TLR Polymorphism, ASO and Beta-hemolytic Group A Streptococcus Infections in ADHD: an Observational Study

Study Overview
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Brief Summary
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The aim of this observational cross-sectional study is to evaluate the streptococcal infection (clinical history, ASLO title and anti-DNAse title B) and autoimmunity (ABGA antibodies) in a sample of 100 adult patients diagnosed with ADHD (ie in patients in whom the disorder is permanent). Another objective will be to evaluate the frequency and types of genetic alterations of innate immunity (TLR polymorphisms, MyD88, IRAK-4) that can determine an infantile susceptibility to gram positive infections (ie S. pyogenes, S. pneumoniae, S. aureus) and the possible relationship between these elements, also in relation to comorbidity with other ABGA-related pathologies, to identify a possible pathogenetic immune mechanism of ADHD. Prevalence data will be obtained on an outpatient ADHD population for previous (history) and recent streptococcal infection (ASLO and Anti-DNAsiB), for the detection of ABGA and for the co-presence of other ABGA-related pathologies. By comparing the subgroups obtained by dividing the results on the basis of the positive infectious history, anti-streptococcus, autoantibody and comorbidity titers, it will be possible to assess whether the elevation of the ABGA titer is only linked to the previous/current infection (infectious group) or if there is a subpopulation of ADHD patients presenting pathological elevation of ABGA titers in the absence of infectious pictures (immune group). Furthermore, it is expected that the comparison of the descriptive polymorphisms TLR, MyD88 and IRAK-4 between the infectious and immune group may show a predisposition in subjects of the immune group.

Detailed Description
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Attention Deficit / Hyperactivity Disorder (ADHD) is the most widespread neurodevelopmental disorder (prevalence 3-7% in preschool age) and is characterized by persistent inattention and / or hyperactivity-impulsivity which results in significant impairment in at least two areas of operation (usually scholastic / working and relational) with consequent impact even on the child's self-esteem. It is estimated that one-third of children with ADHD continue to be affected in adulthood and that around one-third have remission of symptoms with persisting changes in functioning and development of psychiatric disorders in adulthood (eg anxiety disorders mood and personality). The pathogenetic model of ADHD is still poorly characterized: several biological, psychological and environmental causes have been identified that would seem to interact in a complex way in determining the pathology. Several studies have hypothesized and confirmed an association between streptococcal infections, increased titer of antibodies to the basal nuclei (ABGA), different neurological and psychiatric disorders (eg, Sydenham chorea, Tic Disorders, Obsessive-Compulsive Disorder) and ADHD. ADHD is diagnosed in 40% of autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) and Sydenham Korea and a temporal connection between onset / exacerbation of ADHD and pharyngeal streptococcal infection has been described in literature. High titers of anti-streptococcal antibodies and larger size of putamen and pallidum were found in ADHD patients. However, the permanence of symptoms ADHD at a distance from streptococcal infection has led to hypothesize, as already done for PANDAS and Sydenham Korea, a miminking mechanism with consequent cross-reactivity towards host tissues that would support an autoimmune disorder characterized by the production of ABGA. According to some authors, therefore, ADHD and other ABGA-related neurological and psychiatric disorders (eg, Sydenham Korea, Tic Disorders, Obsessive-Compulsive Disorder) would be different phenotypic manifestations of a common immunological disorder affecting the nuclei of the base, triggered from group A beta-hemolytic streptococcus. The search for ABGA in ADHD patients with Tic Disorders and Obsessive-Compulsive Disorder has largely confirmed this hypothesis, however, the finding of ABGA titres in ADHD patients without comorbidities with other ABGA-related disorders is still controversial. A first study found no differences significant in terms of ABGA positivity frequency among ADHD patients without ABGA related disorders and controls while a more recent study conducted confirmed that children with ADHD without ABGA-related disorders are more frequently positive for ABGA than the control group (30% vs 4.8%; χ2 = 4.33; p = 0.04) and that, among these, those with Anti-Streptolysinic Title (ASLO) show significantly higher percentages of ABGA positivity (χ2 = 10.95; p <.001). On the other hand, greater susceptibility by ADHD patients to contracting streptococcal infections was confirmed by the finding of significantly higher titers of ASLO and anti-DNAse B in ADHD patients. The predisposition to infections and the high familiarity of ADHD (90% of cases have at least one affected parent), suggest an immune pathogenetic mechanism based on a genetic predisposition. Although several studies have established, in an inconclusive way, a relationship between ADHD and some regulatory genes, the major histocompatibility complex (MHC), such as HLA-DR4, HLA-DRB1 and C4B, to date no one has yet evaluated the role of Toll-type receptor (TLR) genes, which are more responsible for innate immunity, ie the recognition of pathogenic structural molecules. In particular, some variants of the TLR genes could affect the immune response to strepotococcus or other pathogens, favoring damage to the nuclei of the base which would in turn lead to ADHD symptoms. Recently, an association between susceptibility to serious or recurrent infections from group A beta-hemolytic streptococcus, Streptococcus pneumoniae, Haemophilus influenza and particular polymorphisms of TLR2, TLR4 and TLR9 has been demonstrated. The altered functioning consequent to these TLR polymorphisms could explain both the vulnerability to certain types of pathogens responsible for lesions to the central nervous system (among which the most studied so far is Group A beta-hemolytic streptococcus), whether the incongruous or excessive immune activation even in the absence of contact with pathogens producing autoantibodies against the nerve structures of the base nuclei.

Official Title
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Toll-Like Receptor Polymorphism, Antinuclear Antibodies and Beta-hemolytic Group A Streptococcus Infections in Attention-Deficit/Hyperactivity Disorder: an Observational Study

Conditions
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Attention Deficit-Hyperactivity Disorder

Intervention / Treatment
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* Diagnostic Test: Antistreptolysin O Test
* Diagnostic Test: Anti-Deoxyribonuclease B
* Diagnostic Test: TLR, MyD88, IRAK-4 polymorphism
* Diagnostic Test: Anti-Basal Ganglia Antibody


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosis of ADHD according to DSM-5 criteria

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| ADHD<br>Attention Deficit/Hyperactivity Disorder | Diagnostic Test: Antistreptolysin O Test<br>* Test to evaluate of any histories of streptococcal infections<br>* Other names: ASO;Diagnostic Test: Anti-Deoxyribonuclease B<br>* Test to evaluate of any histories of streptococcal infections<br>* Other names: Anti-DNase B;Diagnostic Test: TLR, MyD88, IRAK-4 polymorphism<br>* Test to evaluate of the frequency and types of genetic alterations of innate immunity<br>Diagnostic Test: Anti-Basal Ganglia Antibody<br>* Test to evaluate the autoimmune component<br>* Other names: ABGA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of Antistreptolysin O and Anti-Deoxyribonuclease B | diagnostic blood sample test to measure streptococcal infections | up to 1 year till the end of the study | 
| Measurement of TLR, MyD88, IRAK-4 polymorphism | diagnostic blood sample test to measure genetic alterations of innate immunity | up to 1 year till the end of the study | 
| Measurement of Anti-Basal Ganglia Antibody | diagnostic blood sample test to assess the autoimmune component | up to 1 year till the end of the study |