A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells.

Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina's Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region.

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

CDKL5 Deficiency Disorder Without Epilepsy.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) has epilepsy as a cardinal feature. Here we report two new female patients and review six previously published patients, one male and five females, with features of CDD but who never developed epilepsy. In contrast with the classical and severe CDD phenotype, they presented with milder gross motor delays, autism spectrum disorder, and no visual cortical impairment. Prolonged video electroencephalography was normal in adult cases but showed interictal frontal-temporal bilateral spikes and sharp waves in sleep in the three-year-old girl. Causative CDKL5 variants included two likely gene damaging (nonsense and frameshift) and six missense variants, being de novo or maternally inherited from asymptomatic females with skewed X-chromosome inactivation (two missense variants). Our data indicate that a milder form of CDD without epilepsy can occur in some cases without clear correlation with specific variants in the CDKL5 gene.

Comprehensive molecular testing in patients with high functioning autism spectrum disorder.

Autism spectrum disorders (ASD) include a range of complex neurodevelopmental disorders with extreme genetic heterogeneity. Exome and target sequencing studies have shown to be an effective tool for the discovery of new ASD genes. The aim of this study was to design an ASD candidate gene panel that covers 44 of the top ASD candidate genes. As a pilot study we performed comprehensive molecular diagnostic testing, including the study of the FMR1 and FMR2 repeat regions, copy number variant analysis in a collection of 50 Spanish ASD cases and mutation screening using targeted next generation sequencing-based techniques in 44 out of the total cohort. We evaluated and clinically selected our cohort, with most of the cases having high functioning ASD without facial dysmorphic features. The results of the present study allowed the detection of copy number and single nucleotide variants not yet identified. In addition, our results underscore the difficulty of the molecular diagnosis of ASD and confirm its genetic heterogeneity. The information gained from this and other genetic screenings is necessary to unravel the clinical interpretation of novel variants.

Targeting tryptophan and tyrosine metabolism by liquid chromatography tandem mass spectrometry.

An imbalance in tryptophan (Trp) and tyrosine (Tyr) metabolites is associated with neurological and inflammatory disorders. The accurate and precise measurement of these compounds in biological specimens is a powerful tool to understand the biochemical state in several diseases. In this study, a rapid, accurate and sensitive method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the targeted analysis of the metabolism of Trp and Tyr has been developed and validated. The method allows for the adequate quantification of Trp, Tyr and, eight Trp metabolites, three Tyr metabolites, together with four competitive large neutral amino acids. Serotonin, 5-hydroxyindoleacetic acid, kynurenine, kynurenic acid, dopamine, and homovanilic acid were among the targeted compounds. Sample preparation, chromatographic separation and mass spectrometric detection were optimized in human urine, human plasma and mice prefrontal cortex extracts. The method was shown to be linear (r>0.98) in the range of endogenous concentrations for all studied metabolites. In general, the limits of detection were suitable for the detection of the endogenous levels. Intra- and inter-assay precisions below 25% and accuracies ranging from 80 to 120% were found for most of the analytes. The use of labeled internal standards corrected the moderate matrix effect observed for some compounds. The applicability of the method was confirmed by analyzing urine samples collected from 13 healthy volunteers and comparing the results with previously established normal ranges. In addition, urine samples from two patients and a heterozygous carrier of a family with disturbed monoamine metabolism due to a loss of function mutation in the MAOA gene (X-linked) were analyzed and compared with samples from controls. All data together show the potential of the developed approach for targeted metabolomic studies.

Síndrome cerebeloso cognitivo-afectivo / Cerebellar cognitive affective syndrome

Introducción. El diagnóstico de síndrome cerebeloso cognitivo afectivo se debe realizar en aquellos pacientes con lesiones cerebelosas y con déficit cognitivo asociado a deficiencias neuropsicológicas visoespaciales o ejecutivas, trastornos del lenguaje expresivo y trastornos afectivos. Caso clínico. Adolescente de 16 años diagnosticada con trastorno por déficit de atención e hiperactividad a los 7 años, que presenta inestabilidad emocional, apatía y discurso y lectura poco fluidos. Se observan deficiencias visoespaciales en los tests neuropsicológicos. Se realiza una resonancia magnética cerebral por presentar alteración de la coordinación y motricidad fina, y se evidencia atrofia de vermis cerebeloso. La sintomatología es compatible con síndrome cerebeloso cognitivo afectivo. Clásicamente, el cerebelo es conocido por su rol motor. Sin embargo, está implicado en funciones cognitivas superiores, en la expresión emocional y en la regulación conductual. El síndrome cerebeloso cognitivo afectivo es una entidad no bien conocida que debemos incluir en el diagnóstico diferencial de trastornos neuropsiquiátricos con lesión cerebelar.(AU)

Introduction. The diagnosis of Cerebellar Cognitive Affective Syndrome should be considered in patients with cerebellar lesions who also suffer cognitive deficits associated with visuospatial or executive neuropsychological disorders, expressive language disorders and affective disorders. Clinical case. A 16 year old adolescent diagnosed with Attention Deficit Hyperactivity Disorder at the age of 7 presents with emotional instability, apathy, and speech and reading difficulties. Neuropsychological tests show visuospatial difficulties. A brain magnetic resonance imaging is performed due to impaired coordination and fine motor movements and shows atrophy of the cerebellar vermis. The clinical picture suggests a diagnosis of Cerebellar Cognitive Affective Syndrome. The cerebellum is mostly known for its motor role. However, it is also involved in higher cognitive functions, expression of emotion and behavioral regulation. Cerebellar Cognitive Affective Syndrome is a relatively unknown diagnosis and should be included in the differential diagnosis of neuropsychiatric disorders with cerebellar lesion.(AU)

Síndrome cerebeloso cognitivo-afectivo / Cerebellar cognitive affective syndrome

Introducción. El diagnóstico de síndrome cerebeloso cognitivo afectivo se debe realizar en aquellos pacientes con lesiones cerebelosas y con déficit cognitivo asociado a deficiencias neuropsicológicas visoespaciales o ejecutivas, trastornos del lenguaje expresivo y trastornos afectivos. Caso clínico. Adolescente de 16 años diagnosticada con trastorno por déficit de atención e hiperactividad a los 7 años, que presenta inestabilidad emocional, apatía y discurso y lectura poco fluidos. Se observan deficiencias visoespaciales en los tests neuropsicológicos. Se realiza una resonancia magnética cerebral por presentar alteración de la coordinación y motricidad fina, y se evidencia atrofia de vermis cerebeloso. La sintomatología es compatible con síndrome cerebeloso cognitivo afectivo. Clásicamente, el cerebelo es conocido por su rol motor. Sin embargo, está implicado en funciones cognitivas superiores, en la expresión emocional y en la regulación conductual. El síndrome cerebeloso cognitivo afectivo es una entidad no bien conocida que debemos incluir en el diagnóstico diferencial de trastornos neuropsiquiátricos con lesión cerebelar.

Introduction. The diagnosis of Cerebellar Cognitive Affective Syndrome should be considered in patients with cerebellar lesions who also suffer cognitive deficits associated with visuospatial or executive neuropsychological disorders, expressive language disorders and affective disorders. Clinical case. A 16 year old adolescent diagnosed with Attention Deficit Hyperactivity Disorder at the age of 7 presents with emotional instability, apathy, and speech and reading difficulties. Neuropsychological tests show visuospatial difficulties. A brain magnetic resonance imaging is performed due to impaired coordination and fine motor movements and shows atrophy of the cerebellar vermis. The clinical picture suggests a diagnosis of Cerebellar Cognitive Affective Syndrome. The cerebellum is mostly known for its motor role. However, it is also involved in higher cognitive functions, expression of emotion and behavioral regulation. Cerebellar Cognitive Affective Syndrome is a relatively unknown diagnosis and should be included in the differential diagnosis of neuropsychiatric disorders with cerebellar lesion.

[Cerebellar cognitive affective syndrome]. / Síndrome cerebeloso cognitivo-afectivo.

INTRODUCTION: The diagnosis of Cerebellar Cognitive Affective Syndrome should be considered in patients with cerebellar lesions who also suffer cognitive deficits associated with visuospatial or executive neuropsychological disorders, expressive language disorders and affective disorders. CLINICAL CASE: A 16 year old adolescent diagnosed with Attention Deficit Hyperactivity Disorder at the age of 7 presents with emotional instability, apathy, and speech and reading difficulties. Neuropsychological tests show visuospatial difficulties. A brain magnetic resonance imaging is performed due to impaired coordination and fine motor movements and shows atrophy of the cerebellar vermis. The clinical picture suggests a diagnosis of Cerebellar Cognitive Affective Syndrome. The cerebellum is mostly known for its motor role. However, it is also involved in higher cognitive functions, expression of emotion and behavioral regulation. Cerebellar Cognitive Affective Syndrome is a relatively unknown diagnosis and should be included in the differential diagnosis of neuropsychiatric disorders with cerebellar lesion.

Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.

BACKGROUND: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with high heritability. Recent findings support a highly heterogeneous and complex genetic etiology including rare de novo and inherited mutations or chromosomal rearrangements as well as double or multiple hits. METHODS: We performed whole-exome sequencing (WES) and blood cell transcriptome by RNAseq in a subset of male patients with idiopathic ASD (n = 36) in order to identify causative genes, transcriptomic alterations, and susceptibility variants. RESULTS: We detected likely monogenic causes in seven cases: five de novo (SCN2A, MED13L, KCNV1, CUL3, and PTEN) and two inherited X-linked variants (MAOA and CDKL5). Transcriptomic analyses allowed the identification of intronic causative mutations missed by the usual filtering of WES and revealed functional consequences of some rare mutations. These included aberrant transcripts (PTEN, POLR3C), deregulated expression in 1.7% of mutated genes (that is, SEMA6B, MECP2, ANK3, CREBBP), allele-specific expression (FUS, MTOR, TAF1C), and non-sense-mediated decay (RIT1, ALG9). The analysis of rare inherited variants showed enrichment in relevant pathways such as the PI3K-Akt signaling and the axon guidance. CONCLUSIONS: Integrative analysis of WES and blood RNAseq data has proven to be an efficient strategy to identify likely monogenic forms of ASD (19% in our cohort), as well as additional rare inherited mutations that can contribute to ASD risk in a multifactorial manner. Blood transcriptomic data, besides validating 88% of expressed variants, allowed the identification of missed intronic mutations and revealed functional correlations of genetic variants, including changes in splicing, expression levels, and allelic expression.

Envenenamiento por talio en una adolescente / Thallium poisoning in an adolescent girl

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Children often present with infantile spasms after herpetic encephalitis.

PURPOSE: To determine what epilepsy types occur after herpetic encephalitis and what are the determinant factors for subsequent infantile spasms. METHODS: We analyzed retrospectively the clinical history of 22 patients, referred to Necker and Saint Vincent de Paul Hospitals (Paris) through the French pediatric epilepsy network from March 1986 to April 2010 and who developed epilepsy some months after herpetic encephalitis. We focused on seizure semiology with video-electroencephalography (EEG) recording, and on neuroradiology and epilepsy follow-up. KEY FINDINGS: Fourteen patients developed pharmacoresistant spasms, and eight developed focal epilepsy, but none had both. The patients who developed spasms were more frequently younger than 30 months at age of onset of epilepsy and had herpetic encephalitis earlier (mean 10.6 months of age) than those who developed focal epilepsy (mean 59.7 and 39.6 months, respectively). Epilepsy follow-up was similar in both groups (8.5 and 11 years, respectively). We found 26 affected cerebral areas; none alone was related to the development of epileptic spasms. SIGNIFICANCE: Risk factors to develop epileptic spasms were to have had herpetic encephalitis early (mean 10 months); to be significantly younger at onset of epilepsy (mean 22.1 months); and to have cerebral lesions involving the insula, the hippocampus, and the temporal pole.