Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder involving multiple organs and tissues, which is caused by a mutation in either TSC1 or TSC2, tumor suppressor genes. TSC has wide spectrum of clinical manifestations, which might be associated with genetic heterogeneity and incomplete penetrance. It has been reported that various neurocognitive phenotypes are correlated with genotype of TSC. However, to date, there are only a few reports correlating the genotype with epilepsy.

Patients and Methods: We performed mutational analyses on 60 unrelated patients diagnosed as definite TSC. Genetic testing was performed using direct DNA sequencing and/or multiplex ligation-dependent probe amplification. Clinical data of the patients were obtained by retrospective chart review. 

Results: We identified pathogenic mutations in 45 patients (75%). There were 10 TSC1 mutations and 35 TSC2 mutations. Six patients had unclassified variants. No mutation was identified in nine patients. TSC1 mutations included 7 frameshift (70%) and 3 nonsense mutations (30%). TSC2 mutations included 9 frameshift (25.7%), 9 nonsense (25.7%), 4 splicing mutations (11.4%), 4 large deletions (11.4%), 6 missense mutations (17.1%) and 3 in-frame deletions (8.6%). All hamartin interaction domain mutations were protein-truncating. Fifty-one patients had epilepsy (85%). Of patients with epilepsy, 14 of 45 developed refractory epilepsy. Epilepsy was significantly associated with cognitive impairments (p=0.03). Eighteen of 51 epileptic patients had a history of infantile spasms (35.3%). No significant difference was observed in the phenotype and outcome of epilepsy among patients with TSC1, TSC2 and no mutations. Unexpectedly epilepsy was frequently involved in the patients with no mutations, although most were focal epilepsy.

Conclusions: We could not find any significant differences among TSC mutation groups. However, the group with no mutations identified had epilepsy, notably focal with higher frequency than expected. Patients with TSC2 mutations are more likely to have infantile spasms than patients with TSC1 mutations