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.

Background Mitochondrial respiratory chain consists of five complexes encoded by nuclear and mitochondrial genomes. Mitochondrial aminoacyl-tRNA synthetases are key enzymes in the synthesis of such complexes. Bi-allelic variants of VARS2 , a nuclear gene encoding for valyl-tRNA (Val-tRNA) synthetase, are associated to several forms of mitochondrial encephalopathies or cardiomyoencephalopathies. Among these, the rare homozygous c.1100C > T (p.Thr367Ile) mutation variably presents with progressive developmental delay, axial hypotonia, limbs spasticity, drug-resistant epilepsy leading, in some cases, to premature death. Yet only six cases, of which three are siblings, harbouring this homozygous mutation have been described worldwide. Case presentation Hereby, we report two additional cases of two non-related young girls from Sardinia, born from non-consanguineous and healthy parents, carrying the aforesaid homozygous VARS2 variant. At onset both the patients presented with worsening psychomotor delay, muscle hypotonia and brisk tendon reflexes. Standard genetic tests were normal, as well as metabolic investigations. Brain MRI showed unspecific progressive abnormalities, such as corpus callosum hypoplasia (patient A) and cerebellar atrophy (patient A and B). Diagnosis was reached by adopting massive parallel next generation sequencing. Notably clinical phenotype of the first patient appears to be milder compared to previous known cases. The second patient eventually developed refractory epilepsy and currently presents with severe global impairment. Because no specific treatment is available as yet, both patients are treated with supporting antioxidant compounds along with symptomatic therapies. Conclusions Given the paucity of clinical data about this very rare mitochondrial encephalopathy, our report might contribute to broaden the phenotypic spectrum of the disorder. Moreover, noteworthy, three out of five pedigrees so far described belong to the Northern Sardinia ethnicity.

BackgroundSleep disturbances are common in children affected by Autism Spectrum Disorder (ASD). The aim of our study was to describe sleep characteristics and disturbances in children with ASD, to evaluate possible related factors, and to assess parental stress.MethodsHundred children with a diagnosis of ASD (mean age: 66.7 months, SD: 27.4, range: 24.7–152.1 months, n = 79 males) were included in the study. We collected data on sociodemographic, clinical, genetic and instrumental variables as well as comorbid conditions. Parents filled out the Questionnaire on sleep behavior in the first years of life, the BEARS questionnaire, and the Parenting Stress Index Short Form. From the analysis on sleep characteristics, we excluded 25 children treated with melatonin.ResultsFifty-seven (57%) out of 100 children met the criteria for insomnia. Sleep disorders were associated with developmental or cognitive delay, emotional and behavioral problems (such as anxiety problems and aggressive behaviors) and absence of strategies for inducing sleep after nocturnal awakenings. From parents' reports, sleep disorders had diurnal repercussions on their offspring; however, we found no statistical correlation between disturbances and family stress. Also, no significant correlation was found between sleep disturbances and epilepsy. Finally, a statistical correlation was found between the regular intake of melatonin and the resolution of insomnia.ConclusionsMultifactorial variables may be associated to insomnia that could have an impact on the children' behavior. Clinicians need to be aware of the value of screening for sleep disturbance in children with ASD to integrate sleep interventions in the treatment plan.

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While the genetics of autism spectrum disorders (ASD) has been intensively studied, resulting in the identification of over 100 putative risk genes, the epigenetics of ASD has received less attention, and results have been inconsistent across studies. We aimed to investigate the contribution of DNA methylation (DNAm) to the risk of ASD and identify candidate biomarkers arising from the interaction of epigenetic mechanisms with genotype, gene expression, and cellular proportions. We performed DNAm differential analysis using whole blood samples from 75 discordant sibling pairs of the Italian Autism Network collection and estimated their cellular composition. We studied the correlation between DNAm and gene expression accounting for the potential effects of different genotypes on DNAm. We showed that the proportion of NK cells was significantly reduced in ASD siblings suggesting an imbalance in their immune system. We identified differentially methylated regions (DMRs) involved in neurogenesis and synaptic organization. Among candidate loci for ASD, we detected a DMR mapping to CLEC11A (neighboring SHANK1) where DNAm and gene expression were significantly and negatively correlated, independently from genotype effects. As reported in previous studies, we confirmed the involvement of immune functions in the pathophysiology of ASD. Notwithstanding the complexity of the disorder, suitable biomarkers such as CLEC11A and its neighbor SHANK1 can be discovered using integrative analyses even with peripheral tissues.