The Use of CGH Arrays for Identifying Copy Number Variations in Children with Autism Spectrum Disorder.

Autism spectrum disorders (ASDs) encompass a broad group of neurodevelopmental disorders with varied clinical symptoms, all being characterized by deficits in social communication and repetitive behavior. Although the etiology of ASD is heterogeneous, with many genes involved, a crucial role is believed to be played by copy number variants (CNVs). The present study examines the role of copy number variation in the development of isolated ASD, or ASD with additional clinical features, among a group of 180 patients ranging in age from two years and four months to 17 years and nine months. Samples were taken and subjected to array-based comparative genomic hybridization (aCGH), the gold standard in detecting gains or losses in the genome, using a 4 × 180 CytoSure Autism Research Array, with a resolution of around 75 kb. The results indicated the presence of nine pathogenic and six likely pathogenic imbalances, and 20 variants of uncertain significance (VUSs) among the group. Relevant variants were more prevalent in patients with ASD and additional clinical features. Twelve of the detected variants, four of which were probably pathogenic, would not have been identified using the routine 8 × 60 k microarray. These results confirm the value of microarrays in ASD diagnostics and highlight the need for dedicated tools.

The Clinical and Epidemiological Profile of Paediatric-Onset Multiple Sclerosis in Poland.

Background. Paediatric-onset MS (POMS) has a unique clinical profile compared to the more prevalent adult-onset MS. For this study, we aimed to determine the demographic and clinical characteristics of POMS in Poland as well as addressing some of its epidemiological aspects. Methods. A retrospective study was conducted based on the Polish Multiple Sclerosis Registry, considering a population of children and adolescents with MS (age ≤ 18 years). Data were collected by all 13 centres across Poland specializing in diagnosing and treating POMS. The actual course of the disease and its clinical properties were compared between child (≤12 years) and juvenile (>12 years) patients. MS onset and its prevalence were assessed at the end of 2019, stratified by age range. Results. A total of 329 paediatric or juvenile patients (228 girls, 101 boys) with a clinically definite diagnosis of MS, in conformity with the 2017 McDonald Criteria, were enrolled. For 71 children (21.6%), the first symptoms appeared before the age of 12. The female: male ratio increased with age, amounting to 1:1 in the ≤12 years group and to 2.9:1 in the >12 years group. In most cases, the disease had multi-symptomatic onset (31.3%), and its course was mostly of a relapsing−remitting character (95.7%). The initial Expanded Disability Status Score for both groups was 1.63 ± 1.1, whereas the annual relapse rate was 0.84 during the first 2 years. The time between the onset of symptoms and diagnosis was longer in the younger patients (8.2 ± 4.2 vs. 4.6 ± 3.6 months; p < 0.005). On 31 December 2019, the age-adjusted prevalence standardized to the European standard population was 5.19/100,000 (95% CI, 4.64−5.78). Significantly higher prevalence was noted in the 13−18 years group (7.12; 95% CI, 6.64−7.86) than in the 9−12 years group (3.41; 95% CI, 2.98−3.86) and the <9 years group (0.56; 95% CI, 0.46−0.64; p < 0.001). Conclusion. POMS commencing at the age of ≤12 years is rare, differing significantly from the juvenile-onset and adult MS in terms of clinical characteristics, course, and incidence, as stratified by gender.

TCEAL1 loss-of-function results in an X-linked dominant neurodevelopmental syndrome and drives the neurological disease trait in Xq22.2 deletions.

An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.2 genes (BEX3, RAB40A, TCEAL4, TCEAL3, TCEAL1, and MORF4L2) associate with an early-onset neurological disease trait (EONDT) consisting of hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. None of the genes within the SRO have been associated with monogenic disease in OMIM. Through local and international collaborations facilitated by GeneMatcher and Matchmaker Exchange, we have identified and herein report seven de novo variants involving TCEAL1 in seven unrelated families: three hemizygous truncating alleles; one hemizygous missense allele; one heterozygous TCEAL1 full gene deletion; one heterozygous contiguous deletion of TCEAL1, TCEAL3, and TCEAL4; and one heterozygous frameshift variant allele. Variants were identified through exome or genome sequencing with trio analysis or through chromosomal microarray. Comparison with previously reported Xq22 deletions encompassing TCEAL1 identified a more-defined syndrome consisting of hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features include strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. An additional maternally inherited hemizygous missense allele of uncertain significance was identified in a male with hypertonia and spasticity without syndromic features. These data provide evidence that TCEAL1 loss of function causes a neurological rare disease trait involving significant neurological impairment with features overlapping the EONDT phenotype in females with the Xq22 deletion.

Pediatric-onset multiple sclerosis in Poland: A registry-based retrospective cohort study.

BACKGROUND: Epidemiologic data on pediatric-onset multiple sclerosis (POMS) in Central and Eastern Europe are limited. The aim of this study was to determine the incidence, prevalence and the clinical features of POMS in Poland. METHODS: Registry-based retrospective study was conducted among Polish children population (age ≤ 18 years), between 1 January 2010 and 31 December 2019. A total of 329 pediatric or juvenile patients fulfilled the International Pediatric MS Study Group (IPMSSG) criteria for MS, reported to the Polish Multiple Sclerosis Registry, were considered for estimation of age- and sex-specific prevalence (per 100,000 persons), and incidence rates (per 100,000 person-years). The demographic data, clinical presentation and treatment strategies also were investigated. RESULTS: On December 31, 2019 in the database were collected data of 329 patients up to 18 years with POMS diagnosis (101 boys and 228 girls; mean age 15.3 ± 3.8 years). The age-adjusted prevalence standardized to the European Standard Population was 5.19/100,000 (95% confidence interval (CI), 4.64-5.78). A significantly higher prevalence was recorded in girls (7.41; 95% CI, 6.48-8.44) than in boys (3.08; 95% CI, 2.50-3.74; P<0.001). The mean annual standardized incidence in Poland between 2015 - 2019 was 0.77 (95%CI, 0.45-1.02) per 100,000 person-years. The highest overall standardized incidence 1.06 (95%CI, 0.82-1.34) was noted in 2018. Most of patients (95.7%) had relapsing-remitting disease with polysymptomatic onset in one-thirds of the cases, and 82.3% were treated with disease-modifying drugs. Family history of MS was reported in 26 cases (7.9%). CONCLUSION: In this first report of registry-based study from Poland an increasing prevalence and incidence of POMS was found during the last years. This temporal trend corroborate the findings of studies conducted elsewhere.

No evidence for change in expression of TBC1D1 and TBC1D4 genes in cultured human adipocytes stimulated by myokines and adipokines.

TBC1D1 and TBC1D4 proteins play analogous, but not identical role in governing insulin-signalling pathway. Little is known about changes in expression levels of TBC1D1 and TBC1D4 genes in mammals, including humans. Number of factors were studied, but data remain controversial. The aim of this study was to evaluate the effect of selected cytokines, adipokines and myokines with known or putative insulin sensitivity regulation activity (adiponectin, irisin, omentin, interleukin 6, leptin, resistin, and tumour necrosis factor) on TBC1D1 and TBC1D4 expression levels in cultured differentiated human adipocytes. No significant differences were found between the adipocytes treated with different stimuli and this effect was determined not dose dependent. It is reasonable to conclude that relative shortage of data showing no change in TBC1D1 and TBC1D4 from literature results from publication bias; therefore, our finding provides additional insight into the role of both genes.

Age of natural menopause onset in BRCA1/2 carriers - systematic review and meta-analysis.

INTRODUCTION: Germinal pathogenic variants in BRCA1 and BRCA2 genes are associated with high risk of cancers, including breast, ovary, fallopian tubes and primary peritoneal. Non-oncological implications of germline pathogenic variants in BRCA1 and BRCA2 genes, complicating reproductive health are less described. The influence of BRCA1 and BRCA2 on age of natural menopause remains inconclusive and controversial. MATERIAL AND METHODS: PubMed database was searched for potentially relevant abstracts. Studies which were not case-control, cohort or cross-sectional studies were subsequently excluded. Reference lists from systematic reviews or meta-analyses, dealing with the topic of menopause and BRCA1 and BRCA2 germinal pathogenic variants, were also checked to identify eligible studies. We also included our original, unpublished data from families, affected by BRCA1 or BRCA2 pathogenic variant, consisted of at least two postmenopausal female siblings with differing variant status. RESULTS AND CONCLUSIONS: Initial database search retrieved 193 abstracts. We identified 4 eligible studies for meta-analysis. Two studies not reporting dispersion measures and not reporting age of natural menopause in control group were left in summary for illustrational purposes, yet were excluded from meta-analysis. 4 studies and our original, unpublished data, combining data from 1535 germinal BRCA1 and BRCA2 pathogenic variant carriers and 3191 control individuals, did not support the hypothesis of association between germinal pathogenic variants of "breast cancer genes" and premature menopause.

An Increase in Alpha Band Frequency in Resting State EEG after Electrical Stimulation of the Ear in Tinnitus Patients-A Pilot Study.

In our clinic invasive transtympanal promontory positive DC stimulations were first used, with a success rate of 42%. However, non-invasive hydrotransmissive negative DC stimulations are now favored, with improvement being obtained in 37.8% directly after the treatment, and 51.3% in a follow up 1 month after treatment. The further improvement after 1 month may be due to neuroplastic changes at central level as a result of altered peripheral input. The aim of the study was to determine how/whether a single electrical stimulation of the ear influences cortical activity, and whether changes observed in tinnitus after electrical stimulation are associated with any changes in cortical activity recorded in EEG. The study included 12 tinnitus patients (F-6, M-6) divided into two groups. Group I comprised six patients with unilateral tinnitus - unilateral, ipsilateral ES was performed. Group II comprised six patients with bilateral tinnitus-bilateral ES was performed. ES was performed using a custom-made apparatus. The active, silver probe-was immersed inside the external ear canal filled with saline. The passive electrode was placed on the forehead. The stimulating frequency was 250 Hz, the intensity ranged from 0.14 to 1.08 mA. The voltage was kept constant at 3 V. The duration of stimulation was 4 min. The EEG recording (Deymed QEST 32) was performed before and after ES. The patients assessed the intensity of tinnitus on the VAS 1-10. Results: In both groups an improvement in VAS was observed-in group I-in five ears (83.3%), in group II-in seven ears (58.3%). In Group I, a significant increase in the upper and lower limit frequency of alpha band was observed in the central temporal and frontal regions following ES. These changes, however, were not correlated with improvement in tinnitus. No significant changes were observed in the beta and theta bands and in group II. Preliminary results of our research reveal a change in cortical activity after electrical stimulations of the ear. However, it remains unclear if it is primary or secondary to peripheral auditory excitation. No similar studies had been found in the literature.

Association between C3435T polymorphism of MDR1 gene and the incidence of drug-resistant epilepsy in the population of Polish children.

PURPOSE: Epilepsy is a disease of neurological character. Approximately one third of epileptic patients demonstrate a drug-resistant phenotype, which is associated with the development of drug-resistant epilepsy. The multidrug resistance protein 1 and glycoprotein P, encoded by MDR1, play a significant role in the transmembrane transport of anti-epileptic agents. Single nucleotide polymorphism C3435T (rs1045642) within MDR1 gene may be associated with an increased expression of P-gp which affects the levels of antiepileptic drugs in plasma. The presented studies analysed the association between C3435T polymorphism of MDR1 gene and the incidence of drug-resistant epilepsy in the population of Polish children. METHODS: C3435T polymorphism of MDR1 gene was analysed by the high resolution melting technique in a group of patients with drug-resistant (n = 106) and drug-responsive epilepsy (n = 67), as well as in non-epileptic children (n = 98) hospitalised at the Department of Neurology, Polish Mother's Memorial Hospital in Lodz. Genotype and allele distributions were evaluated and their compatibility with the Hardy-Weinberg distribution was assessed by means of the χ(2) test. Genotype and allele evaluation, regarding their relationship with a given feature, was supported by an analysis of odds ratio and 95 % confidence interval, calculated according to the logistic regression model. RESULTS: An association was observed between the incidence rate of DRE and the presence of C allele in C3435T polymorphism of MDR1 gene, which may enhance the risk of the disease. The T allele may then play a protective role. No differences were found in the studied groups, regarding either genotype or allele distribution in reference to patient's gender or concomitant diseases. CONCLUSION: Following the obtained results, C3435T polymorphism of MDR1 gene may be connected with the incidence of drug-resistant epilepsy in the population of Polish children. ISRCTN ISRCTN73824458. Registered 28th September 2014.

Friedreich ataxia is not only a GAA repeats expansion disorder: implications for molecular testing and counselling.

Friedreich ataxia (FRDA) is the most common hereditary ataxia. It is an autosomal recessive disorder caused by mutations of the FXN gene, mainly the biallelic expansion of the (GAA)n repeats in its first intron. Heterozygous expansion/point mutations or deletions are rare; no patients with two point mutations or a point mutation/deletion have been described, suggesting that loss of the FXN gene product, frataxin, is lethal. This is why routine FRDA molecular diagnostics is focused on (GAA)n expansion analysis. Additional tests are considered only in cases of heterozygous expansion carriers and an atypical clinical picture. Analyses of the parent's carrier status, together with diagnostic tests, are performed in rare cases, and, because of that, we may underestimate the frequency of deletions. Even though FXN deletions are characterised as 'exquisitely rare,' we were able to identify one case (2.4 %) of a (GAA)n expansion/exonic deletion in a group of 41 probands. This was a patient with very early onset of disease with rapid progression of gait instability and hypertrophic cardiomyopathy. We compared the patient's clinical data to expansion/deletion carriers available in the literature and suggest that, in clinical practice, the FXN deletion test should be taken into account in patients with early-onset, rapid progressive ataxia and severe scoliosis.