scholarly journals A novel TSC2 c.4511 T > C missense variant associated with tuberous sclerosis complex

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Shunzhi He ◽  
Na Lv ◽  
Hongchu Bao ◽  
Xiong Wang ◽  
Jing Li

Abstract Background Tuberous sclerosis complex (TSC) is an autosomal-dominant hereditary disease characterized by hamartomas of multiple organ systems, including the brain, skin, heart, kidney and lung. Genetically, TSC is caused by pathogenic variants in the TSC1 or TSC2 gene. Case presentation We reported a sporadic case of a 32-year-old Han Chinese male diagnosed with TSC, whose spouse had a history of two spontaneous miscarriages and an induced abortion of a 30-week fetus identified with cardiac rhabdomyoma by ultrasound. A novel heterozygous missense variant in the TSC2 gene (Exon35:c.4511 T > C:p.L1504P) was identified in the male patient and the aborted fetus by next-generation sequencing, but not in his wife or both his parents. According to the ACMG/AMP criteria, this variant was classified as a “likely pathogenic” variant. Conclusion The novel TSC2:c.4511 T > C variant identified was highly likely associated with TSC and could potentially lead to adverse reproductive outcomes. IVF-ET and pre-implantation genetic diagnosis for TSC are recommended for this patient in the future to prevent fetal TSC.

2021 ◽  
pp. 98-105
Author(s):  
Julie Loft Nagel ◽  
Maja Patricia Smerdel ◽  
Lisbeth Birk Møller ◽  
Lotte Andreasen ◽  
Anette Bygum

Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disease with hamartomatous growths in multiple organs due to loss-of-function variants in TSC1 or TSC2. In approximately 15% of patients with clinical TSC, no pathogenic variant can be identified, and low-level mosaicism is suggested to be one of the reasons. Mosaicism is well-known in TSC and challenges the molecular genetic diagnosis. The advent of next-generation sequencing has improved the diagnostics in TSC including in patients with mosaicism. The TSC phenotype varies widely, and mosaic patients with TSC are often considered to have a milder phenotype. Here, the authors describe a patient with mosaic TSC with a 10% variant allele fraction and manifestations in three organ systems (skin, eyes, and kidneys). Furthermore, the authors studied existing literature about phenotypic organ manifestations in patients with mosaic TSC. No clear definition of the phenotype of patients with mosaic TSC could be established, but unilateral angiofibromas and the absence of tubers and a subependymal nodule could indicate mosaicism. The case shows that patients with low-level mosaic TSC can have multiple affected organ systems though still a mild clinical picture.


Author(s):  
Gajanan A. Surwade ◽  
Uddhav S. Khaire ◽  
Sagar P. Patil ◽  
Mamta K. Mulay ◽  
Mangala S. Borkar

<p class="abstract"><span lang="EN-US">Tuberous sclerosis is a neurocutaneous syndrome with an autosomal dominant inheritance. Tuberous sclerosis complex Syndrome caused by mutations of either the TSC1 orTSC2 gene encoding hamartin and tuberin respectively. It is characterized by the development of benign tumors; the most common oral manifestations of TSC are fibromas (angiofibromas), gingival hyperplasia and enamel hypoplasia and the formation of hamartomas in multiple organ systems leading to morbidity and mortality. Familial tuberous sclerosis probably occurs more often than is indicated by the literature: many family members show signs of being carriers of gene for the disease when carefully examined. We report a case of 25 year old female with the features of Tuberous sclerosis complex like seizures, papules over the cheek, shagreen patch, hypomelanotic macule on arm, buttacks, pulmonary lymphangioleiomyomatosis, subependymal nodules and tubers in brain, angiomyolipoma in both kidneys and Cardiac rhabdomyoma. This article reports on a family with documented tuberous sclerosis in three generations.</span></p>


2020 ◽  
Vol 7 (3) ◽  
pp. 5-19
Author(s):  
Nikhil Nair ◽  
Ronith Chakraborty ◽  
Zubin Mahajan ◽  
Aditya Sharma ◽  
Sidarth Sethi ◽  
...  

Tuberous sclerosis complex (TSC) is a genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Disruption of either of these genes leads to impaired production of hamartin or tuberin proteins, leading to the manifestation of skin lesions, tumors and seizures. TSC can manifests in multiple organ systems with the cutaneous and renal systems being the most commonly affected. These manifestations can secondarily lead to the development of hypertension, chronic kidney disease, and neurocognitive declines. The renal pathologies most commonly seen in TSC are angiomyolipoma, renal cysts and less commonly, oncocytomas. In this review, we highlight the current understanding on the renal manifestations of TSC along with current diagnosis and treatment guidelines.


2019 ◽  
Vol 20 (1) ◽  
pp. 217-240 ◽  
Author(s):  
Catherine L. Salussolia ◽  
Katarzyna Klonowska ◽  
David J. Kwiatkowski ◽  
Mustafa Sahin

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems due to an inactivating variant in either TSC1 or TSC2, resulting in the hyperactivation of the mechanistic target of rapamycin (mTOR) pathway. Dysregulated mTOR signaling results in increased cell growth and proliferation. Clinically, TSC patients exhibit great phenotypic variability, but the neurologic and neuropsychiatric manifestations of the disease have the greatest morbidity and mortality. TSC-associated epilepsy occurs in nearly all patients and is often difficult to treat because it is refractory to multiple antiseizure medications. The advent of mTOR inhibitors offers great promise in the treatment of TSC-associated epilepsy and other neurodevelopmental manifestations of the disease; however, the optimal timing of therapeutic intervention is not yet fully understood.


2020 ◽  
Vol 7 (3) ◽  
pp. 5-19
Author(s):  
Nikhil Nair ◽  
Ronith Chakraborty ◽  
Zubin Mahajan ◽  
Aditya Sharma ◽  
Sidharth K. Sethi ◽  
...  

Tuberous sclerosis complex (TSC) is a genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Disruption of either of these genes leads to impaired production of hamartin or tuberin proteins, leading to the manifestation of skin lesions, tumors, and seizures. TSC can manifest in multiple organ systems with the cutaneous and renal systems being the most commonly affected. These manifestations can secondarily lead to the development of hypertension, chronic kidney disease, and neurocognitive declines. The renal pathologies most commonly seen in TSC are angiomyolipoma, renal cysts, and less commonly, oncocytomas. In this review, we highlight the current understanding on the renal manifestations of TSC along with current diagnosis and treatment guidelines.


2021 ◽  
pp. 28-30
Author(s):  
Disha Rama Harikanth ◽  
Manjushri Waikar

Tuberous sclerosis is a multisystemic, autosomal dominant neurocutaneous disorder of hamartoma formation affecting multiple organ systems and hence adversely affecting the maternal and fetal outcome. We report a case of maternal tuberous sclerosis with fetal cardiac rhabdomyoma detected in utero at 22 weeks but presented at 39 weeks of gestation. We conclude that Maternal or Fetal tuberous sclerosis deserves careful monitoring and evaluation so that the patients can be counselled regarding its life threatening complications to the baby and make informed decision regarding continuation of pregnancy


2020 ◽  
Vol 79 (10) ◽  
pp. 1054-1064
Author(s):  
Angelika Mühlebner ◽  
Jackelien van Scheppingen ◽  
Andrew de Neef ◽  
Anika Bongaarts ◽  
Till S Zimmer ◽  
...  

Abstract Tuberous sclerosis complex (TSC) is a monogenetic disease that arises due to mutations in either the TSC1 or TSC2 gene and affects multiple organ systems. One of the hallmark manifestations of TSC are cortical malformations referred to as cortical tubers. These tubers are frequently associated with treatment-resistant epilepsy. Some of these patients are candidates for epilepsy surgery. White matter abnormalities, such as loss of myelin and oligodendroglia, have been described in a small subset of resected tubers but mechanisms underlying this phenomenon are unclear. Herein, we analyzed a variety of neuropathologic and immunohistochemical features in gray and white matter areas of resected cortical tubers from 46 TSC patients using semi-automated quantitative image analysis. We observed divergent amounts of myelin basic protein as well as numbers of oligodendroglia in both gray and white matter when compared with matched controls. Analyses of clinical data indicated that reduced numbers of oligodendroglia were associated with lower numbers on the intelligence quotient scale and that lower amounts of myelin-associated oligodendrocyte basic protein were associated with the presence of autism-spectrum disorder. In conclusion, myelin pathology in cortical tubers extends beyond the white matter and may be linked to cognitive dysfunction in TSC patients.


2012 ◽  
Vol 2012 ◽  
pp. 1-3 ◽  
Author(s):  
Mariya Gusman ◽  
Sabah Servaes ◽  
Tamara Feygin ◽  
Karl Degenhardt ◽  
Monica Epelman

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which benign hamartomas develop in multiple organ systems. Increasingly, stigmata of the disease, such as cardiac rhabdomyomas, are detected on routine prenatal ultrasound. Such a finding should prompt additional imaging studies in order to confirm diagnosis and to identify potential complications, which vary greatly from patient to patient. Early diagnosis allows for accurate parental counseling, coordination of high-level perinatal care, and subspecialty followup. We present a case of TSC in utero wherein access to and use of multiple imaging modalities confirmed diagnosis and allowed the patient to receive optimal care prior to birth.


2019 ◽  
Vol 76 (8) ◽  
pp. 817-821 ◽  
Author(s):  
Ana Kosac ◽  
Nebojsa Jovic

BackgroundAim. Common features of tuberous sclerosis complex (TSC) arise from the formation of hamartomas both in the brain and multiple organ systems, mainly due to a mutation in one of two genes, TSC1 or TSC2, with well described inter- and intrafamilial different phenotypic outcomes. The aim of this work was to make a synthesis of the patients data with diagnosed tuberous sclerosis in order to better understand the disease in our environment. Methods. We reviewed retrospectively the clinical records of all patients with TSC, diagnosed and regularly followed at the Clinic of Neurology and Psychiatry for Children and Youth in Belgrade, Serbia during the period of more than two decades. Statistical analyses were performed using descriptive statistics as well as the Fisher?s exact test. Results. Cohort of 44 patients with the diagnosis of definitive TSC were included. The mean age at last follow-up was 19.4 years [age range 1?58, standard deviation (SD) 11.8]. Family history for TSC was noted in 25% of patients. Dermatological manifestations were described in 93.2%, retinal astrocytoma and cardiac rhabdomyomas was found in 36.4% each, nephrological manifestations in 34.1% and lymphangioleiomyomatosis was diagnosed in two female patients. All patients presented with the structural lesions of central nervous system; epilepsy was diagnosed in 88.6%, out of whom 59 % of patients had seizure onset in the first year of life. The West syndrome was diagnosed in 27.3% of patients. Complete seizure control was achieved in 30.8%, in a majority with valproic acid or cabamazepine, but also with topiramate, lamotrigine and vigabatrin. At least two antiepileptic drugs were administered in 82% of patients. Mental retardation was noted in 50% of patients. Psychiatric manifestations were found in 40.9%, with attention deficit hyperactivity disorder diagnosed in 27.3%, autism spectrum disorder in 13.6 %, and psychosis and depression observed in 11.4% each. Conclusion. This kind of synthesis of the data certainly contributes to better understanding of the disease in our environment, as TSC, although well-known disease, still remains diagnostic and therapeutic challenge in daily clinical practice.


2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Filipe Palavra ◽  
Conceição Robalo ◽  
Flávio Reis

Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of benign, noninvasive, and tumor-like lesions called hamartomas that can affect multiple organ systems and are responsible for the clinical features of the disease. In the majority of cases, TSC results from mutations in the TSC1 and TSC2 genes, leading to the overactivation of the mammalian target of rapamycin (mTOR) signalling pathway, which controls several cell functions, including cell growth, proliferation, and survival. The establishment of a connection between TSC and mTOR led to the clinical use of drugs known as mTOR inhibitors (like rapamycin, also known as sirolimus and everolimus), which are becoming an increasingly interesting tool in the management of TSC-associated features, such as subependymal giant cell astrocytomas, renal angiomyolipomas, and also epilepsy. However, the intrinsic characteristics of these drugs and their systemic effects in such a heterogeneous condition pose many challenges in clinical practice, so that some questions remain unanswered. This article provides an overview of the pharmacological aspects of mTOR inhibitors about the clinical trials leading to their approval in TSC-related conditions and exposes current challenges and future directions associated with this promising therapeutic line.


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