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

The outcomes of alpha-mannosidosis after hematopoietic stem cell transplantation (HSCT) are incompletely described. This retrospective multi-center study evaluated the outcomes of patients who underwent HSCT for their alpha-mannosidosis after 2010. Twenty-one children (11 females) with enzymatically and/or genetically confirmed alpha-mannosidosis, diagnosed at a mean age of 14 months (0-60 months), were included. The median age at HSCT was 3.9 years (10 months to 13.3 years) with a median follow-up of 2.3 years (0.3-14.1 years). Seventy-four percent (14/19) of patients received an unrelated graft while the rest had a matched sibling donor. Primary engraftment was reached in 17 of 21 patients; four patients required a second HSCT with successful subsequent engraftment. Nine patients had severe post-HSCT infections, five patients developed acute graft-versus-host disease (GvHD) (> = grade II), and one patient had chronic GvHD. No patient died during follow-up. Seven out of ten patients received enzyme replacement therapy both pre- and post-HSCT. Among children with clinical symptoms, improvement was documented in hepatomegaly (40% of patients before HSCT, down to 10% after), recurrent infections (62%/30%), and hearing disorder (85%/65%). In 13 patients with developmental data, outcomes after HSCT suggested at least mild delays persisted post-HSCT in the majority (85%), with some trends of higher functioning with earlier treatment. Findings suggest HSCT has shown notable improvements in safety and is associated with clinical benefit in alpha-mannosidosis. Neurodevelopmental findings require longer-term study to account for phenotypic diversity.

• MeSH
• alpha-Mannosidosis * therapy   diagnosis   complications   MeSH
• Child MeSH
• Enzyme Replacement Therapy MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Follow-Up Studies MeSH
• Graft vs Host Disease etiology   MeSH
• Child, Preschool MeSH
• Retrospective Studies MeSH
• Hematopoietic Stem Cell Transplantation * adverse effects   methods   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

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

Poruchy autistického spektra jsou pervazivní vývojové poruchy. Ovlivněny jsou tak v podstatě všechny složky vývoje již od raného věku. Rodiče si všímají odlišností ze- jména v sociální oblasti, děti často nesdílejí pozornost, nekomunikují a nesdělují svoje potřeby a přání. Již ve věku 18 měsíců se dělá screening M-CHAT-R, který může zachytit nápadnosti ve vývoji (možné neurovývojové poruchy) a pediatr může rodiče směřovat k odborníkům – klinickým psychologům zaměřujícím se na práci s dětmi s PAS (poruchou autistického spektra), pedopsychiatrovi, dětskému neurologovi či specializovanému klinickému logopedovi. V tomto článku vám představíme kazuistiku s diferenciální diagnostikou odlišující PAS od dalších vývojových poruch (zejména vývojové dysfázie) a zaměřenou na stanovení stupně symptomů v kontextu poruch autistického spektra. Je to jedna z typických diferenciálních diagnostik, které na Soukromé klinice LOGO, s.r.o. děláme.

Autism Spectrum Disorders are pervasive developmental disorders. This means that they influence almost all areas of early development. Parents can see differences mainly in the social area. Children with ASD do not share activities, do not communicate their needs and wishes. At the age of 18 months, parents fill in the M-CHAT-R screening, which is sensitive to possible neurodevelopmental problems. A paediatrician can send the child to specialists in ASD diagnosis - clinical psychologist, child psychiatrist, neurologist and clinical speech therapist. In this article, we introduce you to a case study with differential diagnoses, showing the differences between Autism Spectrum Disorders and other developmental diseases (especially specific developmental disorders of speech and language). The focus is on the determination of the autistic symptoms level. This is one of the typical differential diagnoses we carry out at LOGO Clinic.

• MeSH
• Cognitive Dysfunction diagnosis   MeSH
• Communication Disorders diagnosis   MeSH
• Humans MeSH
• Autism Spectrum Disorder * diagnosis   psychology   MeSH
• Child, Preschool MeSH
• Psychological Tests MeSH
• Stereotyped Behavior MeSH
• Language Development Disorders diagnosis   MeSH
• Developmental Disabilities diagnosis   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Child, Preschool 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

BACKGROUND: The European Medicines Agency has recommended a series of restrictions on the use of sodium valproate (valproate) following research linking its exposure in utero to adverse congenital and neurodevelopmental effects in offspring. Recent research has highlighted a potential increased risk of neurodevelopmental disorders in children born to males taking valproate prior to conception. Clinicians and patients require guidance regarding suitable alternatives. AIM: To provide an overview of suitable alternatives to valproate in the management of bipolar disorder. METHOD: A narrative review was conducted. Only medications with an established evidence base in managing different phases of bipolar disorder and endorsed within clinical practice guidelines were considered. Eligible guidelines included those (i) where recommendations were informed by a formal guideline development process and (ii) published in English within the last 15 years. REPROTOX® was chosen as the primary information source regarding reproductive safety of alternative medications. RESULTS: Of all second-generation antipsychotics, quetiapine should be considered a first-line alternative to valproate. Lithium has been associated with an increased risk of cardiac malformations, especially Ebstein anomaly, following in utero exposure. However, given its robust efficacy as an antimanic agent and the absolute risk of cardiac abnormalities being low, it's use can still be considered in individuals of child-bearing potential with appropriate monitoring. Carbamazepine treatment should be avoided due to concerns for teratogenicity. Although considered safe in pregnancy, lamotrigine is largely effective at preventing relapse of bipolar depression. Thus, lamotrigine offers limited clinical utility as an alternative to valproate. CONCLUSION: Specific recommendations are made regarding alternatives to valproate in managing bipolar disorder.

• MeSH
• Antimanic Agents * adverse effects   therapeutic use   MeSH
• Antipsychotic Agents * adverse effects   therapeutic use   MeSH
• Bipolar Disorder * drug therapy   MeSH
• Valproic Acid * adverse effects   therapeutic use   MeSH
• Humans MeSH
• Disease Management * MeSH
• Pregnancy MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Comparative Study MeSH
• Geographicals
• Europe 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