Objective Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants. Method The 1,402 participants with 22q11.2 deletion syndrome, ages 6–68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years. Results Attention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were overrepresented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills. Conclusions To the authors' knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome.

Phenylalanine hydroxylase (PAH) deficiency, traditionally called phenylketonuria (PKU) due to characteristic phenylketones accumulating in the urine of affected individuals, has a significant place in history as the first inborn error of metabolism identified through population-based screening, initiating a new era in the diagnosis and treatment of genetic disorders. PKU was first described in 1934 by the Norwegian physician Asbjörn Fölling, but it was not until the mid-1950s that a patient with PAH deficiency was treated with a low phenylalanine (PHE) diet. Although this first patient already had irreversible Phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of affected individuals and was the first inborn error of metabolism to be identified through population screening. Early identification and treatment prevent the most dramatic clinical sequelae of the disorder, but new neurodevelopmental and psychological problems have emerged in individuals treated from birth. The additional unanticipated recognition of a toxic effect of elevated maternal phenylalanine on fetal development has added to a general call in the field for treatment for life. Two major conferences sponsored by the National Institutes of Health held >10 years apart reviewed the state of knowledge in the field of phenylalanine hydroxylase deficiency, but there are no generally accepted recommendations for therapy. The purpose of this guideline is to review the strength of the medical literature relative to the treatment of phenylalanine hydroxylase deficiency and to develop recommendations for diagnosis and therapy of this disorder. Evidence review from the original National Institutes of Health consensus conference and a recent update by the Agency for Healthcare Research and Quality was used to address key questions in the diagnosis and treatment of phenylalanine hydroxylase deficiency by a working group established by the American College of Medical Genetics and Genomics. The group met by phone and in person over the course of a year to review these reports, develop recommendations, and identify key gaps in our knowledge of this disorder.Above all, treatment of phenylalanine hydroxylase deficiency must be life long, with a goal of maintaining blood phenylalanine in the range of 120-360 µmol/l. Treatment has predominantly been dietary manipulation, and use of low protein and phenylalanine medical foods is likely to remain a major component of therapy for the immediate future. Pharmacotherapy for phenylalanine hydroxylase deficiency is in early stages with one approved medication (sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase) and others under development. Eventually, treatment of phenylalanine hydroxylase deficiency will be individualized with multiple medications and alternative medical foods available to tailor therapy. The primary goal of therapy should be to lower blood phenylalanine, and any interventions, including medica...

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The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. Imaging data was collected from 10 centers worldwide, including 474 subjects with 22q11DS (age=18.2±8.6; 46.9% female) and 315 typically-developing, matched controls (age=18.0±9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen’s d=0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d=−1.01/−1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

The extent to which the phenotype of children comorbid for velocardiofacial syndrome (VCFS) and autism spectrum disorders (ASD) differs from that of VCFS-only has not been studied. The sample consisted of 41 children (20 females) with VCFS, ranging in age from 6.5 years to 15.8 years. Eight children with VCFS met formal DSM-IV diagnostic criteria for autism based upon the ADI-R. These eight plus an additional nine participants met diagnostic criteria for an autistic spectrum disorder (VCFS + ASD). Ninety-four percent of the children with VCFS + ASD had a co-occurring psychiatric disorder while 60% of children with VCFS had a psychiatric disorder. Children with VCFS + ASD had larger right amygdala volumes. All other neuroanatomic regions of interest were statistically similar between the two groups.

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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...

Attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) commonly co-occur. With the DSM-5, clinicians are permitted to make an ASD diagnosis in the context of ADHD. In earlier versions of the DSM, this was not acceptable. Both ASD and ADHD are reported to have had substantial increases in prevalence within the past 10 years. As a function of both the increased prevalence of both disorders as well as the ability to make an ASD diagnosis in ADHD, there has been a significant amount of research focusing on the comorbidity between ADHD and ASD in the past few years. Here, we provide an update on the biological, cognitive and behavioral overlap/distinctiveness between the two neurodevelopmental disorders with a focus on data published in the last four years. Treatment strategies for the comorbid condition as well as future areas of research and clinical need are discussed.