Schizophrenic‐like neurocognitive deficits in children and adolescents with 22q11 deletion syndrome

22q11.2 Deletion Syndrome (22q11DS) is the most common genetic microdeletion syndrome affecting humans. The syndrome is associated with general cognitive impairments and specific deficits in visual‐spatial ability, non‐verbal reasoning, and planning skills. 22q11DS is also associated with behavioral and psychiatric abnormalities, including a markedly elevated risk for schizophrenia. Research findings indicate that people with schizophrenia, as well as those identified as schizoptypic, show specific cognitive deficits in the areas of sustained attention, executive functioning, and verbal working memory. The present study examined such schizophrenic‐like cognitive deficits in children and adolescents with 22q11DS (n = 26) and controls (n = 25) using a cross‐sectional design. As hypothesized, 22q11DS participants exhibited deficits in intelligence, achievement, sustained attention, executive functioning, and verbal working memory compared to controls. Furthermore, deficits in attention and executive functioning were more pronounced in the 22q11DS sample relative to general cognitive impairment. These findings suggest that the same pattern of neuropsychological impairment seen in patients with schizophrenia is present in non‐psychotic children identified as at‐risk for the development of schizophrenia based on a known genetic risk marker. © 2006 Wiley‐Liss, Inc.

[1]  T. Wassink,et al.  Defining the phenotype of schizophrenia: cognitive dysmetria and its neural mechanisms , 1999, Biological Psychiatry.

[2]  K. Nuechterlein,et al.  Neurocognitive vulnerability factors for schizophrenia: Convergence across genetic risk studies and longitudinal trait–state studies. , 1998 .

[3]  G. Donnan,et al.  Disorders of memory in vertebrobasilar disease , 1980 .

[4]  M. Keshavan,et al.  Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome , 2006, Clinical genetics.

[5]  D. Housman,et al.  Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. , 1994, The Journal of nervous and mental disease.

[6]  J M Fuster,et al.  Synopsis of function and dysfunction of the frontal lobe , 1999, Acta psychiatrica Scandinavica. Supplementum.

[7]  R. Buchanan,et al.  Association between Val108/158 met polymorphism of the COMT gene and schizophrenia , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[8]  M. Egan,et al.  Prefrontal neurons and the genetics of schizophrenia , 2001, Biological Psychiatry.

[9]  D. R. Smith,et al.  CHAPTER 6 – Wechsler Individual Achievement Test , 2001 .

[10]  J. Jonides,et al.  Storage and executive processes in the frontal lobes. , 1999, Science.

[11]  A. Malhotra,et al.  A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. , 2002, The American journal of psychiatry.

[12]  G. Chelune,et al.  Developmental norms for the Wisconsin Card Sorting test. , 1986, Journal of clinical and experimental neuropsychology.

[13]  E. Zackai,et al.  Cognitive and behavior profile of preschool children with chromosome 22q11.2 deletion. , 1999, American journal of medical genetics.

[14]  R. Straub,et al.  Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Barbara A. Cornblatt,et al.  The continuous performance test, identical pairs version: II. Contrasting attentional profiles in schizophrenic and depressed patients , 1989, Psychiatry Research.

[16]  R. Engle,et al.  The role of prefrontal cortex in working-memory capacity, executive attention, and general fluid intelligence: An individual-differences perspective , 2002, Psychonomic bulletin & review.

[17]  K. Murphy,et al.  Annotation: velo-cardio-facial syndrome. , 2005, Journal of child psychology and psychiatry, and allied disciplines.

[18]  Stephan Eliez,et al.  COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome , 2005, Nature Neuroscience.

[19]  J M Fuster,et al.  The prefrontal cortex and its relation to behavior. , 1991, Progress in brain research.

[20]  I. Waldman Statistical Approaches to Complex Phenotypes: Evaluating Neuropsychological Endophenotypes for Attention-Deficit/Hyperactivity Disorder , 2005, Biological Psychiatry.

[21]  A. Bassett,et al.  22q11 deletion syndrome: a genetic subtype of schizophrenia , 1999, Biological Psychiatry.

[22]  R. Heinrichs,et al.  Quantification of frontal and temporal lobe brain-imaging findings in schizophrenia: a meta-analysis , 2003, Psychiatry Research: Neuroimaging.

[23]  M. Frydman,et al.  Velocardiofacial manifestations and microdeletions in schizophrenic inpatients. , 1997, American journal of medical genetics.

[24]  K. Devriendt,et al.  Neuropsychological, learning and psychosocial profile of primary school aged children with the velo-cardio-facial syndrome (22q11 deletion): evidence for a nonverbal learning disability? , 1999, Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence.

[25]  J. Rapoport,et al.  Velocardiofacial syndrome in childhood-onset schizophrenia. , 1999, Journal of the American Academy of Child and Adolescent Psychiatry.

[26]  R Kucherlapati,et al.  Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? , 1996, The American journal of psychiatry.

[27]  Michael F. Green,et al.  NIMH-MATRICS survey on assessment of neurocognition in schizophrenia , 2004, Schizophrenia Research.

[28]  M. Owen,et al.  Cognitive deficits associated with schizophrenia in velo-cardio-facial syndrome , 2004, Schizophrenia Research.

[29]  M. Lenzenweger,et al.  Perceptual aberrations, schizotypy, and the Wisconsin Card Sorting Test. , 1994, Schizophrenia bulletin.

[30]  Tyrone D. Cannon,et al.  The Neurocognitive Phenotype of the 22Q11.2 Deletion Syndrome: Selective Deficit in Visual-Spatial Memory , 2001, Journal of clinical and experimental neuropsychology.

[31]  N. Risch,et al.  The continuous performance test, identical pairs version (CPT-IP): I. new findings about sustained attention in normal families , 1988, Psychiatry Research.

[32]  R. Gur,et al.  Neuropsychological function in schizophrenia. Selective impairment in memory and learning. , 1991, Archives of general psychiatry.

[33]  D. Weinberger Implications of normal brain development for the pathogenesis of schizophrenia. , 1987, Archives of general psychiatry.

[34]  S. Faraone,et al.  Verbal learning and memory in relatives of schizophrenics: Preliminary findings , 1995, Biological Psychiatry.

[35]  Philip D. Harvey,et al.  Verbal learning and memory in schizotypal personality disorder. , 1998, Schizophrenia bulletin.

[36]  Philip D. Harvey,et al.  Cognitive deficits in schizophrenia. , 1993, The Psychiatric clinics of North America.

[37]  High Rates of Schizophrenia in Adults With Velo-Cardio-Facial Syndrome , 1999 .

[38]  J. Cummings,et al.  Anatomic and Behavioral Aspects of Frontal‐Subcortical Circuits a , 1995, Annals of the New York Academy of Sciences.

[39]  R. Dworkin,et al.  Origins and development of schizophrenia : advances in experimental psychopathology , 1998 .

[40]  A. Darvasi,et al.  A survey of the 22q11 microdeletion in a large cohort of schizophrenia patients , 2005, Schizophrenia Research.

[41]  K. Nuechterlein Signal detection in vigilance tasks and behavioral attributes among offspring of schizophrenic mothers and among hyperactive children. , 1983, Journal of abnormal psychology.

[42]  R. Shprintzen Velo-cardio-facial syndrome: a distinctive behavioral phenotype. , 2000, Mental retardation and developmental disabilities research reviews.

[43]  S. Faraone,et al.  Sex differences in olfactory identification and Wisconsin card sorting performance in schizophrenia: Relationship to attention and verbal ability , 1997, Biological Psychiatry.

[44]  W. Iacono,et al.  Schizophrenia through the lens of a developmental psychopathology perspective. , 1995 .

[45]  L. Cohen Wechsler Individual Achievement Test. , 1993 .

[46]  D. Shaffer,et al.  NIMH Diagnostic Interview Schedule for Children Version IV (NIMH DISC-IV): description, differences from previous versions, and reliability of some common diagnoses. , 2000, Journal of the American Academy of Child and Adolescent Psychiatry.

[47]  T. Goldberg,et al.  An investigation of semantic space in patients with schizophrenia , 1996, Journal of the International Neuropsychological Society.

[48]  A F Monk,et al.  Evidence for distinct verbal memory pathologies in severely and mildly disturbed schizophrenics. , 1983, Schizophrenia bulletin.

[49]  L J Horwood,et al.  Prevalence and comorbidity of DSM-III-R diagnoses in a birth cohort of 15 year olds. , 1993, Journal of the American Academy of Child and Adolescent Psychiatry.

[50]  August B. Hollingshead,et al.  Two Factor Index of Social Position , 1957 .

[51]  B. Rourke Syndrome of nonverbal learning disabilities : neurodevelopmental manifestations , 2006 .

[52]  E. Zackai,et al.  Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. , 2004, The American journal of psychiatry.

[53]  J. Sattler Assessment of Children , 1992 .

[54]  T. Goldberg,et al.  Probing prefrontal function in schizophrenia with neuropsychological paradigms. , 1988, Schizophrenia bulletin.

[55]  R. Shprintzen,et al.  Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[56]  K. Tallent,et al.  Wisconsin Card Sorting Test deficits in schizotypic individuals , 1999, Schizophrenia Research.

[57]  K. Devriendt,et al.  Chromosome 22q11 deletion syndrome: update and review of the clinical features, cognitive-behavioral spectrum, and psychiatric complications. , 2000, American journal of medical genetics.

[58]  D. Diforio,et al.  Executive functions in adolescents with schizotypal personality disorder , 2000, Schizophrenia Research.

[59]  S. Antonarakis,et al.  Young children with Velo-Cardio-Facial syndrome (CATCH-22). Psychological and language phenotypes , 2000, European Child & Adolescent Psychiatry.

[60]  J M Trent,et al.  Chromosome 22q11.2 interstitial deletions among childhood-onset schizophrenics and "multidimensionally impaired". , 1998, American journal of medical genetics.

[61]  R. Gur,et al.  Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. , 1994, Archives of general psychiatry.

[62]  I. Gottesman,et al.  Attention, memory, and motor skills as childhood predictors of schizophrenia-related psychoses: the New York High-Risk Project. , 2000, The American journal of psychiatry.

[63]  D. Yurgelun-Todd,et al.  Contributions of clinical neuropsychology to the study of schizophrenia. , 1989, Journal of abnormal psychology.

[64]  L. Cronbach,et al.  Construct validity in psychological tests. , 1955, Psychological bulletin.

[65]  J. Lieberman,et al.  Neurocognitive correlates of the COMT Val158Met polymorphism in chronic schizophrenia , 2002, Biological Psychiatry.

[66]  J. Cummings,et al.  Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. , 2002, Journal of psychosomatic research.

[67]  R. Kessler,et al.  Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. , 1994, Archives of general psychiatry.

[68]  R. McCarley,et al.  Neuropsychological dysfunction in schizotypal personality disorder: A profile analysis , 1997, Biological Psychiatry.

[69]  M. Owen,et al.  An investigation of the neuropsychological profile in adults with velo-cardio-facial syndrome (VCFS) , 2000, Neuropsychologia.

[70]  N. Andreasen A unitary model of schizophrenia: Bleuler's "fragmented phrene" as schizencephaly. , 1999, Archives of general psychiatry.

[71]  R. Knight,et al.  Role of human prefrontal cortex in attention control. , 1995, Advances in neurology.

[72]  R. Shprintzen,et al.  Velo-cardio-facial syndrome: language and psychological profiles. , 1985, Journal of craniofacial genetics and developmental biology.

[73]  T. Amelsvoort,et al.  Neuropsychological Profile and Neuroimaging in Patients with 22Q11.2 Deletion Syndrome: A Review Keywords: , 2005, Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence.

[74]  J. Fleiss,et al.  The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. , 1976, Archives of general psychiatry.

[75]  L. Roberts,et al.  Psychiatric evaluation of a "monk" requesting castration: a patient's fable, with morals. , 1998, The American journal of psychiatry.

[76]  J. Sweeney,et al.  Genetically predisposed offspring with schizotypal features: An ultra high-risk group for schizophrenia? , 2006, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[77]  Tyrone D. Cannon,et al.  The inheritance of intermediate phenotypes for schizophrenia , 2005, Current opinion in psychiatry.

[78]  Robert K. Heaton,et al.  Wisconsin Card Sorting Test Manual – Revised and Expanded , 1993 .

[79]  B. Cornblatt,et al.  Global attentional deviance as a marker of risk for schizophrenia: specificity and predictive validity. , 1985, Journal of abnormal psychology.

[80]  J. Sweeney,et al.  Impairment of verbal memory and learning in antipsychotic-naı̈ve patients with first-episode schizophrenia , 2004, Schizophrenia Research.

[81]  L. Erlenmeyer‐Kimling,et al.  Neurobehavioral deficits in offspring of schizophrenic parents: liability indicators and predictors of illness. , 2000, American journal of medical genetics.

[82]  I. Gottesman,et al.  The endophenotype concept in psychiatry: etymology and strategic intentions. , 2003, The American journal of psychiatry.

[83]  R. Weksberg,et al.  22q11 deletion syndrome in adults with schizophrenia. , 1998, American journal of medical genetics.

[84]  A. Rosenblatt,et al.  Prevalence of psychopathology among children and adolescents. , 1998, The American journal of psychiatry.