Tuberous Sclerosis Complex Patients Research Articles

Clinical profile of tuberous sclerosis complex patients with and without epilepsy: a need for awareness for early diagnosis.

Tuberous sclerosis complex (TSC) is a multisystemic disorder. Its clinical features manifest differently in several organs, prompting the need for better knowledge. The goal of the present study is to evaluate the neurological findings of TSC, such as cerebral lesions and epilepsy, and to raise awareness of non-neurological findings that could contribute to an earlier diagnosis and treatment. This was a natural history study of patients with a definitive diagnosis of TSC who were referred to a specialized outpatient clinic and followed-up for 2 years with clinical and radiological exams. A total of 130 TSC patients (59 males [45.4%], mean age 20.4 years old [1 to 56 years old]); 107 patients (82.3%) were diagnosed with epilepsy. Seizures predominantly began at < 1 year old (72.8%); focal seizures predominated (86.9%); epileptic spasms occurred in 34.5% of patients, and refractory epilepsy was present in 55.1%. Neuropsychiatric disorders, cortical tubers and cerebellar tubers were significantly more frequent in the epilepsy group. Moreover, rhabdomyomas were significantly more frequent in the epilepsy group (p = 0.044), while lymphangioleiomyomatosis was significantly less frequent in the epilepsy group (p = 0.009). Other non-neurological findings did not differ significantly between the groups with and without epilepsy. The present study of TSC patients demonstrated the predominantly neurological involvement and significantly higher proportion of TSC-associated neuropsychiatric disorders in the epilepsy group. Higher proportions of cortical and cerebellar tubers may be a risk factor for epilepsy and neurodevelopmental disorders.

Hyperactivation of mTORC1 in a double hit mutant zebrafish model of tuberous sclerosis complex causes increased seizure susceptibility and neurodevelopmental abnormalities.

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by pathogenic variants in TSC1 and TSC2 genes. TSC patients present with seizures and brain abnormalities such as tubers and subependymal giant cells astrocytoma (SEGA). Despite common molecular and clinical features, the severity of the disease varies greatly, even intrafamilially. The second hit hypothesis suggests that an additional, inactivating mutation in the remaining functional allele causes a more severe phenotype and therefore explains the phenotypic variability. Recently, second hit mutations have been detected frequently in mTORopathies. To investigate the pathophysiological effects of second hit mutations, several mouse models have been developed. Here, we opted for a double mutant zebrafish model that carries a LOF mutation both in the tsc2 and the depdc5 gene. To the best of our knowledge, this is the first time a second-hit model has been studied in zebrafish. Significantly, the DEP domain-containing protein 5 (DEPDC5) gene has an important role in the regulation of mTORC1, and the combination of a germline TSC2 and somatic DEPDC5 mutation has been described in a TSC patient with intractable epilepsy. Our depdc5 −/− x tsc2 −/− double mutant zebrafish line displayed greatly increased levels of mammalian target of rapamycin (mTORC1) activity, augmented seizure susceptibility, and early lethality which could be rescued by rapamycin. Histological analysis of the brain revealed ventricular dilatation in the tsc2 and double homozygotes. RNA-sequencing showed a linear relation between the number of differentially expressed genes (DEGs) and the degree of mTORC1 hyperactivity. Enrichment analysis of their transcriptomes revealed that many genes associated with neurological developmental processes were downregulated and mitochondrial genes were upregulated. In particular, the transcriptome of human SEGA lesions overlapped strongly with the double homozygous zebrafish larvae. The data highlight the clinical relevance of the depdc5 −/− x tsc2 −/− double mutant zebrafish larvae that showed a more severe phenotype compared to the single mutants. Finally, analysis of gene-drug interactions identified interesting pharmacological targets for SEGA, underscoring the value of our small zebrafish vertebrate model for future drug discovery efforts.

Genotype and Phenotype Landscape of 283 Japanese Patients with Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by multiple dysplastic organ lesions and neuropsychiatric symptoms, caused by loss of function mutations in either TSC1 or TSC2. Genotype and phenotype analyses are conducted worldwide, but there have been few large-scale studies on Japanese patients, and there are still many unclear points. This study analyzed 283 Japanese patients with TSC (225 definite, 53 possible, and 5 genetic diagnoses). A total of 200 mutations (64 TSC1, 136 TSC2) were identified, of which 17 were mosaic mutations, 11 were large intragenic deletions, and four were splicing abnormalities due to deep intronic mutations. Several lesions and symptoms differed in prevalence and severity between TSC1 and TSC2 patients and were generally more severe in TSC2 patients. Moreover, TSC2 missense and in-frame mutations may attenuate skin and renal symptoms compared to other TSC2 mutations. Genetic testing revealed that approximately 20% of parents of a proband had mild TSC, which could have been missed. The patient demographics presented in this study revealed a high frequency of TSC1 patients and a low prevalence of epilepsy compared to global statistics. More patients with mild neuropsychiatric phenotypes were diagnosed in Japan, seemingly due to a higher utilization of brain imaging, and suggesting the possibility that a significant amount of mild TSC patients may not be correctly diagnosed worldwide.

Characterization and management of facial angiofibroma related to tuberous sclerosis complex in the United States: retrospective analysis of the natural history database

BackgroundFacial angiofibroma is the most predominant cutaneous manifestation of tuberous sclerosis complex (TSC), a rare autosomal dominant genetic disorder impacting the mechanistic target of rapamycin (mTOR). Facial angiofibroma can bleed spontaneously, impair eyesight, and cause aesthetic disfiguration causing psychological and social stress. To date, there is little or no evidence on the demographics, and other TSC features associated with facial angiofibroma or the use of mTOR inhibitor for the management of facial angiofibroma. This is a retrospective study of TSC Alliance’s Natural History Database aimed to characterize facial angiofibroma and to evaluate features associated with a higher risk of facial angiofibroma or the use of topical mTOR inhibitors for the management of facial angiofibroma. Data in the NHD was obtained from 18 clinical sites in the US since 2006.ResultsOf the 2240 patients, 2088 patients were enrolled in the US and data from 2057 patients were included in this analysis. The mean (median) age of overall TSC patients was 22.4 (19.0) years. A total of 69 patients were ≤ 5 years of age. Facial angiofibroma was noted in 1329 (64.6%) patients with TSC. Patients with facial angiofibroma were older on average (Mean: 25.9 [median, 23.0] vs. 16.0 [12.4 years] years, p < 0.0001). In patients with vs. without facial angiofibroma, TSC2 mutation (38.9% vs. 34.8%) was more common than TSC1 mutation (12.3% vs. 18.1%), and the incidence rate of most of the other TSC-related manifestations was significantly higher in patients with facial angiofibroma. Majority of patients had focal seizures (72.8% vs. 60.7%), followed by angiomyolipoma (63.7% vs. 21.8%) and renal cysts (59.4% vs. 33.5%). The age groups, 11–17 (odds ratio [OR], 2.53) and 18–45 years (5.98), TSC2 mutation (1.31), focal seizures (1.50), ADHD (1.47) angiomyolipoma (2.79), and renal cysts (2.63) were significantly associated with a higher risk of facial angiofibroma based on multivariate logistic regression. Abrasive or laser therapy was used by 17.1% and 2.6% patients, respectively. Topical mTOR inhibitor use was noted for 329 (24.8%) patients with facial angiofibroma. Overall systemic mTOR inhibitor use was observed in 399 (30.0%) patients for management of one or more TSC manifestations. Use of systemic mTOR inhibitor for facial angiofibroma was noted for 163 (12.3%) patients, among whom only 9 (0.7%) patients used exclusively for the management of facial angiofibroma. Of the patients with facial angiofibroma, 44.6% did not receive any treatment. Significantly higher use of topical mTOR inhibitor was associated with the 11–17 years age group (OR, 1.67), anxiety (1.57), angiomyolipoma (1.51), and renal cysts (1.33).ConclusionsThe presence of TSC2 mutations and most other TSC-related manifestations was significantly higher in patients with facial angiofibroma. About one-fourth of patients with facial angiofibroma used a topical mTOR inhibitor and use of systemic mTOR inhibitor for the management of facial angiofibroma or for the other manifestations was noted for 30.0%. About 44.6% of patients did not receive any treatment for the management of facial angiofibroma.

Mosaicism in tuberous sclerosis complex:Lowering the threshold for clinical reporting.

Tuberous sclerosis complex (TSC) is a multi-system genetic disorder. Most patients have germline mutations in TSC1 or TSC2 but, 10%-15% patients do not have TSC1/TSC2 mutations detected on routine clinical genetic testing. We investigated the contribution of low-level mosaic TSC1/TSC2 mutations in unsolved sporadic patients and families with TSC. Thirty-one sporadic TSC patients negative on routine testing and eight families with suspected parental mosaicism were sequenced using deep panel sequencing followed by droplet digital polymerase chain reaction. Pathogenic variants were found in 22/31 (71%) unsolved sporadic patients, 16 were mosaic (median variant allele fraction [VAF] 6.8% in blood) and 6 had missed germline mutations. Parental mosaicism was detected in 5/8 families (median VAF 1% in blood). Clinical testing laboratories typically only report pathogenic variants with allele fractions above 10%. Our findings highlight the critical need to change laboratory practice by implementing higher sensitivity assays to improve diagnostic yield, inform patient management and guide reproductive counseling.

Impact of facial angiofibromas in tuberous sclerosis complex and reported efficacy of available treatments.

Tuberous Sclerosis Complex (TSC) is a genetic condition which leads to a loss of inhibition of cellular growth. Facial angiofibromas (FAs) are hamartomatous growths associated with TSC that appear as multiple small, erythematous papules on the skin of the face and may resemble more severe forms of acne vulgaris. FAs have been reported in up to 74.5% of pediatric TSC patients, rising to up to 88% in adults >30 years old. They have not been closely studied, potentially overshadowed by other, systemic features of TSC. To investigate the impact of FAs, a common clinical feature for patients with TSC, we performed a non-interventional study in the form of a survey, completed by people living with TSC and FAs, or their caregiver as a proxy, if necessary. Patients were recruited via patient organizations in the UK and Germany. Data was received from 108 families in the UK (44 patients, 64 caregivers) and 127 families in Germany (50 patients, 64 caregivers). Exclusion criteria were those outside of 6-89 years, those without FAs, or those enrolled in a clinical trial. Where caregivers reported on behalf of an individual unable to consent, they were required to be adults (>18 years). Patient experience in the design of the survey was considered from practical and logistical perspectives with survey questions assessing multiple aspects relating to FAs including age of onset, perceived severity, treatments, perceived efficacy of treatments and perceived psychosocial impacts of the FAs. The psychosocial impacts of FAs for the individuals as well as for caregivers were explored in terms of social, occupational and leisure activities. Results of the survey demonstrated that for those with TSC-related moderate or severe FAs, there is an impact on quality of life and psychosocial impacts in the form of anxiety and depression. This finding was also noted by caregivers of TSC individuals in these categories. The treatment most frequently received to improve FAs, topical rapamycin/sirolimus, was found to be successful in the majority of those who received it.

Dissecting the roles of the Tuberin protein in the subcellular localization of the G2/M Cyclin, Cyclin B1.

Tuberin is a major component of the protein regulatory complex known as the Tuberous Sclerosis Complex and plays a crucial role in cell cycle progression and protein synthesis. Mutations in the Tuberin gene, TSC2, lead to the formation of benign tumors in many organ systems and causes the Tuberous Sclerosis Complex disorder. Genotypes ranging from point mutations to large deletions in the TSC2 gene have been clinically characterized with a wide range of phenotypes from skin tumors to large brain tumors. Our lab has previously demonstrated that Tuberin can directly bind and regulate the timing of nuclear transport of the G2/M cyclin, Cyclin B1. Herein we study the consequence of one clinically relevant truncation in the Tuberin protein on cell cycle function. We demonstrate that exogenous expression of a fragment of the N-term region of Tuberin alters the subcellular localization of Cyclin B1 and increases cell proliferation. This adds to our body of information about the residues within Tuberin responsible for regulating the cytoplasmic retention of Cyclin B1 and supports the phenotypic data seen in the clinic with Tuberous Sclerosis Complex patients harbouring similar large deletions in Tuberin.

Tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is aphakomatosis and is atumor predisposition syndrome. As agenetic multisystem disease, patients present with a broad range of changes in the brain, heart, skin, kidneys, and lungs. Which imaging modalities are required to monitor TSC patients according to current international recommendations? Common findings in TSC are cortical tubers, subependymal nodules, and giant cell astrocytomas in the central nervous system (CNS), rhabdomyomas in the heart, and cysts and angiomyolipomas in the kidneys. Magnetic resonance imaging (MRI) of the brain and kidneys and abdominal ultrasound are the imaging modalities of choice, due to the very good soft tissue contrast and lack of X‑ray radiation. Using standard and functional MRI sequences in a multimodal approach, the type, malignancy, size, and morphology of changes in TSC can be reliably determined. Abdominal ultrasound using high-resolution transducers can be used to rapidly and reliably detect even the smallest changes in the kidneys. Regular follow-up of patients with TSC using MRI and ultrasound is necessary for early detection of complications, for planning individualized therapy, and for optimal lifelong care.

MiRNAs and isomiRs: Serum-Based Biomarkers for the Development of Intellectual Disability and Autism Spectrum Disorder in Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-coding RNAs that regulate the expression of more than 60% of all protein-coding genes in humans and have been reported to be dysregulated in several diseases, including TSC. In the current study, RNA sequencing analysis was performed to define the miRNA and isoform (isomiR) expression patterns in serum. A Receiver Operating Characteristic (ROC) curve analysis was used to identify circulating molecular biomarkers, miRNAs, and isomiRs, able to discriminate the development of neuropsychiatric comorbidity, either ASD, ID, or ASD + ID, in patients with TSC. Part of our bioinformatics predictions was verified with RT-qPCR performed on RNA isolated from patients’ serum. Our results support the notion that circulating miRNAs and isomiRs have the potential to aid standard clinical testing in the early risk assessment of ASD and ID development in TSC patients.

Identification of Children's Tuberous Sclerosis Complex with Multiple-contrast MRI and 3D Convolutional Network.

Identifying rare tuberous sclerosis complex (TSC) children is valuable and crucial. Magnetic resonance imaging (MRI) is used for rare TSC diagnoses. In this work, T2w and FLAIR were combined as a new modality named FLAIR3 to maximize the contrast between TSC lesions and normal-appearing brain tissues. After that, for the first time, we propose to use two different 3D CNN combined with late fusion strategies to diagnose TSC. A total of 520 children were enrolled in the study, including 260 health and 260 TSC children. The experiments had shown that the FLAIR3 could effectively improve the conspicuity of TSC lesions and classification performance. And the results showed the proposed late fusion method can improve the classification performance and achieve the state-of-the-art performance of the AUC of 0.994 and the accuracy of 0.971, which could be treated as an effective computer-aided diagnostic tool to help clinical radiologists diagnose TSC children. Clinical Relevance- Our deep learning method can be a non-invasive, efficient, and reliable way to help clinical radiologists to identify TSC patients. FLAIR3 can provide clinicians with a new modality to accurately localize TSC lesions in TSC patients.

Synthetic MRI in children with tuberous sclerosis complex

ObjectiveThe generation of numerous sequences and quantitative data in a short scanning time is the most potential advantage of Synthetic MRI (SyMRI). We aimed to test detection of the tubers and to determine underlying tissue characteristics, and morphometric alterations in the brain of pediatric tuberous sclerosis complex (TSC) patients, using SyMRI.MethodsConventional brain MRI (cMRI) and SyMRI were prospectively obtained from 10 TSC patients and 18 healthy control subjects (HCs). Two neuroradiologists independently evaluated tubers on both scans. Additionally, automatically segmented volume calculation and myelin quantification, including the subcortical part of the tubers and normal-appearing brain parenchyma (NABP) of patients, were carried out using SyMRI.ResultsThe cMRI and SyMRI comparison showed a very good correlation on the detection of the tubers (k = 0.82–0.94). Automatic segmentation of Non-gray matter/white matter/cerebrospinal fluid (Non), %Non/brain parenchymal volume, and %Non/intracranial volume was significantly higher; however, %Myelin/intracranial volume and %Myelin/brain parenchymal volume were significantly lower in the TSC patients (p < 0.05). The proton density values were significantly increased, and myelin fraction volume and myelin-correlated compound values were significantly decreased in the NABP in TSC patients on myelin maps (p < 0.05). The white-matter volume, myelin and white-matter fractional volume, longitudinal relaxation rate, transverse relaxation rate, and myelin-correlated compound values were significantly decreased in the subcortical part of tubers on quantification maps (p < 0.001) in TSC patients.ConclusionSyMRI enables the detection of cortical tubers and is a developing tool in the quantification of morphometric and tissue alterations in pediatric TSC patients with a rational scanning time.

Monitoring and Managing Patients with Tuberous Sclerosis Complex: Current State of Knowledge.

Tuberous sclerosis complex (TSC) is a rare genetic disease of autosomal dominant transmission that, in most cases, results from the presence of pathogenic variants of the TSC1 or TSC2 genes, encoding hamartin and tuberin, respectively. It is a multisystemic disease, affecting most frequently the brain, skin, kidney, and heart. The wide variety of possible clinical manifestations, given this multisystem dimension, makes the follow-up of patients with TSC an exercise of multidisciplinarity. In fact, these patients may require the intervention of various medical specialties, which thus have to combine their efforts to practice a medicine that is truly holistic. The past few years have witnessed a dramatic leap not only in the diagnosis and management of TSC patients, with standard monitoring recommendations, but also in the therapeutic field, with the use of mTORC1 inhibitors. In this article, we review the clinical manifestations associated with TSC, as well as the treatment and follow-up strategies that should be implemented, from a multidisciplinary perspective.

LINC-13. Subependymal giant cell astrocytoma in a child with tuberous sclerosis complex: a case report

INTRODUCTION: Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder causing the formation of hamartomas in many organs, including the brain. It is generally benign but can block the flow of cerebrospinal fluid that increases intracranial pressure and leads to severe neurologic and behavioural changes. Subependymal giant cell astrocytoma (SEGA) occurs in 10-15% of TSC patients. Routine brain surveillance is important to look for SEGA in all TSC patients. CASE: We report a girl who was previously diagnosed with TSC at the age of two. She had hypomelanotic macules, facial angiofibroma, and a shagreen patch. Her first brain magnetic resonance imaging (MRI) was normal. She had routine consultation until she complained of recurrent headaches, walking instability, and seizures six years later. Her brain MRI showed a solid heterogenous intraventricular mass suggestive SEGA, with multiple subcortical hyperintense lesions (subcortical tubers), and hydrocephalus. She underwent emergency ventriculoperitoneal shunt (VP shunt) and tumor removal surgery. The histopathology examination matches SEGA, World health organization (WHO) grade I. It consists of polygonal to spindle cells with abundant eosinophilic cytoplasm. There are also large to multinucleated cells. After surgery, she had significant clinical improvement, and the seizure was controlled with valproic acid. CONCLUSION: It is essential to do brain evaluation using brain scan or MRI every 1-3 years as surveillance recommendation in all TSC patients. Early detection dramatically increases the chance of giving early treatment or surgery to lower complications and provide better outcomes.Keywords: Subependymal giant cell astrocytoma, tuberous sclerosis complex, surveillance, early diagnosis

Tuberous sclerosis complex-associated nonfunctional pancreatic neuroendocrine tumors: Management and surgical outcomes.

We aimed to further characterize pancreatic involvement in tuberous sclerosis complex (TSC), with a focus on management of TSC-associated nonfunctional pancreatic neuroendocrine tumors (PNETs). This was a retrospective chart review of a large cohort of TSC patients. A total of 637 patients with a confirmed diagnosis of TSC were seen at the Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital. Of the 637 total patients with a confirmed diagnosis of TSC, 28 patients were found to have varying pancreatic findings ranging from simple-appearing cysts to well-differentiated PNETs. Thirteen of the 28 patients had PNET confirmed on pathology; 10 of these tumors were resected at Massachusetts General Hospital. None of the patients had serious perioperative or postoperative complications; only one of the patients had a recurrence following resection. As roughly 4.4% of our TSC patient population had pancreatic involvement, surveillance abdominal imaging should include evaluation of the pancreas instead of limiting to a renal protocol. Additionally, given the low risk of complications and recurrence combined with documented risk of metastasis in TSC-associated PNET, TSC patients with pancreatic lesions suspicious for PNETs should be considered as surgical candidates.

Safety of inactivated COVID-19 vaccine in tuberous sclerosis complex patients with epilepsy treated with rapamycin

PurposeTo assess the safety of inactivated coronavirus 2019 disease (COVID-19) vaccine in tuberous sclerosis complex (TSC) patients with epilepsy. MethodsAll patients with epilepsy were selected from Efficacy and Safety of Sirolimus in Pediatric Patients with Tuberous Sclerosis (ESOSPIT) project and younger than 17 years old. The patients were treated with mTOR inhibitors (rapamycin). A total of 44 patients who completed the two-dose inactivated COVID-19 vaccine between July 7, 2021, and January 1, 2022, were enrolled. ResultsThe median age of seizure onset was 23 months. About two-thirds of patients have focal seizures. Thirty-three patients use antiseizure medications. The mean duration of rapamycin treatment was 55.59 ± 18.42 months. Adverse reactions within 28 days after injection occurred in 11 patients (25%), all were under 12 years old. Injection site pain was the most reported event (20.45%), which was mild in severity and improved within one day. All patients had no seizure-related changes after vaccination. ConclusionThis study shows that the inactivated COVID-19 vaccine was well tolerated and safe in TSC patients with epilepsy, as well as for those treated with mTOR inhibitors.

Reading Ability in Patients With Tuberous Sclerosis Complex: Results of Chinese Character Reading and Reading Comprehension Tests.

BackgroundMost tuberous sclerosis complex (TSC) patients have neurological disorders and are at high risk of academic difficulties. Among academic skills, reading ability is the most important academic skill. The study applied the Chinese character fluency test to measure the word recognition and reading comprehension of TSC children to observe whether they have the characteristics of reading disability, as an indicator of the spectrum of reading ability in TSC patients.MethodsThe patients were assessed using the Chinese character fluency test and reading comprehension test to explore the differences in reading ability in terms of gender, age, epilepsy history, genotype, and intelligence level.ResultsOf the 27 patients, the assessment of reading accuracy showed statistical differences between intellectual level > 80, PR (p = 0.024), and pass numbers (p = 0.018). For the fluency assessment, there was a difference between different intellectual level (p = 0.050). In the reading comprehension test, there was differences for intellectual level in positivity (p = 0.07) and pass numbers (p = 0.06).ConclusionThe Chinese character fluency and reading comprehension test measure the word recognition and reading comprehension and the spectrum of reading ability in TSC patients. All individuals with TSC, especially those with below average of intellectual ability, should be considered for potential academic difficulties.

Postnatal Cytomegalovirus Infection May Increase the Susceptibility of Tuberous Sclerosis Complex to Autism Spectrum Disorders.

ABSTRACTAutism spectrum disorder (ASD), a highly hereditary and heterogeneous neurodevelopmental disorder, is influenced by genetic and environmental factors. Tuberous sclerosis complex (TSC) is a common syndrome associated with ASD. Cytomegalovirus (CMV) infection is an environmental risk factor for ASD. The similarities in pathological and mechanistic pathways of TSC and CMV intrigued us to investigate whether CMV and TSC interacted in ASD’s occurrence. We detected CMV IgG seroprevalence of 308 TSC patients from our prospective cohort (September 2011 to March 2021) and 93 healthy children by magnetic particle indirect chemiluminescence immunoassay. A total of 206 TSC patients enrolled were divided into ASD and non-ASD groups, and the relationship between ASD and CMV seroprevalence was analyzed. Nested PCR and Western blot were used to detect CMV DNAs and proteins in cortical malformations of seven TSC patients with and without ASD. No difference was found in CMV seroprevalence between TSC patients and healthy children (74.0% versus 72.0%, P = 0.704). Univariate analysis showed the seroprevalence in TSC patients with ASD was higher than that in TSC patients without ASD (89.2% versus 75.1%, P = 0.063), and multifactorial analysis showed that CMV seroprevalence was a risk factor for ASD in TSC patients (OR = 3.976, 95% CI = 1.093 to 14.454). Moreover, CMV was more likely to be detected in the cortical malformations in TSC patients with ASD but not in those without ASD. The findings demonstrated that CMV may increase the susceptibility of TSC to ASD.IMPORTANCE CMV is an environmental risk factor for ASD, but its role in syndromic autism with known genetic etiology has been rarely studied. The pathogenesis of ASD is related to the interaction between environmental and genetic factors. This study demonstrated that CMV can contribute to the occurrence of ASD related to TSC, a common genetic syndrome associated with ASD. Our findings provided support for the theory of gene-environment interaction (G × E) in pathogenesis of ASD and a new perspective for the prevention and therapy for TSC related ASD.

Cutaneous and neurological profile of tuberous sclerosis complex in children: A case series and literature review

Tuberous sclerosis complex (TSC) is a rare genetic disease, belongs to the group of neurocutaneous syndrome. The consequence of genetic mutation is inadequate inhibition of the mammalian target of rapamycin (mTOR) signal pathway that results in inactivation of regulated cells growth and formation of dysgenic tissues/ hamartomas in multiple systems. The updated version of diagnostic criteria for TSC and management has been laid down after second International Tuberous Sclerosis Complex Consensus Conference (2012). To describe the clinico-neuroradiological profile and aspects of antiepileptic treatment of “ definite” TSC casesWe report a case series of four TSC cases attended in a teaching hospital. The “ definite” TSC cases are diagnosed by updated diagnostic criteria (2012) and data obtained retrospectively from records. We discuss the present series in the light of the current literature.We report three female and one male TSC patients. The “definite” TSC diagnosed by two major criteria - one or more cutaneous lesions and neuropathological lesion by neuroimaging. No family history of TSCs have been reported in the series.Hypomelanotic macules were observed in all (n=4) patients. Two TSC patients (n=2) had facial angiofibroma and one TSC had (n=1) shagreen patch. In neuroimaging studies, subependymal nodules were reported in three TSC patients (n=3) and one TSC had cortical dysplasias.The most common neurological manifestation in the TCS series is epilepsy; three TSC patients (n=3) had epilepsy. One TSC patient (n=1) did not present with epilepsy. Infantile spasms, tonic-clonic seizure and focal seizure were the phenotype of seizures. Vigabatrin, valporate and phenobarbitone have been prescribed in TSC patients. Scholastic performance was normal in one TSC patient (n=1) and subnormal in another patient(n=1).TSC -associated cutaneous lesions, the major features for diagnosis, develop in age-dependant manner. The prospective evaluation with a neuroimaging is an integral part of TSC management. Infantile spasm, focal seizure are the first manifested seizures with subtle presentation. First-contact physician must be well knowledgeable about updated 2012 diagnostic criteria, so timely management could be advocated. Vigabatrin is the first choice for infantile spsams in TSC patients as well as for focal seizures. Cognitive outcome/ scholastic performance may varies in TSC patients.

Tuberous sclerosis complex: a complex case.

Tuberous sclerosis complex (TSC) is an inheritable disorder characterized by the formation of benign yet disorganized tumors in multiple organ systems. Germline mutations in the TSC1 (hamartin) or more frequently TSC2 (tuberin) genes are causative for TSC. The malignant manifestations of TSC, pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML), may also occur as independent sporadic perivascular epithelial cell tumor (PEComa) characterized by somatic TSC2 mutations. Thus, discerning TSC from the copresentation of sporadic LAM and sporadic AML may be obscured in TSC patients lacking additional features. In this report, we present a case study on a single patient initially reported to have sporadic LAM and a mucinous duodenal adenocarcinoma deficient in DNA mismatch repair proteins. Moreover, the patient had a history of Wilms’ tumor, which was reclassified as AML following the LAM diagnosis. Therefore, we investigated the origins and relatedness of these tumors. Using germline whole-genome sequencing, we identified a premature truncation in one of the patient's TSC2 alleles. Using immunohistochemistry, loss of tuberin expression was observed in AML and LAM tissue. However, no evidence of a somatic loss of heterozygosity or DNA methylation epimutations was observed at the TSC2 locus, suggesting alternate mechanisms may contribute to loss of the tumor suppressor protein. In the mucinous duodenal adenocarcinoma, no causative mutations were found in the DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2. Rather, clonal deconvolution analyses were used to identify mutations contributing to pathogenesis. This report highlights both the utility of using multiple sequencing techniques and the complexity of interpreting the data in a clinical context.

Efficacy and Safety of Topical Mechanistic Target of Rapamycin Inhibitors for Facial Angiofibromas in Patients with Tuberous Sclerosis Complex: A Systematic Review and Network Meta-Analysis.

Previous studies have suggested that the topical mechanistic target of rapamycin (mTOR) inhibitors may be effective in treating facial angiofibromas in patients with tuberous sclerosis complex (TSC). Various concentrations of topical sirolimus for TSC have been tested, but their comparative efficacy and safety remained unclear. To assess the effects of topical mTOR inhibitors in treating facial angiofibromas, we conducted a systematic review and network meta-analysis (NMA) and searched MEDLINE, Embase, and Cochrane Library for relevant randomized controlled trials on 14 February 2022. The Cochrane Collaboration tool was used to assess the risk of bias of included trials. Our outcomes were clinical improvement and severe adverse events leading to withdrawal. We included three trials on 261 TSC patients with facial angiofibromas. The NMA found when compared with placebo, facial angiofibromas significantly improved following the application of various concentrations of topical sirolimus (risk ratio being 3.87, 2.70, 4.43, and 3.34 for 0.05%, 0.1%, 0.2%, and 1%, respectively). When compared with placebo, all concentrations of topical sirolimus did not differ in severe adverse events leading to withdrawal. The ranking analysis suggested topical sirolimus 0.2% as the most effective drug. In conclusion, topical sirolimus 0.05–1% are effective and safe in treating facial angiofibromas in patients with TSC, with topical sirolimus 0.2% being the most effective.