Vitamin D and autism: clinical review

<br>Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with multiple genetic and environmental risk factors. The interplay between genetic and environmental factors has become the subject of intensified research in the last several years. Vitamin D deficiency has recently been proposed as a possible environmental risk factor for ASD.</br> <br>Objective: The aim of the current paper is to systematically review the research regarding the possible connection between ASD and vitamin D, and to provide a narrative review of the literature regarding the role of vitamin D in various biological processes in order to generate hypotheses for future research.</br> <br>Results: Systematic data obtained by different research groups provide some, albeit very limited, support for the possible role of vitamin D deficiency in the pathogenesis of ASD. There are two main areas of involvement of vitamin D in the human body that could potentially have direct impact on the development of ASD: (1) the brain (its homeostasis, immune system and neurodevelopment) and (2) gene regulation.</br> <br>Conclusion: Vitamin D deficiency – either during pregnancy or early childhood – may be an environmental trigger for ASD in individuals genetically predisposed for the broad phenotype of autism. On the basis of the results of the present review, we argue for the recognition of this possibly important role of vitamin D in ASD, and for urgent research in the field.</br&gt

No neurochemical evidence of neuronal injury or glial activation in children with Pediatric Acute-onset Neuropsychiatric Syndrome: An explorative pilot study

OBJECTIVE: Paediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterised by an acute onset of obsessive compulsive disorder, combined with at least two other neuropsychiatric symptoms with acute onset. Diagnostic criteria also require that no specific medical aetiology is identified. Although there are no verified aetiological biomarkers, PANS is assumed to be a neuroinflammatory disorder with a possible autoimmune aetiology. Neurochemical markers such as neurofilament light (NfL, a neuronal injury marker) and glial fibrillary acidic protein (GFAP, an astrocytic activation marker) have not been published for this patient group. METHOD: Blood samples from 17 children meeting diagnostic criteria for PANS, after assessment at a child neuropsychiatry clinic were analysed for serum concentrations of NfL and GFAP. Ten age-matched children without any neurological or psychiatric disorder served as a comparison group. RESULTS: No difference was found in mean NfL and mean GFAP serum concentrations between children with PANS and controls. CONCLUSION: Neuronal injury and astrocyte activation do not seem to be a major event in PANS. The study group was small, and even if findings may be reassuring for parents and patients, they should be interpreted with caution and verified in larger cohorts and possibly with other markers in both serum and CSF

Vitamin D in the general population of young adults with autism in the Faroe Islands

Vitamin D deficiency has been proposed as a possible risk factor for developing autism spectrum disorder (ASD). 25-Hydroxyvitamin D3 (25(OH)D3) levels were examined in a cross-sectional population-based study in the Faroe Islands. The case group consisting of a total population cohort of 40 individuals with ASD (aged 15–24 years) had significantly lower 25(OH)D3 than their 62 typically-developing siblings and their 77 parents, and also significantly lower than 40 healthy age and gender matched comparisons. There was a trend for males having lower 25(OH)D3 than females. Effects of age, month/season of birth, IQ, various subcategories of ASD and Autism Diagnostic Observation Schedule score were also investigated, however, no association was found. The very low 25(OH)D3 in the ASD group suggests some underlying pathogenic mechanism

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

Reduction of astrogliosis and microgliosis by cerebrospinal fluid shunting in experimental hydrocephalus

<p>Abstract</p> <p>Background</p> <p>Reactive gliosis has the potential to alter biomechanical properties of the brain, impede neuronal regeneration and affect plasticity. Determining the onset and progression of reactive astrogliosis and microgliosis due to hydrocephalus is important for designing better clinical treatments.</p> <p>Methods</p> <p>Reactive astrogliosis and microgliosis were evaluated as the severity of hydrocephalus increased with age in hydrocephalic H-Tx rats and control littermates. Previous studies have suggested that gliosis may persist after short-term drainage (shunt treatment) of the cerebrospinal fluid. Therefore shunts were placed in 15d hydrocephalic rats that were sacrificed after 6d (21d of age) or after 21d (36d of age). Tissue was processed for Western blot procedures and immunohistochemistry, and probed for the astrocytic protein, Glial Fibrillary Acidic Protein (GFAP) and for microglial protein, Isolectin B4 (ILB4).</p> <p>Results</p> <p>In the parietal cortex of untreated hydrocephalic animals, GFAP levels increased significantly at 5d and at 12d compared to age-matched control rats. There was a continued increase in GFAP levels over control at 21d and at 36d. Shunting prevented some of the increase in GFAP levels in the parietal cortex. In the occipital cortex of untreated hydrocephalic animals, there was a significant increase over control in levels of GFAP at 5d. This trend continued in the 12d animals, although not significantly. Significant increases in GFAP levels were present in 21d and in 36d animals. Shunting significantly reduced GFAP levels in the 36d shunted group. Quantitative grading of immuno-stained sections showed similar changes in GFAP stained astrocytes.</p> <p>Immuno-stained microglia were altered in shape in hydrocephalic animals. At 5d and 12d, they appeared to be developmentally delayed with a lack of processes. Older 21d and 36d hydrocephalic animals exhibited the characteristics of activated microglia, with thicker processes and enlarged cell bodies. Following shunting, fewer activated microglia were present.</p> <p>Histologic examination of the periventricular area and the periaqueductal area showed similar findings with the 21d and 36d animals having increased populations of both astrocytes and microglia which were reduced following shunting with a more dramatic reduction in the long term shunted animals.</p> <p>Conclusion</p> <p>Overall, these results suggest that reactive astrocytosis and microgliosis are associated with progressive untreated ventriculomegaly, but that shunt treatment can reduce the gliosis occurring with hydrocephalus.</p

Variations of the Candidate SEZ6L2 Gene on Chromosome 16p11.2 in Patients with Autism Spectrum Disorders and in Human Populations

Background: Autism spectrum disorders (ASD) are a group of severe childhood neurodevelopmental disorders with still unknown etiology. One of the most frequently reported associations is the presence of recurrent de novo or inherited microdeletions and microduplications on chromosome 16p11.2. The analysis of rare variations of 8 candidate genes among the 27 genes located in this region suggested SEZ6L2 as a compelling candidate. Methodology/Principal Findings: We further explored the role of SEZ6L2 variations by screening its coding part in a group of 452 individuals, including 170 patients with ASD and 282 individuals from different ethnic backgrounds of the Human Genome Diversity Panel (HGDP), complementing the previously reported screening. We detected 7 previously unidentified non-synonymous variations of SEZ6L2 in ASD patients. We also identified 6 non-synonymous variations present only in HGDP. When we merged our results with the previously published, no enrichment of non-synonymous variation in SEZ6L2 was observed in the ASD group compared with controls. Conclusions/Significance: Our results provide an extensive ascertainment of the genetic variability of SEZ6L2 in human populations and do not support a major role for SEZ6L2 sequence variations in the susceptibility to ASD

CHARGE syndrome: Genetic aspects and dental challenges, a review and case presentation

CHARGE syndrome (CS) is a rare genetic condition (OMIM #214800). The condition has a variable phenotypic expression. Historically, the diagnosis of CHARGE syndrome was based on the presence of specific clinical criteria. The genetic aetiology of CS has since been elucidated and attributed to pathogenic variation in the CHD7 gene (OMIM 608892) at chromosome locus 8q12

Parental phonological memory contributes to prediction of outcome of late talkers from 20 months to 4 years: a longitudinal study of precursors of specific language impairment

Background Many children who are late talkers go on to develop normal language, but others go on to have longer-term language difficulties. In this study, we considered which factors were predictive of persistent problems in late talkers. Methods Parental report of expressive vocabulary at 18 months of age was used to select 26 late talkers and 70 average talkers, who were assessed for language and cognitive ability at 20 months of age. Follow-up at 4 years of age was carried out for 24 late and 58 average talkers. A psychometric test battery was used to categorize children in terms of language status (unimpaired or impaired) and nonverbal ability (normal range or more than 1 SD below average). The vocabulary and non-word repetition skills of the accompanying parent were also assessed. Results Among the late talkers, seven (29%) met our criteria for specific language impairment (SLI) at 4 years of age, and a further two (8%) had low nonverbal ability. In the group of average talkers, eight (14%) met the criteria for SLI at 4 years, and five other children (8%) had low nonverbal ability. Family history of language problems was slightly better than late-talker status as a predictor of SLI.. The best predictors of SLI at 20 months of age were score on the receptive language scale of the Mullen Scales of Early Learning and the parent's performance on a non-word repetition task. Maternal education was not a significant predictor of outcome. Conclusions In this study, around three-quarters of late talkers did not have any language difficulties at 4 years of age, provided there was no family history of language impairment. A family history of language-literacy problems was found to be a significant predictor for persisting problems. Nevertheless, there are children with SLI for whom prediction is difficult because they did not have early language delay