Macrocephaly and the control of brain growth in autistic disorders

Peter John Andrew McCaffery, Curtis K Deutsch

Research output: Contribution to journalArticlepeer-review

77 Citations (Scopus)


Autism is a childhood-onset neuropsychiatric disorder characterized by marked impairments in social interactions and communication, with restricted stereotypic and repetitive patterns of behavior, interests, and activities. Genetic epidemiology studies indicate that a strong genetic component exists to this disease, but these same studies also implicate significant environmental influence. The disorder also displays symptomatologic heterogeneity, with broad individual differences and severity on a graded continuum. In the search for phenotypes to resolve heterogeneity and better grasp autism's underlying biology, investigators have noted a statistical overrepresentation of macrocephaly, an indicator of enlarged brain volume. This feature is one of the most widely replicated biological findings in autism. What then does brain enlargement signify? One hypothesis invoked for the origin of macrocephaly is a reduction in neuronal pruning and consolidation of synapses during development resulting in an overabundance of neurites. An increase in generation of cells is an additional mechanism for macrocephaly, though it is less frequently discussed in the literature. Here, we review neurodevelopmental mechanisms regulating brain growth and highlight one underconsidered potential causal mechanism for autism and macrocephaly--an increase in neurogenesis and/or gliogenesis. We review factors known to control these processes with an emphasis on nuclear receptor activation as one signaling control that may be abnormal and contribute to increased brain volume in autistic disorders.
Original languageEnglish
Pages (from-to)38-56
Number of pages19
JournalProgress in Neurobiology
Issue number1-2
Publication statusPublished - Sept 2005


  • adaptation, physiological
  • animals
  • autistic disorder
  • brain size
  • craniofacial abnormalities
  • humans
  • neurological models
  • cytoplasmic receptor
  • signal transduction
  • genetic syndrome
  • macrocephaly
  • nuclear receptor
  • valproate
  • retinoic acid
  • central nervous system
  • fragile-X-syndrome
  • neural stem cells
  • fetal valproate syndrome
  • cyclase-activating polypeptide
  • dexamethasone-suppression test
  • bronchial epithelial cells
  • complete trisomy 5P
  • dentate gyrus


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