple LD from LD accompanying neurodevelopmental disorders. A special section of the text is devoted to developmental language disorders in the context of diagnostic markers that represent a reliable tool for differential diagnosis, as evidenced by longitudinal studies.

• MeSH
• Diagnosis, Differential MeSH
• Child MeSH
• Humans MeSH
• Neurodevelopmental Disorders MeSH
• Language Development Disorders * diagnosis   etiology   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Review MeSH

Rasopathies are genetic disorders often associated with developmental delay and intellectual disability. Noonan syndrome (NS) is one of the most common Rasopathies, caused by mutations in PTPN11 in more than 50% of cases. In mammalian neurons, PTPN11 controls the trafficking of postsynaptic glutamate receptors. This process is disrupted in neurons expressing PTPN11 variants associated with Rasopathies and is thought to contribute to the cognitive impairments in Noonan syndrome. Recent work revealed presynaptic impairments upon expression of RASopathy-linked PTPN11 variants in Drosophila. However, the presynaptic role of PTPN11 has not yet been addressed in mammals. Here, we investigated membrane trafficking of synaptic vesicles in cultured mouse cortical neurons expressing Rasopathy-associated PTPN11D61Y variant. We observed a significantly smaller readily releasable and total recycling pool of synaptic vesicles. The drop in synaptic vesicle release competence was accompanied by a decreased rate of SV retrieval. Interestingly, the presynaptic phenotype was evident in mature (DIV21) but not in immature (DIV12) neurons. Thus, our data reveal importance of balanced PTPN11 activity for normal trafficking of neurotransmitter-filled synaptic vesicles in the presynaptic ending of mature neurons.

• MeSH
• Cells, Cultured MeSH
• Mutation genetics   MeSH
• Mice MeSH
• Neurons metabolism   MeSH
• Aging genetics   metabolism   MeSH
• Synaptic Vesicles * metabolism   MeSH
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 * metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.

• MeSH
• Chlorocebus aethiops MeSH
• COS Cells MeSH
• Zebrafish genetics   MeSH
• Child MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Intellectual Disability * genetics   MeSH
• Microcephaly * genetics   pathology   MeSH
• Mice MeSH
• Neurons metabolism   pathology   MeSH
• Child, Preschool MeSH
• Microtubule-Associated Proteins genetics   metabolism   MeSH
• Nerve Tissue Proteins genetics   metabolism   MeSH
• Developmental Disabilities * genetics   MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Child, Preschool MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

CDK13-related disorder, also known as congenital heart defects, dysmorphic facial features and intellectual developmental disorder (CHDFIDD) is associated with mutations in the CDK13 gene encoding transcription-regulating cyclin-dependent kinase 13 (CDK13). Here, we focused on the development of craniofacial structures and analyzed early embryonic stages in CHDFIDD mouse models, with one model comprising a hypomorphic mutation in Cdk13 and exhibiting cleft lip/palate, and another model comprising knockout of Cdk13, featuring a stronger phenotype including midfacial cleft. Cdk13 was found to be physiologically expressed at high levels in the mouse embryonic craniofacial structures, namely in the forebrain, nasal epithelium and maxillary mesenchyme. We also uncovered that Cdk13 deficiency leads to development of hypoplastic branches of the trigeminal nerve including the maxillary branch. Additionally, we detected significant changes in the expression levels of genes involved in neurogenesis (Ache, Dcx, Mef2c, Neurog1, Ntn1, Pou4f1) within the developing palatal shelves. These results, together with changes in the expression pattern of other key face-specific genes (Fgf8, Foxd1, Msx1, Meis2 and Shh) at early stages in Cdk13 mutant embryos, demonstrate a key role of CDK13 in the regulation of craniofacial morphogenesis.

• MeSH
• Cyclin-Dependent Kinases metabolism   genetics   MeSH
• Embryo, Mammalian metabolism   MeSH
• Embryonic Development * genetics   MeSH
• Phenotype MeSH
• Skull embryology   pathology   MeSH
• Intellectual Disability genetics   MeSH
• Disease Models, Animal * MeSH
• Mutation genetics   MeSH
• Mice MeSH
• Trigeminal Nerve embryology   MeSH
• Neurogenesis * genetics   MeSH
• Face embryology   abnormalities   MeSH
• Doublecortin Protein MeSH
• Cleft Palate genetics   pathology   embryology   MeSH
• Cleft Lip genetics   pathology   embryology   MeSH
• Gene Expression Regulation, Developmental * MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

RASopathies are a group of genetic disorders caused by mutations in genes encoding components and regulators of the RAS/MAPK signaling pathway, resulting in overactivation of signaling. RASopathy patients exhibit distinctive facial features, cardiopathies, growth and skeletal abnormalities, and varying degrees of neurocognitive impairments including neurodevelopmental delay, intellectual disabilities, or attention deficits. At present, it is unclear how RASopathy mutations cause neurocognitive impairment and what their neuron-specific cellular and network phenotypes are. Here, we investigated the effect of RASopathy mutations on the establishment and functional maturation of neuronal networks. We isolated cortical neurons from RASopathy mouse models, cultured them on multielectrode arrays and performed longitudinal recordings of spontaneous activity in developing networks as well as recordings of evoked responses in mature neurons. To facilitate the analysis of large and complex data sets resulting from long-term multielectrode recordings, we developed MATLAB-based tools for data processing, analysis, and statistical evaluation. Longitudinal analysis of spontaneous network activity revealed a convergent developmental phenotype in neurons carrying the gain-of-function Noonan syndrome-related mutations Ptpn11D61Y and KrasV14l. The phenotype was more pronounced at the earlier time points and faded out over time, suggesting the emergence of compensatory mechanisms during network maturation. Nevertheless, persistent differences in excitatory/inhibitory balance and network excitability were observed in mature networks. This study improves the understanding of the complex relationship between genetic mutations and clinical manifestations in RASopathies by adding insights into functional network processes as an additional piece of the puzzle.

• Publication type
• Journal Article MeSH

N-methyl-D-aspartate receptors (NMDARs) are a subtype of ionotropic glutamate receptors critical for synaptic transmission and plasticity, and for the development of neural circuits. Rare or de-novo variants in GRIN genes encoding NMDAR subunits have been associated with neurodevelopmental disorders characterized by intellectual disability, developmental delay, autism, schizophrenia, or epilepsy. In recent years, some disease-associated variants in GRIN genes have been characterized using recombinant receptors expressed in non-neuronal cells, and a few variants have also been studied in neuronal preparations or animal models. Here we review the current literature on the functional evaluation of human disease-associated variants in GRIN1, GRIN2A and GRIN2B genes at all levels of analysis. Focusing on the impact of different patient variants at the level of receptor function, we discuss effects on receptor agonist and co-agonist affinity, channel open probability, and receptor cell surface expression. We consider how such receptor-level functional information may be used to classify variants as gain-of-function or loss-of-function, and discuss the limitations of this classification at the synaptic, cellular, or system level. Together this work by many laboratories worldwide yields valuable insights into NMDAR structure and function, and represents significant progress in the effort to understand and treat GRIN disorders. Keywords: NMDA receptor , GRIN genes, Genetic variants, Electrophysiology, Synapse, Animal models.

• MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Variation MeSH
• Humans MeSH
• Neurodevelopmental Disorders genetics   MeSH
• Nerve Tissue Proteins genetics   metabolism   MeSH
• Receptors, N-Methyl-D-Aspartate * genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review 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