In the last decade, undiagnosed disease programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases. In our single-center study, we have launched a pilot program for pediatric patients with undiagnosed diseases in the second-largest university hospital in the Czech Republic. This study was prospectively conducted at the Department of Pediatrics at University Hospital Brno between 2020 and 2023. A total of 58 Czech patients with undiagnosed diseases were enrolled in the study. All children underwent singleton WES with targeted phenotype-driven analysis. We identified 28 variants, including 11 pathogenic, 13 likely pathogenic, and 4 VUS according to ACMG guidelines, as diagnostic of genetic diseases in 25 patients, resulting in an overall diagnostic yield of 43%. Eleven variants were novel and had not been previously reported in any public database. The overall clinical utility (actionability) enabling at least one type of change in the medical care of the patient was 76%, whereas the average number of clinical implications to individual patient care was two. Singleton WES facilitated the diagnostic process in the Czech undiagnosed pediatric population. We believe it is an effective approach to enable appropriate counseling, surveillance, and personalized clinical management.

• Klíčová slova
• Rare genetic diseases, Undiagnosed patients, Whole-exome sequencing,
• MeSH
• dítě MeSH
• genetické testování metody   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• nediagnostikované nemoci * genetika   diagnóza   epidemiologie   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• sekvenování exomu * metody   MeSH
• vzácné nemoci * genetika   diagnóza   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

INTRODUCTION: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impairments in communication, social interaction, and repetitive behavior. The declaration of the COVID-19 pandemic in March 2020 resulted in significant changes in daily life due to restrictive measures. This period posed particular challenges for families with children living with autism, given the limitations in medical care and social services. OBJECTIVE: This study aimed to understand how families with autistic children perceive stress during the pandemic and the coping strategies employed in unexpected situations. METHOD: A total of 44 families with children with ASD and 300 control families, including 44 control families in a matched subsample, were included in the study. To assess stress and parental coping with COVID-19-related stress, the Responses to Stress Questionnaire (Adult Self-Report RSQ-COVID-19) was utilized. RESULTS: Caregivers of autistic children experienced significantly higher stress levels (p = .027, d = 0.479) during the pandemic, with notable stressors such as limited access to medical care and challenges associated with remote work. Despite expectations, coping strategy differences were not statistically significant. CONCLUSION: Families and supporters of children with autism naturally encounter various experiences and challenges stemming from their additional needs. Our study's results highlight an accentuation of stress during challenging situations. As these situations may recur in the future, there is a need to design and implement support plans for these families, appropriate intervention programs, and preparations for the utilization of telemedicine tools.

• MeSH
• adaptace psychologická * MeSH
• COVID-19 * psychologie   epidemiologie   MeSH
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• osoby pečující o pacienty psychologie   MeSH
• pandemie MeSH
• poruchy autistického spektra * psychologie   MeSH
• předškolní dítě MeSH
• průzkumy a dotazníky MeSH
• psychický stres * psychologie   MeSH
• rodiče * psychologie   MeSH
• SARS-CoV-2 MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The COVID-19 pandemic revealed the need to develop the field of remote assessment for autism spectrum disorders (ASD). The purpose of the study was to evaluate an online assessment protocol that includes the Brief Observation of Symptoms of Autism (BOSA). The online protocol consisting of BOSA and the Autism Diagnostic Interview-Revised (ADI-R) was administered by experienced examiners to 29 children with suspected ASD. The participants were then evaluated by clinical psychologists in a standard clinical setting using the Autism Diagnostic Observation Schedule-2 (ADOS-2) and other methods, and the ASD diagnosis was confirmed or ruled out. The results show substantial to moderate inter-rater agreement between the online and face-to-face raters with the value of Cohen's Kappa = 0.66 (P < 0.001); this corresponds with 79.8% agreement. The sensitivity of the protocol was approx. 94.7%, the specificity was 70%, the positive predictive value was 85.7%, and the negative predictive value was 87.5%. Further, direct false positive or false negative diagnostic conclusions based on the online protocol were absent when the possible conclusion of "I cannot decide" was included. The items B9 Showing, B10 Spontaneous Initiation of Joint Attention, B1 Unusual Eye Contact, B3 Facial Expressions Directed to Others, and C2 Imagination/Creativity were shown to be well observable in BOSA when related to ADOS-2 scoring. The results indicate that the protocol consisting of BOSA and ADI-R administered by an experienced examiner is a promising combination of tools for remote autism assessment.

• Klíčová slova
• Assessment tools, Autism, Autism assessment, Autism spectrum disorders, Neurodevelopmental disorders, Psychodiagnostics, Telehealth, Telehealth assessment,
• Publikační typ
• časopisecké články MeSH

In this prospective study involving 37 Duchenne muscular dystrophy (DMD) patients aged 8-18 years and older, we examined the impact of neurological and cardiac factors on quality of life (QoL). Our findings revealed a negative correlation between upper limb movement and overall mobility, self-service, and usual activities. Ambulatory and non-ambulatory DMD patients showed significant differences in mobility-related parameters. Cardiac evaluations demonstrated associations between mitral annular plane systolic excursion (MAPSE) and mobility-related aspects. The PEDSQL 3.0 neuromuscular model questionnaire further highlighted age-related and movement-related correlations with QoL. The loss of ambulatory status and reduced upper limb movement were negatively associated with QoL, while upper limb movement positively correlated with septal MAPSE. However, no significant associations were found between MAPSE and anxiety/depression. These findings underscore the multifaceted impact of DMD on QoL and emphasize the importance of considering both neurological and cardiac factors in comprehensive patient care.

• Klíčová slova
• Duchenne muscular dystrophy, cardiac impairment, cardiac magnetic resonance, neurological status, quality of life,
• Publikační typ
• časopisecké články MeSH

Background: The proportion of intensive care unit (ICU) admissions in children that have and have not been directly caused by SARS-CoV-2 remains unclear. The aim of the study is to analyse a cohort of children admitted to the ICU with SARS-CoV-2 and determine whether the infection was the primary cause of their hospitalisation, a significant contributor, a suspected accomplice, or an incidental finding. Methods: This was a retrospective observational study of all the children admitted to the ICU with SARS-CoV-2 from March 2020 to February 2022 from the South Moravia region. The aim of the study was to assess whether the hospitalisation was likely to be directly caused by the virus (i.e., patients with acute COVID-19; the COVID group), whether the virus was a significant contributor to the hospitalisation (i.e., patients with multisystem inflammatory syndrome in children due to COVID-19; the MIS-C group), whether it may have contributed to the worsening of their underlying disease (the WORSENING group), or whether it was an incidental finding very likely unrelated to hospitalisation where SARS-CoV-2 positivity merely placed patients in the COVID-19 unit (the ISOLATION group). The groups were compared using a series of secondary outcomes. Results: The study population represented 150 paediatric ICU cases (age 8.6; IQR 3.5−13.3 years), with 66.7% being male. The COVID group represented 32.7% of cases (49/150); MIS-C, 30% (45/150); WORSENING, 14.7% (22/150); and ISOLATION, 22.7% (34/150). The median length of hospitalisation was found for the MIS-C group (11 days; 9 days in the ICU), the COVID group (6 days; five days in the ICU), WORSENING group (4.5 days; 4.5 days in the ICU) and the ISOLATION group (5.5 days; 3.5 days in the ICU), where the difference was significant (p < 0.001). Asymptomatic and mild cases were most common in the WORSENING (36.4% and 63.6%) and ISOLATION (52.9% and 44.1%) groups. Severe and critical cases were only present in the COVID (6.1% and 12.2%) and MIS-C (4.4% and 11.1%) groups; the severity difference was significant (p < 0.001). The groups did not differ significantly in the proportion of complete recovery and short- and long-term sequelae (p = 0.09). Conclusions: Patients with acute COVID-19 accounted for one-third of all ICU admissions, patients with MIS-C accounted for approximately another third, patients with worsening underlying disease accounted for 15%, and patients with incidental findings of SARS-CoV-2 positivity accounted for one-fifth of ICU admissions. A more significant disease was seen with acute COVID-19 and MIS-C.

• Klíčová slova
• COVID-19, ICU, MIS-C, SARS-CoV-2, children, intensive care, isolation,
• Publikační typ
• časopisecké články MeSH

This work presents a case series of four children diagnosed with severe cerebrovascular disease in association with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, yet no patient from the group met typical diagnostic criteria for multisystem inflammatory syndrome in children. Our aim was to highlight the possible vascular involvement and coagulopathies associated with SARS-CoV-2 infection in the pediatric population. Further data are needed to better understand the pathophysiological basis of this condition in children and to ensure its optimal management.

• Klíčová slova
• Brain vasculopathy, COVID-19, Children, SARS-CoV-2, Stroke,
• MeSH
• COVID-19 * komplikace   MeSH
• dítě MeSH
• lidé MeSH
• SARS-CoV-2 MeSH
• syndrom systémové zánětlivé reakce MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

AIM: The primary goal was to determine the yield of next-generation sequencing (NGS) epilepsy gene panels used for epilepsy etiology diagnosing using a multidisciplinary approach and to demonstrate the importance of genotype-phenotype correlations. The secondary goal was to evaluate the application of precision medicine in selected patients. METHODS: This single-center retrospective study included a total of 175 patients (95 males and 80 females) aged 0-19 years. They were examined between 2015 and 2020 using an NGS epilepsy gene panel (270 genes). A bioinformatic analysis was performed including copy number variation identification. Thorough genotype-phenotype correlation was performed. RESULTS: Out of 175 patients, described pathogenic variants or novel variants with clear pathogenic impact were identified in 30 patients (17.14%). Genotype-phenotype correlations and parental DNA analysis were performed, and genetic diagnosis was confirmed on the basis of the results in another 16 out of 175 patients (9.14%). The diagnostic yield of our study increased from 30 to 46 patients (by 53.33%) by the precise genotype-phenotype correlation. INTERPRETATION: We emphasize a complex genotype-phenotype correlation and a multidisciplinary approach in evaluating the results of the NGS epilepsy gene panel, which enables the most accurate genetic diagnosis and correct interpretation of results.

• Klíčová slova
• Children, Epilepsy, Genetic testing, Next-generation sequencing, Precise medicine,
• MeSH
• epilepsie * diagnóza   genetika   MeSH
• fenotyp MeSH
• genetické asociační studie MeSH
• genetické testování metody   MeSH
• lidé MeSH
• mutace MeSH
• retrospektivní studie MeSH
• variabilita počtu kopií segmentů DNA * MeSH
• vysoce účinné nukleotidové sekvenování metody   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• dystonia, biballism, epilepsy, neurosurgery, next‐generation sequencing,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. METHODS: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. FINDINGS: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. INTERPRETATION: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations. FUNDING: Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

• MeSH
• dítě MeSH
• dystonie diagnóza   epidemiologie   genetika   MeSH
• exom genetika   MeSH
• genetická variace genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• sekvenování exomu metody   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

PURPOSE: The aim of this study was to evaluate seizure outcome in children with hematological malignancies and PRES and to identify prognostic factors that could help manage the syndrome. METHOD: We retrospectively reviewed the report data of 21 patients diagnosed with hematological malignancy or aplastic anemia and PRES between 2008 and 2018. Basic demographic data, oncology treatment, presymptomatic hypertension before PRES manifestation, neurological status, seizure type, and EEG and MRI findings at PRES onset and at the one-year follow-up visit were studied. Patients who developed remote symptomatic seizures or epilepsy were identified. RESULTS: We included 21 children (11 females and 10 males) in the study. Sixteen patients (76.2%) were diagnosed with ALL and the rest individually with AML, CML, T-lymphoma, Burkitt lymphoma, and severe aplastic anemia. Presymptomatic hypertension (PSH) was evaluated in 19 patients and was present in 18 (94.7%). The duration was 9 h and more in 16 patients (88.8%); the severity was grade II in 12 patients (66.7%). Seizures as the initial symptom of PRES were present in 17 patients (80.9%). Four patients (19.0%) were assessed with remote symptomatic seizures. Two of them (9.5%) had ongoing seizures at the one-year follow-up visit and were diagnosed with epilepsy. The presence of gliosis on follow-up MRI indicated worse outcome with development of epilepsy (without statistical significance). CONCLUSIONS: PRES syndrome has an overall good prognosis and the evolution to epilepsy is rare. The severity and duration of PSH or seizure severity and EEG findings at PRES onsetwere not associated with worse neurological outcomes in this study.

• Klíčová slova
• Children, MRI, Oncology, PRES, Prognosis, Seizure,
• MeSH
• dítě MeSH
• elektroencefalografie metody   MeSH
• hematologické nádory komplikace   diagnostické zobrazování   patofyziologie   MeSH
• kohortové studie MeSH
• lidé MeSH
• mladiství MeSH
• následné studie MeSH
• předškolní dítě MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• syndrom zadní leukoencefalopatie komplikace   diagnostické zobrazování   patofyziologie   MeSH
• syndromy selhání kostní dřeně komplikace   diagnostické zobrazování   patofyziologie   MeSH
• záchvaty komplikace   diagnostické zobrazování   patofyziologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH