Genotype and cognitive phenotype of patients with tuberous sclerosis complex

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder, which affects 1 in 6000 people. About half of these patients are affected by mental retardation, which has been associated with TSC2 mutations, epilepsy severity and tuber burden. The bimodal intelligence distribution in TSC populations suggests the existence of subgroups with distinct pathophysiologies, which remain to be identified. Furthermore, it is unknown if heterozygous germline mutations in TSC2 can produce the neurocognitive phenotype of TSC independent of epilepsy and tubers. Genotype-phenotype correlations may help to determine risk profiles and select patients for targeted treatments. A retrospective chart review was performed, including a large cohort of 137 TSC patients who received intelligence assessment and genetic mutation analysis. The distribution of intellectual outcomes was investigated for selected genotypes. Genotype-neurocognitive phenotype correlations were performed and associations between specific germline mutations and intellectual outcomes were compared. Results showed that TSC1 mutations in the tuberin interaction domain were significantly associated with lower intellectual outcomes (Po0.03), which was also the case for TSC2 protein-truncating and hamartin interaction domain mutations (both Po0.05). TSC2 missense mutations and small in-frame deletions were significantly associated with higher IQ/DQs (Po0.05). Effects related to the mutation location within the TSC2 gene were found. These findings suggest that TSC2 protein-truncating mutations and small in-frame mutations are associated with distinctly different intelligence profiles, providing further evidence that different types and locations of TSC germline mutations may be associated with distinct neurocognitive phenotypes.

Genotype and brain pathology phenotype in children with tuberous sclerosis complex

“…The added value of the results from these analyses was determined compared to analyses between the TSC1 group and the whole TSC2 group. Our results are consistent with previous studies [6][7][8][9][10][11][12][13][14]21 : the TSC2 group was associated with more and larger tubers, more RMLs, more SEGAs and more SENs. Subdivision of the TSC2 group into TSC2p and TSC2x subgroups did not reveal major differences in TSC-pathology, as detected by MRI, although a higher number and fraction of tubers in the temporal lobe and a higher fraction of cystic tubers in the TSC2x group were observed.…”

“…In most studies, inactivating TSC2 variants are associated with increased numbers of cortical tubers and a higher prevalence of SEGAs. [6][7][8][9][10][11][12][13][14] We investigated whether there was additional clinical value for subdivision of TSC2 variants, as has been described recently for cognitive function in TSC. 15 We compared TSC-related brain pathology as assessed by MRI, in individuals with an inactivating TSC1 variant to brain pathology in individuals with an inactivating TSC2…”

Intellectual ability in tuberous sclerosis complex correlates with predicted effects of mutations on TSC1 and TSC2 proteins

“…To date, only three studies of genotype–phenotype associations in TSC used validated and standardised measures of intellectual ability/developmental level 24 27 28. Lewis et al 24 measured IQ of 92 individuals with TSC and known mutations, performing a categorical genotype–phenotype analysis, dividing subjects into ‘impaired’ and ‘non-impaired’ based on IQ score below or above 70.…”

“…In the most recent genotype–phenotype study of IQ in TSC, van Eeghen et al 28 examined 137 subjects from a clinical case series, using a range of standardised IQ/DQ measures. Rates of ID were 23% in those with TSC1 and 59% in those with TSC2 mutations, and several inter-mutational correlations were observed, some contrasting with earlier findings.…”

Diagnosis, monitoring and treatment of tuberous sclerosis complex: A South African consensus response to international guidelines

“…At present, there are no clinical recommendations regarding differences between TSC1 and TSC2 mutations, but there is significant research interest in the use of genotypic information to predict phenotype and potential for treatment response. [11,12] We also strongly advocate for the relevant regulatory bodies in SA to provide marketing authorisation and reimbursement to support access to mTOR inhibitors for patients in SA for all internationally approved indications. Everolimus, one of the mTOR inhibitors, received marketing authorisation in the USA and Europe for the treatment of SEGAs not amenable to surgery, and for renal angiomyolipomas larger than 3 cm.…”