title: Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications.
abstract: BACKGROUND
  Autism is diagnosed in numerous genetic and genomic developmental disorders associated with an overlap in high-risk genes and loci that underlie intellectual disability (ID) and epilepsy. The aim of this stereological study of neuronal soma volume in 25 brain structures and their subdivisions in eight individuals 9 to 26 years of age who were diagnosed with chromosome 15q11.2-13.1 duplication syndrome [dup(15)], autism, ID and epilepsy; eight age-matched subjects diagnosed with autism of unknown etiology (idiopathic autism) and seven control individuals was to establish whether defects of neuronal soma growth are a common denominator of developmental pathology in idiopathic and syndromic autism and how genetic modifications alter the trajectory of neuronal soma growth in dup(15) autism.
  
  
  RESULTS
  Application of the Nucleator software to estimate neuronal size revealed significant neuronal soma volume deficits in 11 of 25 structures and their subregions (44 %) in subjects diagnosed with dup(15) autism, including consistent neuronal soma volume deficits in the limbic system (sectors CA2, 3 and 4 in Ammon's horn, the second and third layers of the entorhinal cortex and in the amygdala), as well as in the thalamus, nucleus accumbens, external globus pallidus, and Ch3 nucleus in the magnocellular basal complex, and in the inferior olive in the brainstem. The second feature distinguishing dup(15) autism was persistent neuronal soma deficits in adolescents and young adults, whereas in idiopathic autism, neuronal volume deficit is most prominent in 4- to 8-year-old children but affects only a few brain regions in older subjects.
  
  
  CONCLUSIONS
  This study demonstrates that alterations in the trajectory of neuronal growth throughout the lifespan are a core pathological features of idiopathic and syndromic autism. However, dup(15) causes persistent neuronal volume deficits in adolescence and adulthood, with prominent neuronal growth deficits in all major compartments of the limbic system. The more severe neuronal nuclear and cytoplasic volume deficits in syndromic autism found in this study and the more severe focal developmental defects in the limbic system in dup(15) previously reported in this cohort may contribute to the high prevalence of early onset intractable epilepsy and sudden unexpected death in epilepsy.
authors.affiliation: Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA. jerzy.wegiel@opwdd.ny.gov.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Wegiel
authors.affiliation: Infant Development, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Flory
authors.affiliation: Department of Psychiatry, Nemours Biomedical Research, duPont Hospital for Children, Wilmington, DE, USA.
authors.forename: N Carolyn
authors.initials: NC
authors.lastname: Schanen
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.affiliation: Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Nowicki
authors.affiliation: Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA.
authors.forename: Izabela
authors.initials: I
authors.lastname: Kuchna
authors.affiliation: Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA.
authors.forename: Humi
authors.initials: H
authors.lastname: Imaki
authors.affiliation: Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA.
authors.forename: Shuang Yong
authors.initials: SY
authors.lastname: Ma
authors.affiliation: Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA.
authors.forename: Jarek
authors.initials: J
authors.lastname: Wegiel
authors.affiliation: Psychology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: London
authors.affiliation: Departments of Pediatrics and Biomedical Sciences, University of South Carolina School of Medicine, Greenville Health System, Greenville, SC, USA.
authors.forename: Manuel F
authors.initials: MF
authors.lastname: Casanova
authors.affiliation: Departments of Neurology, Pathology, and Psychiatry, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
authors.affiliation: Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, Staten Island, NY, USA.
authors.forename: W Ted
authors.initials: WT
authors.lastname: Brown
mesh_terms: D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000473:pathology; D002648:Child; D002869:Chromosome Aberrations; D002884:Chromosomes, Human, Pair 15; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000473:pathology*; D008032:Limbic System / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D012720:Severity of Illness Index; D055815:Young Adult