title: Everolimus improves neuropsychiatric symptoms in a patient with tuberous sclerosis carrying a novel TSC2 mutation.
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.
authors.affiliation: Department of Pediatrics, Kyungpook National University Hospital, Daegu, 41944, South Korea.
authors.forename: Su-Kyeong
authors.initials: SK
authors.lastname: Hwang
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul, 02447, South Korea.
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, 08826, South Korea.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Yang
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, 08826, South Korea.
authors.forename: Chae-Seok
authors.initials: CS
authors.lastname: Lim
authors.affiliation: Department of Biotechnology and Biological Sciences, Hannam University, Daejeon, 34430, South Korea.
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Lee
authors.affiliation: Department of Life Science, Chung-Ang University, Seoul, 06974, South Korea. yongseok@cau.ac.kr.
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Behavioral Neural Circuitry and Physiology Laboratory, Department of Anatomy, Brain Science & Engineering Institute, Kyungpook National University Graduate School of Medicine, Daegu, 41944, South Korea. iriskim@knu.ac.kr.
authors.forename: Kyungmin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, 08826, South Korea. kaang@snu.ac.kr.
authors.forename: Bong-Kiun
authors.initials: BK
authors.lastname: Kaang
mesh_terms: D000595:Amino Acid Sequence; D001321:Autistic Disorder / Q000150:complications / Q000188:drug therapy; D001483:Base Sequence; D001519:Behavior; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus / Q000627:therapeutic use*; D059472:Exome / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D015151:Immunoblotting; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D010375:Pedigree; D010641:Phenotype; D012640:Seizures / Q000150:complications / Q000188:drug therapy; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000523:psychology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Autism; Everolimus; High throughput nucleotide sequencing; Mutation; Tuberous sclerosis