bims-tubesc 2021-10-03 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2021–10–03
eleven papers selected by

Whole Exome Sequencing in a Series of Patients with a Clinical Diagnosis of Tuberous Sclerosis Not Confirmed by Targeted TSC1/TSC2 Sequencing.
Neuroendocrine pancreatic tumor in a patient with dual diagnosis of tuberous sclerosis complex and basement membrane disease: A case report and review of the literature.
Fibroma-like PEComa: a newly recognized soft tissue neoplasm in tuberous sclerosis patients-imaging features and review of literature.
Collision Tumor of the Kidney: Renal Cell Carcinoma Hidden in a Giant Angiomyolipoma in a Patient With Tuberous Sclerosis Complex.
Historical Patterns of Diagnosis, Treatments, and Outcome of Epilepsy Associated With Tuberous Sclerosis Complex: Results From TOSCA Registry.
Synaptic Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders.
First psychotic episode, related to COVID-19 pandemic, in a patient with tuberous sclerosis complex.
Mechanistic Target of Rapamycin Complex 1 Signaling Links Hypoxia to Increased IGFBP-1 Phosphorylation in Primary Human Decidualized Endometrial Stromal Cells.
Precision Medicine Approaches for Infantile-Onset Developmental and Epileptic Encephalopathies.
Uterine PEComatosis With TSC1 Mutation in a Patient With Tuberous Sclerosis: Case Report and Literature Review.
Persistent mTORC1 activation via Depdc5 deletion results in spontaneous hepatocellular carcinoma but does not exacerbate carcinogen- and high-fat diet-induced hepatic carcinogenesis in mice.

Genes (Basel). 2021 Sep 10. pii: 1401. [Epub ahead of print]12(9):

Whole Exome Sequencing in a Series of Patients with a Clinical Diagnosis of Tuberous Sclerosis Not Confirmed by Targeted TSC1/TSC2 Sequencing.

Erzsebet Kovesdi, Reka Ripszam, Etelka Postyeni, Emese Beatrix Horvath, Anna Kelemen, Beata Fabos, Viktor Farkas, Kinga Hadzsiev, Katalin Sumegi, Lili Magyari, Pilar Guatibonza Moreno, Peter Bauer, Bela Melegh.

   BACKGROUND: Approximately fifteen percent of patients with tuberous sclerosis complex (TSC) phenotype do not have any genetic disease-causing mutations which could be responsible for the development of TSC. The lack of a proper diagnosis significantly affects the quality of life for these patients and their families.
METHODS: The aim of our study was to use Whole Exome Sequencing (WES) in order to identify the genes responsible for the phenotype of nine patients with clinical signs of TSC, but without confirmed tuberous sclerosis complex 1/ tuberous sclerosis complex 2 (TSC1/TSC2) mutations using routine molecular genetic diagnostic tools.
RESULTS: We found previously overlooked heterozygous nonsense mutations in TSC1, and a heterozygous intronic variant in TSC2. In one patient, two heterozygous missense variants were found in polycystic kidney and hepatic disease 1 (PKHD1), confirming polycystic kidney disease type 4. A heterozygous missense mutation in solute carrier family 12 member 5 (SLC12A5) was found in one patient, which is linked to cause susceptibility to idiopathic generalized epilepsy type 14. Heterozygous nonsense variant ring finger protein 213 (RNF213) was identified in one patient, which is associated with susceptibility to Moyamoya disease type 2. In the remaining three patients WES could not reveal any variants clinically relevant to the described phenotypes.
CONCLUSION: Patients without appropriate diagnosis due to the lack of sensitivity of the currently used routine diagnostic methods can significantly profit from the wider application of next generation sequencing technologies in order to identify genes and variants responsible for their symptoms.

Keywords:  Whole Exome Sequencing; no mutation identified; tuberous sclerosis complex

DOI:  https://doi.org/10.3390/genes12091401
Radiol Case Rep. 2021 Nov;16(11): 3581-3588

Neuroendocrine pancreatic tumor in a patient with dual diagnosis of tuberous sclerosis complex and basement membrane disease: A case report and review of the literature.

Saba Kopadze, Inga Shoshiashvili, Anna Dumbadze, Tinatin Tkemaladze, Ivane Kiladze.

  Tuberous Sclerosis is a complex genetic disease that has well-defined clinical criteria. These criteria don't include pancreatic neuroendocrine tumors. We represent a rare case of a patient, with a non-functioning pancreatic neuroendocrine tumor and concomitant diagnosis of tuberous sclerosis complex, and basement membrane disease. The patient was diagnosed based on typical radiologic findings. We have suggested close monitoring and during follow-up studies, the disease was stable. Interestingly the patient tested negative for Tuberous Sclerosis Complex (TSC), which suggests that she might be a somatic mosaic and the mutation level in blood lymphocytes was below the detection level. Moreover, a heterozygous pathogenic variant p.(Gly774Arg) and a heterozygous likely pathogenic variant p.(Gly1465Asp) were identified in the COL4A4 gene. COL4A4 gene is responsible for causing autosomal dominant basement membrane disease. In this case report, we discuss clinical, radiologic, and genetic aspects of these diseases, as well as optimal treatment and follow-up strategies. Thus, by presenting this case we would like to increase awareness of pancreatic neuroendocrine tumors in TSC and emphasize the need for follow-up monitoring.

Keywords:  Angiofibroma; Basement membrane disease; PanNET; Renal angiomyolipoma; Retinal hamartoma; Tuberous sclerosis complex

DOI:  https://doi.org/10.1016/j.radcr.2021.08.041
Skeletal Radiol. 2021 Sep 29.

Fibroma-like PEComa: a newly recognized soft tissue neoplasm in tuberous sclerosis patients-imaging features and review of literature.

Gitanjali Bajaj, Matthew R Lindberg, Winson Chee, Debopam Samanta, Avneesh Chhabra.

  Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms composed of spindled to epithelioid cells that co-express both melanocytic and myogenic markers. Recently, in 2018, a distinctive variant of PEComa has been described that arises in association with tuberous sclerosis complex (TSC) and resembles a fibroma by conventional morphology (called fibroma-like PEComa). Herein, we describe a case of a fibroma-like PEComa in a 4-year-old male child with a known diagnosis of tuberous sclerosis who presented with a firm mass along the anteromedial aspect of the right knee. The mass was excised, and microscopic examination showed bland spindled to stellate cells embedded in a dense collagenous stroma, morphologically resembling a fibroma. Immunohistochemistry analysis showed positivity for desmin (a myogenic marker) and HMB45 (a melanocytic marker), a hallmark for PEComas. To our knowledge, only six cases of fibroma-like PEComa have been described in the literature so far and this is the first report of such a tumor in the medial retinaculum of the knee joint with illustrations of conventional and diffusion imaging features. This case highlights the unique association of fibroma-like PEComa lesions with TSC. This should be considered a differential diagnosis for T2 hypointense masses in tuberous sclerosis patients. In addition, a diagnosis of fibroma-like PEComa should prompt further evaluation for associated TSC.

Keywords:  Diffusion-weighted imaging (DWI); Fibroma; Fibroma-like PEComa; Magnetic resonance imaging (MRI); Perivascular epithelioid cell tumor (PEComa); Tenosynovial giant cell tumor (TSGCT); Tuberous sclerosis complex (TSC)

DOI:  https://doi.org/10.1007/s00256-021-03923-4
Ochsner J. 2021 ;21(3): 287-290

Collision Tumor of the Kidney: Renal Cell Carcinoma Hidden in a Giant Angiomyolipoma in a Patient With Tuberous Sclerosis Complex.

José Iván Robles-Torres, José Gustavo Arrambide-Herrera, Max Molina-Ayala, Sergio Alan Dávila-Martínez, Pedro Antonio Madero-Morales, Lauro Salvador Gómez-Guerra.

  Background: A renal angiomyolipoma is a mixed mesenchymal benign tumor composed of smooth muscle, adipose tissue, and blood vessels. Malignant transformation of angiomyolipomas is anecdotal. To our knowledge, only 6 cases have been reported, and 4 of the patients had tuberous sclerosis complex diagnosed. Case Report: We present the case of a 29-year-old male with tuberous sclerosis complex who arrived at the emergency room with gross hematuria and a painful right-sided abdominal mass. Imaging studies revealed active bleeding from a giant angiomyolipoma. An emergency nephrectomy was performed. Histopathology evaluation revealed an angiomyolipoma with a focal lesion and clear cell renal carcinoma within the tumor. Conclusion: Limited evidence is available to dictate management of collision tumors of the kidney in the scenario of tuberous sclerosis complex, so a multidisciplinary approach that includes urology, oncology, genetics, and nephrology intervention needs to be considered. No standardized follow-up modality has been established for angiomyolipomas, so patients should be placed under active surveillance, similar to that carried out in cases of renal cell carcinoma.

Keywords:  Angiomyolipoma; carcinoma–renal cell; tuberous sclerosis

DOI:  https://doi.org/10.31486/toj.20.0075
Front Neurol. 2021 ;12 697467

Historical Patterns of Diagnosis, Treatments, and Outcome of Epilepsy Associated With Tuberous Sclerosis Complex: Results From TOSCA Registry.

Rima Nabbout, Elena Belousova, Mirjana P Benedik, Tom Carter, Vincent Cottin, Paolo Curatolo, Maria Dahlin, Lisa D'Amato, Guillaume Beaure d'Augères, Petrus J de Vries, José C Ferreira, Martha Feucht, Carla Fladrowski, Christoph Hertzberg, Sergiusz Jozwiak, John A Lawson, Alfons Macaya, Ruben Marques, Finbar O'Callaghan, Jiong Qin, Matthias Sauter, Seema Shah, Yukitoshi Takahashi, Renaud Touraine, Sotiris Youroukos, Bernard Zonnenberg, Anna C Jansen, J Chris Kingswood.

  Background: Epilepsy is the most common neurological manifestation in individuals with tuberous sclerosis complex (TSC). However, real-world evidence on diagnosis and treatment patterns is limited. Here, we present data from TuberOus Sclerosis registry to increase disease Awareness (TOSCA) on changes in patterns of epilepsy diagnosis, treatments, and outcomes over time, and detailed epilepsy characteristics from the epilepsy substudy. Methods: TuberOus Sclerosis registry to increase disease Awareness (TOSCA) was a multicentre, international disease registry, consisting of a main study that collected data on overall diagnostic characteristics and associated clinical features, and six substudies focusing on specific TSC manifestations. The epilepsy substudy investigated detailed epilepsy characteristics and their correlation to genotype and intelligence quotient (IQ). Results: Epilepsy was reported in 85% of participants, more commonly in younger individuals (67.8% in 1970s to 91.8% in last decade), while rate of treatments was similar across ages (>93% for both infantile spasms and focal seizures, except prior to 1960). Vigabatrin (VGB) was the most commonly used antiepileptic drugs (AEDs). Individuals with infantile spasms showed a higher treatment response over time with lower usage of steroids. Individuals with focal seizures reported similar rates of drug resistance (32.5-43.3%). Use of vagus nerve stimulation (VNS), ketogenic diet, and surgery remained low. Discussion: The epilepsy substudy included 162 individuals from nine countries. At epilepsy onset, most individuals with infantile spasms (73.2%) and focal seizures (74.5%) received monotherapies. Vigabatrin was first-line treatment in 45% of individuals with infantile spasms. Changes in initial AEDs were commonly reported due to inadequate efficacy. TSC1 mutations were associated with less severe epilepsy phenotypes and more individuals with normal IQ. In individuals with TSC diagnosis before seizure onset, electroencephalogram (EEG) was performed prior to seizures in only 12.5 and 25% of subsequent infantile spasms and focal seizures, respectively. Conclusions: Our study confirms the high prevalence of epilepsy in TSC individuals and less severe phenotypes with TSC1 mutations. Vigabatrin improved the outcome of infantile spasms and should be used as first-line treatment. There is, however, still a need for improving therapies in focal seizures. Electroencephalogram follow-up prior to seizure-onset should be promoted for all infants with TSC in order to facilitate preventive or early treatment.

Keywords:  TOSCA; TSC; epilepsy; registry; tuberous sclerosis complex

DOI:  https://doi.org/10.3389/fneur.2021.697467
Int J Mol Sci. 2021 Sep 17. pii: 10058. [Epub ahead of print]22(18):

Synaptic Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders.

Grzegorz A Czapski, Lidia Babiec, Henryk Jęśko, Magdalena Gąssowska-Dobrowolska, Magdalena Cieślik, Marta Matuszewska, Małgorzata Frontczak-Baniewicz, Karolina Zajdel, Agata Adamczyk.

  Tuberous sclerosis complex (TSC) is a rare, multi-system genetic disease with serious neurological and mental symptoms, including autism. Mutations in the TSC1/TSC2 genes lead to the overactivation of mTOR signalling, which is also linked to nonsyndromic autism. Our aim was to analyse synaptic pathology in a transgenic model of TSC: two-month-old male B6;129S4-Tsc2tm1Djk/J mice with Tsc2 haploinsufficiency. Significant brain-region-dependent alterations in the expression of several synaptic proteins were identified. The most prominent changes were observed in the immunoreactivity of presynaptic VAMP1/2 (ca. 50% increase) and phospho-synapsin-1 (Ser62/67) (ca. 80% increase). Transmission electron microscopy demonstrated serious ultrastructural abnormalities in synapses such as a blurred structure of synaptic density and a significantly increased number of synaptic vesicles. The impairment of synaptic mitochondrial ultrastructure was represented by excessive elongation, swelling, and blurred crista contours. Polyribosomes in the cytoplasm and swollen Golgi apparatus suggest possible impairment of protein metabolism. Moreover, the delamination of myelin and the presence of vacuolar structures in the cell nucleus were observed. We also report that Tsc2+/- mice displayed increased brain weights and sizes. The behavioural analysis demonstrated the impairment of memory function, as established in the novel object recognition test. To summarise, our data indicate serious synaptic impairment in the brains of male Tsc2+/- mice.

Keywords:  animal model; autism; synaptic dysfunction; tuberous sclerosis complex

DOI:  https://doi.org/10.3390/ijms221810058
Clin Case Rep. 2021 Sep;9(9): e04821

First psychotic episode, related to COVID-19 pandemic, in a patient with tuberous sclerosis complex.

Lina Brahmi, Hanen Ben Ammar, Safa Messaoud, Ghada Hamdi, Emira Khelifa, Leila Mnif.

  Clinical symptoms of tuberous sclerosis may occur because of exposure to a stressful event like COVID-19. During pandemics, specific considerations should be deserved to the mental state of people suffering from genetic diseases to prevent mental illness caused by a coronavirus.

Keywords:  COVID‐19; Delusions; Psychotic disorder; Tuberous Sclerosis

DOI:  https://doi.org/10.1002/ccr3.4821
Biomolecules. 2021 Sep 18. pii: 1382. [Epub ahead of print]11(9):

Mechanistic Target of Rapamycin Complex 1 Signaling Links Hypoxia to Increased IGFBP-1 Phosphorylation in Primary Human Decidualized Endometrial Stromal Cells.

Pinki Nandi, Chloe E Jang, Kyle Biggar, Chidambra D Halari, Thomas Jansson, Madhulika B Gupta.

  Insulin-like growth factor-1 (IGF-1) bioavailability in pregnancy is governed by IGF binding protein (IGFBP-1) and its phosphorylation, which enhances the affinity of IGFBP-1 for the growth factor. The decidua is the predominant source of maternal IGFBP-1; however, the mechanisms regulating decidual IGFBP-1 secretion/phosphorylation are poorly understood. Using decidualized primary human endometrial stromal cells (HESCs) from first-trimester placenta, we tested the hypothesis that mTORC1 signaling mechanistically links hypoxia to decidual IGFBP-1 secretion/phosphorylation. Hypoxia inhibited mechanistic target of rapamycin (mTORC1) (p-P70-S6K/Thr389, -47%, p = 0.038; p-4E-BP1/Thr70, -55%, p = 0.012) and increased IGFBP-1 (total, +35%, p = 0.005; phosphorylated, Ser101/+82%, p = 0.018; Ser119/+88%, p = 0.039; Ser 169/+157%, p = 0.019). Targeted parallel reaction monitoring-mass spectrometry (PRM-MS) additionally demonstrated markedly increased dual IGFBP-1 phosphorylation (pSer98+Ser101; pSer169+Ser174) in hypoxia. IGFBP-1 hyperphosphorylation inhibited IGF-1 receptor autophosphorylation/ Tyr1135 (-29%, p = 0.002). Furthermore, silencing of tuberous sclerosis complex 2 (TSC2) activated mTORC1 (p-P70-S6K/Thr389, +68%, p = 0.038; p-4E-BP1/Thr70, +30%, p = 0.002) and reduced total/site-specific IGFBP-1 phosphorylation. Importantly, TSC2 siRNA prevented inhibition of mTORC1 and the increase in secretion/site-specific IGFBP-1 phosphorylation in hypoxia. PRM-MS indicated concomitant changes in protein kinase autophosphorylation (CK2/Tyr182; PKC/Thr497; PKC/Ser657). Overall, mTORC1 signaling mechanistically links hypoxia to IGFBP-1 secretion/phosphorylation in primary HESC, implicating decidual mTORC1 inhibition as a novel mechanism linking uteroplacental hypoxia to fetal growth restriction.

Keywords:  IGF Type 1; fetal development; humans; insulin-like growth factor I; placental insufficiency; receptor

DOI:  https://doi.org/10.3390/biom11091382
Annu Rev Pharmacol Toxicol. 2021 Sep 27.

Precision Medicine Approaches for Infantile-Onset Developmental and Epileptic Encephalopathies.

Kenneth A Myers, Ingrid E Scheffer.

Epilepsy is an etiologically heterogeneous condition; however, genetic factors are thought to play a role in most patients. For those with infantile-onset developmental and epileptic encephalopathy (DEE), a genetic diagnosis is now obtained in more than 50% of patients. There is considerable motivation to utilize these molecular diagnostic data to help guide treatment, as children with DEEs often have drug-resistant seizures as well as developmental impairment related to cerebral epileptiform activity. Precision medicine approaches have the potential to dramatically improve the quality of life for these children and their families. At present, treatment can be targeted for patients with diagnoses in many genetic causes of infantile-onset DEE, including genes encoding sodium or potassium channel subunits, tuberous sclerosis, and congenital metabolic diseases. Precision medicine may refer to more intelligent choices of conventional antiseizure medications, repurposed agents previously used for other indications, novel compounds, enzyme replacement, or gene therapy approaches. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-pharmtox-052120-084449
Int J Gynecol Pathol. 2021 Sep 29.

Uterine PEComatosis With TSC1 Mutation in a Patient With Tuberous Sclerosis: Case Report and Literature Review.

Shula A Schechter, Aaron M Udager, Stephanie L Skala.

Uterine PEComatosis is a rare phenomenon characterized by the presence of multiple perivascular epithelioid cell tumors (PEComas) and/or microscopic proliferations of perivascular epithelioid cells. Herein, we report a case of PEComatosis arising in a 49-yr-old woman with a known history of tuberous sclerosis. Targeted next-generation sequencing revealed a TSC1 stopgain mutation (p.Q732X) in all tested nodules, with single-copy TSC1 loss or copy-neutral TSC1 loss of heterozygosity. To our knowledge, this is the second report of TSC1 inactivation in uterine PEComa and the first report of confirmed TSC1 abnormalities in PEComatosis.

DOI: https://doi.org/10.1097/PGP.0000000000000827
Biochem Biophys Res Commun. 2021 Sep 20. pii: S0006-291X(21)01329-2. [Epub ahead of print]578 142-149

Persistent mTORC1 activation via Depdc5 deletion results in spontaneous hepatocellular carcinoma but does not exacerbate carcinogen- and high-fat diet-induced hepatic carcinogenesis in mice.

Lin Xu, Chenyan Yang, Jing Wang, Zun Li, Rong Huang, Honghui Ma, Jie Ma, Qingzhi Wang, Xiwen Xiong.

  The mechanistic target of rapamycin complex 1 (mTORC1) acts as a central regulator of metabolic pathways that drive cellular growth. Abnormal activation of mTORC1 occurs at high frequency in human and mouse hepatocellular carcinoma (HCC). DEP domain-containing protein 5 (DEPDC5), a component of GATOR1 complex, is a repressor of amino acid-sensing branch of the mTORC1 pathway. In the current study, we found that persistent activation of hepatic mTORC1 signaling caused by Depdc5 ablation was sufficient to induce a pathological program of liver damage, inflammation and fibrosis that triggers spontaneous HCC development. Take advantage of the combinatory treatment with a single dose of diethylnitrosamine (DEN) and chronic feeding with high-fat diet (HFD), we demonstrated that hepatic depdc5 deletion did not aggravate DEN&HFD induced liver tumorigenesis, probably due to its protective effects on diet-induced liver steatosis. In addition, we further showed that chronic rapamycin treatment did not have any apparent tumor-suppressing effects on DEN&HFD treated control mice, whereas it dramatically reduced the tumor burden in mice with hepatic Depdc5 ablation. This study provides the novel in vivo evidence for Depdc5 deletion mediated mTORC1 hyperactivation in liver tumorigenesis caused by aging or DEN&HFD treatment. Moreover, our findings also propose that pharmacological inhibition of mTORC1 signaling maybe a promising strategy to treat HCC patients with mutations in DEPDC5 gene.

Keywords:  DEPDC5; Diethylnitrosamine (DEN); Hepatocellular carcinoma (HCC); High-fat diet (HFD); Liver; mTORC1

DOI:  https://doi.org/10.1016/j.bbrc.2021.09.036