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

Background 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. Methods 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. Discussion 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. Systematic review registration PROSPERO CRD42016042841 Electronic supplementary material The online version of this article (doi:10.1186/s13643-017-0448-0) contains supplementary material, which is available to authorized users.


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(development* next disorder*) or "developmental status" or (disintegrative next disorder*) or pervasive or autism or autistic or asperger* (Word variations have been searched)

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gestation* or embryo* or prenatal* or neonat* or newborn* or infan* or toddler* or child* or preschooler* or pre-schooler* or adolescen* or paediatric* or pediatric* (Word variations have been searched) #20 PubMED (tuberous sclerosis) AND ("asperger syndrome" OR autism OR "autistic disorder" OR "autism spectrum" OR childhood disintegrative disorder* OR disintegrative disorder* OR pervasive OR "pervasive developmental disorder not otherwise specified" OR child development* disorder* OR development* disorder* OR "developmental status") AND ("diffusion magnetic resonance imaging" OR "diffusion MRI" OR "diffusion tensor imagining" OR "diffusion weighted imaging" OR electrophysiologic* OR electroencephalography OR epilepsy OR epileptic OR family OR family's OR familial OR "family history" OR "functional neuroimaging" OR gene OR genes OR genetic* OR genotyp* OR "gene mutation" OR "genotype phenotype" OR "genotype phenotype correlation" OR gender OR " image analysis" OR interictal OR inter-ictal OR "magnetic resonance imagining" OR neuroimaging OR "nuclear magnetic resonance imaging" OR "perfusion weighted imaging" OR "prenatal exposure delayed effects" OR "pregnancy outcome" OR prognostic factor* OR risk OR risk factor* OR seizure OR "social class" OR socioeconomic factor* OR "TOR Serine-Threonine Kinases" OR tuberous OR tuber OR "white matter") AND (embryo* OR prenatal* OR neonat* OR infan* OR toddler* OR child* OR preschooler* OR pre-schooler* OR adolescen* OR paediatric* OR pediatric*) AND ( BACKGROUND: Neuropsychiatric disorders are present in up to 90% of patients with Tuberous Sclerosis Complex (TSC), and represent an important issue for families. Autism Spectrum Disorder (ASD) is the most common neurobehavioral disease, affecting up to 61% of patients. The aims of this study were: 1) to assess the prevalence of ASD in a TSC population; 2) to describe the severity of ASD; 3) to identify potential risk factors associated with the development of ASD in TSC patients. METHODS: We selected 42 individuals over age 4 years with a definite diagnosis of TSC and followed at a TSC clinic in Northern Italy. We collected and reported clinical and genetic data, as well as cognitive level, for each of them. We administered the Social Communication Questionnaire (SCQ) as a reliable screening tool for ASD, and performed comparisons between the average scores and each clinical and genetic feature. RESULTS: Seventeen out of 42 patients (40.5%) had a score at the SCQ suggestive of ASD (>15 points). When calculated for each cognitive level category, the average SCQ score tended to be progressively higher in patients with a worse cognitive level, and the number of pathological SCQ scores increased with worsening of intellectual disability. With respect to ASD severity, the scores were equally distributed, indicating that the degree of

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