Abstract
AimTo investigate the interdependence between risk factors associated with long‐term intellectual development in individuals with tuberous sclerosis complex (TSC).MethodThe Tuberous Sclerosis 2000 Study is a prospective longitudinal study of individuals with TSC. In phase 1 of the study, baseline measures of intellectual ability, epilepsy, cortical tuber load, and mutation were obtained for 125 children (63 females, 62 males; median age=39mo). In phase 2, at an average of 8 years later, intellectual abilities were estimated for 88 participants with TSC and 35 unaffected siblings. Structural equation modelling was used to determine the risk pathways from genetic mutation through to IQ at phase 2.ResultsIntellectual disability was present in 57% of individuals with TSC. Individuals without intellectual disability had significantly lower mean IQ compared to unaffected siblings, supporting specific genetic factors associated with intellectual impairment. Individuals with TSC who had a slower gain in IQ from infancy to middle childhood were younger at seizure onset and had increased infant seizure severity. Structural equation modelling indicated indirect pathways from genetic mutation, to tuber count, to seizure severity in infancy, through to IQ in middle childhood and adolescence.InterpretationEarly‐onset and severe epilepsy in the first 2 years of life are associated with increased risk of long‐term intellectual disability in individuals with TSC, emphasizing the importance of early and effective treatment or prevention of epilepsy.What this paper adds Intellectual disability was present in 57% of individuals with tuberous sclerosis complex (TSC).Those with TSC without intellectual disability had significantly lower mean IQ compared to unaffected siblings.Earlier onset and greater severity of seizures in the first 2 years were observed in individuals with a slower gain in intellectual ability.Risk pathways through seizures in the first 2 years predict long‐term cognitive outcomes in individuals with TSC.
Highlights
CHARLOTTE TYE1,2 | FIONA S MCEWEN1,2,3 | HOLAN LIANG1,4,5 | LISA UNDERWOOD6 | EMMA WOODHOUSE7,8 | EDWARD D BARKER9 | FINTAN SHEERIN10 | JOHN R W YATES11 | PATRICK F BOLTON1,2 | TUBEROUS SCLEROSIS 2000 STUDY GROUP*
Individuals without intellectual disability had significantly lower mean IQ compared to unaffected siblings, supporting specific genetic factors associated with intellectual impairment
Tuberous sclerosis complex (TSC) is a genetic disorder caused by a mutation in the TSC1 or TSC2 genes
Summary
We aimed to build on previous work by investigating: (1) the distribution of IQ and rates of intellectual disability later in childhood and adolescence in individuals with TSC and unaffected siblings; (2) the effect of genetic mutation as well as brain- and epilepsy-related risk factors on long-term change in IQ over childhood and adolescence, by grouping individuals according to a faster versus slower gain in skills; and (3) multifactorial longitudinal pathways to individual differences in intellectual ability in individuals with TSC using structural equation modelling
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