Autistic Spectrum Disorders in Velo-cardio Facial Syndrome (22q11.2 Deletion)

Antshel, Kevin M.; Aneja, Alka; Strunge, Leslie; Peebles, Jena; Fremont, Wanda; Stallone, Kimberly; AbdulSabur, Nuria; Higgins, Anne Marie; Shprintzen, Robert J.; Kates, Wendy R.

doi:10.1007/s10803-006-0308-6

Cited by 160 publications

(157 citation statements)

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“…The tendency for males to exhibit worse premorbidity to schizophrenia than females (87,88), and for earlier-onset schizophrenia to exhibit a higher male bias and a stronger tendency to be mediated by CNVs rather than other factors (89, 90) suggests a notable risk for false-positive diagnoses of autistic spectrum conditions (75)(76)(77)(91)(92)(93). Apparent direct evidence of such risk comes from tendencies to diagnose autism spectrum conditions in children with deletions at 15q11.2, 15q13.3, and 22q11.21, and duplications of 16p11.2, CNVs for which high risk of schizophrenia has been established from studies of adults (16,23,31,(94)(95)(96)(97). To the degree that autism and schizophrenia exhibit diametric genetically-based risk factors, inclusion of children premorbid for schizophreniaspectrum conditions in studies of the genetic bases of autism will substantially dilute and confound the detection of significant results.…”

Section: Discussionmentioning

confidence: 99%

Comparative genomics of autism and schizophrenia

Crespi

Stead

Elliot

2010

Proc. Natl. Acad. Sci. U.S.A.

239

138

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We used data from studies of copy-number variants (CNVs), singlegene associations, growth-signaling pathways, and intermediate phenotypes associated with brain growth to evaluate four alternative hypotheses for the genomic and developmental relationships between autism and schizophrenia: (i) autism subsumed in schizophrenia, (ii) independence, (iii) diametric, and (iv) partial overlap. Data from CNVs provides statistical support for the hypothesis that autism and schizophrenia are associated with reciprocal variants, such that at four loci, deletions predispose to one disorder, whereas duplications predispose to the other. Data from single-gene studies are inconsistent with a hypothesis based on independence, in that autism and schizophrenia share associated genes more often than expected by chance. However, differentiation between the partial overlap and diametric hypotheses using these data is precluded by limited overlap in the specific genetic markers analyzed in both autism and schizophrenia. Evidence from the effects of risk variants on growth-signaling pathways shows that autism-spectrum conditions tend to be associated with upregulation of pathways due to loss of function mutations in negative regulators, whereas schizophrenia is associated with reduced pathway activation. Finally, data from studies of head and brain size phenotypes indicate that autism is commonly associated with developmentally-enhanced brain growth, whereas schizophrenia is characterized, on average, by reduced brain growth. These convergent lines of evidence appear most compatible with the hypothesis that autism and schizophrenia represent diametric conditions with regard to their genomic underpinnings, neurodevelopmental bases, and phenotypic manifestations as reflecting under-development versus dysregulated over-development of the human social brain.genetics | evolution | psychiatry T he Swiss psychiatrist Eugen Bleuler coined the terms "schizophrenia", for the splitting of psychic functions, and "autism", for withdrawal from external reality in patients with schizophrenia, almost exactly a century ago (1). Ever since 1943, when Leo Kanner (2) coopted autism to refer to a new condition involving "disturbance of affective contact" manifested in children, the relationship between schizophrenia and Kanner's autism has remained unclear (3). Kanner originally conceived autism as an early, distinct subtype of schizophrenia (model 1A) (Fig. 1A), a view he later renounced in favor of a model, which was also supported by Rutter (4) with the conditions as distinct, separate, and unrelated (model 1B) (Fig. 1B). Under each of these two hypotheses, autism and schizophrenia may each grade more or less smoothly, and independently, into so-called normality. Schizophrenia and autism have also been considered as diametric, or opposite sets of conditions (model 1C) (Fig. 1C) along a spectrum of social-brain phenotypes from hypodevelopment in autism, to normality, to hyperdevelopment in schizophrenia (5). By a fourth model, autism overlaps broadly yet...

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Section: Discussionmentioning

confidence: 99%

Comparative genomics of autism and schizophrenia

Crespi

Stead

Elliot

2010

Proc. Natl. Acad. Sci. U.S.A.

239

138

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“…However, mitochondrial biogenesis increases dramatically after birth in several tissues, including the brain (10). Deficiencies in mitochondrial metabolism due to altered dosage of one or several 22qDS mitochondrial genes, particularly during early postnatal brain development, could set the basis for a disrupted neuronal metabolism or synaptic signaling during perinatal periods, leading to alterations in neurocognitive development in ways that impair intellectual and social development and increase the risk for schizophrenia (3,4,6,7). Although lower gene expression in individuals with 22qDS is expected, due to the presence of single copy genes, different genotypes from the remaining allele could be associated with specific gene dosage thresholds, as observed in other models (11).…”

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confidence: 99%

Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome

Napoli

Tassone

Wong

et al. 2015

Journal of Biological Chemistry

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Background:The most common microdeletion congenital disorder, 22qDS, is the second risk factor for schizophrenia. Results: Plasma metabolomics in 22qDS consisted of an oxidative phosphorylation-to-glycolysis shift with altered 2-hydroxyglutaric acid, cholesterol, and fatty acid concentrations. Conclusion: Despite the haploinsufficiency of ϳ30 genes, the 22qDS metabolic signature chiefly reflected deficits in the mitochondrial citrate transporter. Significance: Biochemical profiling of 22qDS unveiled the impact of SLC25A1 haploinsufficiency.

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“…The most commonly reported psychiatric disorders are attention deficit/hyperactivity disorder (ADHD) (present in 30-40% of individuals with VCFS) [29][30][31] , anxiety disorders, especially simple phobias and separation anxiety (present in 30-40%) 10,30,32,33 , autism spectrum disorders (10-30%) 34,35 , mood disorders including major depression and bipolar disorder (present in 20-30%) 30,36 and psychotic disorders (25-30%) 37,38 .…”

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confidence: 99%

Cognitive and Psychiatric Predictors to Psychosis in Velocardiofacial Syndrome: A 3-Year Follow-Up Study

Antshel

Shprintzen

Fremont

et al. 2010

Journal of the American Academy of Child & Adolescent Psych

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Objective-To predict prodromal psychosis in adolescents with velocardiofacial syndrome (VCFS).Method-70 youth with VCFS, 27 siblings of youth with VCFS and 25 community controls were followed from childhood (Mean age = 11.8 years) into mid-adolescence (mean age 15.0 years). Psychological tests measuring intelligence, academic achievement, learning/memory, attention and executive functioning as well as measures of parent and clinician ratings of child psychiatric functioning were completed at both time points.Results-Major depressive disorder, oppositional defiant disorder and generalized anxiety disorder diagnoses increased in the VCFS sample. With very low false positives, the best predictor of adolescent prodromal psychotic symptoms was parent ratings of childhood odd/eccentric symptoms and child performance on a measure of executive functioning, the Wisconsin Card Sorting Test.Conclusions-Similar to the non-VCFS prodromal psychosis literature, a combination of cognitive and psychiatric variables appears to predict psychosis in adolescence. A child with VCFS who screens positive is noteworthy and demands clinical attention. KeywordsVelocardiofacial syndrome (VCFS); 22q11 deletion syndrome; cognition; psychosis; longitudinal Velo-cardio-facial syndrome (VCFS) is caused by an interstitial deletion from chromosome 22 at the 22q11 band. The most common microdeletion syndrome yet identified in humans, VCFS has a population prevalence of approximately 1:2000 to 1:6000 live births 1, 2 . In most cases, VCFS is caused by a hemizygous deletion of 3 million base pairs of DNA encompassing 40 genes but approximately 8% have smaller nested deletions of 1.5 million base pairs spanning 34 genes 3 . Structural anomalies affect nearly every part and system of the body and may Correspondence to: Kevin Antshel, Ph.D. SUNY -Upstate Medical University Department of Psychiatry and Behavioral Sciences, 750 East Adams Street, Syracuse, NY 13210; AntshelK@upstate.edu. Disclosure: Dr. Faraone, in the past year, has received consulting fees and has been on Advisory Boards for Eli Lilly, Ortho-McNeil, and Shire Development, and has received research support from Eli Lilly, Pfizer, Shire and the National Institutes of Health. In previous years, Dr. Faraone has received consulting fees or has been on advisory boards, or has been a speaker for the following sources: Shire, McNeil, Janssen, Novartis, Pfizer, and Eli Lilly. In previous years he has received research support from Eli Lilly, Shire, Pfizer and the National Institutes of Health. Drs. Antshel, Shprintzen, Fremont, and Kates, and Ms. Higgins report no biomedical financial interests or potential conflicts of interest.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the prod...

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Autistic Spectrum Disorders in Velo-cardio Facial Syndrome (22q11.2 Deletion)

Cited by 160 publications

References 98 publications

Comparative genomics of autism and schizophrenia

Comparative genomics of autism and schizophrenia

Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome

Cognitive and Psychiatric Predictors to Psychosis in Velocardiofacial Syndrome: A 3-Year Follow-Up Study

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