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      Advances in autism.

      Annual review of medicine

      Humans, pathology, Brain, therapy, genetics, Autistic Disorder

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          Abstract

          Autism is a common childhood neurodevelopmental disorder with strong genetic liability. It is not a unitary entity but a clinical syndrome, with variable deficits in social behavior and language, restrictive interests, and repetitive behaviors. Recent advances in the genetics of autism emphasize its etiological heterogeneity, with each genetic susceptibility locus accounting for only a small fraction of cases or having a small effect. Therefore, it is not surprising that no unifying structural or neuropathological features have been conclusively identified. Given the heterogeneity of autism spectrum disorder (ASD), approaches based on studying heritable components of the disorder, or endophenotypes, such as language or social cognition, provide promising avenues for genetic and neurobiological investigations. Early intensive behavioral and cognitive interventions are efficacious in many cases, but autism does not remit in the majority of children. Therefore, development of targeted therapies based on pathophysiologically and etiologically defined subtypes of ASD remains an important and achievable goal of current research.

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          Most cited references 81

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          Strong association of de novo copy number mutations with autism.

          We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
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            Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample.

            Autism spectrum disorders are now recognized to occur in up to 1% of the population and to be a major public health concern because of their early onset, lifelong persistence, and high levels of associated impairment. Little is known about the associated psychiatric disorders that may contribute to impairment. We identify the rates and type of psychiatric comorbidity associated with ASDs and explore the associations with variables identified as risk factors for child psychiatric disorders. A subgroup of 112 ten- to 14-year old children from a population-derived cohort was assessed for other child psychiatric disorders (3 months' prevalence) through parent interview using the Child and Adolescent Psychiatric Assessment. DSM-IV diagnoses for childhood anxiety disorders, depressive disorders, oppositional defiant and conduct disorders, attention-deficit/hyperactivity disorder, tic disorders, trichotillomania, enuresis, and encopresis were identified. Seventy percent of participants had at least one comorbid disorder and 41% had two or more. The most common diagnoses were social anxiety disorder (29.2%, 95% confidence interval [CI)] 13.2-45.1), attention-deficit/hyperactivity disorder (28.2%, 95% CI 13.3-43.0), and oppositional defiant disorder (28.1%, 95% CI 13.9-42.2). Of those with attention-deficit/hyperactivity disorder, 84% received a second comorbid diagnosis. There were few associations between putative risk factors and psychiatric disorder. Psychiatric disorders are common and frequently multiple in children with autism spectrum disorders. They may provide targets for intervention and should be routinely evaluated in the clinical assessment of this group.
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              The classical complement cascade mediates CNS synapse elimination.

              During development, the formation of mature neural circuits requires the selective elimination of inappropriate synaptic connections. Here we show that C1q, the initiating protein in the classical complement cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina. Mice deficient in complement protein C1q or the downstream complement protein C3 exhibit large sustained defects in CNS synapse elimination, as shown by the failure of anatomical refinement of retinogeniculate connections and the retention of excess retinal innervation by lateral geniculate neurons. Neuronal C1q is normally downregulated in the adult CNS; however, in a mouse model of glaucoma, C1q becomes upregulated and synaptically relocalized in the adult retina early in the disease. These findings support a model in which unwanted synapses are tagged by complement for elimination and suggest that complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease.
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                Author and article information

                Journal
                10.1146/annurev.med.60.053107.121225
                3645857
                19630577

                Humans, pathology, Brain, therapy, genetics, Autistic Disorder

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