Review
Autism Spectrum Disorders and Childhood-Onset Schizophrenia: Clinical and Biological Contributions to a Relation Revisited

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Abstract

Objective

To highlight emerging evidence for clinical and biological links between autism/pervasive developmental disorder (PDD) and schizophrenia, with particular attention to childhood-onset schizophrenia (COS).

Method

Clinical, demographic, and brain developmental data from the National Institute of Mental Health (and other) COS studies and selected family, imaging, and genetic data from studies of autism, PDD, and schizophrenia were reviewed.

Results

In the two large studies that have examined this systematically, COS is preceded by and comorbid with PDD in 30% to 50% of cases. Epidemiological and family studies find association between the disorders. Both disorders have evidence of accelerated trajectories of anatomic brain development at ages near disorder onset. A growing number of risk genes and/or rare small chromosomal variants (microdeletions or duplications) are shared by schizophrenia and autism.

Conclusions

Biological risk does not closely follow DSM phenotypes, and core neurobiological processes are likely common for subsets of these two heterogeneous clinical groups. Long-term prospective follow-up of autistic populations and greater diagnostic distinction between schizophrenia spectrum and autism spectrum disorders in adult relatives are needed.

Section snippets

Phenomenology of COS in Relation to autism/PDD

Childhood-onset schizophrenia is defined as onset of psychosis before age 13 years and is a rare and severe form of schizophrenia. Onset is usually after age 7 years, positive and negative symptoms are prominent, and prognosis is poor.10 In contrast, autism is defined by abnormal behavior in the spheres of communication, social relatedness, and stereotyped behaviors within the first 3 years of life. The broader category, PDD (subsuming autism, Rett syndrome, Asperger syndrome, and childhood

Brain Imaging

The growing literature on brain imaging abnormalities in COS is not reviewed here. In autism, the best agreed on finding is increased head size/total brain volume seen in the first 3 years of age based on crosssectional studies.31, 32 This brain overgrowth that precedes or coincides with the appearance of signs and symptoms of autism suggests that it may be a fundamental aspect of the pathological process.33 There remains controversy, however, as to whether the brain anatomic developmental

Genetics

There are numerous direct and indirect genetic data linking autism and schizophrenia.39, 40, 41, 42 Specifically, various candidate gene and linkage studies and expression studies using postmortem brain samples, as well as studies of copy number variants (CNVs) in schizophrenia, have yielded a handful of genetic associations that have also been reported for autism.43, 44 Large alterations in chromosome region or number are increased in COS.45 Genomic microduplications and deletions or CNVs

Discussion

The subtle developmental delays that are seen in large prospective cohort studies of adult-onset schizophrenia are seen in exaggerated form in childhood-onset cases.10, 75 Early-onset schizophrenia has also shown strong comorbidity with PDDs in two of the three large studies in which this was measured systematically, although, until now, this has received less attention. Comorbidity is the most straightforward way to describe such findings, but as previously noted, this association does not

References (81)

  • JA Lee et al.

    Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders

    Neuron

    (2006)
  • CR Marshall et al.

    Structural variation of chromosomes in autism spectrum disorder

    Am J Hum Genet

    (2008)
  • HG Kim et al.

    Disruption of neurexin 1 associated with autism spectrum disorder

    Am J Hum Genet

    (2008)
  • J Feng et al.

    High frequency of neurexin 1 beta signal peptide structural variants in patients with autism

    Neurosci Lett

    (2006)
  • DH Blackwood et al.

    Schizophrenia and affective disorders-cosegregation with a translocation at chromosome Iq42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family

    Am J Hum Genet

    (2001)
  • M Alarcon et al.

    Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene

    Am J Hum Genet

    (2008)
  • DE Arking et al.

    A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism

    Am J Hum Genet

    (2008)
  • S Akbarian et al.

    Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders

    Brain Res Rev

    (2006)
  • American Psychiatric Association et al.

    Diagnostic and Statistical Manual of Mental Disorders

    (1968)
  • American Psychiatric Association et al.

    Quick Reference to the Diagnostic Criteria from DSM-III

    (1980)
  • American Psychiatric Association

    Diagnostic and Statistical Manual of Psychiatric Disorders

    (1987)
  • J Rapoport et al.

    DSM-III Training Guide for Diagnosis of Childhood Disorders

    (1984)
  • M Rutter

    The Emanuel Miller Memorial Lecture 1998. Autism: twoway interplay between research and clinical work

    J Child Psychol Psychiatry

    (1999)
  • SK Berument et al.

    Autism screening questionnaire: diagnostic validity

    Br J Psychiatry

    (1999)
  • SE Folstein et al.

    Genetics of autism: complex aetiology for a heterogeneous disorder

    Nat Rev Genet

    (2001)
  • SE Folstein et al.

    Autism: familial aggregation and genetic implications

    J Autism Dev Disord

    (1988)
  • M Rutter et al.

    Child and Adolescent Psychiatry

    (2002)
  • C Hollis et al.

    Child and adolescent schizophrenia

  • American Psychiatric Association

    Diagnostic and Statistical Manual of Mental Disorders

    (2000)
  • HB Demb et al.

    The use of the term multiple complex developmental disorder in a diagnostic clinic serving young children with developmental disabilities: a report of 15 cases

    Ment Health Asp Dev Disabil

    (2001)
  • M Sprang et al.

    Pathways to psychosis: a comparison of the pervasive developmental disorder subtype multiple complex developmental disorder and the “at risk mental state.”

    Schizophr Res

    (2008)
  • EI de Bruin et al.

    Multiple complex developmental disorder delineated from PDD-NOS

    J Autism Dev Disord

    (2007)
  • I Kolvin et al.

    Studies in the childhood psychoses. II. The phenomenology of childhood psychoses

    Br J Psychiatry

    (1971)
  • JM Watkins et al.

    Symptom development in childhood onset schizophrenia

    J Child Psychol Psychiatry

    (1988)
  • J Reaven et al.

    Use of ADOS and ADI-R in children with psychosis: importance of clinical judgement

    Clin Child Psychol Psychiatry

    (2008)
  • D Weinberger

    Implications of normal brain development for the pathogenesis of schizophrenia

    Arch Gen Psychiatry

    (1987)
  • DJ Done et al.

    Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11

    BMJ

    (1994)
  • DJ Done et al.

    Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11

    BMJ

    (1994)
  • M Isohanni et al.

    Childhood and adolescent predictors of schizophrenia in the Northern Finland 1966 birth cohort-a descriptive life-span model

    Eur Arch Psychiatry Clin Neurosci

    (2000)
  • M Cannon et al.

    Evidence for early-childhood, pan-developmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort

    Arch Gen Psychiatry

    (2002)
  • Cited by (0)

    Support for this work has come from the National Institute of Mental Health intramural program.

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