Abstract
Tuberous sclerosis complex (TSC) is a neurocutaneous disorder characterized by multiple symptoms including neuropsychological deficits such as seizures, intellectual disability, and autism. TSC is inherited in an autosomal dominant pattern and is caused by mutations in either the TSC1 or TSC2 genes, which enhance activation of the mammalian target of rapamycin (mTOR) signaling pathway. Recent studies have suggested that mTOR inhibitors such as rapamycin can reverse TSC-associated deficits in rodent models of TSC. In addition, clinical trials are ongoing to test the efficacy of mTOR inhibitors toward the psychiatric symptoms associated with TSC. Here, we report a case study of a Korean patient with TSC, who exhibited multiple symptoms including frequent seizures, intellectual disability, language delays, and social problems. We performed whole exome sequencing and identified a novel small deletion mutation in TSC2. Expressing the novel deletion mutant in HEK293T cells significantly increased mTOR pathway activation. Furthermore, everolimus treatment showed not only reduction in SEGA size, but dramatically improved behavioral deficits including autism related behaviors in the patient. In summary, we identified a novel small deletion mutation in TSC2 associated with severe TSC in a Korean family that enhances the activation of mTOR signaling in vitro. Everolimus treatment improved behavioral deficits in the patient.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0222-6) contains supplementary material, which is available to authorized users.
Highlights
Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the presence of benign hamartomas in any organ system, with highly variable, unpredictable, and potentially devastating neurological outcomes [1, 2]
In the present study, we describe a case of a Korean family in which three of the members have been diagnosed with TSC
We found that the expression of the newly identified mutant TSC2 protein enhanced the activation of the mammalian target of rapamycin (mTOR) signaling pathway in HEK293T cells, suggesting that the novel mutation represents a loss-of-function mutation as are other TSC mutations associated with TSC [28]
Summary
Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the presence of benign hamartomas in any organ system, with highly variable, unpredictable, and potentially devastating neurological outcomes [1, 2]. TSC is the second most common identified neurocutaneous disorder with an estimated incidence of 1:6000, affecting more than 1 million individuals worldwide [3, 4]. TSC is inherited in an autosomal dominant pattern and haploinsufficiency of TSC causes neurological phenotypes including learning disability and social deficits [10, 11]. De novo mutations account for approximately 80 % of TSC cases. TSC2 mutations are four times as common as TSC1 mutations among de novo cases, whereas the prevalence of TSC1 and TSC2 mutations is approximately equal among familial TSC cases [12].
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