A single-center observational study on long-term neurodevelopmental outcomes in children with tuberous sclerosis complex

Abstract

Background Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by mutations in the TSC1 or TSC2 gene. More than 90% of patients with TSC develop neurological and/or neuropsychiatric manifestations. The aim of the present study was to determine the developmental and cognitive long-term outcomes of pediatric TSC patients. Methods This cross-sectional, monocenter study included pediatric TSC patients who received multidisciplinary long-term care with a last visit between 2005 and 2019. Neurological manifestations and cognitive development (BSID, K-ABC) were analyzed in relation to age and type of mutation. Results Thirty-five patients aged 13.5 ± 7.8 years were included in the study. Diagnosis was confirmed genetically in 65.7% of patients (TSC1, 26.1%; TSC2, 65.2%; NMI, 8.7%). Mean age at diagnosis was 1.3 ± 3.5 years; 74.3% of the patients had been diagnosed within the first year of life due to seizures (62.9%) or/and cardiac rhabdomyomas (28.6%). The most common TSC manifestations included structural brain lesions (cortical tubers, 91.4%; subependymal nodules, 82.9%), epilepsy (85.7%), and cardiac rhabdomyomas (62.9%). Mean age at seizure onset was 1.5 ± 2.3 years, with onset in 80.0% of patients within the first two years of life. Infantile spasms, which were the first seizure type in 23.3% of the patients, developed earlier (0.6 ± 0.4 years) than focal seizures (1.8 ± 2.5 years). Refractory epilepsy was present in 21 (70.0%) patients, mild or severe intellectual impairment in 66.6%, and autism spectrum disorders in 11.4%. Severe cognitive impairment (33.3%) was significantly associated with epilepsy type and age at seizure onset (p < 0.05). Conclusions The results emphasized the phenotypic variability of pediatric-onset TSC and the high rate of neurological and neuropsychiatric morbidity. Early-onset refractory epilepsy was associated with impaired cognitive development. Children of all ages with TSC require multidisciplinary long-term care and individual early-intervention programs.

The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions

“…In addition, simplex cases are more likely to involve TSC2 pathogenic variants, while inherited pathogenic variants are more evenly split between TSC1 and TSC2 [ 64 ]. Furthermore, TSC2 pathogenic variant carriers are at greater risk for renal malignancies, cardiac rhabdomyomas, intellectual disability, infantile epileptic spasms, and drug-resistant epilepsy [ 81 , 87 , 88 , 89 ]. In infancy, up to 24 months of age, TSC2 pathogenic variant carriers are at higher risk for significant developmental delays [ 90 ].…”