Mitochondrial dysfunction and autism: comprehensive genetic analyses of children with autism and mtDNA deletion.

BACKGROUND: The etiology of autism spectrum disorders (ASD) is very heterogeneous. Mitochondrial dysfunction has been described in ASD; however, primary mitochondrial disease has been genetically proven in a small subset of patients. The main goal of the present study was to investigate correlations between mitochondrial DNA (mtDNA) changes and alterations of genes associated with mtDNA maintenance or ASD. METHODS: Sixty patients with ASD and sixty healthy individuals were screened for common mtDNA mutations. Next generation sequencing was performed on patients with major mtDNA deletions (mtdel-ASD) using two gene panels to investigate nuclear genes that are associated with ASD or are responsible for mtDNA maintenance. Cohorts of healthy controls, ASD patients without mtDNA alterations, and patients with mitochondrial disorders (non-ASD) harbouring mtDNA deletions served as comparison groups. RESULTS: MtDNA deletions were confirmed in 16.6% (10/60) of patients with ASD (mtdel-ASD). In 90% of this mtdel-ASD children we found rare SNVs in ASD-associated genes (one of those was pathogenic). In the intergenomic panel of this cohort one likely pathogenic variant was present. In patients with mitochondrial disease in genes responsible for mtDNA maintenance pathogenic mutations and variants of uncertain significance (VUS) were detected more frequently than those found in patients from the mtdel-ASD or other comparison groups. In healthy controls and in patients without a mtDNA deletion, only VUS were detected in both panel. CONCLUSIONS: MtDNA alterations are more common in patients with ASD than in control individuals. MtDNA deletions are not isolated genetic alterations found in ASD; they coexist either with other ASD-associated genetic risk factors or with alterations in genes responsible for intergenomic communication. These findings indicate that mitochondrial dysfunction is not rare in ASD. The occurring mtDNA deletions in ASD may be mostly a consequence of the alterations of the causative culprit genes for autism or genes responsible for mtDNA maintenance, or because of the harmful effect of environmental factors.

[Child-adolescent psychiatry to adult psychiatry: can we find those disorders in adulthood which are typically diagnosed in childhood?]. / Gyermekpszichiátria a felnott pszichiátriának: hova lesznek a tipikusan gyermekkori kórképek felnottkorban?

The aim of the current study is to provide a short overview on autism, attention deficit hyperactivity disorder (ADHD) and Tourette syndrome. According to international data, the prevalence of autism is 2-60/10000 and the symptoms persist during the entire life; the prevalence of ADHD among children and adolescents is 2,4-12,0% and the symptoms cause problem in 30-50% in adults as well; while the prevalence of tic disorder is 1-6,6% among children and adolescents and the symptoms persist in 10% in adulthood. According to Hungarian data, these disorders are relatively rare in adult psychiatric practice. Presenting case reports of adults with autism, ADHD and Tourette syndrome, we would like to demonstrate the symptoms, treatment possibilities of these disorders and how they can influence the patients' quality of life.

Comprehensive Analysis of Rare Variants of 101 Autism-Linked Genes in a Hungarian Cohort of Autism Spectrum Disorder Patients.

BACKGROUND: Autism spectrum disorder (ASD) is genetically and phenotypically heterogeneous. Former genetic studies suggested that both common and rare genetic variants play a role in the etiology. In this study, we aimed to analyze rare variants detected by next generation sequencing (NGS) in an autism cohort from Hungary. METHODS: We investigated the yield of NGS panel sequencing of an unselected ASD cohort (N = 174 ) for the detection of ASD associated syndromes. Besides, we analyzed rare variants in a common disease-rare variant framework and performed rare variant burden analysis and gene enrichment analysis in phenotype based clusters. RESULTS: We have diagnosed 13 molecularly proven syndromic autism cases. Strongest indicators of syndromic autism were intellectual disability, epilepsy or other neurological plus symptoms. Rare variant analysis on a cohort level confirmed the association of five genes with autism (AUTS2, NHS, NSD1, SLC9A9, and VPS13). We found no correlation between rare variant burden and number of minor malformation or autism severity. We identified four phenotypic clusters, but no specific gene was enriched in a given cluster. CONCLUSION: Our study indicates that NGS panel gene sequencing can be useful, where the clinical picture suggests a clinically defined syndromic autism. In this group, targeted panel sequencing may provide reasonable diagnostic yield. Unselected NGS panel screening in the clinic remains controversial, because of uncertain utility, and difficulties of the variant interpretation. However, the detected rare variants may still significantly influence autism risk and subphenotypes in a polygenic model, but to detect the effects of these variants larger cohorts are needed.

Reduced fronto-cortical brain connectivity during NREM sleep in Asperger syndrome: an EEG spectral and phase coherence study.

OBJECTIVE: To investigate whether sleep macrostructure and EEG power spectral density and coherence during NREM sleep are different in Asperger syndrome (AS) compared to typically developing children and adolescents. METHODS: Standard all night EEG sleep parameters were obtained from 18 un-medicated subjects with AS and 14 controls (age range: 7.5-21.5years) after one adaptation night. Spectral, and phase coherence measures were computed for multiple frequency bands during NREM sleep. RESULTS: Sleep latency and wake after sleep onset were increased in AS. Absolute power spectrum density (PSD) was significantly reduced in AS in the alpha, sigma, beta and gamma bands and in all 10 EEG derivations. Relative PSD showed a significant increase in delta and a decrease in the sigma band for frontal, and in beta for centro-temporal derivations. Intrahemispheric coherence measures were markedly lower in AS in the frontal areas, and the right hemisphere over all EEG channels. The most prominent reduction in intrahemispheric coherence was observed over the fronto-central areas in delta, theta, alpha and sigma EEG frequency bands. CONCLUSION: EEG power spectra and coherence during NREM sleep, in particular in fronto-cortical derivations are different in AS compared to typically developing children and adolescents. SIGNIFICANCE: Quantitative analysis of the EEG during NREM sleep supports the hypothesis of frontal dysfunction in AS.