Matteo Chiappedi

SNAP-25 single nucleotide polymorphisms are associated with hyperactivity in autism spectrum disorders

Synaptosomal-associated protein of 25kD (SNAP-25), a protein participating in the regulation of synaptic vesicle exocytosis and in calcium homeostasis, was recently involved in neuropsychiatric conditions. Because alterations affecting the homeostasis of calcium are described in patients affected by autism spectrum disorders (ASD) we investigated a possible involvement of SNAP-25 in ASD by evaluating five SNAP-25 gene polymorphisms in a cohort of 67 ASD children. Data analyzed in relationship with clinical outcomes and compared to those of 205 healthy sex-matched children did not reveal significant differences. Further analyses nevertheless showed the presence of highly significant associations of the rs363043 (CT) genotype, localized in the intron 1 region that affects the transcription factor binding sites of the SNAP-25 gene, with both increasing CARS (p=0.001) and hyperactivity scores (p=0.006). The finding that polymorphisms of the SNAP-25 gene, a gene involved in neurotransmission and regulation of calcium homeostasis, are associated with the degree of hyperactivity in children with ASD, reinforces the hypothesis that alterations of these mechanisms play a pivotal role in the events leading to ASD-associated behavioral impairment. Modulation of these processes could result in novel therapeutic strategies.

Medication overuse headache in school-aged children: more common than expected?

Objective.— To investigate the prevalence of medication overuse headache (MOH) in a group of children and adolescents seen for headache in a third‐level center in Italy.

Childhood and adolescent migraine: A neuropsychiatric disorder?

Migraine is a neurological disorder characterized by unilateral head pain, nausea and/or vomiting and altered sensory perception (particularly phono- and/or photophobia). It is a common and disabling condition in children and adolescents, just as it is in adults; its origins, pathophysiology and long-term course are still not fully understood. Biological factors are currently held to be crucial in the aetiopathogenesis of primary headaches, such as migraine. In children and adolescents, we hypothesize that for migraine to develop, life events and their psychological processing are fundamental and can act in two different ways: either as a predisposing factor, inducing a chronic state of anxiety or depression (even subclinical), or as a trigger factor, activating a cascade of psychological events which, in turn, activate the biological mechanisms that produce the migraine attack. According to our hypothesis, psychological processing of life events (i.e. how the child perceives and mentally processes them) is the main factor in migraine aetiopathogenesis. This hypothesis has important implications in terms of diagnostic and therapeutic choices for children and adolescents with migraine.

Corpus callosum agenesis and rehabilitative treatment.

Corpus callosum agenesis is a relatively common brain malformation. It can be isolated or included in a complex alteration of brain (or sometimes even whole body) morphology. It has been associated with a number of neuropsychiatric disorders, from subtle neuropsychological deficits to Pervasive Developmental Disorders.Etiology and pathogenetic mechanisms have been better understood in recent years, due to the availability of more adequate animal models and the relevant progresses in developmental neurosciences. These recent findings are reviewed (through a MedLine search including papers published in the last 5 years and most relevant previously published papers) in view of the potential impact on childrens global functioning and on the possible rehabilitative treatment, with an emphasis on the possibility to exploit brain plasticity and on the use of the ICF-CY framework.

HLA polymorphisms in Italian children with autism spectrum disorders: Results of a family based linkage study

To verify correlations between HLA and autism spectrum disorders (ASD) we studied 61 Italian families with an ASD child; results showed such correlation in 65% of cases. Case-control and TDT analysis of intrafamilial transmission of SNPs, Msats, and HLA markers surrounding the α and β blocks, indicated significant positive associations for MOGc*131 and D6S2239*105 alleles in ASD, and a negative association of MIB *332 allele in healthy siblings. Polymorphism haplotype analysis demonstrated that two haplotypes comprising the TNF-238(G)-TNF-308(G)-MIB*332-HLA-B*38-HLA-Cw*12 and the D6S265*218-HLA-A*23-MOGc*131-rs2857766(G) alleles are more frequently transmitted to ASD. MOGc and MIB loci are linked with ASD in Italian patients.

Activating KIR molecules and their cognate ligands prevail in children with a diagnosis of ASD and in their mothers.

The activity of natural killer (NK) cells is modulated by the interaction between killer-cell immune globulin-like receptor (KIR) proteins and their cognate HLA ligands; activated NK cells produce inflammatory cytokines and mediate innate immune responses. Activating KIR/HLA complexes (aKIR/HLA) were recently suggested to prevail in children with autism spectrum disorders (ASD), a neurodevelopmental syndrome characterized by brain and behavioral abnormalities and associated with a degree of inflammation. We verified whether such findings could be confirmed by analyzing two sample cohorts of Sardinian and continental Italian ASD children and their mothers. Results showed that aKIR/HLA are increased whereas inhibitory KIR/HLA complexes are reduced in ASD children; notably this skewing was even more significant in their mothers. KIR and HLA molecules are expressed by placental cells and by the trophoblast and their interactions result in immune activation and influence fetal, as well as central nervous system development and plasticity. Data herein suggest that in utero KIR/HLA immune interactions favor immune activation in ASD; this may play a role in the pathogenesis of the disease.

Pharmacological Treatment of Anorexia Nervosa: A Retrospective Study in Preadolescents and Adolescents

To date, studies addressing the role of pharmacotherapy in the treatment of anorexia nervosa are limited, especially in childhood and adolescence. The aim of this retrospective naturalistic study was to evaluate the efficacy and safety of pharmacotherapy in 19 anorexic preadolescents and adolescents referred, for the first time, to a specialist psychiatry unit. Almost all the patients showed an improvement both in their eating behaviors, and in their mood and obsessive symptoms. No evidence was found of dangerous adverse events. Combined with a multidisciplinary approach that includes nutritional rehabilitation and psychotherapy, adjunctive pharmacotherapy may be useful in addressing both eating disorder psychopathology and comorbid psychiatric disorders.

Neuropsycological gender differences in healthy individuals and in pediatric neurodevelopmental disorders. A role for SNAP-25

Synaptosomal-associated protein of 25 KD (SNAP-25) is a protein that participates in synaptic vesicle exocytosis through the formation of a SNARE complex; SNAP-25 also plays a pivotal role in modulating calcium homeostasis through negative regulation of voltage-gated calcium channels. SNAP-25 has been involved in different neuropsychiatric disorders, including attention deficit hyperactivity disorder. There are well known physiological gender differences in many neuropsychological skills, and there are even more striking gender differences in patients with attention deficit hyperactivity disorder and autism spectrum disorders. We hypothesize that these differences are the result of a mechanism involving SNAP-25 polymorphisms and its differential expression in specific brain areas.

Multiple inflammasome complexes are activated in autistic spectrum disorders.

BACKGROUND Inflammasomes are multimeric protein platforms involved in the regulation of inflammatory responses whose activity results in the production of proinflammatory cytokines. Because neuroinflammation is observed in autistic spectrum disorders (ASD), a neurologic condition of childhood resulting in a complex behavioural impairment, we analyzed the inflammasomes activity in ASD. Additionally we verified whether alterations of the gastrointestinal (GI) barriers might play a role in inflammasomes activation. METHODS The activity of the inflammasomes, the concentration of the inflammasomes-derived proinflammatory cytokines interleukin (IL)-1β and IL-18, and serum parameters of GI damage were analyzed in 25 ASD children, 23 healthy siblings (HS) and 30 unrelated age-matched healthy controls (HC). RESULTS A significant upregulation of the AIM2 and the NLRP3 inflammasomes and an increased production of IL-1β and IL-18 that was associated with a consistent reduction of IL-33, an anti inflammation cytokine were observed in ASD alone. Notably, in a possible immune-mediated attempt to dampen inflammation, IL-37, a suppressor of innate inflammatory responses, was significantly augmented in these same children. Finally, intestinal fatty acid binding protein (IFABP), an index of altered GI permeability, was significantly increased in serum of ASD and HS. CONCLUSIONS These results show that the inflammasomes are activated in ASD and shed light on the molecular mechanisms responsible for ASD-associated neuroinflammation. The observation that GI alterations could be present as well in ASD offers a possible link between such alterations and neuroinflammation. Therapeutic strategies targeting inflammasome activation could be useful in ASD.

Response to rehabilitation of children and adolescents with epilepsy

One hundred fifty-six children and adolescents with epilepsy from six Italian rehabilitation units were retrospectively enrolled to define the proportion of patients with epileptogenic developmental disorders who benefit from comprehensive rehabilitation programs and to identify factors predicting treatment response. The rehabilitation programs were classified as neuromotor, psychomotor, and speech and language. For each program, the response was coded as present or absent according to the caring physicians judgment. Selected demographic and clinical variables were correlated to treatment response. Neuromotor rehabilitation was performed in 86 cases (55%), psychomotor rehabilitation in 54 cases (34%), and speech and language rehabilitation in 40 cases (26%). Response rates were 58, 74, and 90%, respectively. Independent negative predictors of treatment response included severity of functional impairment (odds ratio=0.02, 95% confidence interval=0.01-0.14) and daily seizures (odds ratio=0.22, 95% confidence interval=0.08-0.58).