Euterpe music therapy method for children with cerebral palsy.

Introduction: The main purpose of our study was to evaluate whether involvement in a personalized music therapy program (Euterpe method), could improve the condition of children with cerebral palsy and their parents, compared to a control group. It investigated whether it could positively affect children's sleep quality, temperament and quality of life, quality of family life, and parental stress. Methods: A prospective single-center experimental study was conducted at "Bambino Gesù" Children's Hospital (Rome, Italy). All subjects involved attended an intensive rehabilitation program in the Neurorehabilitation Unit. In a group of patients (n = 25), a music therapy treatment was applied to evaluate the effect before and after the intervention. This group was also compared with a control group (n = 10) undergoing a standard protocol without music therapy. Results: In the experimental group, the analysis shows statistically significant effects in the Disorders of initiating and maintaining sleep (p = 0.050) and the Sleep wake transition disorders (p = 0.026) factors, and the total score (p = 0.031) of Sleep Disturbances Scale for Children; the Positive emotionality scale (p = 0.013) of Italian Questionnaires of Temperament (QUIT); the Emotional Functioning (p = 0.029), Social Functioning (p = 0.012), Worry (p = 0.032), Daily Activities (p = 0.032), Total Score (p = 0.039) and Parent HRQL Summary Score (p = 0.035) dimensions of Pediatric Quality of Life for family. While in the control group, only the Attention scale of QUIT (p = 0.003) reaches statistical significance. Discussion: Our study suggests that music therapy with the Euterpe Method has beneficial effects on fundamental aspects of the child's and his parents' lives, such as sleep, emotion control, and quality of family life.

Molecular, Translational and Clinical Research on the Two Most Common Forms of Neurodegenerative Dementia: Alzheimer's Disease and Dementia with Lewy Bodies.

While not a specific disease, dementia is a term used to describe the deterioration of cognitive function beyond what would be expected because of natural biological aging [...].

Selective Neuronal Knockout of STAT3 Function Inhibits Epilepsy Progression, Improves Cognition, and Restores Dysregulated Gene Networks in a Temporal Lobe Epilepsy Model.

OBJECTIVE: Temporal lobe epilepsy (TLE) is a progressive disorder mediated by pathological changes in molecular cascades and hippocampal neural circuit remodeling that results in spontaneous seizures and cognitive dysfunction. Targeting these cascades may provide disease-modifying treatments for TLE patients. Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) inhibitors have emerged as potential disease-modifying therapies; a more detailed understanding of JAK/STAT participation in epileptogenic responses is required, however, to increase the therapeutic efficacy and reduce adverse effects associated with global inhibition. METHODS: We developed a mouse line in which tamoxifen treatment conditionally abolishes STAT3 signaling from forebrain excitatory neurons (nSTAT3KO). Seizure frequency (continuous in vivo electroencephalography) and memory (contextual fear conditioning and motor learning) were analyzed in wild-type and nSTAT3KO mice after intrahippocampal kainate (IHKA) injection as a model of TLE. Hippocampal RNA was obtained 24 h after IHKA and subjected to deep sequencing. RESULTS: Selective STAT3 knock-out in excitatory neurons reduced seizure progression and hippocampal memory deficits without reducing the extent of cell death or mossy fiber sprouting induced by IHKA injection. Gene expression was rescued in major networks associated with response to brain injury, neuronal plasticity, and learning and memory. We also provide the first evidence that neuronal STAT3 may directly influence brain inflammation. INTERPRETATION: Inhibiting neuronal STAT3 signaling improved outcomes in an animal model of TLE, prevented progression of seizures and cognitive co-morbidities while rescuing pathogenic changes in gene expression of major networks associated with epileptogenesis. Specifically targeting neuronal STAT3 may be an effective disease-modifying strategy for TLE. ANN NEUROL 2023;94:106-122.

Anxiety in Autism Spectrum Disorder: Clinical Characteristics and the Role of the Family.

BACKGROUND: Anxiety Disorder (AD) is among the most common psychiatric comorbidity in children and adolescents with Autism Spectrum Disorder (ASD). Likewise, parental psychological distress (PPD) was linked to anxiety symptoms in children and adolescents with ASD. The aim of this study was to characterise, in a sample of children and adolescents with ASD, anxiety symptoms, the functional impairment associated and the presence of PPD. METHODS: Participants were divided into three groups based on their diagnosis: children and adolescents with a diagnosis of ASD + AD, others with a diagnosis of AD but without a diagnosis of ASD, and others with a diagnosis of ASD but without a diagnosis of AD. RESULTS: Group ASD + AD showed lower global functioning than Group ASD and Group AD. Generalised Anxiety Disorder, Separation Anxiety Disorder and Specific Phobias were more frequent in Group ASD + AD. Our findings also showed higher depressive symptoms in Group ASD + AD, both in the child and parent reports. Finally, parents of the Group ASD + AD revealed higher levels of PPD. CONCLUSIONS: Our findings suggest that early assessment of AD with functional impairment associated with the role of PPD could define individualised treatments and consequently mean a better prognosis in children and adolescents with ASD and AD.

Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder affecting subjects (premutation carriers) with a 55-200 CGG-trinucleotide expansion in the 5'UTR of the fragile X mental retardation 1 gene (FMR1) typically after age 50. As both the presence of white matter hyperintensities (WMHs) and atrophied gray matter on magnetic resonance imaging (MRI) are linked to age-dependent decline in cognition, here we tested whether MRI outcomes (WMH volume (WMHV) and brain volume) were correlated with mitochondrial bioenergetics from peripheral blood monocytic cells in 87 carriers with and without FXTAS. As a parameter assessing cumulative damage, WMHV was correlated to both FXTAS stages and age, and brain volume discriminated between carriers and non-carriers. Similarly, mitochondrial mass and ATP production showed an age-dependent decline across all participants, but in contrast to WMHV, only FADH2-linked ATP production was significantly reduced in carriers vs. non-carriers. In carriers, WMHV negatively correlated with ATP production sustained by glucose-glutamine and FADH2-linked substrates, whereas brain volume was positively associated with the latter and mitochondrial mass. The observed correlations between peripheral mitochondrial bioenergetics and MRI findings-and the lack of correlations with FXTAS diagnosis/stages-may stem from early brain bioenergetic deficits even before overt FXTAS symptoms and/or imaging findings.

Sulforaphane improves mitochondrial metabolism in fibroblasts from patients with fragile X-associated tremor and ataxia syndrome.

CGG expansions between 55 and 200 in the 5'-untranslated region of the fragile-X mental retardation gene (FMR1) increase the risk of developing the late-onset debilitating neuromuscular disease Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). While the science behind this mutation, as a paradigm for RNA-mediated nucleotide triplet repeat expansion diseases, has progressed rapidly, no treatment has proven effective at delaying the onset or decreasing morbidity, especially at later stages of the disease. Here, we demonstrated the beneficial effect of the phytochemical sulforaphane (SFN), exerted through NRF2-dependent and independent manner, on pathways relevant to brain function, bioenergetics, unfolded protein response, proteosome, antioxidant defenses, and iron metabolism in fibroblasts from FXTAS-affected subjects at all disease stages. This study paves the way for future clinical studies with SFN in the treatment of FXTAS, substantiated by the established use of this agent in clinical trials of diseases with NRF2 dysregulation and in which age is the leading risk factor.

Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked FMR1 Gene.

Fifty-five to two hundred CGG repeats (called a premutation, or PM) in the 5'-UTR of the FMR1 gene are generally unstable, often expanding to a full mutation (>200) in one generation through maternal inheritance, leading to fragile X syndrome, a condition associated with autism and other intellectual disabilities. To uncover the early mechanisms of pathogenesis, we performed metabolomics and proteomics on amniotic fluids from PM carriers, pregnant with male fetuses, who had undergone amniocentesis for fragile X prenatal diagnosis. The prenatal metabolic footprint identified mitochondrial deficits, which were further validated by using internal and external cohorts. Deficits in the anaplerosis of the Krebs cycle were noted at the level of serine biosynthesis, which was confirmed by rescuing the mitochondrial dysfunction in the carriers' umbilical cord fibroblasts using alpha-ketoglutarate precursors. Maternal administration of serine and its precursors has the potential to decrease the risk of developing energy shortages associated with mitochondrial dysfunction and linked comorbidities.

Wdfy3 regulates glycophagy, mitophagy, and synaptic plasticity.

Autophagy is essential to cell function, as it enables the recycling of intracellular constituents during starvation and in addition functions as a quality control mechanism by eliminating spent organelles and proteins that could cause cellular damage if not properly removed. Recently, we reported on Wdfy3's role in mitophagy, a clinically relevant macroautophagic scaffold protein that is linked to intellectual disability, neurodevelopmental delay, and autism spectrum disorder. In this study, we confirm our previous report that Wdfy3 haploinsufficiency in mice results in decreased mitophagy with accumulation of mitochondria with altered morphology, but expanding on that observation, we also note decreased mitochondrial localization at synaptic terminals and decreased synaptic density, which may contribute to altered synaptic plasticity. These changes are accompanied by defective elimination of glycogen particles and a shift to increased glycogen synthesis over glycogenolysis and glycophagy. This imbalance leads to an age-dependent higher incidence of brain glycogen deposits with cerebellar hypoplasia. Our results support and further extend Wdfy3's role in modulating both brain bioenergetics and synaptic plasticity by including glycogen as a target of macroautophagic degradation.

Cooperative Parent-Mediated Therapy in Children with Fragile X Syndrome and Williams Beuren Syndrome: A Pilot RCT Study of a Transdiagnostic Intervention-Preliminary Data.

Children with fragile X syndrome and William Beuren syndrome share several socio-communicative deficits. In both populations, around 30/35% of individuals meets criteria for autism spectrum disorder on gold standard instruments. Notwithstanding, few studies have explored feasibility and validity of therapy for socio-communicative deficits in individuals with these genetic conditions. In this study, we present preliminary data on a pilot RCT aimed to verify the effectiveness of cooperative parent-mediated therapy for socio-communicative deficits in a transdiagnostic perspective in a small sample of 12 participants. Our preliminary data showed that the experimental group had significant improvement in one socio-communicative skill (responsivity) and in clinical global impression, while the control group in an adaptive measure of socialization and word production. Implications of these results are then discussed.

Forensic determination of hair deposition time in crime scenes using electron paramagnetic resonance.

Several types of biological samples, including hair strands, are found at crime scenes. Apart from the identification of the value and the contributor of the probative evidence, it is important to prove that the time of shedding of hair belonging to a suspect or victim matches the crime window. To this end, to estimate the ex vivo aging of hair, we evaluated time-dependent changes in melanin-derived free radicals in blond, brown, and black hairs by using electron paramagnetic resonance spectroscopy (EPR). Hair strands aged under controlled conditions (humidity 40%, temperature 20-22°C, indirect light, with 12/12 hour of light/darkness cycles) showed a time-dependent decay of melanin-derived radicals. The half-life of eumelanin-derived radicals in hair under our experimental settings was estimated at 22 ± 2 days whereas that of pheomelanin was about 2 days suggesting better stabilization of unpaired electrons by eumelanin. Taken together, this study provides a reference for future forensic studies on determination of degradation of shed hair in a crime scene by following eumelanin radicals by utilizing the non-invasive, non-destructive, and highly specific EPR technique.

Characterization of the Metabolic, Clinical and Neuropsychological Phenotype of Female Carriers of the Premutation in the X-Linked FMR1 Gene.

The X-linked FMR1 premutation (PM) is characterized by a 55-200 CGG triplet expansion in the 5'-untranslated region (UTR). Carriers of the PM were originally thought to be asymptomatic; however, they may present general neuropsychiatric manifestations including learning disabilities, depression and anxiety, among others. With age, both sexes may also develop the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Among carriers, females are at higher risk for developing immune disorders, hypertension, seizures, endocrine disorders and chronic pain, among others. Some female carriers younger than 40 years old may develop fragile X-associated primary ovarian insufficiency (FXPOI). To date, no studies have addressed the metabolic footprint - that includes mitochondrial metabolism - of female carriers and its link to clinical/cognitive manifestations. To this end, we performed a comprehensive biochemical assessment of 42 female carriers (24-70 years old) compared to sex-matched non-carriers. By applying a multivariable correlation matrix, a generalized bioenergetics impairment was correlated with diagnoses of the PM, FXTAS and its severity, FXPOI and anxiety. Intellectual deficits were strongly correlated with both mitochondrial dysfunction and with CGG repeat length. A combined multi-omics approach identified a down-regulation of RNA and mRNA metabolism, translation, carbon and protein metabolism, unfolded protein response, and up-regulation of glycolysis and antioxidant response. The suboptimal activation of the unfolded protein response (UPR) and endoplasmic-reticulum-associated protein degradation (ERAD) response challenges and further compromises the PM genetic background to withstand other, more severe forms of stress. Mechanistically, some of the deficits were linked to an altered protein expression due to decreased protein translation, but others seemed secondary to oxidative stress originated from the accumulation of either toxic mRNA or RAN-derived protein products or as a result of a direct toxicity of accumulated metabolites from deficiencies in critical enzymes.

mtDNA depletion-like syndrome in Wilson disease.

BACKGROUND AND AIMS: Wilson disease (WD) is caused by mutations in the copper transporter ATP7B, with its main pathology attributed to copper-mediated oxidative damage. The limited therapeutic effect of copper chelators and the early occurrence of mitochondrial deficits, however, undermine the prevalence of this mechanism. METHODS: We characterized mitochondrial DNA copy number and mutations as well as bioenergetic deficits in blood from patients with WD and in livers of tx-j mice, a mouse model of hepatic copper accumulation. In vitro experiments with hepatocytes treated with CuSO4 were conducted to validate in vivo studies. RESULTS: Here, for the first time, we characterized the bioenergetic deficits in WD as consistent with a mitochondrial DNA depletion-like syndrome. This is evidenced by enriched DNA synthesis/replication pathways in serum metabolomics and decreased mitochondrial DNA copy number in blood of WD patients as well as decreased mitochondrial DNA copy number, increased citrate synthase activity, and selective Complex IV deficit in livers of the tx-j mouse model of WD. Tx-j mice treated with the copper chelator penicillamine, methyl donor choline or both ameliorated mitochondrial DNA damage but further decreased mitochondrial DNA copy number. Experiments with copper-loaded HepG2 cells validated the concept of a direct copper-mitochondrial DNA interaction. CONCLUSIONS: This study underlines the relevance of targeting the copper-mitochondrial DNA pool in the treatment of WD separate from the established copper-induced oxidative stress-mediated damage.

Characterization of Clinical Manifestations in the Co-occurring Phenotype of Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder.

Comorbidity between attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) is a frequently reported condition. However, the clinical overlaps between the two disorders are not well characterized. The Child Behavior Checklist (CBCL) is a well-documented measure of emotional and behavioral problems in children and adolescents. The aim of the present study was to evaluate whether CBCL scales were able to detect psychopathological comorbidities as well as emotional and behavioral profiles across three groups of children with ASD, ADHD, and with the co-occurrence of both disorders. The results show that around 30% of participants with ASD exhibited internalizing problems, which was in line with previous findings. Co-occurrence condition showed a clinical intermediate phenotype: relative to ADHD and ASD, youths with co-occurrence of ADHD and ASD phenotype showed respectively lower (p < 0.000) and higher externalizing problems (p < 0.000). No differences emerged in internalizing problems (p > 0.05) across groups. CBCL is a useful measure to study the psychopathological conditions as well as emotional and behavioral profiles associated with ASD, ADHD, and the co-occurrence of ADHD and ASD. The identification of psychopathological and behavioral profiles associated with ASD and ADHD is crucial to perform specific and individualized treatments. Our preliminary findings suggested the existence of an intermediate and independent phenotype between ADHD and ASD that seems to be defined by the externalizing problems. Internalizing problems do not significantly differ between the combined phenotype and the two groups.

Sex Differences in Autism Spectrum Disorder: An Investigation on Core Symptoms and Psychiatric Comorbidity in Preschoolers.

Findings regarding sex differences in autism spectrum disorder (ASD), as far as core symptoms and psychiatric comorbidities (PC) are concerned, are inconsistent, inconclusive, or conflicting among studies. The lower prevalence of ASD in females than in males and the age and intelligence quotient (IQ) heterogeneity among samples made it difficult to investigate these differences. This case-control study tries to deepen the impact of sex differences on core symptoms of autism and PC in 214 preschoolers with ASD (mean age, 45.26) without impairment in non-verbal IQ (nvIQ ≥70). A total of 107 ASD females (mean age, 44.51 ± 13.79 months) were matched one by one with 107 males (mean age, 46.01 ± 13.42 months) for chronological age (±6 months) and nvIQ (±6 points). We used the Autism Diagnostic Observation Schedule 2 (ADOS-2) and the Child Behavior Checklist (CBCL) 1.5-5 to explore autism severity and PC. The results highlight that ASD females did not significantly differ from ASD males regarding the severity of autism. Statistically significant lower levels of emotionally reactive (p = 0.005, η2 = 0.04), anxious-depressed (p = 0.001, η 2 = 0.05), internalizing problems (p = 0.04, η 2 = 0.02), and DSM-Oriented Scales anxiety problems (p = 0.02, η 2 = 0.04) in ASD females than in ASD males were also detected. Our findings of no difference in the autism severity and lower internalizing problems in females than males with ASD extend the knowledge of autism in females during preschool years. Compared to other similar studies on this topic, we can state that these results are not supported by differences in nvIQ between sexes nor by the presence of cognitive impairment. It confirms the need for clinicians to consider sex differences when describing autism psychopathology.

Cooperative parent-mediated therapy for Italian preschool children with autism spectrum disorder: a randomized controlled trial.

Parent-mediated intervention is widely used for pre-schoolers with autism spectrum disorder (ASD). Previous studies indicate small-to-moderate effects on social communication skills, but with a wide heterogeneity that requires further research. In this randomized controlled trial (RCT), cooperative parent-mediated therapy (CPMT) an individual parent coaching program for young children with ASD was administered to preschool children with ASD. All children received the same low-intensity psychosocial intervention (LPI) delivered in community settings, to evaluate the potential additional benefit of CPMT. Thirty-four participants with ASD (7 females; 27 males; aged 2, 6, 11 years) and their parents were included in the trial. The primary blinded outcome was social communication skills, assessed using the ADOS-G social communication algorithm score (ADOS-G SC). Secondary outcomes included ASD symptom severity, parent-rated language abilities and emotional/behavioral problems, and self-reported caregiver stress. Evaluations were made at baseline and post-treatment (at 6 months) by an independent multidisciplinary team. Results documented that CPMT showed an additional benefit on LPI with significant improvements of the primary blinded outcome, socio-communication skills, and of some secondary outcomes such as ASD symptom severity, emotional problems and parental stress related to parent-child dysfunctional interaction. No additional benefit was found for language abilities. Findings of our RCT show that CPMT provide an additional significant short-term treatment benefit on ASD core symptoms, when compared with active control group receiving only LPI.

Executive Functions and Symptom Severity in an Italian Sample of Intellectually Able Preschoolers with Autism Spectrum Disorder.

A novel battery (BAFE; Valeri et al. 2015) was used in order to assess three executive function (EF) abilities (working memory, inhibition and shifting) in a sample of 27 intellectually able preschoolers with autism spectrum disorder (ASD) compared with 27 typically developing children matched on age and nonverbal IQ. Differences in EF skills were analyzed in participants with distinct ASD symptom severity. Children with ASD performed worse than typical controls on both set-shifting and inhibition, but not on visuo-spatial working memory. Additionally, children with more severe ASD symptoms showed a worse performance on inhibition than children with milder symptoms. These results confirm the presence of EF deficits and highlight a link between ASD symptoms and EF impairments in preschool age.

PPARα-targeted mitochondrial bioenergetics mediate repair of intestinal barriers at the host-microbe intersection during SIV infection.

Chronic gut inflammatory diseases are associated with disruption of intestinal epithelial barriers and impaired mucosal immunity. HIV-1 (HIV) causes depletion of mucosal CD4+ T cells early in infection and disruption of gut epithelium, resulting in chronic inflammation and immunodeficiency. Although antiretroviral therapy (ART) is effective in suppressing viral replication, it is incapable of restoring the "leaky gut," which poses an impediment for HIV cure efforts. Strategies are needed for rapid repair of the epithelium to protect intestinal microenvironments and immunity in inflamed gut. Using an in vivo nonhuman primate intestinal loop model of HIV/AIDS, we identified the pathogenic mechanism underlying sustained disruption of gut epithelium and explored rapid repair of gut epithelium at the intersection of microbial metabolism. Molecular, immunological, and metabolomic analyses revealed marked loss of peroxisomal proliferator-activated receptor-α (PPARα) signaling, predominant impairment of mitochondrial function, and epithelial disruption both in vivo and in vitro. To elucidate pathways regulating intestinal epithelial integrity, we introduced probiotic Lactobacillus plantarum into Simian immunodeficiency virus (SIV)-inflamed intestinal lumen. Rapid recovery of the epithelium occurred within 5 h of L. plantarum administration, independent of mucosal CD4+ T cell recovery, and in the absence of ART. This intestinal barrier repair was driven by L. plantarum-induced PPARα activation and restoration of mitochondrial structure and fatty acid ß-oxidation. Our data highlight the critical role of PPARα at the intersection between microbial metabolism and epithelial repair in virally inflamed gut and as a potential mitochondrial target for restoring gut barriers in other infectious or gut inflammatory diseases.

Potential biomarker identification for Friedreich's ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion.

Friedreich's ataxia (FA) is a neurodegenerative disease with no approved therapy that is the result of frataxin deficiency. The identification of human FA blood biomarkers related to disease severity and neuro-pathomechanism could support clinical trials of drug efficacy. To try to identify human biomarkers of neuro-pathomechanistic relevance, we compared the overlapping gene expression changes of primary blood and skin cells of FA patients with changes in the Dorsal Root Ganglion (DRG) of the KIKO FA mouse model. As DRG is the primary site of neurodegeneration in FA, our goal was to identify which changes in blood and skin of FA patients provide a 'window' into the FA neuropathomechanism inside the nervous system. In addition, gene expression in frataxin-deficient neuroglial cells and FA mouse hearts were compared for a total of 5 data sets. The overlap of these changes strongly supports mitochondrial changes, apoptosis and alterations of selenium metabolism. Consistent biomarkers were observed, including three genes of mitochondrial stress (MTIF2, ENO2), apoptosis (DDIT3/CHOP), oxidative stress (PREX1), and selenometabolism (SEPW1). These results prompted our investigation of the GPX1 activity as a marker of selenium and oxidative stress, in which we observed a significant change in FA patients. We believe these lead biomarkers that could be assayed in FA patient blood as indicators of disease severity and progression, and also support the involvement of mitochondria, apoptosis and selenium in the neurodegenerative process.

Assessment of Psychopathological Comorbidities in Children and Adolescents With Autism Spectrum Disorder Using the Child Behavior Checklist.

Autism spectrum disorder (ASD) is characterized by psychiatric and behavioral comorbidities. The Child Behavior Checklist (CBCL) provides valid and well-established measures of emotional, behavioral, and social problems in children and adolescents. The aim of the present study was to verify whether emotional, behavioral, and social problems were modulated by ASD symptom severity, cognitive development, gender, and age by analyzing the CBCL in a large group of children and adolescents with ASD. The results show that around 30% of participants with ASD exhibited internalizing problems and only 6% externalizing problems, with males exhibiting more internalizing problems than females. No correlation was found between CBCL scores and indices of ASD severity. However, higher CBCL Total Problems scores were found in older children and in children with lower cognitive abilities. The detection of behavioral and emotional problems allows children with ASD to undergo specific and individualized treatment that takes into account their psychopathological problems.

Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size.

The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.