The autism spectrum disorder phenotype in children with tuberous sclerosis complex: A systematic review and meta‐analysis

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease that can affect most body systems. It is caused by a pathogenic variation in the TSC1 or TSC2 gene, 1,2 which is responsible for producing the proteins hamartin and tuberin respectively. The proteins form a complex involved in inhibiting the mammalian target of rapamycin pathway, which regulates cellular function, including proliferation, growth, and apoptosis. 3 In TSC, neurological characteristics, including seizures and structural brain changes, are common, occurring in around 90% of affected individuals. 4 Autism spectrum disorder (ASD) and intellectual disability are frequent outcomes occurring in around 50%. 5,6 ASD, which occurs in 1% to 4% of the general population, 7,8 is a lifelong neurodevelopmental disorder with social communication and restrictive and repetitive behaviour (RRB) impairments, with severity ranging from mild to profound. Most ASD is considered to be idiopathic, that is, there is no specific, identifiable, underlying cause; however, twin studies suggest that around 80% to 90% of ASD is due to complex, multifactorial

Heterogeneity of Autism Characteristics in Genetic Syndromes: Key Considerations for Assessment and Support

“…Seizure onset before age 1 year and greater severity of infantile spasms are positively correlated with autism characteristics [ 94 ], although the cause-effect nature of these relationships is not clear [ 95 – 97 ]. Up to 66% of infants with TSC meet the criteria for autism on the ADOS [ 98 ] and demonstrate a profile of social communication differences which are highly similar to that observed in non-syndromic autism [ 99 , 100 ]. Social communication differences, including reduced eye contact, social babbling, and reciprocal smiling, are more frequently reported than RRBIs in infancy [ 101 , 102 ].…”

Describing autism spectrum disorder in tuberous sclerosis complex: Challenges and future opportunities

“…Compared to ASD without a known cause (idiopathic ASD) and TSC without ASD, rates of developmental delay/intellectual disability in TSC-ASD are much higher with a reported rate of 90%. 4 The TSC Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study evaluating early phenotypic features and potential biomarkers of ASD in infants and young children with ASD reported the rate of developmental delay at 45% in all participants with TSC. 3 Differences in rates of developmental delay/ intellectual disability in TSC are likely due to multiple factors, including high rates of comorbid epilepsy with early onset of seizures being associated with an increased risk of developmental delay and autism-related behaviors.…”

“…Compared to ASD without a known cause (idiopathic ASD) and TSC without ASD, rates of developmental delay/intellectual disability in TSC‐ASD are much higher with a reported rate of 90% 4 . The TSC Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study evaluating early phenotypic features and potential biomarkers of ASD in infants and young children with ASD reported the rate of developmental delay at 45% in all participants with TSC 3 .…”