Recessive NUP54 Variants Underlie Early-Onset Dystonia with Striatal Lesions.

Infantile striatonigral degeneration is caused by a homozygous variant of the nuclear-pore complex (NPC) gene NUP62, involved in nucleo-cytoplasmic trafficking. By querying sequencing-datasets of patients with dystonia and/or Leigh(-like) syndromes, we identified 3 unrelated individuals with biallelic variants in NUP54. All variants clustered in the C-terminal protein region that interacts with NUP62. Associated phenotypes were similar to those of NUP62-related disease, including early-onset dystonia with dysphagia, choreoathetosis, and T2-hyperintense lesions in striatum. In silico and protein-biochemical studies gave further evidence for the argument that the variants were pathogenic. We expand the spectrum of NPC component-associated dystonic conditions with localized basal-ganglia abnormalities. ANN NEUROL 2023;93:330-335.

Exploring Mental Health and Development in Refugee Children Through Systematic Play Assessment.

To evaluate a standardized play observation as a measure of young children's mental health and development in a clinical and refugee population. We conducted individual play observations with 70 refugee children aged 3- to 6-years and compared them to a clinical group of 111 age-matched children regarding their level of play development, social interaction during play, traumatic re-enactments, and emotionless-cold play. Additionally, we assessed children's mental health, social-emotional development and markers of adversity by parent and educator report as well as their IQ-test scores and learning performance and related these factors to the play variables. Play variables were significantly correlated with IQ-test scores (r = 0.184, p = 0.037), learning performance (r = 0.208, p = 0.010) and vocabulary (r = 0.208, p = 0.021) in the comparison group and with social-emotional development in educator report (r = 0.368, p = 0.011), time spent in Germany (r = 0.342, p < 0.001) and parental distress (r = - 0.292, p = 0.034) in the refugee group. Children with more parent-reported adverse experiences showed less social-interactive play in the overall sample (r = - 0.178, p = 0.011). Our child-centered approach to standardized play observation augments information obtained from parent and educator reports and can provide valuable insights in subgroups where other commonly used tests are not available or applicable.

[Early childhood mental disorders: excessive crying, sleep and feeding disorders, and interventions using the "Munich model" as an example]. / Frühkindliche psychische Störungen: Exzessives Schreien, Schlaf- und Fütterstörungen sowie Interventionen am Beispiel des "Münchner Modells".

About 20% of all healthy infants and toddlers show problems in the area of mental health during their first years of life such as inconsolable crying (so-called cry-babies), sleeping problems, and feeding problems. The prevalence of enduring feeding problems and sleeping problems is distinctly higher in premature children and in children with neuropediatric disorders. These problems present a higher risk for the development of internalizing and externalizing disorders of mental health in later childhood. The parent-child relationship is often strained. Parents report experiencing severe exhaustion, extreme uncertainty, and helplessness.Pediatricians and midwives are the first points of contact for families. Outpatient clinics for cry-babies such as the "Munich Consultation for Cry-Babies," founded by Mechthild Papousek in 1991 at the kbo-Children's Center Munich, provide a low-threshold service for the highly stressed families. They can contribute to the prevention of neglect, maltreatment, and psychological secondary disorders of the child. Intervention strategies are based on parent-infant and attachment research and integrate child- and parent-oriented approaches.During the COVID-19 pandemic, psychosocial stress factors in families increased. This development was also observable in the outpatient clinics for cry-babies.

Non-verbal cognitive development, learning, and symptoms of PTSD in 3- to 6-year-old refugee children.

As IQ tests are commonly used as key assessment method, we address the question whether our commonly used standardized IQ tests are appropriate for children from families of diverse cultures and different educational levels in a refugee population. We examined 109 refugee children aged 3-7 years (M = 5.10 years, SD = 1.25) with the "Kaufman Assessment Battery for Children " (KABC-II; Kaufmann & Kaufmann, 2015) on a language-free scale (Scale of Intellectual Functioning, SIF) and learning performance (subtest Atlantis). With a non-verbal IQ of 81.5 (SD = 18.01), the population mean of the refugee children is more than one standard deviation lower than the mean of the German norm population. Standardized scores follow the normal distribution and are not correlated to any of the assessed markers of adversity (flight duration, time spent in Germany, child PTSD in parent rating, parental symptom load, and parental education level).Conclusion: The interpretation of IQ test results for refugee children should be done cautiously as results may underestimate their cognitive capacity. Environmental factors, such as high illiteracy among parents in this study, the lack of institutional education of children and high lifetime stress, may explain our findings.Trial registration: DRKS00021150. What is Known: • There is a high pervasiveness for the use of standardized IQ tests in the German health and education system to determine eligibility for special education and social services. What is New: • Refugee children score significantly lower than German children in a language-free IQ test. As results are normally distributed and not correlated to any of the assessed markers of adversity, the low scores in the refugee group might be due to missing formal education.

Population-based screening in children for early diagnosis and treatment of familial hypercholesterolemia: design of the VRONI study.

BACKGROUND: Heterozygous familial hypercholesterolemia (FH) represents the most frequent monogenic disorder with an estimated prevalence of 1:250 in the general population. Diagnosis during childhood enables early initiation of preventive measures, reducing the risk of severe consecutive atherosclerotic manifestations. Nevertheless, population-based screening programs for FH are scarce. METHODS: In the VRONI study, children aged 5-14 years in Bavaria are invited to participate in an FH screening program during regular pediatric visits. The screening is based on low-density lipoprotein cholesterol measurements from capillary blood. If exceeding 130 mg/dl (3.34 mmol/l), i.e. the expected 95th percentile in this age group, subsequent molecular genetic analysis for FH is performed. Children with FH pathogenic variants enter a registry and are treated by specialized pediatricians. Furthermore, qualified training centers offer FH-focused training courses to affected families. For first-degree relatives, reverse cascade screening is recommended to identify and treat affected family members. RESULTS: Implementation of VRONI required intensive prearrangements for addressing ethical, educational, data safety, legal and organizational aspects, which will be outlined in this article. Recruitment started in early 2021, within the first months, more than 380 pediatricians screened over 5200 children. Approximately 50 000 children are expected to be enrolled in the VRONI study until 2024. CONCLUSIONS: VRONI aims to test the feasibility of a population-based screening for FH in children in Bavaria, intending to set the stage for a nationwide FH screening infrastructure. Furthermore, we aim to validate genetic variants of unclear significance, detect novel causative mutations and contribute to polygenic risk indices (DRKS00022140; August 2020).

Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.

Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing ß-propeller repeats. Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.

Scoring Algorithm-Based Genomic Testing in Dystonia: A Prospective Validation Study.

BACKGROUND: Despite the established value of genomic testing strategies, practice guidelines for their use do not exist in many indications. OBJECTIVES: We sought to validate a recently introduced scoring algorithm for dystonia, predicting the diagnostic utility of whole-exome sequencing (WES) based on individual phenotypic aspects (age-at-onset, body distribution, presenting comorbidity). METHODS: We prospectively enrolled a set of 209 dystonia-affected families and obtained summary scores (0-5 points) according to the algorithm. Singleton (N = 146), duo (N = 11), and trio (N = 52) WES data were generated to identify genetic diagnoses. RESULTS: Diagnostic yield was highest (51%) among individuals with a summary score of 5, corresponding to a manifestation of early-onset segmental or generalized dystonia with coexisting non-movement disorder-related neurological symptoms. Sensitivity and specificity at the previously suggested threshold for implementation of WES (3 points) was 96% and 52%, with area under the curve of 0.81. CONCLUSIONS: The algorithm is a useful predictive tool and could be integrated into dystonia routine diagnostic protocols. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Survival states as indicators of learning performance and biological stress in refugee children: a cross-sectional study with a comparison group.

BACKGROUND: Our goal was to accurately detect young children at risk for long-term psychiatric disturbances after potentially traumatic experiences in the course of relocation. In addition to detailed assessment of parent-rated parent and child symptomatology, we focused on disruptive behaviors in the education environment summarized as survival states, as these frequently lead to clinical referral. METHODS: We screened 52 refugee children aged 3-7 (M = 5.14 years, SD = 1.17) for symptoms of Posttraumatic Stress Disorder (PTSD) with the Child and Adolescent Trauma Screening (CATS) in parent rating. The parents' mental health was assessed using the Refugee Health Screener (RHS-15). Furthermore, the child's educators were asked to evaluate the pathological survival states of the child and we made a general assessment of the children's symptoms with the Strengths and Difficulties Questionnaire (SDQ) rated by parents and educators. Children in the refugee sample completed a working memory learning task (Subtest Atlantis from the Kaufmann Assessment Battery for Children, KABC-II) and delivered saliva samples for testing of the cortisol level. RESULTS: The parental rating of their child's PTSD symptoms was significantly related to their own mental well-being (r = .50, p < .001). Children with survival states in educator ratings exhibited weaker learning performance (F = 3.49, p < .05) and higher evening cortisol levels (U = 113, z = - 1.7, p < .05, one-tailed). CONCLUSIONS: Survival states are promising indicators for children's learning performance and distress level complementary to parent rating of child PTSD, which is highly intercorrelated with the parents' own symptom load. TRIAL REGISTRATION: Trial registration number: DRKS00021150 on DRKS Date of registration: 04.08.2020 retrospectively registered.

Electronic Media and Early Childhood: A Review.

BACKGROUND: This review summarizes the state of knowledge of use of new media on the development in early childhood in 6 sections: descriptive utilization data, psychosocial and emotional development, cognition and language, motor development, nutrition and sleep, and influence of parental media consumption. METHODS: The review is based on a literature search of this topic in peer-reviewed journals. We included 87 articles, books, and book chapters. The used literature data bases were ERIC, PsycARTICLES, PsycINFO and PSYNDEX. RESULTS: Manifold studies describe in young children's utilization data the pervasive nature of digital exposure and impressive usage times and availability. They confirm adverse influences of electronic media use (television, video games) on children's emotional and behavioral problems and well-being, e. g. on physical activity, sleep and obesity. In general a positive effect in sense of knowledge transfer of age could be found for high quality educational media, however predominantly the impact of media use at younger age was negative. CONCLUSIONS: High frequent media use in early childhood is likely to have a negative impact on psychosocial development, positive effects such as knowledge transfer may be seen beyond the age of 18 months. As parental media use is a strong predictor of child media habits, reducing parental media use and enhancing parent-child interactions might be important areas to address when trying to change the media behavior of young children. In view of the scarcity of studies for early childhood, it is advisable to use digital play and communication devices cautiously and restrictively in this vulnerable development phase.

De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy.

PURPOSE: This study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene. METHODS: Variants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher. RESULTS: Missense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay. CONCLUSION: Our study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients.

Impaired synaptic plasticity in RASopathies: a mini-review.

Synaptic plasticity in the form of long-term potentiation (LTP) and long-term depression (LTD) is considered to be the neurophysiological correlate of learning and memory. Impairments are discussed to be one of the underlying pathophysiological mechanisms of developmental disorders. In so-called RASopathies [e.g., neurofibromatosis 1 (NF1)], neurocognitive impairments are frequent and are affected by components of the RAS pathway which lead to impairments in synaptic plasticity. Transcranial magnetic stimulation (TMS) provides a non-invasive method to investigate synaptic plasticity in humans. Here, we review studies using TMS to evaluate synaptic plasticity in patients with RASopathies. Patients with NF1 and Noonan syndrome (NS) showed reduced cortical LTP-like synaptic plasticity. In contrast, increased LTP-like synaptic plasticity has been shown in Costello syndrome. Notably, lovastatin normalized impaired LTP-like plasticity and increased intracortical inhibition in patients with NF1. TMS has been shown to be a safe and efficient method to investigate synaptic plasticity and intracortical inhibition in patients with RASopathies. Deeper insights in impairments of synaptic plasticity in RASopathies could help to develop new options for the therapy of learning deficits in these patients.

German translation of the caregiver priorities and child health index of life with disabilities questionnaire: test-retest reliability and correlation with gross motor function in children with cerebral palsy.

We aimed to translate the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) questionnaire into German and to evaluate its reliability and validity by studying the association between CPCHILD scores and gross motor function as measured by the gross motor function classification system (GMFCS) in children with cerebral palsy (CP). The original CPCHILD questionnaire and manual were translated and back translated. It was administered to primary caregivers of persons with CP (GMFCS levels III-V) and was completed a second time 2 weeks after the first to measure test-retest reliability (n = 17). Primary caregivers of 68 children with CP; GMFCS level III (n = 14), level IV (n = 28), and level V (n = 26) completed the questionnaire. Mean total CPCHILD scores across GMFCS levels were 67.1 ± 14.9 for GMFCS level III, 56.6 ± 11.8 for level IV, and 44.3 ± 12.9 for level V. Good correlation (r = - 0.56) was observed between GMFCS and total scores test-retest reliability showed intraclass correlation coefficients between 0.4 and 0.9. The German CPCHILD yielded similar test-retest reliability and score distributions across the GMFCS level as the original version. The best correlations were observed for domains that are close to the functional deficits.

Use of intrathecal baclofen in children and adolescents: interdisciplinary consensus table 2013.

In recent years, intrathecal baclofen (ITB) has attained an important role in the treatment of severe spasticity and dystonia in children. There are principal differences between the use of ITB in children and its use in neurology and oncology in adults. Here, we present a consensus report on best practice for the treatment of severe spastic and dystonic movement disorders with ITB. Using a problem-orientated approach to integrate theories and methods, the consensus was developed by an interdisciplinary group of experienced ITB users and experts in the field of movement disorders involving 14 German centers. On the basis of the data pooled from more than 400 patients, the authors have summarized their experience and supporting evidence in tabular form to provide a concise, but still a comprehensive information base that represents our current understanding regarding ITB treatment options in children and adolescents.

Deficits in motor abilities and developmental fractionation of imitation performance in high-functioning autism spectrum disorders.

The co-occurrence of motor and imitation disabilities often characterises the spectrum of deficits seen in patients with autism spectrum disorders (ASD). Whether these seemingly separate deficits are inter-related and whether, in particular, motor deficits contribute to the expression of imitation deficits is the topic of the present study and was investigated by comparing these deficits' cross-sectional developmental trajectories. To that end, different components of motor performance assessed in the Zurich Neuromotor Assessment and imitation abilities for facial movements and non-meaningful gestures were tested in 70 subjects (aged 6-29 years), including 36 patients with high-functioning ASD and 34 age-matched typically developed (TD) participants. The results show robust deficits in probands with ASD in timed motor performance and in the quality of movement, which are all independent of age, with one exception. Only diadochokinesis improves moderately with increasing age in ASD probands. Imitation of facial movements and of non-meaningful hand, finger, hand finger gestures not related to social context or tool use is also impaired in ASD subjects, but in contrast to motor performance this deficit overall improves with age. A general imitation factor, extracted from the highly inter-correlated imitation tests, is differentially correlated with components of neuromotor performance in ASD and TD participants. By developmentally fractionating developmentally stable motor deficits from developmentally dynamic imitation deficits, we infer that imitation deficits are primarily cognitive in nature.

ADHD Symptoms in Middle Childhood: The Role of Child Attachment and Maternal Emotional Availability in an Inpatient Clinical Sample.

BACKGROUND: Child ADHD symptoms are highly prevalent in middle childhood, alongside impairment in social functioning. The parent-child relationship has been shown to play an important role; however, studies investigating specific facets of the parent-child relationship in ADHD symptomatology in middle childhood have been neglected. We assumed that higher ADHD symptoms were associated with both (1) lower maternal emotional availability (EA) and (2) lower child attachment security. Moreover, (3) we aimed to explore which specific EA dimensions were associated with ADHD symptoms. METHODS: In a socio-pediatric clinic in Germany, 71 inpatient mother-child dyads (child age: M = 7.70, SD = 1.06; n = 54 boys) were assessed. Clinical data about child ADHD symptoms (Child Behavior Checklist 6-18 subscale "attention deficit/hyperactivity problems"), maternal EA (free play), and child attachment representation (Attachment Story Completion Task, GEV-B) were analyzed cross-sectionally. RESULTS: Controlling for child oppositional behavior and sex, child ADHD symptoms were associated with overall maternal EA, and more specifically non-hostility, but not with child attachment representation. CONCLUSIONS: Our results imply that the role of parent-child interaction quality should be considered in the treatment of ADHD. Bidirectional effects cannot be ruled out.

The change of psychosocial stress factors in families with infants and toddlers during the COVID-19 pandemic. A longitudinal perspective on the CoronabaBY study from Germany.

Background: Over nearly three years, the COVID-19 pandemic has had a lasting impact on people's lives and mental health worldwide with its far-reaching restrictions and concerns about infections and other personal consequences. Families were particularly affected and showed increased stress and psychological problems. Long-term effects cannot be ruled out. So far, data on young families are sparse. The present longitudinal analysis (n = 932) of the CoronabaBY study investigated the development of parenting stress, parental affective symptoms, and child's mental health in young families with children aged 0-3 years in Germany as well as potential influencing factors. Methods: The observational study includes two measurement points over the course of the pandemic (baseline and follow-up). Data was collected by app using standardized questionnaires. Results: N = 932 participants, mainly mothers (94.7%) born in Germany (93.1%) with higher education (61.3% with at least high school diploma) and a comfortable financial situation participated in the longitudinal study. Children were on average 14.7 months old at baseline (SD: 12, range: 1-39 months). While the proportion of parents who perceived the pandemic as stressful decreased significantly from baseline (60%) to follow-up (52.3%), the proportion with parenting stress increased significantly (from 40.1% to 45.4%). Both parental and child mental health problems remained constant over time, with infants crying/feeding/sleeping problems ranging above pre-pandemic comparative data. Most predictive for high parenting stress at follow-up was high parenting stress at baseline. This was also true for parental affective symptoms (depression/anxiety) and child mental health problems. Conclusions: Despite faded pandemic restrictions, parents remained burdened. Support services do not appear to have been sufficient to help families out of their stressful situation. Our results indicate a need for action regarding low-threshold services that effectively reach affected families. Trial registration: The study was pre-registered in OSF (https://osf.io/search/?q=tksh5&page=1).

Stability of developmental milestones: Insights from a 44-year analysis.

Using standardized test procedures is a reliable way of assessing early childhood development in the pediatric setting. However, normal population's developmental parameters may change over time. The aim of this study was to determine whether a change of developmental percentiles is present in infants in Germany during recent decades. Measured by an established German diagnostic instrument (Münchener Funktionelle Entwicklungsdiagnostik) we cross-sectionally compared developmental data (cognition, expressive language, language comprehension, fine and gross motor skills, social development, daily-living skills) of children aged 0-36 months collected in the 1970s and in 2018. N = 2065 children and their parents were included (1970s sample: N = 1660 and 2018 sample: N = 405). The T-Test of dependent variables showed nonsignificant differences in the developmental scales. We hypothesized an infant Flynn effect, but the results of this study suggest that there are no developmental changes associated with the 50th percentile. Nevertheless, it is critical to emphasize the need for periodic revision and re-norming of developmental test procedures, even in the absence of significant changes in individual items.

App-based intervention for parents of children with crying, sleeping, and feeding problems: Usability, usefulness and implications for improvement.

Background: There is a lack of evidence-based app guidance for parents of children with crying, sleeping, and feeding problems who are often highly burdened and not likely to seek professional help. A new psychoeducational app for parents providing scientifically sound information via text and videos, a diary function, selfcare strategies, a chat forum and a regional directory of specialized counseling centers may serve as a low-threshold intervention for this target group. Objective: We investigated how parents perceived the app in terms of the following: (1) overall impression and usability, (2) feedback on specific app functions regarding usefulness and (3) possible future improvements. Methods: Our clinical sample of N = 137 parents of children aged from 0 to 24 months was recruited from a cry baby outpatient clinic in Southern Germany between 2019 and 2022. A convergent parallel mixed methods design was used to collect and analyse cross-sectional data on app evaluation. After app use within the framework of a clinical trial, parents filled in an app evaluation questionnaire. Results: Most participants used the app at least once a week (86, 62.8 %) over an average period of 19.06 days (SD = 15.00). Participants rated overall impression and usability as good, and the informational texts, expert videos and regional register of counseling centers as appealing and useful. The diary function and chat forum were found to be helpful in theory, but improvements in implementation were requested, such as a timer function for the diary entry. Regarding future functionality, parents posed several suggestions such as the option to contact counseling centers directly via app, and the inclusion of the profile of their partners. Conclusions: Positive ratings of overall impression, usability, and specific app functions are important prerequisites for the app to be effective. App-based guidance for this target group should include easy-to-use information. The app is intended to serve as a secondary preventive low-threshold offer and to complement professional counseling.

Young children's development after forced displacement: a systematic review.

OBJECTIVES: To examine the impact of displacement experiences on 0- to 6-year-old children's social-emotional and cognitive development, as well as influencing factors on reported outcomes. STUDY DESIGN: We systematically searched MEDline, Psyndex, Cochrane Library, Web of Science, Elsevier, TandF, Oxford Journal of Refugee Studies, Journal of Immigrant & Refugee Studies, and Canada's Journal on Refugees for existing literature regarding social-emotional and cognitive outcomes in children directly exposed to forced displacement due to political violence. Results were synthesized in the discussion and displayed using harvest plots. RESULTS: Our search generated 9,791 articles of which 32 were selected for review and evaluation according to NICE criteria. Included studies provided results for 6,878 forcibly displaced children. Measured outcomes were diverse and included areas such as peer relations, prosocial behavior, family functioning, play, intelligence, learning performance, and language development. Repeated exposure to adverse experiences, separation from parents, parental distress, as well as duration and quality of resettlement in the host country were reported as influencing factors in the reviewed studies. CONCLUSION: As protective factors like secure and stable living conditions help to promote children's development, we call for policies that enhance participation in the welcoming society for refugee families. Early integration with low-threshold access to health and educational facilities can help to mitigate the wide-ranging negative consequences of forced displacement on young children's development.