Risk factors for the development of autism spectrum disorder in children with tuberous sclerosis complex: protocol for a systematic review

Abstract

BackgroundTuberous 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.MethodsOur 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.DiscussionTo 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.Systematic review registrationPROSPERO CRD42016042841 Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-017-0448-0) contains supplementary material, which is available to authorized users.

Physical health in children with neurodevelopmental disorders

“…Phenotypical overlaps cannot be interpreted as causation or shared etiology per se, but a number of medical or genetic syndromes are known to cause physical problems and NDDs alike. Children with tuberous sclerosis have higher prevalence of ASD and learning disabilities (Mitchell et al 2017 ) and studies have shown an association between early exposure of cranial radiation or chemotherapy and later development of neurocognitive problems (Anderson and Kunin-Batson 2009 ; Edelstein et al 2011 ), but still the field of NDD in cancer patients is relatively unexplored. Even though comorbidity of NDDs is the rule rather than the exception (Gillberg 2010 ), no study has of yet specifically investigated the physical health of children with multiple overlapping NDDs, nor does a comprehensive overview of these associations exist.…”

Autism medical comorbidities

“…Therefore, children with TSC have an increased risk of developing ASD, which depends on the presence of several factors, including brain lesion burden, prominent lesion type, the tuber size and location, cyst-like tubers, presence of a TSC2 mutation, early-onset and refractory seizures, and the presence and severity of cognitive impairment. Consequently, early termination of seizures may improve the neuropsychiatric outcome, at least in some cases[ 16 , 17 ]. Because of the increased incidence of genetic disorders in children with autism, any child diagnosed with ASD should have a consultation with a geneticist.…”

Synaptopathology Involved in Autism Spectrum Disorder

“…TSC is a neurocutaneous disorder characterized by the formation of hamartomas in multiple organs, and neurological manifestations including epilepsy, ID and ASD. ASD is estimated to affect about 40% of patients with TSC (Richards et al, 2015), and epilepsy is one of the risk factors for the development of ASD in TSC patients (Vignoli et al, 2015; Mitchell et al, 2017).…”