d Mean phospho-S6K levels generated by TSC2 variants expression relative to wild-type TSC1-TSC2 expression (One-way ANOVA followed by Dunnetts test, * 0

d Mean phospho-S6K levels generated by TSC2 variants expression relative to wild-type TSC1-TSC2 expression (One-way ANOVA followed by Dunnetts test, * 0.05). small deletion mutation in 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 material The online version of this article (doi:10.1186/s13041-016-0222-6) contains supplementary material, which is available to authorized users. or causes neurological phenotypes including learning disability and social deficits [10, 11]. mutations account for approximately 80?% of TSC cases. mutations are four times as common as mutations among cases, whereas the prevalence of and mutations is approximately equal among familial TSC cases [12]. and mutations lead to essentially identical phenotypic manifestations, although there have been some suggestions that the phenotype is typically more severe [13, 14]. The TSC1 and TSC2 proteins act as a heterodimer to suppress mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates cell growth and division [5, 15]. Loss of either or or results in upregulation of the mTOR pathway [10, 17]. The molecular understanding of the TSC pathophysiology has opened up possibilities for molecular targeted treatments of the neuropsychiatric phenotype in TSC using mTOR inhibitors such as rapamycin [16]. Notably, rapamycin treatments have been shown to successfully reverse the deficits in behavior and synaptic plasticity in rodent WYC-209 models of TSC [10, 18C20]. Recently, the WYC-209 mTOR inhibitors everolimus and sirolimus have been shown to exhibit efficacy for the treatment of several manifestations of TSC such as subependymal giant cell astrocytomas (SEGA), seizures, renal angiomyolipomas, lymphangioleiomyomatosis, and facial angiofibroma lesions in patient with TSC [21C24]. Moreover, human and animal studies suggest that mTOR inhibitors improve deficits of sociability, learning and neurodevelopment in TSC mouse models and patients with TSC [18, 25, 26]. On the basis of these findings, although some clinical trials have been completed or initiated to test whether everolimus treatment might improve neurocognition, features of autism, and the neuropsychological deficits in children with TSC (clinicaltrials.gov study ID: “type”:”clinical-trial”,”attrs”:”text”:”NCT01289912″,”term_id”:”NCT01289912″NCT01289912, “type”:”clinical-trial”,”attrs”:”text”:”NCT01730209″,”term_id”:”NCT01730209″NCT01730209), in the present study we present a case of a family with a novel mutation in which the behavioral phenotypes of a 3-year-old boy with TSC accompanied by severe autism could be dramatically improved by everolimus treatment. Results Subject characteristics The proband presented intractable epilepsy Rabbit Polyclonal to RXFP4 and severe developmental delay. He was born WYC-209 at 38?weeks gestation by spontaneous vaginal delivery with a birth weight of 2.4?kg after an uncomplicated pregnancy. At the age of 13?months, he experienced his first episode of febrile status epilepticus with a duration of 40?min; at 17?months, a second episode of febrile status epilepticus persisted for more than an hour. Subsequently, he had frequent seizures with or without fever, and was often admitted with status epilepticus. Physical examination identified scattered hypopigmented lesions on the trunk (Fig.?1a). Brain magnetic resonance imaging (MRI) revealed a SEGA (Fig.?1b), cortical tubers and subependymal nodules consistent with TSC (Fig.?1c). The seizures persisted despite the use of vigabatrin and levetiracetam at the maximum tolerated doses. Open in a separate window Fig. 1 Cutaneous features and brain MRI findings of the patient. a Photographs showing several hypopigmented macules on the chest and abdomen (by whole exome sequencing In the family, three individuals including the grandmother (I-1), father (II-1), and the proband (third son, III-2) met diagnostic criteria for TSC. Definite diagnosis is made by 2 major features or 1 major feature with 2 or more minor features; the grandmother (I-1) and father (II-1) had 3 major features: multiple hypomelanotic macules, angiofibromas, and ungual fibromas. The other family members (including II-2, III-1 and III-3) had WYC-209 no features WYC-209 of TSC (Fig.?2a). In contrast to the proband (III-2), the grandmother (I-1) and.