Background: Tuberous sclerosis (TS) is a multisystem genetic disorder that is associated with mental retardation, autism, and atypical autism. We investigated the basis for these associations by examining whether the liability to mental retardation and autism or atypical autism is related to the number and distribution of hamartomatous brain growths (cortical tubers) that characterise TS.

Methods: 18 patients consecutively referred to our clinic were assessed for the presence of autism or atypical autism, and their IQs were estimated (without awareness of brain-scan results). Brain scans were reviewed by a neuroradiologist (unaware of clinical diagnoses), and the number and location of cortical tubers was examined in relation to the liability to psychopathology.

Findings: Nine of the 18 patients had autism or atypical autism (two with IQ > or = 70; four with IQ 51-69, three with IQ < or = 50; eight with a history of epilepsy). The remaining patients had various other psychiatric disorders (five with IQ > or = 70; four with IQ 51-69; seven had a history of epilepsy). In the group as a whole, the number of tubers was significantly greater (p = 0.005) in patients with mental retardation (median 6 [IQR 4-9]) than in those of normal intelligence (1 [0-3]), and the degree of mental retardation was significantly correlated with the number of brain tubers (rs = 0.64; p = 0.008). Similarly, the number of tubers was significantly greater (p = 0.02) in individuals with a diagnosis of autism or atypical autism (6 [4-8]) than in those without this diagnosis (2 [1-4]). Eight of the nine patients with autism or atypical autism, but none of the non-autistic individuals, had tubers located in the temporal lobes (p = 0.0004). Otherwise, no particular distribution of cortical tubers was associated with a diagnosis of autism or atypical autism.

Interpretation: Our investigation provides evidence of an association between a gross, focal brain abnormality detectable on neuroimaging and autism or atypical autism. The results show the importance of scan findings in the prognosis of TS, and also suggest that temporallobe neurodevelopmental abnormalities may create a risk for autism or atypical autism.