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EudraCT 2012 - 003958 - 82.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by deficits in social communication and stereotypical behaviours. ASD’s aetiology remains mostly unclear, because of a complex interaction between genetic and environmental factors. Recently, a strong consensus has developed around ASD’s immune‐mediated pathophysiology, which is the subject of this review. For many years, neuroimmunological studies tried to understand ASD as a prototypical antibody‐ or cell‐mediated disease. Other findings indicated the importance of autoimmune mechanisms such as familial and individual autoimmunity, adaptive immune abnormalities and the influence of infections during gestation. However, recent studies have challenged the idea that autism may be a classical autoimmune disease. Modern neurodevelopmental immunology shows the double‐edged nature of many immune effectors, which can be either beneficial or detrimental depending on tissue homeostasis, stressors, neurodevelopmental stage, inherited and de novo gene mutations and other variables. Nowadays, mother–child interactions in the prenatal environment appear to be crucial for the occurrence of ASD. Studies of animal maternal–foetal immune interaction are being fruitfully carried out using different combinations of type and timing of infection, of maternal immune response and foetal vulnerability and of resilience factors to hostile events. The derailed neuroimmune crosstalk through the placenta initiates and maintains a chronic foetal neuroglial activation, eventually causing the alteration of neurogenesis, migration, synapse formation and pruning. The importance of pregnancy can also allow early immune interventions, which can significantly reduce the increasing risk of ASD and its heavy social burden.

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

Introduction In the last few months, some pediatric cases with neurological and neuroradiological pictures related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been reported, often associated with multisystem inflammatory syndrome (MIS-C). The most frequently encountered pediatric neurological complications seem to be postinfectious immune-mediated acute disseminated encephalomyelitis (ADEM)-like changes of the brain, myelitis, neural enhancement, and splenial lesions. Concomitant neurological and cardiac involvement has been reported only in MIS-C, although specific clinical details are often not fully available. Methods In this case report, a very young child infected with SARs-CoV-2 and diagnosed as longitudinal extensive transverse myelitis with concomitant myo-pericarditis is presented. Results A previously healthy 7-month-old girl presented with abrupt onset of generalized weakness with inability to sit up. She had had mild respiratory symptoms 1 week earlier. Spinal magnetic resonance imaging (MRI) showed a T2-hyperintense intramedullary lesion extending from C4 to T2, compatible with acute longitudinally extensive transverse myelitis (LETM). Cerebrospinal fluid analysis was negative.Echocardiography and blood tests were suggestive for myo-pericarditis. Real time polymerase chain reaction for SARS-CoV-2 on nasopharyngeal swab sample tested positive. She was promptly treated with high dose of steroids and immunoglobulin with satisfactory clinical response. Conclusion To the evolving literature of neurological complications of SARs-CoV-2 infection, we add the youngest patient described to date with isolated LETM and concomitant cardiac involvement. Our case suggests that clinicians should be aware of this association, although difficult to recognize in infants. Practitioners are encouraged to consider aggressive first-line immunotherapies with the final aim to prevent permanent disability.

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 (P c = 0.03 2 df ) and to a group of 170 Italian healthy women (HC) (P c = 0.04 2 df ). FokI genotype and allelic distribution skewing were also observed in mothers of ASD children compared to HC (P c = 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 (P c = 0.01) and, particularly, with hyperactivity behavior (P c = 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.

Aim We assessed the frequency, characteristics, and future trajectory of monophasic acquired demyelinating syndromes (ADS) associated with conversion to paediatric multiple sclerosis. Method This was a retrospective observational study of Sardinian children (<18y of age) with onset of ADS between 2001 and 2018. Results We identified 44 children with ADS (21 males, 23 females; median age at onset 16y, range 4mo–18y), 21 of whom were already presenting with criteria for paediatric multiple sclerosis. The mean crude prevalence of ADS in Sardinian children was 59.2 per 100 000, while incidence was 3.1 per 100 000 per year (1.3 in children aged ≤10y and 11.9 in those aged 10–17y). After a mean (SD) follow‐up of 8 years 5 months (5y 4mo), the most common (n=32) trajectory was conversion to paediatric multiple sclerosis. At onset, the total prevalence and mean annual incidence of paediatric multiple sclerosis were 35.6 per 100 000 and 2.3 per 100 000 respectively (0.5 in individuals aged ≤10y, 10.0 in the older group). Interpretation Sardinia is a very high risk area for ADS in children. Nearly half of this population can already be diagnosed with paediatric multiple sclerosis at onset. Overall, 72% of those with ADS will have paediatric multiple sclerosis after a mean of 8 years. Sardinia is a very high risk area for paediatric acquired demyelinating syndromes (ADS). A high proportion of those with paediatric multiple sclerosis are diagnosed at onset of ADS. After an average 8 years from onset of paediatric ADS, three‐quarters of patients are diagnosed with paediatric multiple sclerosis.