Marked intrafamilial variability of clinical and neuroimaging manifestations in NFIB-related developmental disorder.

NFIB belongs to the nuclear factor I (NFI) family of transcription factors that, by activating or repressing gene expression during embryogenesis, has a relevant role in the development of several organs including the brain. Heterozygous pathogenic variants of NFIB have recently been associated with developmental delay and mild-to-moderate intellectual disability, macrocephaly, nonspecific facial dysmorphisms, and corpus callosum dysgenesis. We identified a heterozygous missense variant in the NFIB gene in a 15-year-old boy with neurodevelopmental disorder and brain malformations, who inherited the variant from his substantially healthy mother presenting only minor physical and neuroanatomical defects.

The Role of SNAP-25 in Autism Spectrum Disorders Onset Patterns.

Autism spectrum disorders (ASD) can present with different onset and timing of symptom development; children may manifest symptoms early in their first year of life, i.e., early onset (EO-ASD), or may lose already achieved skills during their second year of life, thus showing a regressive-type onset (RO-ASD). It is still controversial whether regression represents a neurobiological subtype of ASD, resulting from distinct genetic and environmental causes. We focused this study on the 25 kD synaptosomal-associated protein (SNAP-25) gene involved in both post-synaptic formation and adhesion and considered a key player in the pathogenesis of ASD. To this end, four single nucleotide polymorphisms (SNPs) of the SNAP-25 gene, rs363050, rs363039, rs363043, and rs1051312, already known to be involved in neurodevelopmental and psychiatric disorders, were analyzed in a cohort of 69 children with EO-ASD and 58 children with RO-ASD. Both the rs363039 G allele and GG genotype were significantly more frequently carried by patients with EO-ASD than those with RO-ASD and healthy controls (HC). On the contrary, the rs1051312 T allele and TT genotype were more frequent in individuals with RO-ASD than those with EO-ASD and HC. Thus, two different SNAP-25 alleles/genotypes seem to discriminate between EO-ASD and RO-ASD. Notably, rs1051312 is located in the 3' untranslated region (UTR) of the gene and is the target of microRNA (miRNA) regulation, suggesting a possible epigenetic role in the onset of regressive autism. These SNPs, by discriminating two different onset patterns, may represent diagnostic biomarkers of ASD and may provide insight into the different biological mechanisms towards the development of better tailored therapeutic and rehabilitative approaches.

HLA-G allelic distribution in Sardinian children with Autism spectrum disorders: A replication study.

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.

HLA-G coding region polymorphism is skewed in autistic spectrum disorders.

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.

Are family relations connected to the quality of the outcome in adolescent anorexia nervosa? An observational study with the Lausanne Trilogue Play.

The study aims to explore the connection between the family interactive patterns, investigated with a standardized observational tool based on a recorded play session, the Lausanne Trilogue Play, and the outcome of adolescent patients with anorexia nervosa after a 6 months treatment, based on the Morgan-Russel Outcome Assessment Schedule. Seventy-two parents and adolescent daughters with anorexia nervosa, consecutively referred to an adolescent neuropsychiatric service, participated in the study and underwent an integrated model of treatment, based on constant neuropsychiatric and dietary monitoring, weekly individual psychotherapy for the daughter, and parental counselling and support. A better adolescents' functioning in family relationships, in particular in the triadic ones, at first assessment, was associated with a better outcome. Data on family interactions may help predict the most appropriate intervention for the patient and his family.

Habit reversal training in children and adolescents with chronic tic disorders: an Italian randomized, single-blind pilot study.

BACKGROUND: The aim of the present study was to test the possibility to apply habit reversal training (HRT) in Italy and to evaluate the effectiveness of HRT in reducing tic severity compared with the "usual care" (UC) in Italian children and adolescents with Tourette Syndrome. METHODS: We performed a single blind, randomized, pilot study comparing HRT (active treatment) and UC (usual treatment). Out of 69 patients seen during the study period, we were able to enroll 21 patients (11 randomized to HRT e 10 to UC). Assessment included in-depth neurological and psychiatric examination, K-SADS-PL, YGTSS, KIDSCREEN, GTS-QOL, CGI and C-GAS. All these evaluations but the K-SADS-PL were used for baseline assessment but also one week after the end of treatment (T1) and then 3, 6 and 9 months later (respectively T2, T3, and T4). RESULTS: The sample was largely composed of patients of relevant clinical severity (CGI≥3: 85%). OCD and ADHD were the most frequent comorbidities (30% each). Only minor differences in terms of treatment effectiveness were found, although the HRT group turned out to include patients with more tics and a more compromised general functioning despite randomization. CONCLUSIONS: We had a high number of patients who refused to be randomized (23 out of 69) and a high number of drop outs (27% in the HRT group, 50% in the UC group). There was an improvement in terms of reduced tics and improved global functioning in both groups, without significant changes in terms of Quality of Life.

Developmental writing disorders: assess to rehabilitate.

BACKGROUND: Writing ability requires to use and control several processes of visual and phonological information processing and an adequate programming and coordination of motor sequences. We studied a writing precursor gesture in children with developmental dysorthography and/or developmental dysgraphia in order to point out anomalies to be treated with specific rehabilitative interventions. METHODS: Twenty-five children affected by developmental dysortography (ICD 9 CM: 315.09; ICD 10: F81.1) and/or developmental dysgraphia (ICD 9 CM: 315.2; ICD 10: F81.8) (mean age 9.1 years [range: 6.3-11.4 years]) ran a maze, project in front of them, using a wireless mouse. Data regarding angular excursions, execution times and gesture accuracy were collected and elaborated using Dartfish 6.0 software and the labyrinth generating program (PRINC), and compared with normative data previously obtained from a sample of 226 healthy children of the same age and grade. RESULTS: The comparison did not evidence significant differences regarding gesture structure (trajectories of arm segments and angular excursions of interested joints). Angular and temporal execution patterns were reached in delay in these children. No correlation was found with general cognitive and visuomotor integration skills; a deficit of visual attention was associated with an abnormal elbow range of motion. CONCLUSIONS: Although these findings need to be confirmed in larger studies, data obtained evidence that children with developmental writing disorders have a time delay in the acquisition of writing motor patterns and not an alteration of gesture structure itself. This has relevant implications for the rehabilitative approach.

Headache and psychological disorders in children and adolescents: a cross-generational study.

BACKGROUND: Headache and psychopathology (especially anxiety and mood disorders) are comorbid across the life span. The present study is a clinical contribution in the direction of studying the familial recurrence of headache, and the interplay of headache and psychopathology in children. METHODS: The clinical sample is composed by 130 headache patients (53 boys and 77 girls, age range 8-18), while the control group is composed by 87 healthy subjects from the general population (39 boys and 48 girls, age range 8-18). A structured interview according to International Classification for Headache Disorders-II criteria has been administered to the clinical group; the Child Behavior Checklist (CBCL) and the Self Administrated Psychiatric Scales for Children and Adolescents (SAFA) have been used in order to assess psychopathology in both groups. RESULTS: The recurrence of headache in family members is confirmed by the present study, albeit limited to paternal side, χ2 (4, N.=130)=10.47, P=0.033. Results also showed that scores obtained by the clinical sample in CBCL and SAFA are generally higher than scores obtained by the control group, but without differences between headache sub-types. Finally, internalizing symptoms (anxiety and depression) in children correlate with mothers' point of view, r≥0.23, P<0.05, outlining a specific attunement between headache patients and their mothers. CONCLUSIONS: Headache runs in families, with high level of psychological disorders. Mothers are particularly attuned with the psychological needs of their headache children.

Multiple inflammasome complexes are activated in autistic spectrum disorders.

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)-1ß 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-1ß 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.

Psychological Therapy in Adolescents with Chronic Daily Headache.

Chronic daily headache is a serious disease, causing significant problems in terms of reduced quality of life and disability, with pain localized to the head (headache) occurring 15 or more days per month for more than 3 months (>180 days per year). Drugs, both used as preventive medications or as pain-killers, are insufficient for the management of these patients; a more global approach has been advocated. This paper reviews existing data concerning different psychological approaches, with a focus on adolescence. This leads to evidence still unanswered questions but also the importance to include psychological treatments in the management of this potentially disabling condition.

Specific learning disorders and anxiety: a matter of school experience?

BACKGROUND: Specific learning disorders (SLDs) are a group of neuropsychological disorders which reduce a child's ability to read and/or write and/or use numbers. Internalizing disorders, and in particular anxiety, has been reported as a relatively common comorbidity in children with reading difficulties. We conducted this study in order to test if school experience (in terms of perceived support from the teacher) is associated with the development of anxiety. METHODS: Twenty patients with SLDs (age: 8-13) were compared to 32 healthy subjects of the same age. All subjects filled the scale to measure anxiety derived from the Self-Administered Psychiatric Scales for Children and Adolescents (SAFA); results were compared using non-parametric statistics after verifying that scores were not normally distributed. RESULTS: Patients more often had a clinically significant level of anxiety (Mann Whitney U Test; P<0.001). We found a significant inverse correlation between a school experience perceived as positive and anxiety (Spearman's rho=- 0.925; P<0.001), while no significant correlation was found for sex, age, timeliness of diagnosis or time since diagnosis. CONCLUSION: Although these findings need to be confirmed in prospective studies, the role of school experience for children with SLDs seems highly relevant also for their psychological well-being.

An HLA-G(∗)14bp insertion/deletion polymorphism associates with the development of autistic spectrum disorders.

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<0.05 in all cases); analysis of the frequency of transmission of the 14bp+ allele from parents to ASD children and their non-ASD siblings showed that the 14bp+ allele was more frequently transmitted (T) to ASD children, whereas it was preferentially not transmitted (NT) to the non-ASD siblings (overall discrepancy: p=0.02; OR: 2.6, 95% CI: 1.1-6.4). Results herein suggest that HLA-G polymorphisms are associated with ASD development, possibly as a consequence of prenatal immune activation. These data infer that the immune alterations seen in ASD are associated with the maternal-fetal interaction alone, and reinforce the observation that different genetic backgrounds characterize ASD children and their non-ASD siblings.

Activating KIR molecules and their cognate ligands prevail in children with a diagnosis of ASD and in their mothers.

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.

Medication overuse headache in children and adolescents.

Medication overuse headache can be described as a chronic headache, presenting 15 or more days per month, in a patient who abuses symptomatic drugs. It has been called an unrecognized epidemic; this is in part true for adults, but is certainly so for children and adolescents. This paper reviews existing data concerning epidemiology, etiopathogenesis and treatment options, with a focus on pediatric age. This leads to evidence of a relevant number of still unanswered questions and some possible strategies to help children and adolescents with this disabling disorder.

Ethics of Bariatric Surgery in Adolescence and Its Implications for Clinical Practice.

Obesity is increasingly prevalent among adolescents. Clinical and research data support the use of bariatric surgery (BS) as a treatment option for severely obese adolescents, with good results in terms of weight loss, improvement or resolution of comorbidities, and compliance to follow up. Nevertheless, concerns still remain, with significant disparities among countries and ethical concerns mainly raised by performing an irreversible and invasive procedure in adolescence, with potential life-long alterations. In this context, the purpose of this narrative review was to discuss the main current ethical challenges in performing BS in adolescence and to inform appropriate clinical management in the field. The core ethical principles of autonomy, beneficence, nonmaleficence, and justice were revised in terms of patient-centered healthcare through the lens of psychosocial implications. The review concludes with a discussion regarding the potential directives for future research for effective, patient-centered, and ethical management of obesity in the adolescent population.

How parental levels of empathy and alexithymia influence their perception of child's behavior.

BACKGROUND: Literature states that parents of individuals affected by autism spectrum disorder (ASD) can present social and cognitive deficits, restricted behavior patterns and psychiatric difficulties, without meeting standard diagnostic criteria for ASD ("broader autism phenotype"). We explored the relationship between parenting of children affected by ASD and levels of empathy and lack of emotion understanding (alexithymia). METHODS: We enlisted 58 families in which a child was affected by ASD. Parents' empathy and alexithymia were respectively assessed by means of Empathy Quotient (EQ) and Toronto Alexithymia Scale (TAS-20). Additionally, we included the assessment of the perception of children's behavior through the Child Behavior Checklist (CBCL). RESULTS: Our findings suggest that most parents have normal empathy and do not show significant alexithymia. We found lower EQ and higher TAS-20 scores being more frequent in fathers. Moreover, each parent's empathy degree negatively relates to his/her alexithymia and vice versa, showing that these two features are inversely correlated. Our study unveiled a strong correlation between maternal empathy and alexithymia and child's externalizing problems, as reported by mothers. CONCLUSIONS: Our data reveal differences in mothers and fathers' empathy and alexithymia profiles and confirm the importance of considering both parents' points of view either in the diagnostic and the therapeutic interventions. Parental empathy and alexithymia levels not only play a fundamental role in the evaluation of child's difficulties but can also influence the development of a good relationship with the child for what concerns affective resonance.

The Family Caregiving Environment Associates with Adolescent Patients' Severity of Eating Disorder and Interpersonal Problems: A Cross-Sectional Study.

The quality of family interactions may be a critical factor for restrictive eating disorders (REDs). Adolescent patients with RED have interpersonal problems that can be inferred by observing their behaviours during family interactions. To date, the assessment of the association among RED severity, interpersonal problems, and patients' interactive behaviours in the family is partially explored. This cross-sectional study aimed to explore how adolescent patients' interactive behaviours observed during the Lausanne Trilogue Play-clinical version (LTPc) were associated with both RED severity and interpersonal problems. Sixty adolescent patients completed the EDI-3 questionnaire to assess RED severity using the Eating Disorder Risk Composite (EDRC) and Interpersonal Problems Composite (IPC) subscales. Moreover, patients and their parents took part in the LTPc, and patients' interactive behaviours were coded as participation, organization, focal attention, and affective contact in all the LTPc four phases. A significant association emerged between patients' interactive behaviours during the LTPc triadic phase and both EDRC and IPC. Better patients' organization and affective contact significantly correlated with lower RED severity and fewer interpersonal problems. These findings suggest that investigating the quality of family relationships and patients' interactive behaviours may contribute to better identifying adolescent patients at risk for more severe conditions.

Empathy and behavior in children affected by autism spectrum disorders.

BACKGROUND: Many studies have already shown that individuals suffering from autism spectrum disorders (ASD) present low levels of empathy: in fact, reduced emotional reciprocity is considered a clinically significant indicator of autistic functioning. We decided to investigate the role of empathy in determining pathological behaviors in children affected by ASD considering parents' point of view; and to evaluate the presence of differences between mothers and fathers' perception of their child's empathy and behaviors. METHODS: We compared empathy levels in a sample of 58 patients with ASD as reported by a parent-filled questionnaire with the results of a global evaluation conducted by means of play observations, clinician-rated scales, a semistructured interview with both caregivers and parent-filled questionnaires. RESULTS: The majority of ASD patients have low levels of empathy according to both parents' points of view; noteworthy, mothers and fathers are highly concordant in this respect. Children's levels of empathy negatively correlate with many behavioral problems, both internalizing and externalizing. Furthermore, we found that mothers tend to perceive more internalizing problems, while fathers are more willing to notice externalizing ones. CONCLUSIONS: Involving both caregivers in children's diagnostic assessment could deepen patient's evaluation and finally the therapeutic results. Mothers and fathers seem to be highly consistent in describing the psychological characteristics of their child, but not in respect to symptoms.

SNAP-25 Polymorphisms in Autism Spectrum Disorder: A Pilot Study towards a Possible Endophenotype.

While there is substantial agreement on the diagnostic criteria for autism spectrum disorder, it is also acknowledged that it has a broad range of clinical presentations. This can complicate the diagnostic process and aggravate the choice of the most suitable rehabilitative strategy for each child. Attentional difficulties are among the most frequently reported comorbidities in autism spectrum disorder. We investigated the role of SNAP-25 polymorphisms. Synaptosome-associated protein 25 (SNAP25) is a presynaptic membrane-binding protein; it plays a crucial role in neurotransmission and has already been studied in numerous psychiatric disorders. It was also seen to be associated with hyperactivity in children with autism spectrum disorder. We collected clinical, behavioral and neuropsychological data on 41 children with a diagnosis of autism spectrum disorder, and then genotyped them for five single-nucleotide polymorphisms of SNAP-25. Participants were divided into two groups according to the Autism Diagnostic Observation Schedule (ADOS-2) Severity Score. In the group with the highest severity score, we found significant associations of clinical data with polymorphism rs363050 (A/G): children with the GG genotype had lower total IQ, more severe autistic functioning and more attentional difficulties. Our research could be the starting point for outlining a possible endophenotype among patients with autism spectrum disorder who are clinically characterized by severe autistic functioning and significant attentional difficulties.