Konstantinos Francis

Novel therapeutic targets for autism

Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders, diagnosed in early childhood when acquired skills are lost or the acquisition of new skills becomes delayed. ASDs are associated with varying degrees of dysfunctional communication and social skills, in addition to repetitive and stereotypic behaviors. The diagnosis has increased considerably to approximately one in 180 people, but it is not clear whether this is because of a higher prevalence of the disorder, improved awareness by clinicians or a combination of both. There are no defined mechanisms of pathogenesis or curative therapy presently available. Oxidative stress, overactivation of the hypothalamic-pituitary-adrenal axis and increased gut-blood-brain-barrier permeability might be involved. The scope of this article is to integrate these findings and present the opinion that non-allergic activation of gastrointestinal and brain mast cells could contribute to many of the pathologic findings and provide unique targets for ASD therapy. We make suggestions for new research directives and possible novel therapies from readily available molecules.

Brief Report: “Allergic Symptoms” in Children with Autism Spectrum Disorders. More than Meets the Eye?

Many children with Autism Spectrum Disorders (ASD) have either family and/or personal history of “allergic symptomatology”, often in the absence of positive skin or RAST tests. These symptoms may suggest mast cell activation by non-allergic triggers. Moreover, children with mastocytosis or mast cell activation syndrome (MCAS), a spectrum of rare diseases characterized by increased number of activated mast cells in many organs, appear to have ASD at a rate tenfold higher (1/10 children) than that of the general population (1/100 children). Mast cell activation by allergic, infectious, environmental and stress-related triggers, especially perinatally, would release pro-inflammatory and neurotoxic molecules. We speculate these could disrupt the gut–blood–brain barriers, thus contributing to brain inflammation and ASD pathogenesis. Increased mast cell responsiveness may define at least a subgroup of ASD subjects, who could benefit from inhibition of mast cell activation.

Grammatical Abilities of Greek-Speaking Children with Autism

This study investigates pronoun reference and verbs with nonactive morphology in high-functioning Greek-speaking children with Autism Spectrum Disorders (ASD). It is motivated by problems with reflexive pronouns demonstrated by English-speaking children with ASD and the fact that reflexivity is also expressed via nonactive (reflexive) verbs in Greek. Twenty 5- to 8-year-old children with ASD and 20 vocabulary-matched typically developing controls of the same age range completed a sentence-picture matching, an elicitation, and a judgment task. Children with ASD did not differ from controls in interpreting reflexive and strong pronouns but were less accurate in the comprehension of clitics and omitted clitics in their production. The findings render clitics a vulnerable domain for autism in Greek, and potentially for other languages with clitics, and suggest that this could be a consequence of difficulties in the syntax-pragmatics or the syntax-phonology interface. The two groups did not differ in the comprehension of nonactive morphology but were less accurate in passive than reflexive verbs. We argue that this is likely to stem from the linguistic representation associated with each type of verb, rather than their input frequency.

Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by defects in communication and social interactions, as well as stereotypic behaviors. Symptoms typically worsen with anxiety and stress. ASD occur in early childhood, often present with regression and have a prevalence of 1 out of 68 children. The lack of distinct pathogenesis or any objective biomarkers or reliable animal models hampers our understanding and treatment of ASD. Neurotensin (NT) and corticotropin-releasing hormone (CRH) are secreted under stress in various tissues, and have proinflammatory actions. We had previously shown that NT augments the ability of CRH to increase mast cell (MC)-dependent skin vascular permeability in rodents. CRH also induced NT receptor gene and protein expression in MCs, which have been implicated in ASD. Here we report that serum of ASD children (4–10 years old) has significantly higher NT and CRH levels as compared with normotypic controls. Moreover, there is a statistically significant correlation between the number of children with gastrointestinal symptoms and high serum NT levels. In Bull Terriers that exhibit a behavioral phenotype similar to the clinical presentation of ASD, NT and CRH levels are also significantly elevated, as compared with unaffected dogs of the same breed. Further investigation of serum NT and CRH, as well as characterization of this putative canine breed could provide useful insights into the pathogenesis, diagnosis and treatment of ASD.

Perinatal Immune Activation and Risk of Autism

He could fit in the palms of both hands, seemed to look at you beseechingly while you rushed to thread a vein and snake a tube down a tiny nostril of this 24 week preemie. Already exposed to the prenatal stress that culminated in premature delivery, he has been further exposed to the stress associated with the separation from his mother and multiple medical interventions. Like other premature babies, he is more vulnerable to invasive infections from bacteria and viruses; moreover, the delayed development of his gut-blood-brain barriers could expose him to potential neurotoxins. Such infants are up to 4 times more likely to develop autism. If their mothers had allergies, mastocytosis or an autoimmune disease, this risk almost doubles. Autism Spectrum Disorders (ASD) are pervasive developmental disorders that include Autistic Disorder and Asperger’s Disorder, although Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) is frequently included (Johnson & Myers, 2007). ASD are characterized by variable deficits in social skills, stereotypic behaviors, and a wide range of behavioral and learning problems. ASD manifest during early childhood and at least 30% present with sudden clinical regression of development around 3 years of age (Matson J.L. & Kozlowski A.M., 2010; Zappella, 2010). Over the last 20 years, there has been an impressive rise in ASD with current prevalence estimates of 1/100 children (Fombonne, 2009; Kogan et al., 2009). In the majority of cases, the cause of ASD is unknown (Levy et al., 2009). Some autism susceptibility genes have been identified (Weiss et al., 2009), but gene interactions with environmental factors are increasingly suspected (Deth et al., 2008; Herbert, 2010). Recent reviews have focused mostly on genomic screens that suggest there are multiple gene interactions in autism; however no gene abnormality alone can explain the apparent increase in ASD prevalence (Durkin et al., 2010; Herbert, 2010; Miles, 2011). Increasing evidence suggests that there are different ASD endophenotypes, even within the ASD spectrum (Palmieri & Persico, 2010).