Does minimal central nervous system involvement in childhood acute lymphoblastic leukemia increase the risk for central nervous system toxicity?

Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) implicates enhanced intrathecal chemotherapy, which is related to CNS toxicity. Whether CNS involvement alone contributes to CNS toxicity remains unclear. We studied the occurrence of all CNS toxicities, seizures, and posterior reversible encephalopathy syndrome (PRES) in children with ALL without enhanced intrathecal chemotherapy with CNS involvement (n = 64) or without CNS involvement (n = 256) by flow cytometry. CNS involvement increased the risk for all CNS toxicities, seizures, and PRES in univariate analysis and, after adjusting for induction therapy, for seizures (hazard ratio [HR] = 3.33; 95% confidence interval [CI]: 1.26-8.82; p = 0.016) and PRES (HR = 4.85; 95% CI: 1.71-13.75; p = 0.003).

Rare copy number variants are common in young children with autism spectrum disorder.

AIM: Several studies have suggested that rare copy number variants (CNVs) are an important genetic contributor to autism spectrum disorders. The aims of the study were to use chromosomal microarray to investigate the presence of rare copy number variants in a population-based cohort of well-characterised young children with autism spectrum disorders and to relate the genetic results to neurodevelopmental profiles and medical conditions. METHODS: We performed chromosomal microarray on samples from 162 children who had been referred to the Stockholm Autism Centre for Young Children in Sweden after being diagnosed with autism spectrum disorder between 20 and 54 months of age. RESULTS: Pathogenic aberrations were detected in 8.6% of the children and variants of uncertain significance were present in another 8.6%. CNVs were more frequent in children with congenital malformations or dysmorphic features as well as in the subgroup with intellectual disability. CONCLUSION: Our results support the use of chromosomal microarray methods for the first tier genetic analysis of autism spectrum disorder. However, it is likely in the near future that chromosomal microarray methods will probably be replaced by whole-exome and whole-genome sequencing technologies in clinical genetic testing.

Medical conditions affect the outcome of early intervention in preschool children with autism spectrum disorders.

The aim was to explore the frequency of genetic and other medical conditions, including epilepsy, in a population-based group of 208 preschool children with early diagnosis of Autism spectrum disorders (ASD) and to relate outcome at a 2-year follow-up to the co-existing medical findings. They had all received early intervention. The Vineland Adaptive Behaviour Scales (VABS-II) composite score served as the primary outcome measure. In the total group, 38/208 children (18 %) had a significant medical or genetic condition. Epilepsy was present in 6.3 % at the first assessment and in 8.6 % at follow-up and was associated with more severe intellectual impairment. A history of regression was reported in 22 %. Children with any medical/genetic condition, including epilepsy, as well as children with a history of regression had significantly lower VABS-II scores at the 2-year follow-up. Children with a medical/genetic condition, including epilepsy, had been diagnosed with ASD at an earlier age than those without such conditions, and early age at diagnosis also correlated negatively with adaptive functioning outcome. The results underscore the importance of considering medical/genetic aspects in all young children with ASD and the requirement to individualize and tailor interventions according to their specific needs.

HLA Polymorphism in Regressive and Non-Regressive Autism: A Preliminary Study.

Autism spectrum disorders (ASD) comprises heterogeneous neurodevelopmental conditions with symptom onset usually during infancy. However, about 10%-30% of affected cases experience a loss of language and social skills around 18-30 months, so-called regressive autism. In this subset with regression, immune dysfunctions including inflammation and autoimmunity have been proposed to be at risk factors. Given the implication of the human histocompatibility antigens (HLA) system in various aspects of immune responses, including autoimmunity, and in ASD, we investigate here the distribution of the HLA Class I and Class II haplotypes in 131 children with ASD meeting DSM-IV TR criteria, with and without regression. We found that 62 of the 98 non-regressive ASD patients carry the HLA-DPA1*01-DPB1*04 sub-haplotype as compared to 14 of the 33 patients with regression (63% vs. 43% respectively, Pc = 0.02), suggesting that this HLA haplotype may exert a protective effect against regression. Similarly, the HLA-DPA1*01-DPB1*04 has also been found to be more represented in healthy controls as compared to patients affected with common nonpsychiatric autoimmune disorders. Overall our findings suggest a possible involvement of HLA polymorphism in the context of regressive ASD. Autism Res 2020, 13: 182-186. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Immune dysfunctions including inflammatory and autoimmune processes have been reported in autism, particularly in regressive forms. In this study, we analyzed the distribution of HLA haplotypes among children with autism spectrum disorder (ASD), with and without regression from Sweden and observed that HLA-DPA1*01-DPB1*04 sub-haplotype was less represented in patients with regressive autism as compared with those without regression. Such possible protective effect, also observed in other common autoimmune disorders, may constitute a link between HLA-mediated immune processes and regressive ASD.

Early diagnosis of autism and impact on prognosis: a narrative review.

Autism spectrum disorders involve a set of clinical phenotypes that mirror an early onset of neurodevelopmental deviations, with core symptoms that can probably be related to a deficiency in the social instinct. Underlying the cognitive impairments there are physiological brain problems, caused by a large number of medical factors. This narrative review of systematic reviews and meta-analyses from the last 5 years (2008-2012) presents aspects from many areas in autism spectrum disorder research, with a particular focus on early intervention and the subsequent impact on prognosis. Other major areas discussed are epidemiology, early symptoms and screening, early diagnosis, neuropsychology, medical factors, and the existence of comorbidities. There is limited evidence that any of the broadband "early intervention" programs are effective in changing the natural long-term outcome for many individuals with an early diagnosis of autism. However, there is some evidence that Early Intensive Behavioral Intervention (EIBI) is an effective treatment for some children with ASD. Nevertheless, there is emerging consensus that early diagnosis and information are needed in order that an autism-friendly environment be "created" around affected individuals.

First-degree relatives of young children with autism spectrum disorders: some gender aspects.

Prenatal risk factors, with special focus on gender distribution of neurodevelopmental and psychiatric conditions were analysed in first-degree relatives in a population-based group of young children with autism spectrum disorders (ASD). Multiple information sources were combined. This group was contrasted with the general population regarding data from the Swedish Medical Birth register. In the ASD group, information was also obtained at parental interviews focusing on developmental and psychiatric disorders in the family. Compared to the general population, fathers of children with ASD were older and parents more often of non-European origin. Mothers of children with ASD had an increased rate of antidepressant and psychoactive medication use, and of scheduled caesarean sections. Fathers and brothers of children with ASD had high rates of ASD including the broader phenotype. Mothers of children with ASD had high rates of depression and other psychiatric disorders. These findings, hypothetically, could reflect a different ASD phenotype and difficulties diagnosing ASD in females or be an example of the close genetic relation between ASD and other psychiatric disorders. The results suggest that, in clinical and research settings, the familial background in ASD should be reviewed with a broader approach, and not be restricted to "looking out" only for diagnoses and symptoms traditionally accepted as being part of or typical of ASD. The high rate of parents of non-European origin has been noted in many Swedish studies of ASD, but the reason for this association, remains unclear.