Re: Comparative Genomics of Autism, Tourette syndrome and Autoimmune/Inflammatory Di

[Guest guest]

Bingo Cheryl, it's almost a hypothesis document...they still got there

stats wrong on incidence...but a powerful document considering their

conservatism....

Comparative Genomics of Autism, Tourette syndrome and

Autoimmune/Inflammatory Di

> This is so cool!!! The science is growing strong for !! Note the

> mention of immune " dysregulation " , neuroimmune, etc. It's nice when the

> validation is coming from the top.

>

> I was searching for a specific item and I really lucked out when this popped

> up <grin>.

> Cheryl

>

>

> Part one...

>

> Comparative Genomics of Autism, Tourette syndrome and

> Autoimmune/Inflammatory Disorders

> 4-23-03

>

> G. Becker1*, Boris Freidlin2, and M. Simon21DNA Array Unit,

> National Institute on Aging, National Institutes of Health, Baltimore, MD

> 21224; 2Biometrics Research Branch, National Cancer Institute, Rockville, MD

> 20892

>

> Key words: Autism, Tourette syndrome, Autoimmune Abbreviations: autism Aut

> Tourette Syndrome TS autoimmune/ inflammatory disorders AI multiple

> sclerosis MS systemic lupus erythematosus SLE systemic lupus erythematosus

> SLE-NP with neuropsychiatric phenotype Crohn's disease CD Psoriasis PS Type

> I diabetes IDDM Ankylosing spondylitis ANK Obsessive compulsive disorder OCD

> Attention Deficit Hyperactivity Disorder ADHD * Manuscript

>

> Abstract

> Autism and Tourette syndrome are complex enigmatic disorders. Both are

> childhood neurological syndromes affecting behavior, social interaction,

> movement, and language. Like many complex disorders, autism and Tourette

> syndrome are thought to have complex genetic and environmental etiologies.

>

> Similarly, autoimmune and inflammatory (AI) disorders have complex

> multigenic and environmental origins. Genetic loci for AI disorders have

> previously been shown to cluster non-randomly in several regions throughout

> the human genome, suggesting in some cases, shared genetic etiologies.

>

> Here, we show that genetic loci for autism and Tourette syndrome tend to

> cluster with each other and also tend to cluster with previously defined

> loci for inflammatory disorders. This suggests a genetic relationship

> between autism and Tourette syndrome, as well as a genetic relationship of

> both with disorders of immune dysregulaton.

>

> Introduction

> Autism and Tourette syndrome are found in all populations, cultures, and

> racial groups [1,2].Both disorders are considered spectrum disorders with a

> range of clinical symptoms and intermediate phenotypes including individuals

> with high function to those with profound disability [3,4]. Although both

> disorders are distinct clinical entities, there are a number of

> epidemiological and clinical characteristics that are similar between autism

> and Tourette syndrome including disease prevalence, sex ratio, overlapping

> traits or intermediate phenotypes, and co-morbidity. The prevalence in the

> population is similar, with approximately 2-5 cases per 10,000 for autism

> [2] and approximately 5 per 10,000 for Tourette syndrome [5]. The age of

> diagnosis for autism is approximately 2-4 years [2] while the age of onset

> of tics in Tourette syndrome is 2-11 years, with a mean of age of onset of

> 5.6 years [5]. In both syndromes there is a skewed sex ratio of

> approximately 4:1 males versus females [2,5]. It has been suggested that the

> prevalence for both disorders has been increasing, although in both cases it

> is unclear whether this is a true increase or a change in diagnostic

> classification and reporting [3,6].

>

> Both disorders were earlier thought to have neuropsychological origins but

> now both are considered to have complex genetic, environmental, or

> developmental etiologies [1,2]. In both disorders there is little evidence

> of degenerative neuropathology, however in both cases subtle anomalies in

> brain imaging have been observed [7-10]. Autism is characterized primarily

> by social withdrawal, language impairment, and repetitive behaviors [2],

> while Tourette syndrome, often grouped with obsessive compulsive disorder

> (OCD), is generally characterized by vocal and motor tics, behavior

> problems, impulse control, and compulsive behaviors [1]. Individuals with

> one disorder sometimes share characteristics of the other, such as verbal

> and motor tics being found in some autistic individuals, as well social

> withdrawal found in some Tourette syndrome or OCD patients [3,11,12]. Both

> disorders have overlapping clinical characteristics associated with

> attention deficit hyperactivity disorder (ADHD) [1,5], and co-localization

> of loci between autism and ADHD has been noted [13]. Co-morbidity for autism

> and Tourette syndrome has been shown with a dual diagnosis of autism and

> Tourette syndrome [14-17] within individual patients. Moreover, in both

> disorders individual clinical characteristics of the respective disorder has

> been observed in unaffected parents and family members [1,2]. Immune

> imbalances have been demonstrated in both autism and Tourette syndrome and

> suggestions of immune or infectious etiology have been made for both

> disorders [18-21].

>

> Genetics of Autism and Tourette syndrome

>

> The familal nature of both autism and Tourette syndrome has been well

> established. Through twin studies and family studies, both disorders have

> been shown to have a significant genetic component with a high heritability

> estimate of approximately 90% for autism [2,22] and 89-94% for Tourette

> syndrome [1]. Linkage studies using whole genome scanning approaches have

> been used in both autism and Tourette syndrome. In both disorders, multiple

> loci have been identified on different chromosomes suggesting heterogeneity

> and non-Mendelian inheritance. In most studies, candidate loci are of

> suggestive significance, rather than confirmed, and in no case has a

> specific gene been identified for either disorder. As with many genome scans

> of complex heterogeneous disorders, there are concerns with regard to

> replication between different studies within a given disorder.

>

> Autism

> At least eleven studies have reported whole genome scans of autism or

> autistic spectrum disorders using sib pair and family studies [4,23-32]. In

> these reports, no loci of major effect were found, however, all studies

> found multiple loci of suggestive significance. These loci include positive

> genome scan results on chromosome 1p, 1q, 2p, 2q, 3p, 3q, 4p, 5p, 6q, 7q,

> 13q, 15q, 16p, 19p, 19q, Xq, and, Xq-ter, among others (supp.1, supp. 2).

> Each study analyzed different patient collections, using somewhat different

> diagnostic criteria, statistical models, and different polymorphic marker

> panels. Even so, there was replication and overlap of findings between

> studies (fig 1a-1d; supp. 1), particularly on chromosomes 2q, 7q, 15q, 16p,

> and 19q. In no case have genes been identified as the source of the genetic

> linkage.

>

> Tourette syndrome

> Likewise, genome-scanning approaches have been used in Tourette syndrome and

> related disorders such as OCD, by at least 6 groups [33-39]. Also, as

> before, in most studies no loci of major effect were found, however multiple

> loci of suggestive significance were identified, including 1p, 2p, 2q, 4p,

> 4q, 5p, 6p, 7q, 8p, 8q, 11p, 11q, 12p, 12q, 13q, 14q, 16p, 17p, 19p, 20q,

> and 21q. (supp.1, supp. 2). Replication between different studies has been

> shown on chromosomes 1p, 2q, 4p, 11q, and 13q.

>

> Immune imbalance in Autism and Tourette syndrome

> Both autism and Tourette syndrome have long been suspected to have an immune

> or infectious component [20,40-43]. The immune component suggested in both

> disorders is not of a classical autoimmune pattern, such as found in Type I

> diabetes or multiple sclerosis, with overt immune cellular infiltration or

> immune mediated tissue destruction. It may involve subtle antibody mediated

> effects on brain structures or dysregulation of immune mediators in the

> context of developmental/ neuroimmune interactions.

>

> Autism has been shown to be associated with cytokine imbalances [44-46] as

> well as antibody abnormalities including antibodies directed against brain

> and neuronal factors [47-49]. infectious agents [50-51], and food allergies

> [52] have also been suspected to play a role in disease etiology. Autism has

> been treated with immunological approaches [53]. Interestingly, the

> frequency of autoimmune disorders has been shown to be increased in families

> of autistic patients [54] while language impairment and auditory processing

> deficits have been shown in infants of families with a history of autoimmune

> disorders [55].

>

> Recently, an association between autism and bowel inflammation has been

> suggested [56-57] with MMR vaccination in the context of enterocolitis being

> suggested to play a part in autistic disorder [56,58,59]. The role, if any,

> of vaccination has been highly debated [60-62], and evidence for this

> association has not been confirmed in larger studies [63].

>

> Similarly, Tourette syndrome and related disorders have been associated with

> immune imbalances [18,44,64-66] suggesting an immune component in the

> etiology of Tourette syndrome. Antibodies have been found in Tourette

> syndrome patients to phospholipids [67], putamen [68], and other neural and

> brain epitopes [69]. An association of Tourette syndrome and OCD with

> streptococcal infections has been demonstrated [70-71] as well. Increased

> titers of anti-streptococcal antibodies have been found in Tourette syndrome

> patients [72-73]. These observations and the similarity of Tourette syndrome

> to the post streptococcal disorder Syndenhamn's chorea have suggested an

> antibody mediated or autoimmune model in the etiology of Tourette syndrome

> and OCD [74-77]. Rat models of Tourette syndrome using serum from neuronal

> antibody positive patients resulted in neuronal dysfunction, unprovoked

> audible vocalizations and increased stereotypies [78-79]. Interestingly, the

> B-cell marker D8/17 has been found in autism, Tourette syndrome, and OCD

> patients [80-82].

>

> Paradoxically, none of the whole genome scans that studied autism or

> Tourette syndrome have found statistically significant linkage to the major

> histocompatibility complex (MHC) on human chromosome 6p. Recently,

> and coworkers have demonstrated linkage of the MHC to autism spectrum

> disorder [83]. Immunological aspects of both autism and Tourette syndrome

> have been recently reviewed [18,20,42,43,64,78].

>

> Clustering of Loci in Autoimmune / Inflammatory disorders

>

> Classical autoimmune disorders are common chronic conditions of immune

> dysregulation affecting approximately 4% of the population. These include

> over 30 diseases such as Type 1 diabetes (IDDM), multiple sclerosis (MS),

> rheumatoid arthritis (RA), psoriasis (PS), systemic lupus erythematosus

> (SLE), among many others. Table 1 lists AI disorders described in this

> study. These disorders involve perturbations in humoral or cellular immune

> compartments that often lead to chronic immune mediated destruction of organ

> or tissue targets. In each case, the entire clinical phenotype is largely

> determined by the extent and functional consequences of immune attack on the

> target organ. Interestingly, a higher incidence of other autoimmune

> disorders, but not necessarily the primary disorder, has been demonstrated

> in families of patients with specific autoimmune disorders. Likewise,

> co-morbidity of multiple inflammatory or autoimmune disorders within

> individuals has been well documented.

> SNIP> to be continued.........

>

> _________________________________________________________________

>

> Responsibility for the content of this message lies strictly with

> the original author, and is not necessarily endorsed by or the

> opinion of the Research Institute.

[Guest guest]

Yes, cheryl could you please supply us with date and publication on thed

piece from yesterday.

Re: Comparative Genomics of Autism, Tourette syndrome and

Autoimmune/Inflammatory Di

> Hey Cheryl -

>

> That is so great. I can't wait to give this to my

> pediatrician. Hah!

>

> Is this published? I have a hard time telling...

> Does this come directly from the NIH? I just need to

> have the validation when I pass this on...

>

> Thanks so much! Awesome find!

>

>

>

[Guest guest]

----Original Message Follows----

From: " NewMail " <ldugua@...>

Yes, cheryl could you please supply us with date and publication on thed

piece from yesterday.

From: " " <thecolemans4@...>

Is this published? I have a hard time telling...

> Does this come directly from the NIH? I just need to

> have the validation when I pass this on...

It's a manuscript that has not been published..............yet. Originating

from

Array Unit, National Institute on Aging, National Institutes of Health,

Baltimore, MD 21224;

2Biometrics Research Branch, National Cancer Institute, Rockville, MD 20892

Comparative Genomics of Autism, Tourette syndrome and

Autoimmune/Inflammatory Disorders 4-23-03

Key words: Autism, Tourette syndrome, Autoimmune Abbreviations: autism Aut

Tourette Syndrome TS autoimmune/ inflammatory disorders AI multiple

sclerosis MS systemic lupus erythematosus SLE systemic lupus erythematosus

SLE-NP with neuropsychiatric phenotype Crohn’s disease CD Psoriasis PS Type

I diabetes IDDM Ankylosing spondylitis ANK Obsessive compulsive disorder OCD

Attention Deficit Hyperactivity Disorder ADHD * Manuscript

_________________________________________________________________

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