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The current genetic diagnostic workup of congenital cataract (CC) is mainly based on NGS panels, whereas exome sequencing (ES) has occasionally been employed. In this multicentre study, we investigated by ES the detection yield, mutational spectrum and genotype-phenotype correlations in a CC cohort recruited between 2020 and mid-2022. The cohort consisted of 67 affected individuals from 51 unrelated families and included both non-syndromic (75%) and syndromic (25%) phenotypes, with extra-CC ocular/visual features present in both groups (48% and 76%, respectively). The functional effect of variants was predicted by 3D modelling and hydropathy properties changes. Variant clustering was used for the in-depth assessment of genotype-phenotype correlations. A diagnostic (pathogenic or likely pathogenic) variant was identified in 19 out of 51 probands/families (~37%). In a further 14 probands/families a candidate variant was identified: in 12 families a VUS was detected, of which 9 were considered plausibly pathogenic (i.e., 4 or 5 points according to ACMG criteria), while in 2 probands ES identified a single variant in an autosomal recessive gene associated with CC. Eighteen probands/families, manifesting primarily non-syndromic CC (15/18, 83%), remained unsolved. The identified variants (8 P, 12 LP, 10 VUS-PP, and 5 VUS), half of which were unreported in the literature, affected five functional categories of genes involved in transcription/splicing, lens formation/homeostasis (i.e., crystallin genes), membrane signalling, cell-cell interaction, and immune response. A phenotype-specific variant clustering was observed in four genes (KIF1A, MAF, PAX6, SPTAN1), whereas variable expressivity and potential phenotypic expansion in two (BCOR, NHS) and five genes (CWC27, KIF1A, IFIH1, PAX6, SPTAN1), respectively. Finally, ES allowed to detect variants in six genes not commonly included in commercial CC panels. These findings broaden the genotype-phenotype correlations in one of the largest CC cohorts tested by ES, providing novel insights into the underlying pathogenetic mechanisms and emphasising the power of ES as first-tier test.
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Infant attention is a cognitive function that underlines sensory-motor integration processes at the interface between the baby and the surrounding physical and socio-relational environment, mainly with the caregivers. The investigation of the role of non-visual inputs (i.e., vocal and tactile) provided by the caregivers in shaping infants' attention in the context of visual impairment is relevant from both a theoretical and clinical point of view. This study investigated the social attention (i.e., gaze orientation) skills in a group of visually impaired (VI) and age-matched sighted controls (SCs) between 9 and 12 months of age. Moreover, the role of VI severity and maternal vocalizations and touch in shaping the social attention were investigated. Overall, 45 infants and their mothers participated in a video-recorded 4 min interaction procedure, including a play and a still-face episode. The infants' gaze orientation (i.e., mother-directed, object-directed, or unfocused) and the types of maternal vocalizations and touch (i.e., socio-cognitive, affective) were micro-analytically coded. Maternal vocalizations and touch were found to influence gaze orientation differently in VI infants compared SCs. Moreover, the group comparisons during the play episode showed that controls were predominantly oriented to the mothers, while VI infants were less socially oriented. Visual impairment severity did not emerge as linked with social attention. These findings contribute to our understanding of socio-cognitive developmental trajectories in VI infants and highlight the need for tailored interventions to promote optimal outcomes for VI populations.
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The relationship between cerebral rhythms and early sensorimotor development is not clear. In recent decades, evidence revealed a rhythmic modulation involving sensorimotor processing. A widely corroborated functional role of oscillatory activity is to coordinate the information flow across sensorimotor networks. Their activity is coordinated by event-related synchronisation and desynchronisation in different sensorimotor rhythms, which indicate parallel processes may be occurring in the neuronal network during movement. To date, the dynamics of these brain oscillations and early sensorimotor development are unexplored. Our study investigates the relationship between the cerebral rhythms using EEG and a typical rhythmic movement of infants, the non-nutritive sucking (NNS) behaviour. NNS is an endogenous behaviour that originates from the suck central pattern generator in the brainstem. We find, in 17 infants, that sucking frequency correlates with beta synchronisation within the sensorimotor area in two phases: one strongly anticipating (~3 s) and the other encompassing the start of the motion. These findings suggest that a beta synchronisation of the sensorimotor cortex may influence the sensorimotor dynamics of NNS activity. Our results reveal the importance of rapid brain oscillations in infants and the role of beta synchronisation and their possible role in the communication between cortical and deep generators.
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Sleep plays a crucial role in brain development, sensory information processing, and consolidation. Sleep spindles are markers of these mechanisms as they mirror the activity of the thalamocortical circuits. Spindles can be subdivided into two groups, slow (10-13 Hz) and fast (13-16 Hz), which are each associated with different functions. Specifically, fast spindles oscillate in the high-sigma band and are associated with sensorimotor processing, which is affected by visual deprivation. However, how blindness influences spindle development has not yet been investigated. We recorded nap video-EEG of 50 blind/severely visually impaired (BSI) and 64 sighted children aged 5 months to 6 years old. We considered aspects of both macro- and micro-structural spindles. The BSI children lacked the evolution of developmental spindles within the central area. Specifically, young BSI children presented low central high-sigma and high-beta (25-30 Hz) event-related spectral perturbation and showed no signs of maturational decrease. High-sigma and high-beta activity in the BSI group correlated with clinical indices predicting perceptual and motor disorders. Our findings suggest that fast spindles are pivotal biomarkers for identifying an early developmental deviation in BSI children. These findings are critical for initial therapeutic intervention.
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Encéfalo , Sueño , Niño , Humanos , Electroencefalografía , Cognición , Ceguera , Fases del SueñoRESUMEN
AIM: To describe visual function in children with Joubert syndrome and to investigate its possible association with diagnostic and developmental aspects. METHOD: This retrospective cross-sectional work included 59 patients (33 male; mean age 9 years 2 months, standard deviation 6 years 3 months, range 4 months to 23 years) diagnosed with Joubert syndrome from January 2002 to December 2020. Data about clinical (neurological, neuro-ophthalmological, developmental/cognitive) and diagnostic (e.g. genetic testing, neuroimaging, systemic involvement) evaluations were collected in a data set during a review of medical records. Clinical and diagnostic variables were described in terms of raw counts and percentages. A χ2 test was conducted to investigate their association with neuropsychological skills. RESULTS: Ocular motor apraxia was highly represented in our cohort (75%), with a high prevalence of refractive defects and retinal abnormalities. Developmental delay/intellectual disability was frequent (in 69.5% of the sample), associated with retinal dystrophy (p = 0.047) and reduced visual acuity both for near (p = 0.014) and for far distances (p = 0.017). INTERPRETATION: On the basis of the relevance of oculomotor and perceptual alterations and their impact on overall and cognitive impairment, we encourage early and multidisciplinary assessment and follow-up of visual function in children with Joubert syndrome. This would help in planning a personalized rehabilitation to sustain functional vision. Further studies will be important to explore the link between biological aspects and global functioning in children with Joubert syndrome. WHAT THIS PAPER ADDS: Perceptual deficits and oculomotor impairments frequently coexist in Joubert syndrome. Retinal dysfunction may be present despite the absence of funduscopic abnormalities. Both perceptual and oculomotor impairments negatively affect cognitive development in Joubert syndrome.
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Anomalías Múltiples , Anomalías del Ojo , Enfermedades Renales Quísticas , Trastornos de la Motilidad Ocular , Niño , Humanos , Masculino , Lactante , Cerebelo/diagnóstico por imagen , Anomalías del Ojo/complicaciones , Enfermedades Renales Quísticas/complicaciones , Retina/diagnóstico por imagen , Trastornos de la Motilidad Ocular/genética , Estudios Retrospectivos , Estudios Transversales , Imagen por Resonancia MagnéticaRESUMEN
Though considered a benign condition, idiopathic infantile nystagmus (IIN) may be associated with decreased visual acuity and oculo-motor abnormalities, resulting in developmental delays and poor academic performance. Nevertheless, the specific visual function profile of IIN and its possible impact on neuropsychological development have been poorly investigated. To fill this gap, we retrospectively collected the clinical data of 60 children presenting with IIN over a 10-year period (43 male; mean age of 7 years, range of 2 months-17 years, 9 months). The majority of the subjects in our cohort presented with reduced visual acuity for far distances and normal visual acuity for near distances, associated with oculo-motor abnormalities. The overall scores of cognitive and visual-cognitive tests were in the normal range, but revealed peculiar cognitive and visual-cognitive profiles, defined by specific frailties in processing speed and visual-motor integration. The same neuropsychological profiles characterize many neurodevelopmental disorders and may express a transnosographic vulnerability of the dorsal stream. As the first study to explore the neuropsychologic competencies in children with IIN, our study unveils the presence of subclinical frailties that need to be addressed to sustain academic and social inclusion.
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We developed the TechArm system as a novel technological tool intended for visual rehabilitation settings. The system is designed to provide a quantitative assessment of the stage of development of perceptual and functional skills that are normally vision-dependent, and to be integrated in customized training protocols. Indeed, the system can provide uni- and multisensory stimulation, allowing visually impaired people to train their capability of correctly interpreting non-visual cues from the environment. Importantly, the TechArm is suitable to be used by very young children, when the rehabilitative potential is maximal. In the present work, we validated the TechArm system on a pediatric population of low-vision, blind, and sighted children. In particular, four TechArm units were used to deliver uni- (audio or tactile) or multi-sensory stimulation (audio-tactile) on the participant's arm, and subject was asked to evaluate the number of active units. Results showed no significant difference among groups (normal or impaired vision). Overall, we observed the best performance in tactile condition, while auditory accuracy was around chance level. Also, we found that the audio-tactile condition is better than the audio condition alone, suggesting that multisensory stimulation is beneficial when perceptual accuracy and precision are low. Interestingly, we observed that for low-vision children the accuracy in audio condition improved proportionally to the severity of the visual impairment. Our findings confirmed the TechArm system's effectiveness in assessing perceptual competencies in sighted and visually impaired children, and its potential to be used to develop personalized rehabilitation programs for people with visual and sensory impairments.
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Background: Face-to-face visual contact is a key component of the early parent-child interaction, therefore a visual impairment condition of the parent or the child represents a risk factor for dyadic patterns' development. Aims: The study presents a critical single case of a blind father and a 18-month-old visually impaired child. The study aims to explore changes in the relational functioning of this dyad during an early family-centered intervention. Methods and procedures: Ten parent-child sessions were videotaped and micro-analytically coded. Data were analyzed through a State Space Grid crossing child's social cues and types of father verbalizations. Outcomes and results: Findings showed a stable increase in the amount of child social cues over time. Moreover, the dyad exhibited progressive changes in dyadic regulation, stability, and organization. The return time to the "active interaction" region of interest decreased progressively. A reduction was observed also for the time spent by the dyad in the region "no vocal contact." Conclusions and implications: This critical single case highlighted the benefits of parental engagement in early interventions for the dyadic regulation in parent-child interaction.
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In the pediatric context, parents' and patients' engagement in the care process is strongly recommended and could be pursued using patient-reported outcome measures (PROMs), which therefore become useful for planning and monitoring treatments. Nevertheless, few data are available from families of children with neurodevelopmental disorders such as visual impairment (VI). The Visual Impairment Developmental Autonomy (VIDA) project aims to develop and validate a patient- and parent-reported tool to measure the most relevant aspects concerning everyday adaptive abilities in children and adolescents with visual impairment: the VIDA scale. The present paper illustrates the Delphi process of item generation engaging parents and patients and presents a protocol for the validation of this new co-designed tool in an Italian visually impaired pediatric population. Twenty-three families and five adolescents provided a list of 192 items and assessed their relevance. Items were categorized in 5 areas of adaptive abilities (i.e., table manners, clothing, personal hygiene, orientation and mobility, and socio-affectivity) and into three age ranges based on the patient's age. The final 102-item Vida Scale will be administered to a minimum of 300 visually impaired children together with measures of quality of life and child adjustment to investigate its psychometric properties.
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Calidad de Vida , Baja Visión , Adolescente , Humanos , Niño , Trastornos de la Visión , Encuestas y Cuestionarios , Medición de Resultados Informados por el Paciente , PadresRESUMEN
Cerebral Visual Impairment (CVI) has become the leading cause of children's visual impairment in developed countries. Since CVI may negatively affect neuropsychomotor development, an early diagnosis and characterization become fundamental to define effective habilitation approaches. To date, there is a lack of standardized diagnostic methods to assess CVI in children, and the role of visual functions in children's neuropsychological profiles has been poorly investigated. In the present paper, we aim to describe the clinical and neuropsychological profiles and to investigate the possible effects of visual functions on neuropsychological performance of a cohort of children diagnosed with CVI. Fifty-one children with CVI were included in our retrospective analysis (inclusion criteria: verbal IQ > 70 in Wechsler scales; absence of significant ocular involvement). For each participant, we collected data on neuropsychological assessment (i.e., cognitive, cognitive visual, and learning abilities), basic visual functions (e.g., Best Corrected Visual AcuityBCVA, contrast sensitivity, and ocular motor abilities) and global development features (e.g., neurological signs and motor development delay) based on standardized tests, according to patients' ages. The results showed that oculomotor dysfunction involving saccades and smooth pursuit may be a core symptom of CVI and might have a significant impact on cognitive visual and other neuropsychological abilities. Furthermore, visual acuity and contrast sensitivity may influence cognitive, cognitive visual, and academic performances. Our findings suggest the importance of a comprehensive assessment of both visual and neuropsychological functions in children when CVI is suspected, which is needed to provide a more comprehensive functional profile and define the best habilitation strategy to sustain functional vision.
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Introduction: A comprehensive assessment of visual functioning at an early age is important not only for identifying and defining visual impairment but also for planning personalized rehabilitation programs based on the visual diagnosis. Since existing tools to evaluate visual functioning present some important limitations (e.g., they are based on qualitative reports, they do not take into account environmental adaptations of visual testing or they have not been formally validated as clinical instruments), the present work has the main aim to propose a new clinical tool (Visual Function Score, VFS) to detect and define visual disorders at an early age. Methods: The Visual Function Score was administered to one hundred visually impaired children (age range 4 months to 17.75 years old) in the form of a professional-reported protocol for a total of 51 items, each of which is assigned a score from 1 to 9 (or from 0 to 9 in some specific cases). The VFS produces three sub-scores and a global score (from 0 to 100), resulting in a quantitative evaluation of visual functioning. Results: The VFS can detect the well-known differences between different types of visual impairment (cerebral, oculomotor, and peripheral or grouped as central and peripheral) and takes into account different environments in the definition of a quantitative score of visual functioning. Discussion: Overall, the use of a quantitative tool to evaluate visual functions and functional vision such as the VFS would be fundamental to monitor the progresses of patients over time in response to rehabilitation interventions.
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One of the critical events that regulates muscle cell differentiation is the replacement of the lamin B receptor (LBR)-tether with the lamin A/C (LMNA)-tether to remodel transcription and induce differentiation-specific genes. Here, we report that localization and activity of the LBR-tether are crucially dependent on the muscle-specific chaperone HSPB3 and that depletion of HSPB3 prevents muscle cell differentiation. We further show that HSPB3 binds to LBR in the nucleoplasm and maintains it in a dynamic state, thus promoting the transcription of myogenic genes, including the genes to remodel the extracellular matrix. Remarkably, HSPB3 overexpression alone is sufficient to induce the differentiation of two human muscle cell lines, LHCNM2 cells, and rhabdomyosarcoma cells. We also show that mutant R116P-HSPB3 from a myopathy patient with chromatin alterations and muscle fiber disorganization, forms nuclear aggregates that immobilize LBR. We find that R116P-HSPB3 is unable to induce myoblast differentiation and instead activates the unfolded protein response. We propose that HSPB3 is a specialized chaperone engaged in muscle cell differentiation and that dysfunctional HSPB3 causes neuromuscular disease by deregulating LBR.
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Proteínas de Choque Térmico Pequeñas/genética , Proteínas de Choque Térmico/metabolismo , Desarrollo de Músculos/inmunología , Músculo Esquelético/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Línea Celular , Células HeLa , Humanos , Músculo Esquelético/citología , Transfección , Receptor de Lamina BRESUMEN
Visual experience is crucial for the development of neural processing. For example, alpha activity development is a vision-dependent mechanism. Indeed, studies report no alpha activity is present in blind adults. Nevertheless, studies have not investigated the developmental trajectory of this activity in infants and children with blindness. Here, we hypothesize that the difference in neural activity of blind compared to sighted subjects is: absent at birth, progressive with age, specifically occipital and linked to a gradual motor impairment. Therefore, we consider spectral power of resting-state EEG and its association with motor impairment indices, in blind subjects and in sighted controls between 0 and 11 years of age. Blind subjects show posterior alpha activity during the first three years of life, although weaker and slower maturing compared to sighted subjects. The first great differentiation between blind and sighted subjects occurs between 3 and 6 years of age. Starting in this period, reduced alpha activity increases the probability of motor impairment in blind subjects, likely because of impaired perception/interaction. These results show that visual experience mediates the neural mechanisms generating alpha oscillations during the first years of life, suggesting that it is a sensitive period for the plasticity of this process.
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Plasticidad Neuronal , Ceguera , Niño , Preescolar , Femenino , Humanos , Lactante , Recién NacidoRESUMEN
The acquisition of spatial cognition is essential for both everyday functioning (e.g., navigation) and more specific goals (e.g., mathematics), therefore being able to assess and monitor spatial cognition from the first years of life would be essential to predict developmental outcomes and timely intervene whenever spatial development is compromised. Several shreds of evidence have indicated that spatial development can be compromised in the case of development with atypical sensory experience such as blindness. Despite the massive importance of spatial abilities for the development of psychomotor competencies across childhood, only a few standardized and experimental methods have been developed to assess them in visually impaired children. In this review, we will give a short overview of current formal (standardized) and informal (experimental) methods to assess spatial cognition in visually impaired children, demonstrating that very few validated tools have been proposed to date. The main contribution of this current work is to highlight the need of ad hoc studies to create and validate clinical measures to assess spatial cognition in visually impaired individuals and address potential future developments in this area of research.
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Congenital visual impairment may have a negative impact on spatial abilities and result in severe delays in perceptual, social, motor, and cognitive skills across life span. Despite several evidences have highlighted the need for an early introduction of re-habilitation interventions, such interventions are rarely adapted to children's visual capabilities and very few studies have been conducted to assess their long-term efficacy. In this work, we present a case study of a visually impaired child enrolled in a newly developed re-habilitation intervention aimed at improving the overall development through the diversification of re-habilitation activities based on visual potential and developmental profile, with a focus on spatial functioning. We argue that intervention for visually impaired children should be (a) adapted to their visual capabilities, in order to increase re-habilitation outcomes, (b) multi-interdisciplinary and multidimensional, to improve adaptive abilities across development, (c) multisensory, to promote the integration of different perceptual information coming from the environment.
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BACKGROUND: The questionnaires completed by the parents give a first general information on the behavioral problems of the child-adolescent, as a useful orientation to the clinical evaluation. The Child and Adolescent Behavior Inventory (CABI) is a 75-item parent questionnaire, which explores a large number of problem areas. The study of its predictive validity for the clinical diagnosis, in comparison with the Diagnostic and Statistical Manual of Mental Disorders (DSM)-oriented scales of the Child Behavior Checklist (CBCL), can assess whether its use may be advantageous. MATERIAL AND METHODS: Parents/caregivers of 462 children and adolescents responded to both CABI and CBCL as a preliminary routine investigation. The results were compared with those of diagnoses obtained after the completion of the usual clinical procedure. RESULTS: Accuracy values (probability of correct classification) resulted high for both instruments and significantly better for CABI anxiety and attention-deficit hyperactivity disorder (ADHD) scales, and for CBCL oppositional defiant disorder (ODD) and conduct disorder (CD) scales; no significant difference was found for depression scales. All the areas under the curve (AUC) of the receiver operating characteristic analysis reached excellent values, suggesting a very good predictive ability of the five scales of the two instruments. The comparison of AUC showed the CABI's anxiety and ADHD scales to give significantly higher values than those of CBCL, indicating that these two scales have a better predictive ability. CONCLUSION: The study indicates a very good comparative (vs CBCL) and predictive validity of the CABI, suggesting an advantage in the use of this shorter questionnaire, available for free use both for clinical practice and supposedly for screening and epidemiological evaluations.
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Ansiedad/diagnóstico , Déficit de la Atención y Trastornos de Conducta Disruptiva/diagnóstico , Trastornos de la Conducta Infantil/diagnóstico , Depresión/diagnóstico , Escalas de Valoración Psiquiátrica/normas , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Lista de Verificación , Niño , Trastorno de la Conducta/diagnóstico , Femenino , Humanos , Masculino , Valor Predictivo de las PruebasRESUMEN
It has been shown that the total or partial lack of visual experience is associated with a plastic reorganization at the brain level, more prominent in congenital blind. Cortical thickness (CT) studies, to date involving only adult subjects, showed that only congenital blind have a thicker cortex than age-matched sighted population while late blind do not. This was explained as a deviation from the physiological mechanism of initial neural growth followed by a pruning mechanism that, in congenital blind children, might be reduced by their visual deprivation, thus determining a thicker cortex. Since those studies involved only adults, it is unknown when these changes may appear and whether they are related to impairment degree. To address this question, we compared the CT among 28 children, from 2 to 12 years, with congenital visual impairments of different degree and an age-matched sighted population. Vertex-wise analysis showed that blind children, but not low vision one, had a thicker cortical surface in few clusters located in occipital, superior parietal, anterior-cingular, orbito-frontal, and mesial precentral regions. Our data suggest that the effect of visual impairment on determining thicker cortex is an early phenomenon, is multisystemic, and occurs only when blindness is almost complete.
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Nuclear protein aggregation has been linked to genome instability and disease. The main source of aggregation-prone proteins in cells is defective ribosomal products (DRiPs), which are generated by translating ribosomes in the cytoplasm. Here, we report that DRiPs rapidly diffuse into the nucleus and accumulate in nucleoli and PML bodies, two membraneless organelles formed by liquid-liquid phase separation. We show that nucleoli and PML bodies act as dynamic overflow compartments that recruit protein quality control factors and store DRiPs for later clearance. Whereas nucleoli serve as constitutive overflow compartments, PML bodies are stress-inducible overflow compartments for DRiPs. If DRiPs are not properly cleared by chaperones and proteasomes due to proteostasis impairment, nucleoli undergo amyloidogenesis and PML bodies solidify. Solid PML bodies immobilize 20S proteasomes and limit the recycling of free ubiquitin. Ubiquitin depletion, in turn, compromises the formation of DNA repair compartments at fragile chromosomal sites, ultimately threatening cell survival.
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Núcleo Celular/metabolismo , Inestabilidad Genómica , Ribosomas/metabolismo , Ubiquitina/metabolismo , Núcleo Celular/genética , Reparación del ADN , Células HeLa , Humanos , Chaperonas Moleculares/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
Epidemiological data indicate that subjects affected by obesity have an increased risk of developing mood disorders. The relationship between obesity and mood disorders is bidirectional. We assessed whether a Hericium erinaceus treatment improved depression, anxiety, sleep, and binge eating disorders after 8 weeks of supplementation in subjects affected by overweight or obesity under a low calorie diet regimen. Looking for a possible clinical biomarker, we assessed the serum balance between brain-derived neurotrophic factor (BDNF) and its precursor pro-BDNF before and after H. erinaceus supplementation. Seventy-seven volunteers affected by overweight or obesity were recruited at the offices of the Department of Preventive Medicine, Luigi Devoto Clinic of Work, Obesity Centre, at the IRCCS Foundation Policlinico Hospital of Milan (Italy). Patients were recruited only if they had a mood and/or sleep disorder and/or were binge eating as evaluated through self-assessment questionnaires. We used two different enzyme-linked immunosorbent assays kits to discriminate circulating levels of pro-BDNF and BDNF. Eight weeks of oral H. erinaceus supplementation decreased depression, anxiety, and sleep disorders. H. erinaceus supplementation improved mood disorders of a depressive-anxious nature and the quality of the nocturnal rest. H. erinaceus increased circulating pro-BDNF levels without any significant change in BDNF circulating levels.