[Fetal alcohol spectrum disorders-diagnosis, prognosis, and prevention]. / Fetale Alkoholspektrumstörungen ­ Diagnose, Prognose und Prävention.

Fetal alcohol spectrum disorder is one of the most common chronic diseases at birth. It is very often not or falsely diagnosed. This leads to inadequate, ineffective care and treatment of the affected children as well as to insufficient support of their families. The result is not only a high rate of secondary disorders, but it also leads to fewer opportunities for secondary and tertiary prevention for each child and family. With the right diagnosis these opportunities are guaranteed. The primary prevention in the field of alcohol consumption during pregnancy and fetal alcohol spectrum disorder should be planned and performed by the medical and political partners in a structured interdisciplinary and scientifically based way. Besides health promotion and education of the general population, the knowledge transfer to doctors and other medical, psychological, and pedagogical professionals is of particular relevance.

Ethical aspects of diagnosis and interventions for children with fetal alcohol Spectrum disorder (FASD) and their families.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) is an umbrella term covering several conditions for which alcohol consumption during pregnancy is taken to play a causal role. The benefit of individuals being identified with a condition within FASD remains controversial. The objective of the present study was to identify ethical aspects and consequences of diagnostics, interventions, and family support in relation to FASD. METHODS: Ethical aspects relating to diagnostics, interventions, and family support regarding FASD were compiled and discussed, drawing on a series of discussions with experts in the field, published literature, and medical ethicists. RESULTS: Several advantages and disadvantages in regards of obtaining a diagnosis or description of the condition were identified. For instance, it provides an explanation and potential preparedness for not yet encountered difficulties, which may play an essential role in acquiring much needed help and support from health care, school, and the social services. There are no interventions specifically evaluated for FASD conditions, but training programs and family support for conditions with symptoms overlapping with FASD, e.g. ADHD, autism, and intellectual disability, are likely to be relevant. Stigmatization, blame, and guilt are potential downsides. There might also be unfortunate prioritization if individuals with equal needs are treated differently depending on whether or not they meet the criteria for a specific condition. CONCLUSIONS: The value for the concerned individuals of obtaining a FASD-related description of their condition - for instance, in terms of wellbeing - is not established. Nor is it established that allocating resources based on whether individuals fulfil FASD-related criteria is justified, compared to allocations directed to the most prominent specific needs.

Social Perspective Taking and Empathy in Children with Fetal Alcohol Spectrum Disorders.

Children with fetal alcohol spectrum disorders (FASD) show sociobehavioral impairments; however, the social cognitive profile contributing to these impairments is poorly understood. This study compared social perspective taking and empathy in children with FASD versus typically developing controls (TDC). Thirty-seven children with FASD and 21 TDC participated. Measures included parent-rated CBCL and SSIS, and NEPSY-II Theory of Mind, Test of Social Cognition and Index of Empathy. Parents rated the FASD group higher than TDC on indices of behavior problems and lower on indices of social skills and empathy. Children with FASD scored significantly below TDC on tasks requiring complex social cognition. The majority of correlations between social cognition and parent-ratings were not significant in FASD and TDC, with the exception of a negative correlation between self-reported empathy and parent-rated behavior difficulties in TDC. FASD subgroup analyses revealed lower theory of mind and empathy scores among children with ARND than pFAS/FAS. With regard to sex, males with FASD were rated as having more behavior difficulties than females, whereas TDC females obtained higher empathy ratings than males. In both groups, females scored higher on theory of mind and empathy indices. On theory of mind tasks, older children with FASD performed below younger, whereas younger TDC children performed more poorly than older. Children with FASD show reduced functioning on indices of sociobehavioral and social cognition, and the effects are influenced by sex and age. These findings provide insight into the clinical and social profile of children with FASD.

Embryonic alcohol exposure: Towards the development of a zebrafish model of fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorder (FASD) is a devastating disease of the brain caused by exposure to alcohol during prenatal development. Its prevalence exceeds 1%. The majority of FASD cases represent the milder forms of the disease which often remain undiagnosed, and even when diagnosed treatment options for the patient are limited due to lack of information about the mechanisms that underlie the disease. The zebrafish has been proposed as a model organism for exploring the mechanisms of FASD. Our laboratory has been studying the effects of low doses of alcohol during embryonic development in the zebrafish. This review discusses the methods of alcohol exposure, its effects on behavioral performance including social behavior and learning, and the potential underlying biological mechanisms in zebrafish. It is based upon a recent keynote address delivered by the author, and it focuses on findings obtained mainly in his own laboratory. It paints a promising future of this small vertebrate in FASD research.

Secondary physical features in children with FASD.

OBJECTIVE: The diagnoses included within the umbrella term fetal alcohol spectrum disorders (FASD), are based on the documentation of prenatal alcohol exposure (PAE), growth deficits and a pattern of dysmorphic physical features and neurobehavioral impairments. Although 3 key facial features (short palpebral fissures, a smooth philtrum and a thin vermilion of the upper lip) are the only dysmorphic features taken into account for the diagnosis of Fetal Alcohol Syndrome (FAS) or partial FAS (pFAS), several other features are commonly seen in individuals with these diagnoses. The goals of our study were to determine if some of these secondary physical features also occur more frequently in children with alcohol-related neurodevelopmental disorder (ARND) relative to controls, and if a cluster of these features combined in a dysmorphology score could be used to identify those negatively impacted by PAE but who do not have the cardinal physical features that led to a diagnosis of FAS or pFAS. METHODS: Among 2681 children recruited for the Collaboration on Fetal Alcohol Spectrum Disorders Prevalence (CoFASP) study, 1726 had an FASD or sufficient evidence of PAE having occurred or not in their pregnancy. Children were then categorized into groups using the modified Hoyme diagnostic criteria (FAS (n = 24), pFAS (n = 99) and ARND (n = 87), and No FASD (n = 1516), including those with No FASD and a history of PAE (No FASD/PAE, n = 498) and those with No FASD and no history of PAE (No FASD/No PAE, n = 1018). The frequencies of 26 secondary dysmorphic features were compared among these groups, both individually and combined in non-weighted and weighted dysmorphic scores. Correlations of the total dysmorphic scores with an index of overall cognitive ability were also compared by group status. RESULTS: Several of these features were significantly more frequent in children with FAS than in those with No FASD diagnosis with or without PAE but not in comparison to those with ARND. The number of features was also significantly higher in the FAS group as compared to all other groups for both weighted and unweighted dysmorphology scores but were not higher in the group with ARND when compared to the groups with No FASD either in the presence or absence of PAE. Although not diagnostic, higher total dysmorphology scores were predictive of lower general cognitive abilities in the group with ARND, suggesting severity of alcohol-related dysmorphology is predictive of severity of alcohol-related neurobehavioral impairment. CONCLUSION: Secondary physical features were not more frequent in children with ARND compared to children without an FASD diagnosis but were a marker for lower cognitive function. The use of secondary physical features to support a diagnosis of ARND was not supported in this sample.

An anti-inflammatory and anti-fibrotic proprietary Chinese medicine nasal spray designated as Allergic Rhinitis Nose Drops (ARND) with potential to prevent SARS-CoV-2 coronavirus infection by targeting RBD (Delta)- angiotensin converting enzyme 2 (ACE2) binding.

BACKGROUND: Since the outbreak of COVID-19 has resulted in over 313,000,000 confirmed cases of infection and over 5,500,000 deaths, substantial research work has been conducted to discover agents/ vaccines against COVID-19. Undesired adverse effects were observed in clinical practice and common vaccines do not protect the nasal tissue. An increasing volume of direct evidence based on clinical studies of traditional Chinese medicines (TCM) in the treatment of COVID-19 has been reported. However, the safe anti-inflammatory and anti-fibrotic proprietary Chinese medicines nasal spray, designated as Allergic Rhinitis Nose Drops (ARND), and its potential of re-purposing for suppressing viral infection via SARS-CoV-2 RBD (Delta)- angiotensin converting enzyme 2 (ACE2) binding have not been elucidated. PURPOSE: To characterize ARND as a potential SARS-CoV-2 entry inhibitor for its possible preventive application in anti-virus hygienic agent. METHODS: Network pharmacology analysis of ARND was adopted to asacertain gene targets which were commonly affected by COVID-19. The inhibitory effect of ARND on viral infection was determined by an in vitro pseudovirus assay. Furthermore, ARND was confirmed to have a strong binding affinity with ACE2 and SARS-CoV-2 spike-RBD (Delta) by ELISA. Finally, inflammatory and fibrotic cell models were used in conjunction in this study. RESULTS: The results suggested ARND not only inhibited pseudovirus infection and undermined the binding affinity between ACE2 and the Spike protein (Delta), but also attenuated the inflammatory response upon infection and may lead to a better prognosis with a lower risk of pulmonary fibrosis. The data in this study also provide a basis for further development of ARND as an antiviral hygienic product and further investigations on ARND in the live virus, in vivo and COVID-19 patients. ARND holds promise for use in the current COVID-19 outbreak as well as in future pandemics. CONCLUSION: ARND could be considered as a safe anti-SARS-CoV-2 agent with potential to prevent SARS-CoV-2 coronavirus infection.

Does early ethanol exposure increase seeking-like behavior in zebrafish?

Fetal alcohol spectrum disorder (FASD) is the most common cause of birth defects. The severe variations are in fetal alcohol syndrome (FAS) but the most frequent cases are alcohol-related neurodevelopmental disorder (ARND), which is of a difficult diagnosis. ARND characteristics include impaired social behavior, anxiety and depression prevalence, cognitive deficits, and an increased chance for drug addiction. Here, we aimed to test whether early alcohol exposure leads to later alcohol preference. We hypothesize that early alcohol exposure increases the reinforcing effects on later experiences, raising the chance of addiction in adult life. Lately, the zebrafish has been a valuable model on alcohol research, allowing embryonic exposure and the study of the ontogenetic effects. For this, embryos were exposed to three different alcohol treatments: 0.0%, 0.25% and 0.5%, for 2 hr, at 24-hr post-fertilization. Then we evaluated the effects of embryonic alcohol exposure on conditioned place preference in two developmental stage: fry (10 days post-fertilization (dpf)) and young (90 dpf) zebrafish. Results show that control fish presented alcohol associative learning, which means, changes in place preference due to alcohol exposure, at both ontogenetic phases. However, zebrafish exposed to 0.25 and 0.5% alcohol during embryogenesis did not show conditioning response at any evaluated stage. These results suggest perception and cognitive deficits due to embryonic alcohol exposure that can alter alcohol responsiveness throughout a lifetime. Although low alcohol doses do not provoke malformation, it has been shown to induce several neurological and behavioral changes that are termed as Alcohol-Related Neurodevelopmental Disorders. These results may contribute to future investigations on how embryonic exposure affects the neurocircuitry related to perception and associative learning processing.

Visual search for feature conjunctions: an fMRI study comparing alcohol-related neurodevelopmental disorder (ARND) to ADHD.

BACKGROUND: Alcohol-related neurodevelopmental disorder (ARND) falls under the umbrella of fetal alcohol spectrum disorder (FASD). Diagnosis of ARND is difficult because individuals do not demonstrate the characteristic facial features associated with fetal alcohol syndrome (FAS). While attentional problems in ARND are similar to those found in attention-deficit/hyperactivity disorder (ADHD), the underlying impairment in attention pathways may be different. METHODS: Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) was conducted at 3 T. Sixty-three children aged 10 to 14 years diagnosed with ARND, ADHD, and typically developing (TD) controls performed a single-feature and a feature-conjunction visual search task. RESULTS: Dorsal and ventral attention pathways were activated during both attention tasks in all groups. Significantly greater activation was observed in ARND subjects during a single-feature search as compared to TD and ADHD groups, suggesting ARND subjects require greater neural recruitment to perform this simple task. ARND subjects appear unable to effectively use the very efficient automatic perceptual 'pop-out' mechanism employed by TD and ADHD groups during presentation of the disjunction array. By comparison, activation was lower in ARND compared to TD and ADHD subjects during the more difficult conjunction search task as compared to the single-feature search. Analysis of DTI data using tract-based spatial statistics (TBSS) showed areas of significantly lower fractional anisotropy (FA) and higher mean diffusivity (MD) in the right inferior longitudinal fasciculus (ILF) in ARND compared to TD subjects. Damage to the white matter of the ILF may compromise the ventral attention pathway and may require subjects to use the dorsal attention pathway, which is associated with effortful top-down processing, for tasks that should be automatic. Decreased functional activity in the right temporoparietal junction (TPJ) of ARND subjects may be due to a reduction in the white matter tract's ability to efficiently convey information critical to performance of the attention tasks. CONCLUSIONS: Limited activation patterns in ARND suggest problems in information processing along the ventral frontoparietal attention pathway. Poor integrity of the ILF, which connects the functional components of the ventral attention network, in ARND subjects may contribute to the attention deficits characteristic of the disorder.

Parietal dysfunction during number processing in children with fetal alcohol spectrum disorders.

Number processing deficits are frequently seen in children prenatally exposed to alcohol. Although the parietal lobe, which is known to mediate several key aspects of number processing, has been shown to be structurally impaired in fetal alcohol spectrum disorders (FASD), effects on functional activity in this region during number processing have not previously been investigated. This fMRI study of 49 children examined differences in activation associated with prenatal alcohol exposure in five key parietal regions involved in number processing, using tasks involving simple addition and magnitude comparison. Despite generally similar behavioral performance, in both tasks greater prenatal alcohol exposure was related to less activation in an anterior section of the right horizontal intraparietal sulcus known to mediate mental representation and manipulation of quantity. Children with fetal alcohol syndrome and partial fetal alcohol syndrome appeared to compensate for this deficit by increased activation of the angular gyrus during the magnitude comparison task.

Cortical morphology in children with alcohol-related neurodevelopmental disorder.

INTRODUCTION: It is well established that individuals exposed to alcohol in utero have reduced cortical grey matter volumes. However, the candidate determinants of these reductions, cortical thickness (CT) and surface area (SA), have not been investigated exclusively in alcohol-related neurodevelopmental disorder (ARND), the most prevalent fetal alcohol spectrum disorder subgroup that lacks the characteristic facial dysmorphology. METHODS: T1-weighted magnetic resonance imaging scans were obtained from 88 participants (8-16 years), 36 diagnosed with ARND and 52 typically developing controls. Scans were submitted to the CIVET pipeline (version 1.1.10). Deformable models were used to construct the inner white matter surfaces and pial surfaces from which CT and SA measures were derived. Group differences in cortical volume, CT, and SA were computed using a general linear model covaried for age, sex, and handedness. RESULTS: Global cortical volume reductions in ARND did not reflect CT, which did not differ between groups. Instead, volume decreases were consistent with global SA reductions in bilateral frontal and temporal as well as right occipital regions. Local reductions in SA were observed in the right superior temporal gyrus and the right occipital-temporal region. CONCLUSION: Results suggest that in ARND, prenatal alcohol exposure perturbs global SA to a greater degree than CT, particularly in the right temporal lobe.

Choline supplementation in children with fetal alcohol spectrum disorders has high feasibility and tolerability.

There are no biological treatments for fetal alcohol spectrum disorders (FASDs), lifelong conditions associated with physical anomalies, brain damage, and neurocognitive abnormalities. In preclinical studies, choline partially ameliorates memory and learning deficits from prenatal alcohol exposure. This phase I pilot study evaluated the feasibility, tolerability, and potential adverse effects of choline supplementation in children with FASD. We hypothesized that choline would be well tolerated with minimal adverse events. The study design was a double-blind, randomized, placebo-controlled trial. Participants included 20 children aged 2.5 to 4.9 years with prenatal alcohol exposure and FASD diagnoses. Participants were randomly assigned to 500 mg choline or placebo daily for 9 months (10 active, 10 placebo). Primary outcome measures included feasibility, tolerability, adverse effects, and serum choline levels. Seventeen participants completed the study. Compliance was 82% to 87%, as evidenced by parent-completed log sheets and dose counts. Periodic 24-hour dietary recalls showed no evidence of dietary confounding. Adverse events were minimal and were equivalent in the active and placebo arms with the exception of fishy body odor, which occurred only in the active group. There were no serious adverse events to research participants. This phase I pilot study demonstrates that choline supplementation at 500 mg/d for 9 months in children aged 2 to 5 years is feasible and has high tolerability. Further examination of the efficacy of choline supplementation in FASD is currently underway.

Alcohol exposure during development: Impact on the epigenome.

Fetal alcohol spectrum disorders represent a wide range of symptoms associated with in utero alcohol exposure. Animal models of FASD have been useful in determining the specific neurological consequences of developmental alcohol exposure, but the mechanisms of those consequences are unclear. Long-lasting changes to the epigenome are proposed as a mechanism of alcohol-induced teratogenesis in the hippocampus. The current study utilized a three-trimester rodent model of FASD to examine changes to some of the enzymatic regulators of the epigenome in adolescence. Combined pre- and post-natal alcohol exposureresulted in a significant increase in DNA methyltransferase activity (DNMT), without affecting histone deacetylase activity (HDAC). Developmental alcohol exposure also caused a change in gene expression of regulators of the epigenome, in particular, DNMT1, DNMT3a, and methyl CpG binding protein 2 (MeCP2). The modifications of the activity and expression of epigenetic regulators in the hippocampus of rodents perinatally exposed to alcohol suggest that alcohol's impact on the epigenome and its regulators may be one of the underlying mechanisms of alcohol teratogenesis.