TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study

Abstract

Purpose: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. Methods: Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. Results: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizurefree survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. Conclusion: TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.

Quality of life in children with tuberous sclerosis complex: A pediatric cohort study

“…It was first found that the TSC1/TSC2 group reported significantly worse QOL. Similar to previous studies, TSC1/TSC2 pathogenic variants could generally cause a more severe clinical phenotype 4,24‐28 …”

Prediction of Neurodevelopment in Infants With Tuberous Sclerosis Complex Using Early EEG Characteristics

“…Besides clinical and quantitative EEG features, other characteristics, such as the pathogenic TSC variant, the epilepsy course (including the development of refractory epilepsy or epileptic spasms), MRI features and early development, can help to identify young infants with TSC at risk of developmental comorbidities (6,12,16,(42)(43)(44)(45)(46)(47).…”

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

“…Notably, treatment of Tsc1 GFAP mice with the mTOR inhibitor rapamycin suppressed seizures, whereas vigabatrin reduced seizures and partially inhibited mTOR activity, astrogliosis, and neuronal disorganization ( 29 , 78 ). Interestingly, TSC patients present with differences in disease severity, depending on the underlying mutation, with TSC2 mutations causing a more severe neurological and cognitive phenotype ( 22 , 79 – 81 ). In conjunction with this, Tsc2 GFAP mice present with more severe epilepsy than Tsc1 GFAP mice ( 82 ).…”

“…TSC is caused by loss-of-function mutations in the tumor suppressors TSC1 or TSC2 , both of which are negative regulators of the mTOR ( 20 , 21 ). Purely heterozygous germline mutations, as well as mosaic mutations, have been detected in TSC patients ( 21 , 22 ). mTOR is a serine/threonine protein kinase and the catalytic subunit of mTOR complex 1 (mTORC1) and mTORC2.…”