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.

Diastolic Dysfunction Is a Contributing Factor to Exercise Intolerance in COPD.

Right ventricular (RV) systolic failure is rare in patients with COPD, but they often develop RV diastolic dysfunction. Left ventricular (LV) diastolic dysfunction is also common in this population. Nevertheless, data are scarce regarding the effect of diastolic dysfunction on the functional capacity in patients with COPD. We investigated the correlation between echocardiographic parameters of RV and LV diastolic function and the exercise capacity in COPD, by using conventional echocardiographic methods and tissue Doppler imaging. 65 patients with COPD (61 ± 9 years) in stages GOLD II-IV were investigated. Functional capacity was measured with 6-minute walk test (6MWT). Right (RA) and left atrial (LA) area index were measured; collapsibility index inferior vena cava was calculated. Parameters of the mitral and tricuspid inflow (E, A) as well as annular systolic (S), early- (e') and late- (a') diastolic myocardial longitudinal velocities were measured. E/A, E/e' and e'/a' ratios were calculated. 6MWT distance was 330 ± 76 m. LV diastolic dysfunction was found in 48 (74%) patients. LV and RV filling pressures were elevated in 28 (43%) and in 29 (45%) patients, respectively. In the left heart, LA area index showed significant correlation with the functional capacity (r = -0.319; p = 0.011). In stepwise multiple linear regression analysis tricuspid e'/a' (r = 0.611; p = 0.000), collapsibility index (r = 0.505; p = 0.000), RA area index (r = -0.445; p = 0.000) and body surface area (r = 0.314; p = 0.011) were independent predictors of 6MWT distance. Right ventricular diastolic function and filling pressure have strong influence on the functional capacity in patients with COPD.

Deep brain stimulation or thalamotomy in fragile X-associated tremor/ataxia syndrome? Case report.

We present the case of a 66-year-old man who has been treated for essential tremor since the age of 58. He developed mild cerebellar gait ataxia seven years after tremor onset. Moderate, global brain atrophy was identified on MRI scans. At the age of 68, only temporary tremor relief could be achieved by bilateral deep brain stimulation of the ventral intermedius nucleus of the thalamus. Bilateral stimulation of the subthalamic nucleus also resulted only in transient improvement. In the meantime, progressive gait ataxia and tetraataxia developed accompanied by other cerebellar symptoms, such as nystagmus and scanning speech. These correlated with progressive development of bilateral symmetric hyperintensity of the middle cerebellar peduncles on T2 weighted MRI scans. Genetic testing revealed premutation of the FMR1 gene, establishing the diagnosis of fragile X-associated tremor/ataxia syndrome. Although this is a rare disorder, it should be taken into consideration during preoperative evaluation of essential tremor. Postural tremor ceased two years later after thalamotomy on the left side, while kinetic tremor of the right hand also improved.

Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications.

We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the cariprazine treatment. He had delayed speech development and later experienced severe social anxiety, learning disabilities, cognitive slowing, and predominant negative psychiatric symptoms associated with rigidity. Clinical examinations showed multisystemic involvement. Together with elevated ergometric lactate levels, the clinical picture suggested mitochondrial disease, which was also supported by muscle histopathology. Exploratory transcriptome analysis also revealed the involvement of metabolic and oxidative phosphorylation pathways. Whole-exome sequencing identified a pathogenic MECP2 variant, which can explain both the dopamine imbalance and mitochondrial dysfunction in this patient. Mitochondrial dysfunction was previously suggested in classical Rett syndrome, and we detected related phenotype evidence on multiple consistent levels for the first time in a MECP2 variant carrier male. This study further supports the importance of the MECP2 gene in the mitochondrial pathways, which can open the gate for more personalized therapeutic interventions. Good cariprazine response highlights the role of dopamine dysfunction in the complex psychiatric symptoms of Rett syndrome. This can help identify the optimal treatment strategy from a transdiagnostic perspective instead of a classical diagnostic category.

Optically Guided High-Frequency Ultrasound to Differentiate High-Risk Basal Cell Carcinoma Subtypes: A Single-Centre Prospective Study.

BACKGROUND: Basal cell carcinoma (BCC) is the most common type of skin cancer in the Caucasian population. Currently, invasive biopsy is the only way of establishing the histological subtype (HST) that determines the treatment options. Our study aimed to evaluate whether optically guided high-frequency ultrasound (OG-HFUS) imaging could differentiate aggressive HST BCCs from low-risk tumors. METHODS: We conducted prospective clinical and dermoscopic examinations of BCCs, followed by 33 MHz OG-HFUS imaging, surgical excision, and a histological analysis. We enrolled 75 patients with 78 BCCs. In total, 63 BCCs were utilized to establish a novel OG-HFUS risk classification algorithm, while 15 were employed for the validation of this algorithm. The mean age of the patients was 72.9 ± 11.2 years. Histology identified 16 lesions as aggressive HST (infiltrative or micronodular subtypes) and 47 as low-risk HST (superficial or nodular subtypes). To assess the data, we used a one-sided Fisher's exact test for a categorical analysis and a Receiver Operating Characteristic (ROC) curve analysis to evaluate the diagnostic accuracy. RESULTS: OG-HFUS distinguished aggressive BCC HSTs by their irregular shape (p < 0.0001), ill-defined margins (p < 0.0001), and non-homogeneous internal echoes (p = 0.004). We developed a risk-categorizing algorithm that differentiated aggressive HSTs from low-risk HSTs with a higher sensitivity (82.4%) and specificity (91.3%) than a combined macroscopic and dermoscopic evaluation (sensitivity: 40.1% and specificity: 73.1%). The positive and negative predictive values (PPV and NPV, respectively) for dermoscopy were 30.2% and 76.8%, respectively. In comparison, the OG-HFUS-based algorithm demonstrated a PPV of 94.7% and an NPV of 78.6%. We verified the algorithm using an independent image set, n = 15, including 12 low-risk and 3 high-risk (high-risk) with two blinded evaluators, where we found a sensitivity of 83.33% and specificity of 91.66%. CONCLUSIONS: Our study shows that OG-HFUS can identify aggressive BCC HSTs based on easily identifiable morphological parameters, supporting early therapeutic decision making.

Optically Guided High-Frequency Ultrasound Shows Superior Efficacy for Preoperative Estimation of Breslow Thickness in Comparison with Multispectral Imaging: A Single-Center Prospective Validation Study.

Melanoma is the most aggressive form of skin cancer that is known for its metastatic potential and has an increasing incidence worldwide. Breslow thickness, which determines the staging and surgical margin of the tumor, is unavailable at initial diagnosis. Novel imaging techniques for assessing Breslow thickness lack comparative data. This study evaluates optically guided high-frequency ultrasound (OG-HFUS) and multispectral imaging (MSI) for preoperative estimation of Breslow thickness and staging. We enrolled 101 patients with histologically confirmed primary melanoma and categorized them based on tumor thickness. Optically guided 33 MHz HFUS and MSI were utilized for the assessment. Our MSI-based algorithm categorized melanomas into three subgroups with a sensitivity of 62.6%, specificity of 81.3%, and fair agreement (κ = 0.440, CI: 0.298-0.583). In contrast, OG-HFUS demonstrated a sensitivity of 91.8%, specificity of 96.0%, and almost perfect agreement (κ = 0.858, CI: 0.763-0.952). OG-HFUS performed better than MSI in estimating Breslow thickness, emphasizing its potential as a valuable tool for melanoma diagnosis and patient management. OG-HFUS holds promise for enhancing preoperative staging and treatment decision-making in melanoma.

Determinants of the heart rate variability in type 1 diabetes mellitus.

Background: Evaluation of heart rate variability (HRV) detects the early subclinical alterations of the autonomic nervous system. Thus, impaired HRV is the earliest subclinical marker of cardiac autonomic neuropathy (CAN) in type 1 diabetes mellitus (T1DM). Objectives: We aimed to explore the HRV parameters in asymptomatic T1DM patients and compare them with the results obtained in healthy subjects. Potential associations between HRV parameters and the established risk factors for CAN and cardiovascular diseases were also investigated. Methods: Seventy T1DM patients (38 ± 12 years, 46 females) and 30 healthy subjects were enrolled into the study. For HRV analysis, beat-to-beat heart rate was recorded for 30 min. The less noisy 5-min segment of the recording was analyzed by Bittium Cardiac Navigator HRV analysis software. Time domain, frequency domain, and nonlinear indices were calculated. Results: Regarding ratio of low to high frequency component (LF/HF), no differences were found between the two populations (p = 0.227). All the further, time domain, frequency domain, and nonlinear HRV indices were significantly lower in T1DM patients (each p < 0.001). In multiple linear models, disease duration remained the only independent predictor of LF/HF ratio (p = 0.019). HbA1c was found to be significant independent predictor of all further time domain (SDNN, p < 0.001; rMSSD, p < 0.001), frequency domain (VLF, p < 0.001; LF, p = 0.002; HF, p = 0.006; Total Power, p = 0.002), and nonlinear indices (SD1, p = 0.006; SD2, p = 0.007), alone, or in combination with other factors, such as age or body mass index. Conclusion: Asymptomatic T1DM patients have significantly reduced overall HRV as compared with healthy subjects, indicating subclinical CAN. Quality of the glycemic control is important determinant of HRV among T1DM patients. This relationship is independent of other risk factors for CAN or cardiovascular diseases.

Assessment of Frontal Hemispherical Lateralization in Plaque Psoriasis and Atopic Dermatitis.

BACKGROUND: Each brain hemisphere plays a specialized role in cognitive and behavioral processes, known as hemispheric lateralization. In chronic skin diseases, such as plaque psoriasis (Pso) and atopic dermatitis (AD), the degree of lateralization between the frontal hemispheres may provide insight into specific connections between skin diseases and the psyche. This study aims to analyze the hemispherical lateralization, neurovegetative responses, and psychometric characteristics of patients with Pso and AD. METHODS: The study included 46 patients with Pso, 56 patients with AD, and 29 healthy control (Ctrl) subjects. The participants underwent frontal electroencephalogram (EEG) measurement, heart rate variability (HRV) assessment, and psychological tests. Statistical analyses were performed using ANOVA, with Bonferroni correction applied for multiple comparisons. RESULTS: This study shows a significant right-lateralized prefrontal activity in both AD patients (p < 0.001) and Pso patients (p = 0.045) compared with Ctrl, with no significant difference between the AD and Pso groups (p = 0.633). AD patients with right-hemispheric dominant prefrontal activation exhibited increased inhibition and avoidance markers, while Pso patients showed elevated sympathetic nervous system activity. CONCLUSION: Psychophysiological and psychometric data suggest a shared prevalence of right-hemispheric dominance in both AD and Pso patient groups. However, the findings indicate distinct psychodermatological mechanisms in AD and Pso.

Quality of glycemic control has significant impact on myocardial mechanics in type 1 diabetes mellitus.

The potential associations between disease duration, glycemic control, and the echocardiographic markers of the myocardial mechanics were investigated in asymptomatic T1DM patients. Seventy T1DM patients (38.2 ± 11.7 years, 46 female) and 30 healthy volunteers were investigated. Besides the conventional and tissue Doppler measurements, left ventricular global longitudinal (GLS) and circumferential (GCS) strain as well as left and right atrial strain parameters were measured with 2D speckle tracking technique. Median HbA1c level was 7.4 (1.8)%. Even when added age and hypertension to the model, current HbA1c level remained independent predictor of left ventricular GLS (p = 0.002), GCS (p < 0.001), mitral e' (p = 0.018), tricuspid e' (p = 0.018) and left (p = 0.039) and right atrial conduit strain (p = 0.047) in multiple linear regression models. Correlations between disease duration and the echocardiographic variables lost their significance in multiple models. In patients with a combination of HbA1c ≤ 7.4% and no hypertension, echocardiographic findings did not differ from those in healthy volunteers. Patients with HbA1c > 7.4% and no hypertension and especially patients with coexisting hypertension and HbA1c > 7.4%, exhibited significantly impaired myocardial mechanics. Quality of glycemic control has a significant impact on myocardial mechanics in T1DM patients. Regarding disease duration this relationship was not proved.

Multispectral Imaging Algorithm Predicts Breslow Thickness of Melanoma.

Breslow thickness is a major prognostic factor for melanoma. It is based on histopathological evaluation, and thus it is not available to aid clinical decision making at the time of the initial melanoma diagnosis. In this work, we assessed the efficacy of multispectral imaging (MSI) to predict Breslow thickness and developed a classification algorithm to determine optimal safety margins of the melanoma excision. First, we excluded nevi from the analysis with a novel quantitative parameter. Parameter s' could differentiate nevi from melanomas with a sensitivity of 89.60% and specificity of 88.11%. Following this step, we have categorized melanomas into three different subgroups based on Breslow thickness (≤1 mm, 1-2 mm and >2 mm) with a sensitivity of 78.00% and specificity of 89.00% and a substantial agreement (κ = 0.67; 95% CI, 0.58-0.76). We compared our results to the performance of dermatologists and dermatology residents who assessed dermoscopic and clinical images of these melanomas, and reached a sensitivity of 60.38% and specificity of 80.86% with a moderate agreement (κ = 0.41; 95% CI, 0.39-0.43). Based on our findings, this novel method may help predict the appropriate safety margins for curative melanoma excision.

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.

Implementation of personalized medicine in Central-Eastern Europe: pitfalls and potentials based on citizen's attitude.

OBJECTIVE: Next-generation sequencing is increasingly utilized worldwide as a research and diagnostic tool and is anticipated to be implemented into everyday clinical practice. Since Central-Eastern European attitude toward genetic testing, especially broad genetic testing, is not well known, we performed a survey on this issue among Hungarian participants. METHODS: A self-administered questionnaire was distributed among patients and patient relatives at our neurogenetic outpatient clinic. Members of the general population were also recruited via public media. We used chi-square testing and binary logistic regression to examine factors influencing attitude. RESULTS: We identified a mixed attitude toward genetic testing. Access to physician consultation positively influenced attitude. A higher self-determined genetic familiarity score associated with higher perceived genetic influence score, which in turn associated with greater willingness to participate in genetic testing. Medical professionals constituted a skeptical group. CONCLUSIONS: We think that given the controversies and complexities of the next-generation sequencing field, the optimal clinical translation of NGS data should be performed in institutions which have the unique capability to provide interprofessional health education, transformative biomedical research, and crucial patient care. With optimization of the clinical translational process, improvement of genetic literacy may increase patient engagement and empowerment. RELEVANCE OF THE ARTICLE FOR PREDICTIVE PREVENTIVE AND PERSONALIZED MEDICINE: The paper highlights that in countries with relatively low-genetic literacy, a special strategy is needed to enhance the implementation of personalized medicine.