Autism: Many Genes, Common Pathways?

Neurogenetics Program, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Cell (Impact Factor: 33.12). 11/2008; 135(3):391-5. DOI: 10.1016/j.cell.2008.10.016
Source: PubMed

ABSTRACT Autism is a heterogeneous neurodevelopmental syndrome with a complex genetic etiology. It is still not clear whether autism comprises a vast collection of different disorders akin to intellectual disability or a few disorders sharing common aberrant pathways. Unifying principles among cases of autism are likely to be at the level of brain circuitry in addition to molecular pathways.

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    • "etiology (Chapters 2.1–2.4). Currently, there are several dozen genes and loci known to contribute to ASD and accounting for at most 30% of ASD cases, with more loci being discovered (Abrahams and Geschwind, 2008; Sakai et al., 2011; see also Chapters 2.1–2.4). p0025 How can a multitude of genetic variants cause the disease specificity of ASD? Emerging views of the field indicate that: 1. Functions of the susceptible genes must converge onto a few common molecular pathways that subserve the observed ASD phenotypes; 2. The core features of ASD are the most difficult tasks that involve association of multiple areas, and therefore any mild global impairment has the greatest impact on these tasks while sparing the simpler ones; and/or 3. The expression patterns of the affected genes collectively affect specific brain regions that give rise to the normal functions which are disrupted in ASD. "
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    • "This implies that ASD is heterogenetic, with the located genes reflecting various mechanisms (Geschwind 2011; Happe et al. 2006). The variation of cellular mechanisms of possible ASD-linked genes reflects the multiple pathways affected and diverse traits in autism (Geschwind 2008; Losh et al. 2009). If the multiple pathways converged in certain brain regions, this may implicate that ASD is an integrative disorder. "
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    ABSTRACT: Autism is a neurodevelopmental disorder that has been associated with atypical brain functioning. Functional connectivity MRI (fcMRI) studies examining neural networks in autism have seen an exponential rise over the last decade. Such investigations have led to the characterization of autism as a distributed neural systems disorder. Studies have found widespread cortical underconnectivity, local overconnectivity, and mixed results suggesting disrupted brain connectivity as a potential neural signature of autism. In this review, we summarize the findings of previous fcMRI studies in autism with a detailed examination of their methodology, in order to better understand its potential and to delineate the pitfalls. We also address how a multimodal neuroimaging approach (incorporating different measures of brain connectivity) may help characterize the complex neurobiology of autism at a global level. Finally, we also address the potential of neuroimaging-based markers in assisting neuropsychological assessment of autism. The quest for a neural marker for autism is still ongoing, yet new findings suggest that aberrant brain connectivity may be a promising candidate.
    Neuropsychology Review 02/2014; 24(1). DOI:10.1007/s11065-014-9250-0 · 5.40 Impact Factor
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    • "Autism is a complex 'system' disorder that involves the interactions among multiple organs, including the brain, immune, gastrointestinal and other systems (Geschwind, 2008; Kesli et al., 2014; Matson et al., 2012). Recognized for its 'spectrum' nature, autism spectrum disorder (ASD) is a serious neurodevelopmental illness that affects approximately 1–2% of the general population, and has a significant societal and mental health impact (Evans, 2013; Mayes et al., 2011). "
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    ABSTRACT: Autism spectrum disorder (ASD) is a debilitating brain illness causing social deficits, delayed development and repetitive behaviors. ASD is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis. Genes encoding various elements of this system (including dopamine receptors, the dopamine transporter or enzymes of synthesis and catabolism) have been linked to ASD. Here, we comprehensively evaluate known molecular interactors of dopaminergic genes, and identify their potential molecular partners within up/down-steam signaling pathways associated with dopamine. These in-silico analyses allowed us to construct a map of molecular pathways, regulated by dopamine and involved in ASD. Clustering these pathways reveals groups of genes associated with dopamine metabolism, encoding proteins that control dopamine neurotransmission, cytoskeletal processes, synaptic release, Ca(2+) signaling, as well as the adenosine, glutamatergic and gamma-aminobutyric systems. Overall, our analyses emphasize the important role of the dopaminergic system in ASD, and implicate several cellular signaling processes in its pathogenesis.
    Neurochemistry International 01/2014; 66(1). DOI:10.1016/j.neuint.2014.01.002 · 2.65 Impact Factor
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