Neurodevelopmental Milestones Research Articles

Abstract 4120856: Abdominal Aortic Blood Flow and Interstage Growth and Neurodevelopment in Patients with Single Ventricle Heart Disease

Background: Achieving normal somatic growth and neurodevelopmental (ND) milestones is a common challenge for children with single ventricle heart disease (SV) prior to stage 2 palliation (S2P). This study aimed to characterize the potential association with poor splanchnic and cerebral circulations. Methods: This retrospective single centre study included SV patients born February 1, 2012, to May 30, 2022 who underwent MRI evaluation and S2P <12 months of age. Blood flow indices, including descending aorta flow (DAoNet), were measured by phase-contrast MRI. Primary outcomes were weight-for-age Z score (WFAZ) at S2P, and 18-month ND outcomes measured by Bayley Scales of Infant and Toddler Development 3rd Ed. Spearman’s correlation was used to model associations; statistical significance was considered for p<0.05. Results: A total of 144 patients were included: 61% (n=88) male, 12% (n=17) with genetic anomalies/syndrome, median (interquartile range) gestational age was 38.7 (38, 39.6) weeks, birth weight of 3.2 (2.8-3.6) kg, and birth WFAZ -0.23 (-1.1-0.6). Stage-1 palliation (n=130) was completed at 6 (3-23) days, 34% (n=49) for hypoplastic left heart syndrome, and S2P at 6.1 (5.3-7.1) months with a WFAZ of -1.4 (-2.3- (-0.5)). S2P WFAZ did not correlate with DAoNet (Figure 1), systemic cardiac output, or other blood flow indices. Lower S2P WFAZ was associated with lower birth WFAZ, and perioperative gastrointestinal complications. Lower 18-month motor development score was associated with lower birth WFAZ, native high pulmonary blood flow physiology, and indices of increase pulmonary blood flow: superior vena cava flow (b=8.8; [95% CI: 0.7 to17], p=0.03) and pulmonary venous to systemic blood flow (Qp:Qs) (b=-7, [95% CI: -11.1 to -2.9], p=0.001). Other ND domains were associated with lower birth WFAZ, not blood flow indices. Conclusion: In SV patients, DAoNet did not correlate with growth at S2P. Modifiable factors studied were not associated with somatic growth. DAoNet, superior vena cava flow, and Qp:Qs were associated with 18-months motor development, which may indicate long-term risks of high pulmonary blood flow. Studies are needed to delineate the pathophysiology by which these findings are mediated.

Similar disease progression in nonsense Duchenne Muscular Dystrophy boys as general natural history: single Brazilian center 15 years registry view.

Duchenne muscular dystrophy is a progressive and fatal X-linked neuromuscular disease. Emergent disease-modifying therapy (DMT) in nonsense Duchenne muscular dystrophy (nmDMD) has brought new perspectives to slow down functional decline in this fatal disease. To investigate if there are differences in natural history between nmDMD and other genotypes, we described a retrospective cohort analysis of 25 nonsense mutation DMD (nmDMD) boys without disease-modifying therapy, aged between 1 and 22 years, over the last 15 years (2007-2022) in a single neuromuscular center in Rio de Janeiro and use published data on DMD natural history for comparison. Regarding prognostic factors, there were remarkable and statistically significant early loss of ambulation (at 9.1y ±2.1) and shortening of life expectancy (17.6y ±2.1) in our nmDMD group. Late acquisition of neurodevelopmental milestones and annual rates of decline in respiratory, cardiac, and timed motor function tests are the same between nmDMD patients with standard care and other DMD genotypes as described in the literature. Our data indicates the similarity of natural history and disease progression among DMD boys with nmDMD mutations compared to different mutations.

Single institution review of operative management of giant omphalocele

PurposeOperative management of giant omphalocele that cannot be closed primarily varies based on several factors, and there is little data to guide choice of operative approach and how this impacts long-term outcomes. We aimed to characterize whether surgical approach – staged closure during the neonatal period, or delayed closure – affects outcomes. MethodsWe conducted a retrospective review of children treated for giant omphalocele who did not undergo primary closure at Children's Hospital Colorado from 2010–2022. We included patients with giant omphalocele who underwent treatment at the study site. Data collected included patient characteristics, clinical course, and outcomes. Comparisons were made based on type of closure, delayed versus staged. ResultsWe identified 24 patients; 6 delayed and 16 staged. 2 patients died prior to closure. Delayed and staged groups did not differ regarding demographics. Infants undergoing staged repair tended to have more total hospital and total ventilator days, and more post-closure ventral hernia requiring repair; short-term outcomes were otherwise comparable. There was no difference between groups in long-term outcomes, including neurodevelopmental milestones and mortality. ConclusionsLong term outcomes are equivalent between staged repair and delayed repair of giant omphalocele. However, staged repair may be associated with more ventilator days, total hospital days and higher risk of ventral hernia.

Early childhood neurodevelopmental milestones in children with allergic diseases: the Japan Environment and Children’s Study (JECS)

This study investigated the potential link between early childhood allergic diseases and neurodevelopmental milestone attainment during the first 3 years of life. Utilizing data from a large-scale prospective birth cohort study in Japan, encompassing 87,986 children, we examined physician-diagnosed and caregiver-reported allergic conditions, including atopic dermatitis (AD), asthma, and food allergy (FA). Neurodevelopmental milestones were assessed using the Ages and Stages Questionnaires at 1, 1.5, 2, 2.5, and 3 years of age. Stabilized inverse probability-weighted generalized estimating equation models were employed to estimate odds ratios (ORs). Our analysis revealed no significant association of AD and asthma with delay in communication, gross motor, fine motor, problem-solving, and personal-social skills during the initial 3 years of life. However, children with FA showed an increased likelihood of experiencing gross motor delay compared with that shown by those without FA (weighted adjusted OR: 1.14). Despite this, no significant association of FA with other developmental domains was observed. Early childhood allergies may not influence neurodevelopmental delays. However, there is a potential association between FA and delays, specifically in gross motor skills, that warrants routine developmental monitoring and additional investigations.

Novel phenotype associated with homozygous likely pathogenic variant in the POP1 gene.

The biallelic variants of the POP1 gene are associated with the anauxetic dysplasia (AAD OMIM 607095), a rare skeletal dysplasia, characterized by prenatal rhizomelic shortening of limbs and generalized joint hypermobility. Affected individuals usually have normal neurodevelopmental milestones. Here we present three cases from the same family with likely pathogenic homozygous POP1 variant and a completely novel phenotype: a girl with global developmental delay and autism, microcephaly, peculiar dysmorphic features and multiple congenital anomalies. Two subsequent pregnancies were terminated due to multiple congenital malformations. Fetal DNA samples revealed the same homozygous variant in the POP1 gene. Expression of the RMRP was reduced in the proband compared with control and slightly reduced in both heterozygous parents, carriers for this variant. To our knowledge, this is the first report of this new phenotype, associated with a novel likely pathogenic variant in POP1. Our findings expand the phenotypic spectrum of POP1-related disorders.

Sexually dimorphic effects of a modified adolescent social isolation paradigm on behavioral risk factors of alcohol use disorder in Long Evans Rats

Early life stress (ELS) is a major risk factor for alcohol use disorder (AUD) and comorbid neuropsychiatric conditions. We previously demonstrated that an adolescent social isolation (aSI) model of ELS significantly increased behavioral risk factors for these disorders (e.g. anxiety-like behaviors, alcohol drinking) in male, but not female rats. Since many neurodevelopmental milestones are accelerated in females, we investigated whether an earlier/shorter isolation window (PND 21-38) would yield comparable phenotypes in both sexes. In two experiments, Long Evans rats were socially isolated (SI) or group-housed (GH) on postnatal day (PND) 21 and locomotion was assessed in the open field test (OFT; PND 30). Experiment 1 also assessed behavior on the elevated plus-maze (EPM) (PND 32). In Experiment 2, all rats were single housed on PND 38 to assess home cage alcohol drinking. Experiment 1 revealed that SI females had increased locomotor activity in the OFT but did not differ from GH subjects on the EPM. The OFT results were replicated in both sexes in Experiment 2 and both male and female SI rats had significantly greater ethanol consumption during an eight day continuous access paradigm. In contrast, during subsequent intermittent two-bottle choice drinking, only SI females displayed greater ethanol intake and preference and increased consumption of a quinine-adulterated alcohol solution. These findings demonstrate that early life social isolation can promote AUD vulnerability-related phenotypes in female rats but that there are profound sex differences in the vulnerability window to this early life stressor. Uncovering the neural mechanisms responsible for these sexually dimorphic differences in sensitivity to ELS may shed light on the biological substrates associated with vulnerability to AUD and comorbid disorders of negative emotion in men and women.

Neurodevelopmental Outcomes Among Offspring Exposed to Corticosteroid and B2-Adrenergic Agonists In Utero

Corticosteroids and β2-adrenergic agonists are commonly used during pregnancy to treat asthma. However, offspring neurodevelopmental outcomes following in utero exposure to these medications remain unclear. To investigate the association between timing of in utero exposure to corticosteroids and β2-adrenergic agonists and offspring neurodevelopmental milestones during the first 3 years of life. This cohort study obtained data from the Japan Environment and Children's Study, an ongoing birth cohort study conducted in collaboration with 15 Regional Centers across Japan. Participants were mother-offspring pairs who were recruited between January 1, 2011, and March 31, 2014. Data were analyzed between January and February 2023. Corticosteroids and β2-adrenergic agonists were the exposure of interest. Timing of corticosteroid and β2-adrenergic agonist exposure included early pregnancy (weeks 0-12), mid- to late pregnancy (weeks >12), and both stages of pregnancy. Offspring neurodevelopmental milestones (communication, gross motor, fine motor, problem-solving, and personal-social skills) were assessed using the Japanese version of the Ages and Stages Questionnaires, 3rd edition, at 6, 12, 18, 24, 30, and 36 months. In total, 91 460 mother-offspring pairs were analyzed. Among mothers, the mean (SD) age at delivery was 31.20 (5.05) years. Among offspring, 46 596 (50.9%) were males and 44 864 (49.1%) were females, of whom 66.4% had a gestational age of 39 to 41 weeks. During early, mid- to late, and both stages of pregnancy, 401 (0.4%), 935 (1.0%), and 568 (0.6%) offspring, respectively, were exposed to corticosteroids, whereas 170 (0.2%), 394 (0.4%), and 184 (0.2%), respectively, were exposed to β2-adrenergic agonists. No association of corticosteroid exposure during early, mid- to late, and both stages of pregnancy with all 5 neurodevelopmental milestones was found. Similarly, no association between β2-adrenergic agonist use during early pregnancy and all 5 neurodevelopmental milestones was observed. An association was found between β2-adrenergic agonist exposure during mid- to late pregnancy and delayed personal-social skills (adjusted odds ratio, 1.48; 95% CI, 1.01-2.32; P = .045). Results of this study found no association between in utero corticosteroid and β2-adrenergic agonist exposure and offspring neurodevelopmental outcomes, regardless of the timing of exposure. Despite the limitations and low power of the study, the findings suggest that corticosteroids and β2-adrenergic agonists are safe for pregnant individuals with asthma and the neurodevelopment of their offspring.

Neonatal herpes simplex virus infection: From the maternal infection to the child outcome.

This review examines the recent literature on the management of herpes simplex virus (HSV) infections in neonates. We summarized the three clinical categories of maternal HSV infection during pregnancy (primary first episode, nonprimary first episode, or recurrent episode) and the mechanisms of fetal damage. Considering when the transmission of the infection from the mother to the fetus/newborn occurs, three types of neonatal infection can be distinguished: intrauterine infection (5% of cases), postnatal infection (10% of cases), and perinatal infections (85% of cases). Neonatal presentation could range from a limited disease with skin, eye, and mouth disease to central nervous system disease or disseminated disease: the treatment with acyclovir should be tailored according to symptoms and signs of infection, and virological tests. These children need a multidisciplinary follow-up, to timely intercept any deviation from normal neurodevelopmental milestones. Prevention strategies remain a challenge, in the absence of an available vaccine against HSV.

Lipid peroxidation and neuroinflammation: A possible link between maternal fructose intake and delay of acquisition of neonatal reflexes in Wistar female rats.

Fructose is a common sweetener found in the daily diet supplemented to many processed and ultra-processed foods and beverages. Consumption of fructose-sweetened beverages has drastically increased in the last decades and is widely associated with metabolic disease, systemic pro-inflammatory status, and adverse transgenerational effects. To date, the impact of maternal fructose intake in brain function of the offspring is less explored. Therefore, the aim of this study was first, to investigate adverse effects in developmental milestones of the progeny of mothers with metabolic syndrome (MetS), induced by ad libitum consumption of a 20% fructose solution, and second to identify possible molecular changes in the nervous system of the newborns associated with maternal fructose intake. Wistar rats were randomly separated into two groups with access to water or fructose (20% w/v in water) for 10 weeks. After MetS was confirmed, dams were mated with control males and continued drinking water or fructose solution during gestation. At postnatal day (PN) 1, a subgroup of offspring of each sex was sacrificed and brains were dissected for oxidative stress and inflammatory status analysis. Changes in the developmental milestones due to maternal fructose consumption were studied (PN3-PN21) in another subgroup of offspring. Sexually dimorphic effects were found on the progeny's acquisition of neurodevelopmental milestones, in brain lipid peroxidation, neuroinflammation, and antioxidative defensive response. Our results suggest that dams' MetS, induced by fructose intake, disrupts brain redox homeostasis in female offspring and affects sensorimotor brain circuitry which may have a translational value for studying neurodevelopmental diseases.

Zika Virus affects neurobehavioral development, and causes oxidative stress associated to blood–brain barrier disruption in a rat model of congenital infection

Zika virus (ZIKV) is a mosquito-borne flavivirus associated with several neurodevelopmental outcomes after in utero infection. Here, we studied a congenital ZIKV infection model with immunocompetent Wistar rats, able to predict disabilities and that could pave the way for proposing new effective therapies. We identified neurodevelopmental milestones disabilities in congenital ZIKV animals. Also, on 22nd postnatal day (PND), blood–brain barrier (BBB) proteins disturbances were detected in the hippocampus with immunocontent reduction of β_Catenin, Occludin and Conexin-43. Besides, oxidative stress imbalance on hippocampus and cortex were identified, without neuronal reduction in these structures. In conclusion, even without pups’ microcephaly-like phenotype, congenital ZIKV infection resulted in neurobehavioral dysfunction associated with BBB and oxidative stress disturbances in young rats. Therefore, our findings highlighted the multiple impact of the congenital ZIKV infection on the neurodevelopment, which reinforces the continuity of studies to understand the spectrum of this impairment and to provide support to future treatment development for patients affected by congenital ZIKV.

Sex-specificities in offspring neurodevelopment and behaviour upon maternal glycation: Putative underlying neurometabolic and synaptic changes

AimLactation is an important programming window for metabolic disease and neuronal alterations later in life. We aimed to study the effect of maternal glycation during lactation on offspring neurodevelopment and behaviour, assessing possible sex differences and underpinning molecular players. MethodsFemale Wistar rats were treated with Glyoxalase-1 inhibitor S-p-Bromobenzylguthione cyclopentyl diester (BBGC 5 mg/kg). A control and vehicle group treated with dimethyl sulfoxide were also considered. Male and female offspring were tested at infancy for neurodevelopment hallmarks. After weaning, triglycerides and total antioxidant capacity were measured in breast milk. At adolescence, offspring were tested for locomotor ability, anxious-like behaviour, and recognition memory. Metabolic parameters were assessed, and the hippocampus and prefrontal cortex were collected for molecular analysis. Key findingsMaternal glycation reduced triglycerides and total antioxidant capacity levels in breast milk. At infancy, both male and female offspring presented an anticipation on the achievement of neurodevelopmental milestones. At adolescence, male offspring exposed to maternal glycation presented hyperlocomotion, whereas offspring of both sexes presented a risk-taking phenotype, accompanied by increase GABAA receptor levels in the hippocampus. Females also demonstrated GABAA and PSD-95 changes in prefrontal cortex. Furthermore, lower levels of GLO1 and consequently higher accumulation of AGES were also observed in both male and female offspring hippocampus. SignificanceEarly exposure to maternal glycation induces changes in milk composition leading to neurodevelopment changes at infancy, and sex-specific behavioural and neurometabolic changes at adolescence, further evidencing that lactation period is a critical metabolic programming window and in sculpting behaviour.

Synaptic alterations as a common phase in neurological and neurodevelopmental diseases: JNK is a key mediator in synaptic changes.

Synaptic alterations as a common phase in neurological and neurodevelopmental diseases: JNK is a key mediator in synaptic changes.

Transtorno do espectro autista e diagnóstico diferencial do atraso de fala na infância: uma revisão da literatura

OBJECTIVE: The aim of this article is to describe the main differential diagnosis of speech delay in childhood, with an emphasis on the current diagnostic criteria for differentiating between neurodevelopmental disorders, such as Autism Spectrum Disorder, and other differential diagnosis. METHODS: A non-systematic literature review was performed, using the most recent diagnostic criteria and definitions. RESULTS: Speech delay is a common symptom in the pediatric age group which may be present in children with neurodevelopmental disorders, being frequently associated with the Autism Spectrum Disorder. There is, however, a range of possible alternative diagnoses that may present with language delay and that must be considered in the differential diagnosis, such as other neurodevelopmental disorders, hearing impairment, and language disorders. CONCLUSION: Pediatricians play an important role in the assessment, investigation and management of children with speech delay. Thus, they must be familiar with expected neurodevelopmental milestones, as well as with red flags for development delay in all domains, including language, and for the diagnostic criteria for the most common disorders.

Air pollution during the perinatal period and neurodevelopment in children: A national population study in Taiwan.

To evaluate the association between ambient particulate matter no larger than 2.5 μm in diameter (PM2.5 ) during the prenatal and postnatal periods and infant neurodevelopmental parameters. We conducted a population-based birth cohort study using the Taiwan Birth Cohort Study. Participants were assessed for developmental conditions through home interviews at 6 months and 18 months of age. Exposure to PM2.5 of mothers and infants during perinatal periods was estimated using hybrid kriging/land-use regression. The exposure was linked to each participant by home address. Logistic regression was then conducted to determine the risk of neurodevelopmental delay in relation to PM2.5 . A total of 17 683 term singletons without congenital malformations were included in the final analysis. PM2.5 during the second trimester was associated with increased risks of delays in gross motor neurodevelopmental milestones (adjusted odds ratio [aOR] 1.09 per 10 μg/m3 increase in exposure to PM2.5 ). Delayed fine motor development was also found to be related to exposure to PM2.5 in the second and third trimesters (aOR 1.06), as was personal-social skill (aOR 1.11 for the second trimester and 1.06 for the third). These neurodevelopmental parameters were unrelated to postnatal PM2.5 exposure. Exposure to ambient PM2.5 during pregnancy was significantly related to delay in gross motor, fine motor, and personal-social development in this population-based study. Prenatal exposure to higher PM2.5 was associated with increased risk of delayed early neurodevelopment. The critical period for delayed gross motor development was the second trimester. The critical period for fine motor and personal-social development was the second and third trimesters.

Quantification of Behavioral Deficits in Developing Mice With Dystonic Behaviors.

Converging evidence from structural imaging studies in patients, the function of dystonia-causing genes, and the comorbidity of neuronal and behavioral defects all suggest that pediatric-onset dystonia is a neurodevelopmental disorder. However, to fully appreciate the contribution of altered development to dystonia, a mechanistic understanding of how networks become dysfunctional is required for early-onset dystonia. One current hurdle is that many dystonia animal models are ideally suited for studying adult phenotypes, as the neurodevelopmental features can be subtle or are complicated by broad developmental deficits. Furthermore, most assays that are used to measure dystonia are not suited for developing postnatal mice. Here, we characterize the early-onset dystonia in Ptf1a Cre ;Vglut2 fl/fl mice, which is caused by the absence of neurotransmission from inferior olive neurons onto cerebellar Purkinje cells. We investigate motor control with two paradigms that examine how altered neural function impacts key neurodevelopmental milestones seen in postnatal pups (postnatal day 7-11). We find that Ptf1a Cre ;Vglut2 fl/fl mice have poor performance on the negative geotaxis assay and the surface righting reflex. Interestingly, we also find that Ptf1a Cre ;Vglut2 fl/fl mice make fewer ultrasonic calls when socially isolated from their nests. Ultrasonic calls are often impaired in rodent models of autism spectrum disorders, a condition that can be comorbid with dystonia. Together, we show that these assays can serve as useful quantitative tools for investigating how neural dysfunction during development influences neonatal behaviors in a dystonia mouse model. Our data implicate a shared cerebellar circuit mechanism underlying dystonia-related motor signs and social impairments in mice.

Sex-specific associations among infant food and atopic sensitizations and infant neurodevelopment.

Food sensitization is a first and strong indicator of immune deviation in the progression to other allergic conditions. Sensitization to food or other allergens and related inflammation during critical windows of infant development may adversely affect neurodevelopmental milestones. However, additional research is needed to test this association further. Associations between atopic (any food or aeroallergen) or food sensitization (specific to egg, soybean, peanut, and milk) at age 1 year and neurodevelopment up to 2 years of age were evaluated in the national CHILD Cohort Study, with a secondary aim examining whether these associations were sex-specific. Food and atopic sensitization were assessed by skin prick tests (SPT) in 1-year-old infants, with neurodevelopment assessed using the cognitive, language, motor, and social-emotional subscales of the Bayley Scales of Infant Development (BSID-III) administered at 1 and 2 years of age. Atopic sensitization was present among 16.4% of infants, while 13.4% had food sensitizations. Only socioemotional scores reached statistical significance among the four BSID-III domains. Both atopic and food sensitization at 1 year of age was associated with lower social-emotional scores, independent of the infant's ethnicity. These findings were sex-specific and only observed among boys, among whom social-emotional scores were lowered by 5 points if atopic sensitization was present (-5.22 [95% CI: -9.96, -0.47], p = 0.03) or if food sensitization was present (-4.85 [95% CI: -9.82,0.11], p = 0.06). Similar results were observed using the standard SPT cut-off of ≥3 mm - for atopic sensitization (-5.17 [95% CI: -11.14, -0.80], p = 0.09) and for food sensitization (-4.61 [95% CI: -10.96, 1.74], p = 0.15). In our study of term infants, we found an inverse, cross-sectional association between atopic and food sensitization status and social-emotional development scores in male children but not female children.

The spatiotemporal dynamics of microglia across the human lifespan.

Microglia, the brain's resident macrophages, shape neural development and are key neuroimmune hubs in the pathological signatures of neurodevelopmental disorders. Despite the importance of microglia, their development has not been carefully examined in the human brain, and most of our knowledge derives from rodents. We aimed to address this gap in knowledge by establishing an extensive collection of 97 post-mortem tissues in order to enable quantitative, sex-matched, detailed analysis of microglia across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing waves in microglial density across gestation, infancy, and childhood, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNA-seq and single-cell RNA-seq datasets. This study provides a detailed insight into the spatiotemporal dynamics of microglia across the human lifespan and serves as a foundation for elucidating how microglia contribute to shaping neurodevelopment in humans.

Evaluation of Neurodevelopmental Outcomes in Premature Twins (Multigestations) with Retinopathy of Prematurity Receiving Anti-VEGF: A Comparison Study.

Purpose To assess possible neurodevelopmental delay (NDD) following intravitreal antivascular endothelial growth factor (VEGF) injection in neonates with retinopathy of prematurity (ROP). Methods In this retrospective cohort study, neurodevelopmental milestones in patients with a history of ROP and intravitreal bevacizumab (IVB) injection were compared with other gestations that received either no treatment or only a laser for treatment. Results One hundred and twenty-five neonates (of 59 multi-gestation pregnancies) were included in this study (with the range of age 1–7 years old). Sixty-five (51.18%) were male and sixty-two (48.81%) were female. The mean gestational age (GA) and birth weight of all neonates were 29.69 ± 1.57 weeks (ranges: 26–33 weeks) and 1312.50 ± 269.33 grs (ranges: 730–2100 grs). None of the neurodevelopmental outcomes were statistically different when two subgroups in group A (IVB vs. control) were compared. None of the differences between IVB and laser treated subgroups is statistically significant, except for “reaching for toys,” which was delayed in the laser treated subgroup (6.6 ± 2.5 and 6.9 ± 2.5 months in IVB and laser treated subgroups, respectively). Conclusion In neonates with ROP, there is no linear correlation between intravitreal anti-VEGF injection and neurodevelopmental delay.

Self injuries in adolescence, an unusual clinical presentation of autism

IntroductionAlthough autism is only twice more common in men than women in general population, in clinical samples women are underrepresented. This difference may be due to a poor sensitivity of current diagnostic criteria of autism related to females. We present a 13-year-old woman referred to the adolescent psychiatric unit for anxiety, self injuries and suicidal ideation. After careful assessment of current symptoms and neurodevelopmental milestones, deficits in emotional-comunicational reciprocity, nonverbal comunication and relationships emerged, as well as inflexible adherence to routines and restricted interests. The diagnose of autism spectrum disorder was made and the patient started a specific treatment.ObjectivesTo review the clinical features of autism spectrum disorders in adolescent females and its differential diagnosis.MethodsReview of the literature on autism spectrum disorders in female and its specific features.ResultsThe “Female Autism Phenotype” is a group features that are more common in autistic women, as opposed to the classic symptoms of autism in men. Some of these differential characteristics are: fewer social impairments and higher levels of social motivation; more age and gender appropriate restricted and repetitive interests; more internalizing rather than externalizing symptoms; and a tendency towards camouflagingConclusions- Autism in women is frequently underdiagnosed. - Females express autism in ways that not allways meet the current diagnostic criteria. - The “Female Autism Phenotype” has been proposed as an specific way of expression of autism in females.DisclosureNo significant relationships.

S-Adenosyl-Methionine alleviates sociability aversion and reduces changes in gene expression in a mouse model of social hierarchy

Epigenetic changes are an important pathogenic mechanism in many diseases, including a variety of psychiatric disorders such as Autism Spectrum Disorder (ASD) and depression. Methyl donors such as S-Adenosyl-Methionine (SAMe) may cause epigenetic modifications, especially during embryonic development when the epigenetic memory is established. We treated pregnant submissive (Sub) mice exhibiting depressive-like phenotype with SAMe during days 12–14 of gestation aiming to alleviate the depressive – like symptoms in their offspring and normalize the expression in their prefrontal cortex of several genes possibly involved in depression. We also aimed to define possible gender differences of the effects of SAMe on the measured parameters. Treatment of the Dams with SAMe did not affect the early neurodevelopmental milestones in males or females. The results of the behavioral tests showed improvement in some behavioral parameters compared to saline treated Sub mice. Several of these improvements were gender related. Prenatal SAMe treatment mainly improved sociability, as observed in the three chambers social interaction test, in both genders. It also improved the increased locomotion (as observed by the open field test) in the female mice, but not in males. Prenatal SAMe increased the expression of Vegfa and Flt1 in males, but not in females. The expression of IgfII and SynIIb increased in males and decreased in females and the expression of serotonin receptor Htr2A did not change in both genders. In our mouse model of depression, prenatal treatment with SAMe significantly improved some parameters of depressive like behavior and normalized the expression of several genes related to depression. The gender differences observed in our studies may explain the sex related differences in the clinical presentation of depression and the different gender related response to treatment.