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Vitamin D is endowed with a number of biological properties, including down-regulation of inflammation, and might contribute to the pathogenesis of autism spectrum disorders (ASD). Vitamin D binds to the vitamin D Receptor (VDR); the biological activity of the ensuing complex depends on VDR FokI, BsmI, ApaI, and TaqI gene polymorphisms. We evaluated such Single Nucletoide Polymorphismsm (SNPs) in a cohort of 100 Italian families with ASD children. FokI genotype distribution was skewed in ASD children compared with their healthy sibs (Pc = 0.03 2 df) and to a group of 170 Italian healthy women (HC) (Pc = 0.04 2 df). FokI genotype and allelic distribution skewing were also observed in mothers of ASD children compared to HC (Pc = 0.04 2 df). Both Transmission Disequilibrium Test for single loci and haplotype analysis distribution revealed a major FokI (C) allele-mediated protective effect, which was more frequently transmitted (73%) than not transmitted to healthy sibs (P = 0.02). A protective FokI-, BsmI-, ApaI-, and TaqI (CCAG) haplotype was more frequently carried by healthy sibs than by ASD children (P = 1 × 10-4 ; OR: 0.1, 95% CI: 0.03-0.4) too. Finally, a strong gene-dose association of FokI (T) allele with both higher Childhood Autism Rating Scale score (Pc = 0.01) and, particularly, with hyperactivity behavior (Pc = 0.006) emerged in ASD children. Because the protein produced by the FokI (T) allele is transcriptionally less active than that produced by the FokI (C) allele, the reduced biological activity of the vitamin D/VDR complex prevalent in ASD could favor ASD- and maternal immune activation- associated inflammation. Vitamin D supplementation might be useful in preventative and rehabilitation protocols for ASD. Autism Res 2020, 13: 680-690. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Vitamin D deficiency and Vitamin D receptor (VDR) polymorphisms are associated with structural and functional brain abnormalities and behavioral disorders. We analyzed the association of VDR gene polymorphisms in a cohort of 100 Italian families with ASD children. A strong correlation between one of the VDR polymorphisms and hyperactivity behavior was evidenced in ASD children. In healthy mothers, the same VDR polymorphism was also correlated with an increased risk of giving birth to children with ASD.

The borderline intellectual functioning (BIF) is a neurodevelopmental condition characterized by a borderline intelligence quotient (range 70–85) with difficulties in cognitive and social domains. Children with BIF often live in adverse conditions and show academic and behavioral difficulties. Rehabilitation programs for these children focus mainly on cognitive aspects, sometimes with the aid of new technologies that are able to engage and motivate. In this framework, the affective development of children with BIF and its possible role both in the difficulties they manifest and in the rehabilitation is still poorly investigated. In this work, we investigate the characteristics of the internal working models of these children by applying the separation anxiety test, using both the classical and a new coding system to identify the specific features of the attachment representation. Results delineate a profile characterized by low self-confidence and high separation anxiety, with a tendency to somatization. In the light of these results, we suggest that this attachment profile has an impact on the therapeutic relationships and on the efficacy in the use of technological devices. We propose a new perspective in which the interpersonal relationship with the psychologist and the support of the self-confidence of children are crucial to treating cognitive and behavioral difficulties in children with BIF. Only in this case, the use of new technologies and tools may be effective in promoting the greatest possible benefit from therapeutic interventions.

Recent results show that in mainland Italian children with Autism spectrum disorder (ASD), HLA-G coding alleles distribution is skewed and an association between HLA-G*01:05N and ASD is present. Herein, in an independent cohort of Sardinian ASD (sASD) children and their relatives, we verify whether HLA-G allele association with ASD could be confirmed in this genetically peculiar insular population. One hundred children with a diagnosis of ASD, born in Sardinia and of Sardinian descent, 91 of their mothers, and 40 of their healthy siblings were enrolled. DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies. Alleles distribution was compared with that of continental ASD children and with a control group of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. Skewing of HLA-G allele distribution was replicated in sASD children; in particular, the HLA-G*01:03 allele, associated with reduced fetal tolerogenicity and development of myeloid leukemia, was more common in both ASD groups compared to controls (pc = 1 × 10−3; OR:3.5, 95%CI: 1.8–6.8). However, given the lack of data on HLA-G*01:03 allelic distribution among Sardinian healthy subjects, we cannot exclude a population effect. These data confirm an association of HLA-G locus with ASD development, particularly with those alleles linked to a lower expression of tolerogenic HLA-G protein, thus warranting further studies on HLA-G polymorphism distribution in different ASD populations.

Background The costs and benefits of full lockdown measures are debated. Neurologically impaired children are a vulnerable population with specific needs in terms of protection against infection and access to health services. Objectives We investigated the effects of lockdown on the health of children with neurological disorders and on their access to care during lockdown. Methods Data from 514 children (282 males – 232 females) were collected through physician-administered interviews to investigate: the occurrence of viral-like physical symptoms, the correlation between the risk of developing such symptoms and several demographic and clinical variables, the occurrence of any worsening of the children's neurological conditions during lockdown, and their access to care services during this period. Results 49.1% experienced at least one symptom during the study period, but no child developed severe complications. The prevalence of symptoms was significantly lower during lockdown than during the previous two months. The underlying neurological condition worsened in 11.5% of the patients. Children who regularly left the home during lockdown were greater risk of exhibiting symptoms. During lockdown, 67.7% had a specialist appointment cancelled, 52.6% contacted their paediatrician, and 30.9% contacted their child neuropsychiatrist. Among patients who usually receive rehabilitation, 49.5% continued remotely. Conclusion Lockdown protected children from infections. Telemedicine and telerehabilitation constituted a valid alternative for the care and treatment of these children, but they should not become a widespread and definitive model of care. COVID-19 and other emergency response plans must take into account the specific needs of children with disabilities.

Epigenetic factors related to early life adversity (ELA) in childhood are major risk factors for borderline intellectual functioning (BIF). BIF affects both adaptive and intellectual abilities, commonly leading to school failure and to an increased risk to develop mental and social problems in the adulthood. This study aimed to investigate the neurobiological underpinnings of ELA associated with BIF in terms of global topological organization and structural connectivity and their relation with intellectual functioning.BIF (N=32) and age-matched typical development (TD, N=14) children were evaluated for intelligence quotient (IQ), behavioral competencies, and ELA. Children underwent an anatomical and diffusion-weighted MR imaging (DWI) protocol. Global brain topological organization was assessed measuring segregation and integration indexes. Moreover, structural matrices, measuring normalized number of fibers (NFn), were compared between the 2 groups using network-based statistics. Finally, a linear regression model was used to explore the relationship between network parameters and clinical measures.Results showed increased behavioral difficulties and ELA, together with decreased network integration in BIF children. Moreover, significantly lower NFn was observed in the BIF group (p=.039) in a sub-network comprising anterior and posterior cingulate, the pericallosal sulcus, the orbital frontal areas, amygdala, basal ganglia, the accumbens nucleus, and the hippocampus. Linear regression showed that NFn significantly predicted IQ (pThis study demonstrated that ELA in children with BIF is associated with a decreased information integration at the global level, and with an altered structural connectivity within the limbic system strictly related to the intellectual functioning.

Activating KIR-HLA-C ligand complexes and HLA-G∗14bp insertion/deletion (+/−) polymorphism were associated to Autism Spectrum Disorders (ASD) and were suggested to correlate with inflammation during fetal development. We evaluated whether HLA-G∗14bp(+/−) and KIR-HLA-C complexes are associated with cognitive and behavioral scores and EEG profile in 119 ASD children (58 from Sardinia, 61 from Peninsular Italy). KIR2DS1-C2; KIR2DS2-C1; KIR2DL1-C2; KIR2DL2-C1; KIR2DL3-C1 and HLA-G∗14bp(+/−) were molecularly genotyped by Single Specific Primer PCR and gel electrophoresis. Univariate linear model analysis adjusted for age, gender and provenience showed statistically higher scores of Childhood Autism Rating Scale (CARS) and Autistic Core Behavior in KIR2DS1-C2 + /HLA-G∗14bp +ASD children (43.7 ± 1.5, p = 0.03; 3.3 ± 0.1, p = 0.03, respectively). These results suggested a synergistic polygenic association of KIR2DS1-HLAC2+/HLA-G∗14bp+ pattern with behavioral impairment in ASD children.

Different isoforms of HLA-G protein are endowed with a differential ability to induce allogenic tolerance during pregnancy. As prenatal immune activation is suggested to play a role in the onset of autistic spectrum disorders (ASD), we evaluated HLA G*01:01-*01:06 allelic polymorphism in a cohort of Italian children affected by ASD (N=111) their mothers (N=81), and their healthy siblings (N=39). DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies; alleles distribution was compared with that of two control groups of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. HLA-G distribution was significantly different in ASD children compared to both control groups (Brazilian pc=1×10-4; Danish pc=1×10-3). Since HLA-G distribution was similar in the two control groups, their data were pooled. Results indicated that HLA-G*01:01 was significantly less frequent (pc=1×10-4; OR:0.5, 95%CI: 0.3-0.7) whereas HLA-G*01:05N was significantly more frequent (pc=2×10-3; OR:7.3, 95%CI: 2.4-26.6) in ASD children compared to combined controls. Finally, no clear pattern emerged when HLA-G allelic distribution was analyzed in healthy sibs. Notably, HLA-G allelic distribution found in ASD mothers was similar to that observed in the control subgroup of women with recurrent miscarriages, whilst it was significantly different compared to women without miscarriages (pc=6×10-4 df=12). Since HLA-G*01:01 is associated with the elicitation of KIR-mediated tolerogenic responses and HLA-G*01:05N correlates with NK cells activation, results herein indicate that an immune activating milieu during pregnancy is more likely observed in association with the development of ASD, similarly to what occurs in women with recurrent miscarriages.

Background Borderline intellectual functioning (BIF) is defined as a “health meta-condition… characterized by various cognitive dysfunctions associated with an intellectual quotient (IQ) between 71 and 85 which determines a deficit in the individual’s functioning both in the restriction of activities and in the limitation of social participation”. It can be caused by many factors, including a disadvantaged background and prematurity. BIF affects 7–12% of primary school children that show academic difficulties due to poor executive functioning. In many children with BIF, language, movement and social abilities are also affected, making it difficult to take part in daily activities. Dropping out of school and psychological afflictions such as anxiety and depression are common in children with BIF. This study investigates whether an intensive rehabilitation program that involves all of the areas affected in children with BIF (Movement, Cognition and Narration of emotions, MCNT) is more effective than Standard Speech Therapy (SST). Methods This is a multicenter interventional single blind randomized controlled study. Children aged between 6 to 11 years who attend a mainstream primary school and have multiple learning difficulties, behavioral problems and an IQ ranging between 85 to 70 have been enrolled. Participants are randomly allocated to one of three groups. The first group receives individual treatment with SST for 45 min, twice a week for 9 months. The second group receives the experimental treatment MCNT for 3 h per day, 5 days/ week for 9 months and children work in small groups. The third group consists of children on a waiting list for the SST for nine months. Discussion BIF is a very frequent condition with no ad hoc treatment. Over the long term, there is a high risk to develop psychiatric disorders in adulthood. Due to its high social impact, we consider it very important to intervene during childhood so as to intercept the remarkable plasticity of the developing brain. Trial registration “Study Let them grow: A new intensive and multimodal Treatment for children with borderline intellectual functioning based on Movement, Cognition and Narration of emotions”, retrospectively registered in ISRCTN Register with ISRCTN81710297 at 2017–01-09.

Early life adversity (ELA) in childhood is a major risk factor for borderline intellectual functioning (BIF). BIF affects both adaptive and intellectual abilities, commonly leading to school failure and to an increased risk to develop mental and social problems in the adulthood. This study aimed to investigate the neurobiological underpinnings of ELA associated with BIF in terms of global topological organization and structural connectivity and their relation with intellectual functioning. BIF (N=32) and age-matched typical development (TD, N=14) children were evaluated for intelligence quotient (IQ), behavioral competencies, and ELA. Children underwent an anatomical and diffusion-weighted MR imaging (DWI) protocol. Global brain topological organization was assessed measuring segregation and integration indexes. Moreover, structural matrices, measuring normalized number of fibers (NFn), were compared between the 2 groups using network-based statistics. Finally, a linear regression model was used to explore the relationship between network parameters and clinical measures. Results showed increased behavioral difficulties and ELA, together with decreased network integration in BIF children. Moreover, significantly lower NFn was observed in the BIF group (p=.039) in a sub-network comprising anterior and posterior cingulate, the pericallosal sulcus, the orbital frontal areas, amygdala, basal ganglia, the accumbens nucleus, and the hippocampus. Linear regression showed that NFn significantly predicted IQ (p

Mentalization defines the capacity to attribute mental states such as desires and beliefs to others and to understand that these can differ from our own. Such a capacity can be compromised in several psychiatric conditions and is the main target of many types of psychotherapy. Here we propose a theoretic model in which mentalization is achieved through a process we have termed “alphabetization” of the emotions. In this model, the patient–analyst relationship is observed within the analytic field so that all the communications of the patient and/or the analyst can be considered as “dreams” narrating the emotional “climate” of the field itself. Both the analyst and the patient contribute to the generation of the “climate,” and the analyst’s role is to promote the patient’s capacity to convert the unknown sensations into “dreams” or stories so as to make the emotional experience symbolized and meaningful.

Background Inflammasomes are multimeric protein platforms involved in the regulation of inflammatory responses whose activity results in the production of proinflammatory cytokines. Because neuroinflammation is observed in autistic spectrum disorders (ASD), a neurologic condition of childhood resulting in a complex behavioural impairment, we analyzed the inflammasomes activity in ASD. Additionally we verified whether alterations of the gastrointestinal (GI) barriers might play a role in inflammasomes activation. Methods The activity of the inflammasomes, the concentration of the inflammasomes-derived proinflammatory cytokines interleukin (IL)-1β and IL-18, and serum parameters of GI damage were analyzed in 25 ASD children, 23 healthy siblings (HS) and 30 unrelated age-matched healthy controls (HC). Results A significant upregulation of the AIM2 and the NLRP3 inflammasomes and an increased production of IL-1β and IL-18 that was associated with a consistent reduction of IL-33, an anti inflammation cytokine were observed in ASD alone. Notably, in a possible immune-mediated attempt to dampen inflammation, IL-37, a suppressor of innate inflammatory responses, was significantly augmented in these same children. Finally, intestinal fatty acid binding protein (IFABP), an index of altered GI permeability, was significantly increased in serum of ASD and HS. Conclusions These results show that the inflammasomes are activated in ASD and shed light on the molecular mechanisms responsible for ASD-associated neuroinflammation. The observation that GI alterations could be present as well in ASD offers a possible link between such alterations and neuroinflammation. Therapeutic strategies targeting inflammasome activation could be useful in ASD.

During adolescence and early adulthood, individuals deal with important developmental changes, especially in the context of complex social interactions. Previous studies demonstrated that those changes have a significant impact on the social decision making process, in terms of a progressive increase of intentionality comprehension of others, of the sensitivity to fairness, and of the impermeability to decisional biases. However, neither adolescents nor adults reach the ideal level of maximization and of rationality of the homo economicus proposed by classical economics theory, thus remaining more close to the model of the “bounded rationality” proposed by cognitive psychology. In the present study, we analyzed two aspects of decision making in 110 participants from early adolescence to young adulthood: the sensitivity to fairness and the permeability to decisional biases (Outcome Bias and Hindsight Bias). To address these questions, we adopted a modified version of the Ultimatum Game task, where participants faced fair, unfair, and hyperfair offers from proposers described as generous, selfish, or neutral. We also administered two behavioral tasks testing the influence of the Outcome Bias and of the Hindsight Bias in the evaluation of the decision. Our behavioral results highlighted that the participants are still partially consequentialist, as the decisional process is influenced by a complex balance between the outcome and the psychological description of the proposer. As regards cognitive biases, the Outcome Bias and the Hindsight Bias are present in the whole sample, with no relevant age differences.

Borderline intellectual functioning (BIF) is characterized by heterogeneous cognitive difficulties, with an intelligence quotient (IQ) between 70 and 85 points, and a failure to meet the developmental and sociocultural standards for personal independence and social responsibility required in daily life. The fact that this population still remain a marginal clinical category, with no ad hoc diagnostic and therapeutic approaches, has stimulated the present research. Our goal was to study children with BIF investigating the development of Theory of Mind (ToM) as a pillar of social competence. Children with BIF (N = 28, 16 male/12 female, and mean age 9.46 ± 1.26 years) and children with typical development (TD; N = 31, 17 male/14 female; mean age 8.94 years ± 0.99) underwent a neurocognitive assessment and a ToM assessment. Children with BIF showed a significant lower performance across all the levels of ToM development investigated compared to the control group, and a correlation between executive functions and the advanced levels of ToM reasoning. These results constitute a first step in the direction of defining the clinical profile of children with BIF concerning ToM development, opening the way to future interventions in order to support the developmental evolution of this population in an adaptive direction.

HLA-G expressed by the trophoblast ligates KIR molecules expressed by maternal NK cells at the uterine fetal/maternal interface: this interaction is involved in generating immune tolerance during pregnancy. A 14-bp insertion in the HLA-G 3'-UTR associates with significantly reduced levels of both HLA-G mRNA and soluble HLA-G, thus hampering the efficacy of HLA-G-mediated immune tolerance during pregnancy. Because prenatal immune activation is suggested to play an important role in the onset of autistic spectrum disorders (ASD) we performed an in-depth evaluation of HLA-G polymorphisms in a well-characterized cohort of Italian families of ASD children. Results showed that frequency of both homozygous 14bp+/14bp+ genotype and 14bp+ allele was significantly higher in ASD children and their mothers compared to controls (p

The activity of natural killer (NK) cells is modulated by the interaction between killer-cell immune globulin-like receptor (KIR) proteins and their cognate HLA ligands; activated NK cells produce inflammatory cytokines and mediate innate immune responses. Activating KIR/HLA complexes (aKIR/HLA) were recently suggested to prevail in children with autism spectrum disorders (ASD), a neurodevelopmental syndrome characterized by brain and behavioral abnormalities and associated with a degree of inflammation. We verified whether such findings could be confirmed by analyzing two sample cohorts of Sardinian and continental Italian ASD children and their mothers. Results showed that aKIR/HLA are increased whereas inhibitory KIR/HLA complexes are reduced in ASD children; notably this skewing was even more significant in their mothers. KIR and HLA molecules are expressed by placental cells and by the trophoblast and their interactions result in immune activation and influence fetal, as well as central nervous system development and plasticity. Data herein suggest that in utero KIR/HLA immune interactions favor immune activation in ASD; this may play a role in the pathogenesis of the disease.

The medical records of 358 children and adolescents with specific language disorders (SLD; 122 girls and 236 boys) seen in rehabilitation centers from Northern and Central Italy were examined to compare season of birth in these cases to those of the Italian population. Exposure was calculated using univariate and multivariate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to the Italian population, patients with SLD had a 1.67 (95% CI [1.35-2.07]) chance of birth in October-December. Independent predictors were younger age at inclusion and being firstborn. Different neurobiological hypotheses can be drawn to explain these findings.

To verify correlations between HLA and autism spectrum disorders (ASD) we studied 61 Italian families with an ASD child; results showed such correlation in 65% of cases. Case-control and TDT analysis of intrafamilial transmission of SNPs, Msats, and HLA markers surrounding the α and β blocks, indicated significant positive associations for MOGc*131 and D6S2239*105 alleles in ASD, and a negative association of MIB *332 allele in healthy siblings. Polymorphism haplotype analysis demonstrated that two haplotypes comprising the TNF-238(G)-TNF-308(G)-MIB*332-HLA-B*38-HLA-Cw*12 and the D6S265*218-HLA-A*23-MOGc*131-rs2857766(G) alleles are more frequently transmitted to ASD. MOGc and MIB loci are linked with ASD in Italian patients.