title: Risk factors for the development of autism spectrum disorder in children with tuberous sclerosis complex: protocol for a systematic review.
abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant condition, caused by mutations in either the TSC1 or TSC2 gene. It has widespread systemic manifestations and is associated with significant neurological morbidity. In addition to seizures and cerebral pathology including cortical tubers, subependymal nodules, subependymal giant cell astrocytoma and abnormal white matter, there are recognised neuropsychiatric difficulties including intellectual disability, autism spectrum disorder (ASD) and a range of learning and behaviour problems, recently conceptualised as "tuberous sclerosis-associated neuropsychiatric disorders", or "TAND". ASD in TSC is of particular importance because (1) it affects up to 50% of people with TSC and is a source of considerable difficulty for them and their families and (2) it provides a model for considering neurobiological pathways involved in ASD. Multiple factors are implicated in the development of ASD in TSC, including (1) seizures and related electrophysiological factors, (2) cerebral pathology, (3) genotype and (4) child characteristics. However, the neurobiological pathway remains unclear. We will conduct a systematic review to investigate and synthesise existing evidence about the role of these risk factors, individually and in combination, in leading to the development of ASD.
  
  
  
  Our review will report on all studies that include one or more of four predefined risk factors in the development of ASD in children with TSC. We will search five databases: MEDLINE, EMBASE, PubMed, The Cochrane Library and Web of Science (Conference Proceedings Citation Index). Studies will be selected for reporting after two authors independently (1) review all titles and abstracts, (2) read full text of all appropriate papers and (3) assess for bias using the Newcastle-Ottawa Scale recommended by the Guidelines for Meta-Analysis and Systematic Reviews of Observational Studies (MOOSE guidelines) and the ROBINS-I.
  
  
  
  To our knowledge, this is the first systematic review investigating multiple risk factors in the development of ASD in children with TSC. Clarifying the evidence in this area will be important to researchers in the field and to clinicians providing prognostic information to families.
  
  
  
  PROSPERO CRD42016042841.
authors.affiliation: Developmental Medicine, The Royal Children's Hospital, 50 Flemington Road, Parkville, Victoria, 3052, Australia. bec.mitchell@rch.org.au.
authors.forename: Rebecca
authors.identifier: 0000-0001-9783-3495
authors.initials: R
authors.lastname: Mitchell
authors.affiliation: Department of Neurology, The Royal Children's Hospital, 50 Flemington Road, Parkville, Victoria, 3052, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Barton
authors.affiliation: Department of Neurology, The Royal Children's Hospital, 50 Flemington Road, Parkville, Victoria, 3052, Australia.
authors.forename: A Simon
authors.initials: AS
authors.lastname: Harvey
authors.affiliation: Developmental Medicine, The Royal Children's Hospital, 50 Flemington Road, Parkville, Victoria, 3052, Australia.
authors.forename: Katrina
authors.initials: K
authors.lastname: Williams
mesh_terms: D000067877:Autism Spectrum Disorder / Q000453:epidemiology*; D002648:Child; D055724:Electrophysiological Phenomena; D005838:Genotype; D006801:Humans; D012107:Research Design; D012307:Risk Factors; D012640:Seizures / Q000453:epidemiology; D000078202:Systematic Reviews as Topic; D014402:Tuberous Sclerosis / Q000453:epidemiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D066127:White Matter / Q000473:pathology
keywords: Autism spectrum disorder; Children; Genotype; Risk factors; Seizures; Systematic review; Tuberous sclerosis complex; Tubers; White matter disorders