Symptoms Of Tuberous Sclerosis Complex Research Articles

Childhood tuberous sclerosis complex in southern Sweden: a paradigm shift in diagnosis and treatment

AimTo investigate the complete clinical spectrum of individuals with paediatric tuberous sclerosis complex in southern Sweden and explore changes over time.MethodsIn this retrospective observational study, 52 individuals aged up to 18 years at the study start were followed-up at regional hospitals and centres for habilitation from 2000 to 2020.ResultsCardiac rhabdomyoma was detected prenatally/neonatally in 69.2% of the subjects born during the latest ten years of the study period. Epilepsy was diagnosed in 82.7% of subjects, and 10 (19%) were treated with everolimus, mainly (80%) for a neurological indication. Renal cysts were detected in 53%, angiomyolipomas in 47%, astrocytic hamartomas in 28% of the individuals. There was a paucity of standardized follow-up of cardiac, renal, and ophthalmological manifestations and no structured transition to adult care.ConclusionOur in-depth analysis shows a clear shift towards an earlier diagnosis of tuberous sclerosis complex in the latter part of the study period, where more than 60% of cases showed evidence of this condition already in utero due to the presence of a cardiac rhabdomyoma. This allows for preventive treatment of epilepsy with vigabatrin and early intervention with everolimus for potential mitigation of other symptoms of tuberous sclerosis complex.

Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease characterized by systemic hamartomas, neuropsychiatric symptoms known as TAND (TSC-associated neuropsychiatric disorders), and vitiligo. These symptoms are attributed to the constant activation of mechanistic target of rapamycin complex 1 (mTORC1) caused by genetic mutations in the causative genes TSC1 or TSC2. The elucidation of the pathogenesis of this disease and advances in diagnostic technologies have led to dramatic changes in the diagnosis and treatment of TSC. Diagnostic criteria have been created at a global level, and mTORC1 inhibitors have emerged as therapeutic agents for this disease. Previously, the treatment strategy was limited to symptomatic treatments such as surgery. Inhibitors of mTORC1 are effective against all symptoms of TSC, but they also have systemic side effects. Therefore, the need for a cross-disciplinary, collaborative medical care system has increased, resulting in the establishment of a practice structure known as the "TSC Board." Furthermore, to reduce the side effects of systemic administration of mTORC1 inhibitors, a topical formulation of mTORC1 inhibitor was developed in Japan for the treatment of skin lesions caused by TSC. This report summarizes the pathogenesis and current status of TSC and the contribution of the Neurocutaneous Syndrome Policy Research Group to the policies of the Ministry of Health, Labor, and Welfare with respect to this rare, intractable disease.

Abnormal White Matter Microstructure in the Limbic System Is Associated With Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders.

ObjectiveTuberous sclerosis complex (TSC) is a genetic disease that arises from TSC1 or TSC2 abnormalities and induces the overactivation of the mammalian/mechanistic target of rapamycin pathways. The neurological symptoms of TSC include epilepsy and tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Although TAND affects TSC patients' quality of life, the specific region in the brain associated with TAND remains unknown. We examined the association between white matter microstructural abnormalities and TAND, using diffusion tensor imaging (DTI).MethodsA total of 19 subjects with TSC and 24 age-matched control subjects were enrolled. Tract-based spatial statistics (TBSS) were performed to assess group differences in fractional anisotropy (FA) between the TSC and control groups. Atlas-based association analysis was performed to reveal TAND-related white matter in subjects with TSC. Multiple linear regression was performed to evaluate the association between TAND and the DTI parameters; FA and mean diffusivity in seven target regions and projection fibers.ResultsThe TBSS showed significantly reduced FA in the right hemisphere and particularly in the inferior frontal occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), and genu of corpus callosum (CC) in the TSC group relative to the control group. In the association analysis, intellectual disability was widely associated with all target regions. In contrast, behavioral problems and autistic features were associated with the limbic system white matter and anterior limb of the internal capsule (ALIC) and CC.ConclusionThe disruption of white matter integrity may induce underconnectivity between cortical and subcortical regions. These findings suggest that TANDs are not the result of an abnormality in a specific brain region, but rather caused by connectivity dysfunction as a network disorder. This study indicates that abnormal white matter connectivity including the limbic system is relevant to TAND. The analysis of brain and behavior relationship is a feasible approach to reveal TAND related white matter and neural networks. TAND should be carefully assessed and treated at an early stage.

Brain Symptoms of Tuberous Sclerosis Complex: Pathogenesis and Treatment.

The mammalian target of the rapamycin (mTOR) system plays multiple, important roles in the brain, regulating both morphology, such as cellular size, shape, and position, and function, such as learning, memory, and social interaction. Tuberous sclerosis complex (TSC) is a congenital disorder caused by a defective suppressor of the mTOR system, the TSC1/TSC2 complex. Almost all brain symptoms of TSC are manifestations of an excessive activity of the mTOR system. Many children with TSC are afflicted by intractable epilepsy, intellectual disability, and/or autism. In the brains of infants with TSC, a vicious cycle of epileptic encephalopathy is formed by mTOR hyperactivity, abnormal synaptic structure/function, and excessive epileptic discharges, further worsening epilepsy and intellectual/behavioral disorders. Molecular target therapy with mTOR inhibitors has recently been proved to be efficacious for epilepsy in human TSC patients, and for autism in TSC model mice, indicating the possibility for pharmacological treatment of developmental synaptic disorders.

RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex

Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections formed during development which may contribute to symptoms of TSC, such as intellectual disabilities, autism, and epilepsy. Yet models examining the molecular basis for axonal guidance defects in developing human neurons have not been developed. Here, we generate human induced pluripotent stem cell (hiPSC) lines from a patient with TSC and genetically engineer counterparts and isogenic controls. By differentiating hiPSCs, we show that control neurons respond to canonical guidance cues as predicted. Conversely, neurons with heterozygous loss of TSC2 exhibit reduced responses to several repulsive cues and defective axon guidance. While TSC2 is a known key negative regulator of MTOR-dependent protein synthesis, we find that TSC2 signaled through MTOR-independent RHOA in growth cones. Our results suggest that neural network connectivity defects in patients with TSC may result from defects in RHOA-mediated regulation of cytoskeletal dynamics during neuronal development.

The characteristics and optimal treatment of urolithiasis associated with tuberous sclerosis complex

PurposeThe most common renal symptoms of tuberous sclerosis complex (TSC) are angiomyolipomas (AMLs) and renal cysts; however, some patients with TSC also develop urolithiasis. We retrospectively investigated the characteristics and treatment of urolithiasis associated with TSC.MethodsWe analyzed 142 patients who met the diagnostic criteria for TSC, of whom 20 (14.1%) had urolithiasis. We compared the patients’ characteristics, urinary specific gravity, urine pH, serum calcium and intact parathyroid hormone in the urolithiasis and non-urolithiasis groups. In the urolithiasis group, the stone characteristics and various treatments were analyzed.ResultsThe antiepileptic drugs topiramate and zonisamide were more frequently administered to the urolithiasis group than the non-urolithiasis group (P = 0.013, P = 0.048, respectively). The urine specific gravity and urine pH levels were higher in the urolithiasis group than in the non-urolithiasis group (P = 0.005, P = 0.042, respectively). A multivariate logistic regression analysis demonstrated that urine-specific gravity (P = 0.018; odds ratio 1.471; 95% confidence interval 1.098–1.872) was a significant predictor of TSC-associated urolithiasis. Four patients could not receive extracorporeal shock wave lithotripsy due to the risk of bleeding from the AML.ConclusionPatients with TSC who have an increased urine specific gravity, alkaline urine, and a longer administration of topiramate and zonisamide tend to demonstrate an increased risk of developing urolithiasis and therefore such cases require adequate care. If urolithiasis is comorbid with TSC-associated AML, the treatment options are more limited in cases with multiple AMLs around the stone due to an increased risk of hemorrhage.

Neuron-Glia Interactions in Tuberous Sclerosis Complex Affect the Synaptic Balance in 2D and Organoid Cultures.

Tuberous sclerosis complex (TSC) is a genetic disease affecting the brain. Neurological symptoms like epilepsy and neurodevelopmental issues cause a significant burden on patients. Both neurons and glial cells are affected by TSC mutations. Previous studies have shown changes in the excitation/inhibition balance (E/I balance) in TSC. Astrocytes are known to be important for neuronal development, and astrocytic dysfunction can cause changes in the E/I balance. We hypothesized that astrocytes affect the synaptic balance in TSC. TSC patient-derived stem cells were differentiated into astrocytes, which showed increased proliferation compared to control astrocytes. RNA sequencing revealed changes in gene expression, which were related to epidermal growth factor (EGF) signaling and enriched for genes that coded for secreted or transmembrane proteins. Control neurons were cultured in astrocyte-conditioned medium (ACM) of TSC and control astrocytes. After culture in TSC ACM, neurons showed an altered synaptic balance, with an increase in the percentage of VGAT+ synapses. These findings were confirmed in organoids, presenting a spontaneous 3D organization of neurons and glial cells. To conclude, this study shows that TSC astrocytes are affected and secrete factors that alter the synaptic balance. As an altered E/I balance may underlie many of the neurological TSC symptoms, astrocytes may provide new therapeutic targets.

Tuberous sclerosis: a review of the past, present, and future

Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder that is characterized by cellular and tissue dysplasia in several organs. With the advent of genetic and molecular techniques, mutations in the TSC1 or TSC2 genes were discovered to be responsible for mTOR overactivation, which is the underlying mechanism of pathogenesis. TSC is a highly heterogenous clinical entity with variable presentations and severity of disease. The brain, heart, skin, eyes, kidneys, and lungs are commonly involved in this syndrome, with neurologic symptoms comprising a significant source of morbidity and mortality. In 2012, the diagnostic criteria for TSC were revised by the International Tuberous Sclerosis Complex Consensus panel, and genetic testing was incorporated into the guidelines. Early detection of cardiac rhabdomyomas or TSC-associated skin lesions can suggest the diagnosis and underlie the importance of clinical vigilance. Animal studies have demonstrated the benefit of using mTOR inhibitors for various symptoms of TSC, and they have been successfully translated into clinical trials with significant improvement in symptom burden. Subependymal giant cell astrocytomas, renal angiomyolipomas, and epilepsy are the three FDA-approved indications in relation to TSC for the use of everolimus, which is a first generation mTOR inhibitor. Rapamycin has been FDA approved for lymphangioleiomyomatosis. Other TSC symptoms that could potentially benefit from this class of medication are currently under investigation. TSC constitutes a unique combination of protean physical symptoms and neurobehavioral abnormalities. TSC associated neuropsychiatric disorders (TAND), including intellectual disability, mood disorders, and autism spectrum disorder, represent significant challenges but remain underdiagnosed and undertreated. The TAND checklist is a useful tool for routine use in the clinical evaluation of TSC patients. A multidisciplinary treatment plan, based on the specific problems and needs of individuals, is the key to management of this genetic condition. Ongoing research studies have been providing promising leads for developing novel mechanistic strategies to address the pathophysiology of TSC.

Mutation Spectrum of Tuberous Sclerosis Complex Patients in Indian Population.

Tuberous sclerosis complex (TSC) is a multiorgan disorder characterized by formation of hamartomas and broad phenotypic spectrum including seizures, mental retardation, renal dysfunction, skin manifestations and brain tubers. It is inherited in an autosomal dominant pattern, caused due to mutation in either TSC1 or TSC2 genes. Seizures are one of the major presenting symptoms of TSC that helps in early diagnosis. The present study describes the mutation spectrum in TSC1 and TSC2 genes in TSC patients and their association with neurocognitive-behavioral phenotypes. Ninety-eight TSC patients were enrolled for TSC genetic testing after detailed clinical and neurobehavioral assessment. Large genomic rearrangement testing was performed by multiplex ligation-dependent probe amplification (MLPA) technique for all cases and Sanger sequencing was performed for MLPA negative cases. Large rearrangements were identified in approximately 1% in TSC1 and 14.3% in TSC2 genes. The present study observed the presence of duplications in two (2%) cases, both involving TSC2/PKD1 contiguous genes which to the best of our knowledge is reported for the first time. 8.1% of small variants were identified in the TSC1 gene and 85.7% in TSC2 gene, out of which 23 were novel variations and no variants were found in six (6.1%) cases. This study provides a representative picture of the distribution of variants in the TSC1 and TSC2 genes in Indian population along with the detailed assessment of neurological symptoms. This is the largest cohort study from India providing an overview of comprehensive clinical and molecular spectrum.

Congenital lymphedema as a rare and first symptom of tuberous sclerosis complex.

Lymphedema are characterized by interstitial edema leading to swelling of extremities. They can be divided into primary and secondary lymphedema. Developmental abnormalities of the lymphatic system are responsible for the primary form of lymphedema. The secondary form of lymphedema is caused by damage of the lymphatic system due to external factors. Lymphedema can rarely be observed in patients with tuberous sclerosis complex (TSC), which is a neurocutaneous syndrome caused by pathogenic variants in the genes TSC1 or TSC2. Patients with TSC usually present with neurological manifestations and the development of multiple benign tumors of ectodermal origin. Typical onset for several symptoms is during the first year of life and in some cases lesions can be detected prenatally. Epilepsy is one of the most common manifestations, affecting up to 90% of TSC patients, and is associated with developmental delay. Early pharmacotherapy improves long term patient outcome. Trio exome sequencing was performed in a 3weeks old girl with congenital lymphedema of the right lower extremity. Using a filter for de novo variants, the heterozygous missense variant c.2524C>T, p.(Gln842Ter) in TSC1 (NM_000368.4) could be identified. After the first onset of infantile spams at age 7months treatment with vigabatrin was started immediately. We propose to include TSC1 and TSC2 analysis in the diagnostic work-up of patients with (isolated) congenital lymphedema as early diagnosis facilitates consequent treatment strategies potentially improving the prognosis of TSC patients.

Counselling in tuberous sclerosis complex: A survey on content and satisfaction in the Netherlands.

Tuberous sclerosis complex (TSC) is a highly variable condition and its clinical features cannot reliably be predicted from the genotype. Counselling of parents of a child with TSC is challenging because of the variability of the condition and the changing outlook due to new treatment options. This study explored current counselling strategies in TSC in the Netherlands, with the aim of developing a recommendation for counselling. We performed a nationwide survey using digital questionnaires. Questionnaires were sent to parents of children diagnosed with TSC, and to medical doctors involved in counselling, both no more than ten years prior to the study. Questions focused on general information about the child with TSC, medical doctors involved in counselling, type of information provided, mode of providing information, and recommendations for improvement of counselling. Parents of 34 children diagnosed with TSC (7 prenatally) and 18 medical doctors from different departments responded to the questionnaires. Almost all parents were informed on the neurological and cardiac symptoms of TSC, other symptoms were mentioned less often. Satisfaction on counselling was higher when more information on the variability of TSC was provided, preferentially during a clinical visit, when emotional support was provided, and when parents were notified of the TSC patient society. Information on the variability in expression and quality of life is highly demanded by (expecting) parents of a child with TSC. Furthermore, reference should be made to institutions such as the support organisation for patients and social services for questions and support.

Fetal heart rhabdomyomatosis: a single-center experience

Objectives: The primary aim of the study was to evaluate the prevalence of fetal heart tumors in a single tertiary referral center over a period of 15 years. The secondary aim was to confirm the presence of tuberous sclerosis complex (TSC) through the evaluation of germline mutation in TSC1/TSC2 and assess the outcomes in affected fetuses and newborns.Methods: A retrospective study was conducted between 2003 and 2017. Fetal echocardiography was performed in the second trimester of pregnancy in the study population. The identification of heart tumors and further follow-up were performed by a pediatric cardiologist. Molecular genetic analysis was conducted on fetuses and children in cases where TSC was suspected.Results: In total, 39,018 fetuses were examined between 2003 and 2017. Heart tumors were detected in nine fetuses and were diagnosed as rhabdomyoma in all cases. We identified mutations in one of the TSC1 or TSC2 genes in all cases with multiple rhabdomyomas (8/9). In all born children (5/9), the genetically confirmed diagnosis of TSC was established, and clinically pathological deposits in the brain were found.Conclusion: Fetal heart tumors are usually represented by rhabdomyomas having a good cardiac prognosis. However, rhabdomyoma is usually the first symptom of TSC with a subsequent brain disorder and impaired neurological development.

Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder affecting the brain and other vital organs. Neurological symptoms include epilepsy, intellectual disability, and autism. TSC is caused by a loss-of-function mutation in the TSC1 or TSC2 gene. These gene products form a protein complex and normally suppress mammalian target of rapamycin (mTOR) activity. mTOR inhibitors have been used to treat subependymal glioma (SEGA) that is a brain tumor characteristic of TSC. However, neuropathology of TSC also involves dysregulated cortical circuit formation including neuronal migration, axodendritic differentiation, and synapse formation. It is currently unknown to what extent mTOR signaling inhibitors correct an alteration in neuronal morphology that have already formed prior to the treatment. Here, we address the efficacy of rapamycin treatment on neuronal migration and dendrite formation. Using in utero electroporation, we suppressed Tsc1 expression in a fraction of neuronal progenitor cells during the fetal period. In embryonic brain slices, we found that more Tsc1-suppressed cells remained within the periventricular zone, and rapamycin treatment facilitated neuronal migration. Postnatally, Tsc1-suppressed pyramidal neurons showed more complex branching of basal dendrites and a higher spine density at postnatal day (P) 28. Aberrant arborization was normalized by rapamycin administration every other day between P1 and P13 but not P15 and P27. In contrast, abnormal spine maturation improved by rapamycin treatment between P15 and P27 but not P1 and P13. Our results indicate that there are multiple critical windows for correcting different aspects of structural abnormalities in TSC, and the responses depend on the stage of neuronal circuit formation. These data warrant a search for an additional therapeutic target to treat neurological symptoms of TSC.

Tuberous Sclerosis Complex: Early Diagnosis in Infants.

Investigators from the Tuberous Sclerosis Complex (TSC) Autism Center of Excellence Research conducted two concurrent prospective longitudinal studies to analyze the timing and pattern of clinical presenting symptoms of TSC in infants to facilitate earlier diagnosis and treatment in this specific population.

Postnatal reduction of tuberous sclerosis complex 1 expression in astrocytes and neurons causes seizures in an age-dependent manner.

Epilepsy is one of the most prominent symptoms of tuberous sclerosis complex (TSC), a genetic disorder, and may be related to developmental defects resulting from impaired TSC1 or TSC2 gene function in astrocytes and neurons. Inactivation of the Tsc1 gene driven by a glial-fibrillary acidic protein (GFAP) promoter during embryonic brain development leads to widespread pathologic effects on astrocytes and neurons, culminating in severe, progressive epilepsy in mice (Tsc1GFAP-Cre mice). However, the developmental timing and cellular specificity relevant to epileptogenesis in this model has not been well defined. The present study evaluates the effect of postnatal Tsc1 gene inactivation on pathologic features of astrocytes and neurons and development of epilepsy. An inducible Tsc1 knock-out mouse was created utilizing a tamoxifen-driven GFAP-CreER line (Tsc1GFAP-CreER mice) with TSC1 reduction induced postnatally at 2 and 6 weeks of age, and compared to conventional Tsc1GFAP-Cre mice with prenatal TSC1 reduction. Western blotting, immunohistochemistry, histology, and video-electroencephalography (EEG) assessed mechanistic target of rapamycin (mTOR) pathway activation, astrogliosis, neuronal organization, and spontaneous seizures, respectively. Tsc1 gene inactivation at 2 weeks of age was sufficient to cause astrogliosis and mild epilepsy in Tsc1GFAP-CreER mice, but the phenotype was much less severe than that observed with prenatal Tsc1 gene inactivation in Tsc1GFAP-Cre mice. Both astrocytes and neurons were affected by prenatal and postnatal Tsc1 gene activation to a degree similar to the severity of epilepsy, suggesting that both cellular types may contribute to epileptogenesis. These findings support a model in which the developmental timing of TSC1 loss dictates the severity of neuronal and glial abnormalities and resulting epilepsy.

Abnormal Neural Progenitor Cells Differentiated from Induced Pluripotent Stem Cells Partially Mimicked Development of TSC2 Neurological Abnormalities.

SummaryTuberous sclerosis complex (TSC) is a disease featuring devastating and therapeutically challenging neurological abnormalities. However, there is a lack of specific neural progenitor cell models for TSC. Here, the pathology of TSC was studied using primitive neural stem cells (pNSCs) from a patient presenting a c.1444-2A>C mutation in TSC2. We found that TSC2 pNSCs had higher proliferative activity and increased PAX6 expression compared with those of control pNSCs. Neurons differentiated from TSC2 pNSCs showed enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells. TSC2 astrocytes had increased saturation density and higher proliferative activity. Moreover, the activity of the mTOR pathway was enhanced in pNSCs and induced in neurons and astrocytes. Thus, our results suggested that TSC2 heterozygosity caused neurological malformations in pNSCs, indicating that its heterozygosity might be sufficient for the development of neurological abnormalities in patients.

Treatment of Renal Angiomyolipoma and Other Hamartomas in Patients with Tuberous Sclerosis Complex.

Tuberous sclerosis complex is an autosomal dominant genetic disease characterized by growth of benign tumors (hamartomas) in multiple organs, especially the kidneys, brain, heart, lungs, and skin. Tuberous sclerosis complex is usually caused by a mutation in either the tuberous sclerosis complex 1 or tuberous sclerosis complex 2 gene, resulting in constitutive activation of mammalian target of rapamycin signaling. Currently, mammalian target of rapamycin inhibitors are recommended in adult patients with tuberous sclerosis complex for the treatment of asymptomatic, growing renal angiomyolipoma that are >3 cm in diameter and pediatric or adult patients with brain lesions (subependymal giant cell astrocytoma) that either are growing or are not amenable to surgical resection. Clinical evidence suggests that systemic administration of a mammalian target of rapamycin inhibitor may provide concurrent improvements in multiple lesions and symptoms of tuberous sclerosis complex. With the major paradigm shift in consensus guidelines toward screening at diagnosis and ongoing monitoring and with the recent availability of an effective oral treatment, it is important that nephrologists have a thorough understanding of our role in the management of patients with tuberous sclerosis complex. Because the various manifestations of tuberous sclerosis complex typically emerge at different periods during patients' lifetimes, patients will need to be followed throughout their lives. Unlike brain and cardiac lesions, renal lesions are more likely to emerge as patients age and can grow at any time. Considerations regarding long-term medication administration for the potential control of multiple tuberous sclerosis complex manifestations will need to be addressed; these include the most appropriate starting dose, appropriate doses for tumor shrinkage versus prevention of regrowth, and management of adverse events. Best practices and potential obstacles for nephrologists treating patients with tuberous sclerosis complex who have multiple manifestations are considered.

Signs and Symptoms of Tuberous Sclerosis Complex

Signs and Symptoms of Tuberous Sclerosis Complex

Tuberous sclerosis complex: From molecular biology to novel therapeutic approaches.

Tuberous sclerosis complex (TSC) is a rare multi-system disorder, primary manifestations of which are benign tumors and lesions in various organs of the body, including the brain. TSC patients often suffer from epilepsy, mental retardation, and autism spectrum disorder (ASD). Therefore, TSC serves as a model of epilepsy, ASD, and tumorigenesis. TSC is caused by the lack of functional Tsc1-Tsc2 complex, which serves as a major cellular inhibitor of mammalian Target of Rapamycin Complex 1 (mTORC1). mTORC1 is a kinase controlling most of anabolic processes in eukaryotic cells. Consequently, mTORC1 inhibitors, such as rapamycin, serve as experimental or already approved drugs for several TSC symptoms. However, rapalogs, although quite effective, need to be administered chronically and likely for a lifetime, since therapy discontinuation results in tumor regrowth and epilepsy recurrence. Recent studies revealed that metabolism and excitability (in the case of neurons) of cells lacking Tsc1-Tsc2 complex are changed, and these features may potentially be used to treat some of TSC symptoms. In this review, we first provide basic facts about TSC and its molecular background, to next discuss the newest findings in TSC cell biology that can be used to improve existing therapies of TSC and other diseases linked to mTORC1 hyperactivation. © 2016 IUBMB Life, 68(12):955-962, 2016.

Systemic disease manifestations associated with epilepsy in tuberous sclerosis complex

Epilepsy is one of the most disabling symptoms of tuberous sclerosis complex (TSC) and is a leading cause of morbidity and mortality in affected individuals. The relationship between systemic disease manifestations and the presence of epilepsy has not been thoroughly investigated. This study utilizes a multicenter TSC Natural History Database including 1,816 individuals to test the hypothesis that systemic disease manifestations of TSC are associated with epilepsy. Univariate analysis was used to identify patient characteristics (e.g., age, gender, race, and TSC mutation status) associated with the presence of epilepsy. Individual logistic regression models were built to examine the association between epilepsy and each candidate systemic or neurologic disease variable, controlling for the patient characteristics found to be significant on univariate analysis. Finally, a multivariable logistic regression model was constructed, using the variables found to be significant on the individual analyses as well as the patient characteristics that were significant on univariate analysis. Nearly 88% of our cohort had a history of epilepsy. After adjusting for age, gender, and TSC mutation status, multiple systemic disease manifestations including cardiac rhabdomyomas (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.3-3.9, p = 0.002), retinal hamartomas (OR 2.1, CI 1.0-4.3, p = 0.04), renal cysts (OR 2.1, CI 1.3-3.4, p = 0.002), renal angiomyolipomas (OR 3.0, CI 1.8-5.1, p < 0.001), shagreen patches (OR 1.7, CI 1.0-2.7, p = 0.04), and facial angiofibromas (OR 1.7, CI 1.1-2.9, p = 0.03) were associated with a higher likelihood of epilepsy. In the multivariable logistic regression model, cardiac rhabdomyomas (OR 1.9, CI 1.0-3.5, p = 0.04) remained significantly associated with the presence of epilepsy. The identification of systemic disease manifestations such as cardiac rhabdomyomas that confer a higher risk of epilepsy development in TSC could contribute to disease prognostication and assist in the identification of individuals who may receive maximal benefit from potentially novel, targeted, preventative therapies.