Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phosphatidylinositol 3-kinase (PI3K) signaling pathway modulates growth, proliferation and cell survival in diverse tissue types and plays specialized roles in the nervous system including influences on neuronal polarity, dendritic branching and synaptic plasticity. The tumor-suppressor phosphatase with tensin homology (PTEN) is the central negative regulator of the PI3K pathway. Germline PTEN mutations result in cancer predisposition, macrocephaly and benign hamartomas in many tissues, including Lhermitte-Duclos disease, a cerebellar growth disorder. Neurological abnormalities including autism, seizures and ataxia have been observed in association with inherited PTEN mutation with variable penetrance. It remains unclear how loss of PTEN activity contributes to neurological dysfunction. To explore the effects of Pten deficiency on neuronal structure and function, we analyzed several ultra-structural features of Pten-deficient neurons in Pten conditional knockout mice. Using Golgi stain to visualize full neuronal morphology, we observed that increased size of nuclei and somata in Pten-deficient neurons was accompanied by enlarged caliber of neuronal projections and increased dendritic spine density. Electron microscopic evaluation revealed enlarged abnormal synaptic structures in the cerebral cortex and cerebellum. Severe myelination defects included thickening and unraveling of the myelin sheath surrounding hypertrophic axons in the corpus callosum. Defects in myelination of axons of normal caliber were observed in the cerebellum, suggesting intrinsic abnormalities in Pten-deficient oligodendrocytes. We did not observe these abnormalities in wild-type or conditional Pten heterozygous mice. Moreover, conditional deletion of Pten drastically weakened synaptic transmission and synaptic plasticity at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. These data suggest that Pten is involved in mechanisms that control development of neuronal and synaptic structures and subsequently synaptic function.
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PMID:Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities. 1808 64

A detailed morphometric analysis of the cerebellum in autism with and without macrocephaly. Four subject groups (N = 65; male; IQs > or = 65; age 7 to 26 years) were studied with quantitative MRI; normocephalic and macrocephalic individuals with autism without mental retardation were compared to normocephalic and benign macrocephalic typically developing individuals. Total cerebellum volumes and surface areas of four lobular midsagittal groups were measured. Independent t-tests between autism and control subjects matched for head size revealed no significant differences. Multivariate analyses of variance were also performed, using the diagnostic group as the fixed factor, cerebellar measures as the dependent variables and total intracranial volume, total brain volume, age, verbal IQ, and performance IQ as covariates. No significant differences were found; however, a trend was noted in which macrocephalic individuals with autism consistently exhibited slightly smaller cerebellar volume or surface area when compared to individuals with benign macrocephaly. In autism, with and without macrocephaly, cerebellar structures were found to be proportional to head size and did not differ from typically developing subjects.
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PMID:Quantitative magnetic resonance image analysis of the cerebellum in macrocephalic and normocephalic children and adults with autism. 1841 39

Previous investigations have reported decreased size of the corpus callosum (CC) in autism. However, little is known of the regional distribution of these callosal abnormalities. Additional uncertainty exists regarding the role of head size with respect to variations in callosal size in individuals with autism. This study investigated the size of the CC in 5 groups of high functioning individuals: (1) normocephalic autistic individuals; (2) autism with macrocephaly; (3) non-autistic normocephalic controls; (4) non-autistic participants with benign macrocephaly; and (5) a reading disordered (RD) group, comprised of non-autistic individuals with a deficit in reading. The CC was traced from midsaggital MRIs and the outlines partitioned into 99 equidistant width measures. Factor analysis of the 99 widths revealed 10 contiguous callosal regions. Individuals with macrocephaly (autistic and non-autistic) had larger total CC size. Regional analysis revealed a significantly larger CC midbody in macrocephaly, regardless of presence or absence of autism. Within normocephalic individuals, those with autism had a smaller CC genu and midbody than either non-autistic controls or RD individuals. These results underscore the importance of considering head size in studies of CC morphology in autism. These findings add to the literature implicating problems of interhemispheric connectivity being present in individuals with autism.
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PMID:Regional callosal morphology in autism and macrocephaly. 1844 71

Macrocephaly is associated with many genetic disorders and is a frequent cause of referral to the clinical geneticist. In this review we classify the commonly encountered macrocephaly disorders into useful categories and summarize recent genetic advances. Conditions where macrocephaly is a predominant aspect of the clinical presentation are discussed and a diagnostic approach to the common macrocephaly disorders is provided. Some emphasis is placed on familial macrocephaly (sometimes referred to as benign external hydrocephalus) and on the macrocephaly associated with autism spectrum disorders. The more recent conditions associated with the leukodystrophies and the organic acidurias are reviewed, but the well known conditions involving storage disorders and bone dysplasias are mentioned but not discussed. The genetic macrocephaly conditions cover a broad spectrum of gene disorders and their related proteins have diverse biological functions. As of yet it is not clear what precise biological pathways lead to generalized brain overgrowth.
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PMID:Genetic disorders associated with macrocephaly. 1862 77

Somatic mutations of the phosphatase and tensin (PTEN) gene have been frequently detected in many types of human cancer. However, germline mutations can determine multiple hamartoma syndromes and, as more recently ascertained, syndromes clinically characterized by autism associated with macrocephaly. To determine whether germline mutations of PTEN may lead to different phenotypes, we screened all the nine exons of the PTEN gene in 40 patients with neurodevelopmental disorders, with or without features of autism spectrum disorder, associated with macrocephaly. Three novel de novo missense mutations were found (p.H118P, p.Y176C, p.N276S) in two severely mentally retarded patients with autism and in a subject with neurodevelopmental disorders without autistic features. Our results provide evidence that PTEN germline mutations may sustain a more wide phenotypical spectrum than previously suggested.
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PMID:Novel PTEN mutations in neurodevelopmental disorders and macrocephaly. 1875 67

This is a case report of macrosomia, obesity, macrocephaly and ocular abnormalities (MOMO syndrome) associated with autism. Studies on genetic or environmental syndromes associated with autism can provide genetic markers or uncover relevant events, and are very important for the definition of autism subgroups in future molecular research.
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PMID:MOMO syndrome associated with autism: a case report. 1904 2

PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a lipid phosphatase that counteracts the function of phosphatidylinositol-3 kinase (PI3K). Loss of function of PTEN results in constitutive activation of AKT and downstream effectors and correlates with many human cancers, as well as various brain disorders, including macrocephaly, seizures, Lhermitte-Duclos disease, and autism. We previously generated a conditional Pten knock-out mouse line with Pten loss in limited postmitotic neurons in the cortex and hippocampus. Pten-null neurons developed neuronal hypertrophy and loss of neuronal polarity. The mutant mice exhibited macrocephaly and behavioral abnormalities reminiscent of certain features of human autism. Here, we report that rapamycin, a specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1), can prevent and reverse neuronal hypertrophy, resulting in the amelioration of a subset of PTEN-associated abnormal behaviors, providing evidence that the mTORC1 pathway downstream of PTEN is critical for this complex phenotype.
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PMID:Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. 1921 84

Autism is thought to be associated with a bias towards detail-focussed processing. While the cognitive basis remains controversial, one strong hypothesis is that there are high processing costs associated with changing from local into global processing. A possible neural mechanism underlying this processing style is abnormal neural connectivity; specifically reduced structural or functional connectivity between brain regions might lead to good exemplar-based processing but poor generalisation. Abnormal neural connectivity has also been suggested to account for the increased incidence of macrocephaly in autism (increased head/brain size). The present study therefore investigated the effect of head size on the ability to switch between global and local processing in autism. 49 high-functioning 7-12 year olds with autism (12 with macrocephaly) were compared to 25 normally developing children in their performance on a Local-Global Switching task. Those children with autism who also had macrocephaly showed a greater processing cost when switching into global processing, or 'zooming out', than both the remaining children with autism and the control children. A second experiment revealed that macrocephaly in the context of normal development is not associated with difficulty switching into global processing but rather occurs in children who are physically large. Macrocephaly in the context of autism may therefore be a biological marker of abnormal neural connectivity, and of a local processing bias.
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PMID:Big heads, small details and autism. 1942 91

Autism spectrum disorders (ASD) are diagnosed on the basis of three behavioral features namely deficits in social communication, absence or delay in language, and stereotypy. The susceptibility genes to ASD remain largely unknown, but two major pathways are emerging. Mutations in TSC1/TSC2, NF1, or PTEN activate the mTOR/PI3K pathway and lead to syndromic ASD with tuberous sclerosis, neurofibromatosis, or macrocephaly. Mutations in NLGN3/4, SHANK3, or NRXN1 alter synaptic function and lead to mental retardation, typical autism, or Asperger syndrome. The mTOR/PI3K pathway is associated with abnormal cellular/synaptic growth rate, whereas the NRXN-NLGN-SHANK pathway is associated with synaptogenesis and imbalance between excitatory and inhibitory currents. Taken together, these data strongly suggest that abnormal synaptic homeostasis represent a risk factor to ASD.
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PMID:A synaptic trek to autism. 1954 94

Lipoblastoma (LPB) is a benign neoplasm that occurs predominantly in early childhood. We investigated clinicopathologic features, associated conditions, immunohistochemistry, and outcome in 59 LPB identified from surgical pathology and consultation files. Pathology materials, cytogenetics reports, and medical records were reviewed. Immunohistochemistry for S100 protein, CD34, and Mib-1 was performed on formalin-fixed, paraffin-embedded tissue using standard techniques. Fifty-nine patients had 74 samples, including 14 patients with one or more with local recurrences among the 30 patients who had available follow-up information. There were 37 males and 22 females (ratio 1.7). Age at diagnosis ranged from 3 months to 16 years with 22% in the first year, 68% at 1 to 9 years, and 10% at 10 to 16 years. Sixty-four percent arose on the trunk, 27% on the extremities, and 8% in the head/neck. Forty-six percent had one or more recurrences. Tumor diameter ranged from 1.2 to 15.5 cm. The white to yellow cut surface showed variable lobulation and myxoid change. Histologically, nodules of adipose and myxoid tissue were demarcated by bands of fibrous tissue. The cells displayed a range of differentiation from multivacuolated lipoblasts to mature adipocytes. Mitoses were nonexistent to rare. Histologic variations included a subtle zonal architecture of fat maturation, abundant myxoid material, primitive mesenchymal cells, a focal plexiform vascular pattern, and multinucleated cells. All cases tested were immunoreactive for S100 and CD34; Mib-1 reactivity was absent to low. Cytogenetic aberrations included chromosome 8 abnormalities in 8 cases, nonspecific numerical abnormalities in 1 case, and a normal karyotype in 1 case. Ten patients had other medical conditions including macrocephaly, seizures, developmental delay, autism, congenital anomalies, Sturge-Weber syndrome, or a family history of multiple lipomas. In summary, this large series of LPB demonstrates its occurrence in older children and adolescents, documents a recurrence rate of 46% and confirms that the degree of adipocytic differentiation does not predict biologic behavior. An unexpected finding was the presence in 17% of patients of central nervous system disorders such as seizures, autism, and developmental delay, congenital anomalies, Sturge-Weber syndrome, or a family history of lipomas. These observations raise the question of whether predisposing genetic or other constitutional factors contribute to the development of LPB or whether LPB is indicative of a syndrome.
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PMID:Lipoblastoma (LPB): a clinicopathologic and immunohistochemical analysis of 59 cases. 1973 56


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