Złośliwość guzowata – Etiologia i przyczyny

Złośliwość guzowata
Etiologia i przyczyny

Złośliwość guzowata (TSC) to autosomalnie dominująca choroba genetyczna wywołana mutacjami w genach TSC1 (chromosom 9q34) lub TSC2 (chromosom 16p13.3), kodujących białka hamartynę i tuberynę. Mutacje te prowadzą do dysfunkcji kompleksu TSC1/TSC2, co skutkuje nadmierną aktywacją szlaku mTORC1, zwiększoną proliferacją komórek i hamowaniem autofagii, sprzyjając powstawaniu mnogich hamartomów w mózgu, nerkach, sercu, płucach i skórze. Mutacje TSC2, stanowiące 55-90% przypadków, wiążą się z cięższym przebiegiem choroby. Diagnostyka molekularna wykrywa mutacje u 80-85% pacjentów, a u pozostałych 15-20% mutacje mogą pozostać niewykryte. Choroba charakteryzuje się zmienną ekspresją i niepełną penetracją, a mechanizm „drugiego uderzenia” (two-hit hypothesis) wyjaśnia rozwój guzów po wtórnej mutacji allelu. W około 2/3 przypadków TSC jest wynikiem mutacji de novo, a ryzyko dziedziczenia wynosi 50% przy obecności mutacji u rodzica. Mozaicyzm gonadalny może zwiększać ryzyko u potomstwa nawet przy braku objawów u rodziców.

Etiologia złośliwości guzowatej

Podstawy genetyczne
Mechanizm molekularny
Dziedziczenie TSC
Hipoteza „drugiego uderzenia”
Badania genetyczne i modele zwierzęce
Zmienność ekspresji i penetracja
Czynniki środowiskowe

Implikacje diagnostyczne i terapeutyczne

Perspektywy badawcze
Podsumowanie etiologii
Kolejne rozdziały

Etiologia złośliwości guzowatej

Złośliwość guzowata (tuberous sclerosis complex, TSC) to rzadka choroba genetyczna charakteryzująca się występowaniem mnogich, niezłośliwych guzów (hamartomów) w różnych narządach, w tym w mózgu, skórze, nerkach, sercu, płucach i wątrobie. Choroba jest wynikiem mutacji genetycznych i ma zróżnicowany obraz kliniczny o różnym stopniu nasilenia.¹²

Podstawy genetyczne

Złośliwość guzowata jest spowodowana mutacjami w jednym z dwóch genów: TSC1 lub TSC2. Gen TSC1, zlokalizowany na chromosomie 9q34, został odkryty w 1997 roku i koduje białko hamartynę. Gen TSC2, zlokalizowany na chromosomie 16p13.3, został odkryty w 1993 roku i koduje białko tuberynę.³⁴ Mutacje w którymkolwiek z tych genów mogą prowadzić do wystąpienia objawów klinicznych TSC. Badania molekularne wykazały, że istnieje ponad 450 różnych mutacji w genie TSC1 i ponad 1300 w genie TSC2, przy czym większość mutacji w TSC1 to mutacje skracające (nonsensowne, przesunięcia ramki odczytu i mutacje splicingowe).⁵

Aktualne technologie badań genetycznych pozwalają na wykrycie mutacji TSC1 lub TSC2 u około 80-85% osób ze zdiagnozowaną TSC na podstawie kryteriów klinicznych. U pozostałych 15-20% pacjentów mutacja może nie zostać wykryta, co nie wyklucza diagnozy.⁶⁷

Mechanizm molekularny

Na poziomie molekularnym, białka hamartyna i tuberyna tworzą kompleks hamujący szlak mTOR (mammalian target of rapamycin), który odgrywa kluczową rolę w regulacji wzrostu i podziału komórek. Gdy geny TSC1 lub TSC2 ulegają mutacji, powstające białka nie funkcjonują prawidłowo, co prowadzi do nadmiernej aktywacji szlaku mTOR.⁸⁹

W normalnych warunkach kompleks TSC1/TSC2 działa jako supresor nowotworowy, hamując białko Rheb, które z kolei aktywuje kompleks mTORC1. Gdy kompleks TSC1/TSC2 nie funkcjonuje prawidłowo z powodu mutacji, dochodzi do hiperaktywacji mTORC1, co prowadzi do zwiększonej proliferacji komórek, zahamowania autofagii i promowania anabolicznego metabolizmu. Te zmiany sprzyjają tworzeniu się guzów w różnych narządach.¹⁰¹¹

Badania wykazały również, że mutacje w genie TSC2 są związane z cięższym przebiegiem choroby niż mutacje w genie TSC1. Szacuje się, że mutacje TSC2 stanowią około 55-90% wszystkich przypadków TSC.¹²¹³¹⁴

Dziedziczenie TSC

Złośliwość guzowata dziedziczy się w sposób autosomalny dominujący, co oznacza, że jeden zmutowany allel jest wystarczający do wystąpienia choroby. W przypadku rodzica z TSC, każde dziecko ma 50% szans na odziedziczenie zmutowanego genu i rozwój choroby.¹⁵¹⁶

Jednakże w około 2/3 przypadków TSC występuje jako wynik nowej, spontanicznej mutacji, czyli bez wcześniejszej historii rodzinnej. Oznacza to, że u większości pacjentów z TSC żadne z rodziców nie ma tej choroby.¹⁷¹⁸ Pozostała 1/3 przypadków to dziedziczenie od rodzica z TSC.¹⁹

Interesujące jest, że nawet gdy rodzice nie wykazują klinicznych objawów TSC, istnieje niewielkie (około 1-2%) ryzyko posiadania kolejnego dziecka z tą chorobą. Wynika to z występowania mozaicyzmu gonadalnego, gdzie mutacja występuje tylko w komórkach rozrodczych jednego z rodziców.²⁰²¹

Hipoteza „drugiego uderzenia”

W rozwoju guzów w TSC istotną rolę odgrywa również mechanizm znany jako hipoteza „drugiego uderzenia” (two-hit hypothesis). Zgodnie z tą teorią, pierwszym „uderzeniem” jest dziedziczna lub spontaniczna mutacja w jednym allelu genu TSC1 lub TSC2. Objawy kliniczne i/lub tworzenie się guzów występują dopiero po kolejnej mutacji lub inaktywacji drugiego, wcześniej niezmienionego allelu (drugie „uderzenie”).²²²³

Badania molekularne potwierdzają, że rozwój guzów w TSC zależy od wielu takich „drugich uderzeń”, które prowadzą do powstawania licznych zmian, np. w nerkach. Niektóre z tych wtórnych mutacji mogą być indukowane przez czynniki środowiskowe, takie jak promieniowanie ultrafioletowe w przypadku naczyniakowłókniaków skóry.²⁴

Badania genetyczne i modele zwierzęce

Postęp w badaniach nad etiologią TSC jest możliwy dzięki rozwojowi technik genetycznych oraz tworzeniu zwierzęcych modeli choroby. Dr Bordey i jej zespół badawczy opracowali model mysi TSC, w którym wyłączenie genu Tsc1 w wybranych grupach neuronów u myszy embrionalnych z już istniejącym zmutowanym allelem Tsc1 (Tsc1flox/mutant) prowadzi do rozwoju zmian podobnych do guzów korowych obserwowanych u ludzi.²⁵

Dzięki temu modelowi zidentyfikowano kilka białek, takich jak czynnik indukowany hipoksją 1 (Hif1a), które są nieprawidłowo regulowane w TSC. Wyniki te sugerują, że Hif1a może odgrywać ważną rolę w formowaniu zmian w TSC. Dalsze badania mają na celu identyfikację dodatkowych białek nieprawidłowo regulowanych w TSC oraz określenie, czy przywrócenie normalnego poziomu Hif1a lub innych cząsteczek może zapobiec powstawaniu zmian w TSC.²⁶²⁷

Zmienność ekspresji i penetracja

TSC charakteryzuje się zmienną ekspresją i niekompletną penetracją. Oznacza to, że nawet w obrębie tej samej rodziny, gdzie występuje ta sama mutacja, objawy kliniczne mogą znacznie się różnić pod względem liczby, lokalizacji i wielkości guzów oraz stopnia zaawansowania choroby.²⁸²⁹

Ta zmienność może być wyjaśniona przez kilka czynników, w tym dodatkowe modyfikacje genetyczne i epigenetyczne, a także mozaicyzm. W rzadkich przypadkach możliwa jest również niepełna penetracja, gdy nie wszyscy nosiciele zmutowanego genu rozwijają objawy choroby.³⁰

Czynniki środowiskowe

Choć złośliwość guzowata jest przede wszystkim chorobą genetyczną, niektórzy badacze badają potencjalne czynniki środowiskowe, które mogą wpływać na nasilenie objawów lub prawdopodobieństwo rozwoju powikłań związanych z TSC. Czynniki takie jak ekspozycja prenatalna na niektóre leki lub toksyny mogą odgrywać rolę, choć potrzebne są dalsze badania, aby ustalić jednoznaczne związki.³¹

Ważne jest podkreślenie, że nie ma dowodów na to, by czynniki środowiskowe, takie jak dieta lub narażenie na toksyny, były bezpośrednimi przyczynami TSC. Choroba jest wynikiem wyłącznie mutacji genetycznych w genach TSC1 lub TSC2.³²³³

Implikacje diagnostyczne i terapeutyczne

Zrozumienie podłoża genetycznego TSC ma istotne znaczenie dla diagnostyki i leczenia. Mutacje w genach TSC1 i TSC2 prowadzą do nadmiernej aktywacji szlaku mTOR, co stało się podstawą terapii celowanej. Inhibitory mTOR, takie jak ewerolimus i sirolimus, zostały zatwierdzone do leczenia określonych powikłań związanych z TSC, takich jak angiomiolipoma nerek i podwyściółkowe gwiaździaki olbrzymiokomórkowe mózgu (SEGA).³⁴³⁵

Badania genetyczne są również ważne dla poradnictwa genetycznego. Dla par z osobistą lub rodzinną historią TSC, które planują potomstwo, dostępna jest diagnostyka prenatalna dla rodzin ze znanym wariantem genu lub historią tego schorzenia. Jednak w większości przypadków TSC pojawia się jako nowa mutacja DNA, której nie można zapobiec.³⁶³⁷

Perspektywy badawcze

Badania nad etiologią TSC nadal trwają. Poza tradycyjnym podejściem skupiającym się na genach TSC1 i TSC2, naukowcy badają również dodatkowe proteiny i szlaki sygnałowe, które mogą być zaangażowane w patogenezę choroby. Złośliwość guzowata została również powiązana z białkiem zwanym naczyniowo-nabłonkowym czynnikiem wzrostu D (VEGF-D), szczególnie w przypadku zmian takich jak limfangioleiomiomatoza i angiomiolipomy nerek.³⁸

Ponadto, zespół badawczy odkrył, że część białka TSC1, tzw. domena, może wiązać się z powierzchniami błon lizosomalnych, a mutacje występują szczególnie często w domenie wiążącej błony. Badacze zakładają, że niektóre z patogennych efektów można teraz wyjaśnić utratą prawidłowej lokalizacji kompleksu TSC.³⁹

Podsumowanie etiologii

Złośliwość guzowata to złożona choroba genetyczna spowodowana mutacjami w genach TSC1 lub TSC2, które prowadzą do nieprawidłowej regulacji szlaku mTOR i niekontrolowanego wzrostu komórek. Choroba może być dziedziczona w sposób autosomalny dominujący, ale w większości przypadków jest wynikiem spontanicznych mutacji. Zrozumienie genetycznego podłoża TSC przyczyniło się do rozwoju terapii celowanych i umożliwiło lepszą diagnostykę i poradnictwo genetyczne.⁴⁰⁴¹

Dalsze badania nad etiologią TSC są niezbędne do opracowania skuteczniejszych strategii leczenia i potencjalnie zapobiegania powikłaniom tej choroby. Szczególnie ważne jest zrozumienie mechanizmów, które prowadzą do różnorodności objawów klinicznych oraz identyfikacja dodatkowych czynników modyfikujących, które mogą wpływać na przebieg choroby.⁴²⁴³

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Materiały źródłowe

#1 Tuberous sclerosis – Wikipedia
https://en.wikipedia.org/wiki/Tuberous_sclerosis
Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. […] TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin, respectively, with TSC2 mutations accounting for the majority and tending to cause more severe symptoms. […] TSC is a genetic disorder with an autosomal dominant pattern of inheritance, variable expressivity, and incomplete penetrance. […] Two-thirds of TSC cases result from sporadic genetic mutations, not inheritance, but their offspring may inherit it from them. […] Current genetic tests have difficulty locating the mutation in roughly 20% of individuals diagnosed with the disease.
#2 Tuberous Sclerosis | UVA Health
https://uvahealth.com/services/neurocutaneous/tuberous-sclerosis
Tuberous sclerosis, also called tuberous sclerosis complex (TSC), is a genetic, life-long condition that causes lesions and benign tumors in your organs (mainly the brain, eyes, heart, kidney, skin and lungs). […] Two genes have been identified as the cause of tuberous sclerosis: TSC1 and TSC2. It only takes a mutation in one of these genes for tuberous sclerosis to develop. You may have inherited the mutated gene from one of your parents. However, in most cases, tuberous sclerosis doesn’t appear to be inherited.
#3 Genetics of Tuberous Sclerosis: Practice Essentials, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/951002-overview
Tuberous sclerosis complex (TSC) is inherited in an autosomal dominant pattern, although the rate of spontaneous mutation is high. […] Mutations in either of two genes (TSC1 and TSC2) have been determined to cause tuberous sclerosis complex; however, diagnosis continues to be based on clinical manifestations. […] The genes responsible for tuberous sclerosis complex have been identified. In 1993, TSC2, located on chromosome 16, was the first gene discovered to be involved in tuberous sclerosis complex. TSC1 is located on chromosome 9 and was identified in 1997. TSC1 encodes for the protein hamartin; TSC2, encodes for the protein tuberin. Mutations in either TSC1 or TSC2, which are tumor suppressor genes that work together to facilitate tumor suppression, cause tuberous sclerosis complex.
#4 Tuberous sclerosis – Wikipedia
https://en.wikipedia.org/wiki/Tuberous_sclerosis
TSC1 encodes for the protein hamartin, is located on chromosome 9 q34, and was discovered in 1997. TSC2 encodes for the protein tuberin, is located on chromosome 16 p13.3, and was discovered in 1993. […] TSC2 has been associated with a more severe form of TSC. […] However, the difference is subtle and cannot be used to identify the mutation clinically. Estimates of the proportion of TSC caused by TSC2 range from 55% to 90%. […] TSC1 and TSC2 are both tumor suppressor genes that function according to Knudson’s „two hit” hypothesis.
#5 Genetics of Tuberous Sclerosis: Practice Essentials, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/951002-overview
More than 450 different disease-causing mutations are known for TSC1, and more than 1300 for TSC2, with most of TSC1 mutations being truncating comprising frameshift, nonsense, and splice mutations. […] Molecular studies suggest that tumor development relies on second-hit events, ie, a storm of them, to produce multifocal renal cell carcinoma in tuberous sclerosis complex. […] Angiofibromas may result from ultraviolet ray-induced mutations.
#6 Oral and skin manifestations of tuberous sclerosis complex | Journal of Oral Medicine and Oral Surgery
https://www.jomos.org/articles/mbcb/full_html/2019/04/mbcb180028/mbcb180028.html
Tuberous sclerosis complex is a genetic disease characterized by multisystemic hamartomas with variable and non-specific clinical manifestations. The disease is associated with mutations of genes encoding the proteins hamartin and tuberin. […] Tuberous sclerosis belongs to the group of classical phacomatoses with neurofibromatosis types 1 and 2, Sturge-Weber-Krabbe syndrome, Von Hippel-Lindau disease, and various neuroectodermal dysembryoplasias. It is an autosomal dominant genetic disease with almost complete penetrance; however, two-thirds of individuals develop the disease following pathogenic de novo variation. […] The disease is associated with a pathogenic mutation of two genes. However, despite the advances in diagnostic techniques, no mutation is detected in 15%20% of the cases, not excluding diagnosis. In 31% of the patients, a mutation is identified in the tuberous sclerosis complex 1 gene (TSC1) located on chromosome 9 (9q34), and in 69% of the patients, a mutation is identified the TSC2 gene located on chromosome 16 (16p13.3). […] The presence of pathogenic mutations of the TSC1 or TSC2 genes allows for a definitive diagnosis of tuberous sclerosis, independent of the associated clinical manifestations.
#7 Facts about TSC: – The Tuberous Sclerosis Association
https://tuberous-sclerosis.org/facts-about-tsc/
1. TSC is genetic disorder that causes tumors to form in vital organs. […] Patient organisation-funded research led to the identification of two genes that cause TSC; these genes are called TSC1 and TSC2. […] Current molecular testing for TSC identifies a TSC1 or TSC2 mutation in up to 85% of individuals with a definite diagnosis of TSC by clinical criteria. […] About 1/3 of the time, when a child is diagnosed with TSC, one of the parents also has TSC. The remaining 2/3 of diagnoses occur due to spontaneous mutation (we donât know why). […] If a parent is affected, his or her children have a 50% chance of inheriting the TSC gene. […] If parents are unaffected, the chance of a sibling of someone diagnosed with TSC also having TSC is 1-2%.
#8 Tuberous Sclerosis Complex | National Institute of Neurological Disorders and Stroke
https://www.ninds.nih.gov/health-information/disorders/tuberous-sclerosis-complex
TSC is caused by variants (or mutations) in either the TSC1 or TSC2 gene. These genes provide instructions for making the proteins hamartin and tuberin, which help regulate cell growth and division. Scientists believe hamartin and tuberin help stop cell growth by silencing or interfering with the function of another protein called mTOR, which also plays a key role in cell growth. When mTOR is not regulated properly, abnormal cell development can lead to the production of enlarged cells like the ones seen in TSC brain lesions. […] Most cases of TSC are sporadic (developing on their own) due to new, spontaneous variations in TSC1 or TSC2 meaning neither parent has the disorder or the genetic variation(s). […] Some cases of TSC are inherited, meaning the mutated gene is passed down from a parent to their child. The inheritance is in an autosomal dominant pattern, meaning a person only needs to inherit one copy of the affected gene from either parent to have the disease. Children who inherit TSC may not have the same symptoms as their parent and may have either a milder or more severe form of the condition. […] In rare instances, people may get TSC through a process called gonadal mosaicism. Even without a parent with mutations in the TSC1 or TSC2 genes, the child may have TSC because some of one parent’s reproductive cells contains the genetic mutation without the other cells of the body being involved.
#9
https://www.tscinternational.org/what-is-tsc/
Both the TSC1 and TSC2 genes suppress tumor growth in the body by carefully regulating cell growth through inhibition of a protein called mammalian target of rapamycin, or mTOR for short. When either the TSC1 or TSC2 gene is defective, cell growth is not adequately supressed and tuberous sclerosis complex results. Hamartin, tuberin, and mTOR are expressed in many different organs throughout the body, which explains why so many organs can be affected by TSC. However, researchers are still working diligently to figure out why TSC is manifested so differently between different people.
#10 Tuberous Sclerosis | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/30666
TSC1/TSC2 mutations inactivate the inhibitory TSC protein complex, allowing aberrant activation of the mTOR pathways. The role of mTOR is to regulate cell growth and metabolism through the multimeric complexes mTORC1 and mTORC2. The complex mTORC1 integrates inputs from growth factors, amino acids, energy status, and hypoxia stressors to phosphorylate p70S6K and 4E-BP1 and promote cell proliferation. Without the TSC protein complex, the RAS homolog Rheb hyperactivates mTORC1. This reprogramming inhibits autophagy and favors anaerobic glycolysis. Therefore, mTORC1 aids solid tumor formation. […] About 75% to 90% of patients with SC carry a mutation in TSC1 or TSC2, which encodes the proteins hamartin and tuberin, which are inhibitor complexes considered to be tumor suppressor genes. Mutations in these proteins cause benign brain, skin, lung, heart, liver, and kidney hamartomas.
#11 Tuberous sclerosis complex | MedLink Neurology
https://www.medlink.com/handouts/tuberous-sclerosis
TSC is caused by defects, or mutations, on two genes TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. […] Scientists believe these proteins act as growth suppressors by inhibiting the activation of a protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions. […] Although some individuals inherit the disorder from a parent with TSC, most cases occur as sporadic cases due to new, spontaneous mutations in TSC1 or TSC2 meaning neither parent has the disorder or the faulty gene(s). Instead, a faulty gene first occurs in the affected individual. […] In cases where TSC is inherited, only one parent needs to have the faulty gene in order to pass it on to a child (called autosomal dominant inheritance). If a parent has TSC, each child has a 50 percent chance of developing the disorder.
#12 Tuberous sclerosis – Wikipedia
https://en.wikipedia.org/wiki/Tuberous_sclerosis
TSC1 encodes for the protein hamartin, is located on chromosome 9 q34, and was discovered in 1997. TSC2 encodes for the protein tuberin, is located on chromosome 16 p13.3, and was discovered in 1993. […] TSC2 has been associated with a more severe form of TSC. […] However, the difference is subtle and cannot be used to identify the mutation clinically. Estimates of the proportion of TSC caused by TSC2 range from 55% to 90%. […] TSC1 and TSC2 are both tumor suppressor genes that function according to Knudson’s „two hit” hypothesis.
#13 Tuberous Sclerosis Complex: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/1177711-overview
Further complicating the high spontaneous mutation rate is the observation that parents of an affected child, who themselves show no sign of TSC, nonetheless have an increased risk (approximately 2% overall) of having additional affected children. This is thought to result from parental mosaicism for one of the TSC genes limited to cells of their germ line (ie, gonadal tissues). True failure of penetrance of the TSC genes is believed to be rare. […] Research has identified phenotypic differences as they may relate to particular genotypes. Linkage studies initially suggested a roughly equal distribution of TSC1 and TSC2 mutations among affected individuals. However, subsequent mutational analysis has shown TSC2 mutations to be present in 80-90% of affected individuals, while TSC1 mutations are present in 10-20%.
#14 Tuberous sclerosis complex — Knowledge Hub
https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/tuberous-sclerosis-complex/
Tuberous sclerosis complex (TSC) is a rare, highly variable genetic condition characterised by the growth of benign tumours in the skin, brain, heart, kidneys, lungs and bones. […] It is caused by constitutional pathogenic variants in either of the tumour suppressor genes: TSC1 or TSC2. […] TSC is caused by heterozygous loss-of-function pathogenic variants in either the TSC2 or TSC1 gene, which result in constitutive activation of the mTOR pathway and cause benign tumour growth in multiple organs and neuropsychiatric symptoms. […] Pathogenic variants in the TSC2 gene are the cause of most cases of TSC, and typically result in a more severe phenotype. […] Incomplete penetrance can occur when not everyone who has the variant develops the disease.
#15 Tuberous Sclerosis – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK538492/
Tuberous sclerosis complex arises from mutations in the genes TSC1 (9q34) or TSC2(16p13.3), encoding hamartin and tuberin, respectively. A broad spectrum of mutations has been described in both genes and while no particular regions seem more liable to mutations, the frequency is consistently higher for TSC2 than TSC1. Among patients who meet the clinical criteria for tuberous sclerosis, approximately 15% have no identifiable genetic mutations. […] There are 2 specific gene mutations: TSC1 mutation occurs on chromosome 9 and is related to hamartin protein production. TSC2 is on chromosome 16 and affects tuberin protein production. These genes are thought to cause the characteristic tumors of the condition. The gene mutation may be inherited or may occur spontaneously. Most cases present sporadically, with no known family history, but approximately 1 in 3 patients inherit a defective TSC1 or TSC2 gene. If a parent has tuberous sclerosis, their children will carry a 50% risk of inheriting the disease. Because it follows an autosomal dominant inheritance pattern, and men and women are equally affected.
#16
https://www.nhs.uk/conditions/tuberous-sclerosis/
Tuberous sclerosis is caused by changes (mutations) in either the TSC1 or TSC2 gene. These genes are involved in regulating cell growth, and the mutations lead to uncontrolled growth and multiple tumours throughout the body. […] In around 3 in every 4 cases, the genetic fault occurs for no apparent reason in people without any other affected family members. […] In the remaining 1 in 4 cases, the fault is passed on to a child by their parents. Only one parent needs to carry the faulty gene to pass it on, and a parent who has one of the faulty genes has a 1 in 2 chance of passing it on to each child they have. […] The parent carrying the faulty gene will also have tuberous sclerosis, although sometimes it may be so mild they do not realise.
#17 Tuberous sclerosis // Middlesex Health
https://middlesexhealth.org/learning-center/diseases-and-conditions/tuberous-sclerosis
Tuberous sclerosis is a genetic disorder caused by gene changes sometimes called mutations in either the TSC1 or the TSC2 gene. These genes are thought to prevent cells from growing too fast or in an out-of-control way. Changes in either of these genes can cause cells to grow and divide more than needed. This leads to multiple growths throughout the body. These growths are considered noncancerous tumors. […] About two-thirds of people who have tuberous sclerosis have a new change in either the TSC1 or the TSC2 gene linked with tuberous sclerosis. Most people do not have a family history of tuberous sclerosis. […] About one-third of people who have tuberous sclerosis get a changed TSC1 or TSC2 gene from a parent who has the disorder.
#18 Tuberous Sclerosis Complex | National Institute of Neurological Disorders and Stroke
https://www.ninds.nih.gov/health-information/disorders/tuberous-sclerosis-complex
TSC is caused by variants (or mutations) in either the TSC1 or TSC2 gene. These genes provide instructions for making the proteins hamartin and tuberin, which help regulate cell growth and division. Scientists believe hamartin and tuberin help stop cell growth by silencing or interfering with the function of another protein called mTOR, which also plays a key role in cell growth. When mTOR is not regulated properly, abnormal cell development can lead to the production of enlarged cells like the ones seen in TSC brain lesions. […] Most cases of TSC are sporadic (developing on their own) due to new, spontaneous variations in TSC1 or TSC2 meaning neither parent has the disorder or the genetic variation(s). […] Some cases of TSC are inherited, meaning the mutated gene is passed down from a parent to their child. The inheritance is in an autosomal dominant pattern, meaning a person only needs to inherit one copy of the affected gene from either parent to have the disease. Children who inherit TSC may not have the same symptoms as their parent and may have either a milder or more severe form of the condition. […] In rare instances, people may get TSC through a process called gonadal mosaicism. Even without a parent with mutations in the TSC1 or TSC2 genes, the child may have TSC because some of one parent’s reproductive cells contains the genetic mutation without the other cells of the body being involved.
#19 Tuberous Sclerosis: What It Is, Symptoms & Treatment
https://my.clevelandclinic.org/health/diseases/17586-tuberous-sclerosis
TSC is a genetic disease, meaning it happens because of DNA mutations. Most cells in your body reproduce and create their replacements. Your body controls this process using tumor-suppressing proteins. […] The mutations that cause TSC can happen in two ways: Sporadic: These are mutations that happen accidentally just after conception (when a sperm fertilizes an egg and becomes an embryo). This is a new error, similar to a misprint or a typo. Sporadic cases are more common than inherited cases. […] Inherited: About one-third of TSC cases happen when a child inherits it from a parent.
#20 Tuberous sclerosis complex | MedLink Neurology
https://www.medlink.com/handouts/tuberous-sclerosis
In rare instances, people acquire TSC through a process called gonadal mosaicism. These individuals have parents with no apparent defects in the two genes that cause the disorder. Yet these parents can have a child with TSC because a portion of one of the parent’s reproductive cells (sperm or eggs) can contain the genetic mutation without the other cells of the body being involved.
#21 Facts about TSC: – The Tuberous Sclerosis Association
https://tuberous-sclerosis.org/facts-about-tsc/
1. TSC is genetic disorder that causes tumors to form in vital organs. […] Patient organisation-funded research led to the identification of two genes that cause TSC; these genes are called TSC1 and TSC2. […] Current molecular testing for TSC identifies a TSC1 or TSC2 mutation in up to 85% of individuals with a definite diagnosis of TSC by clinical criteria. […] About 1/3 of the time, when a child is diagnosed with TSC, one of the parents also has TSC. The remaining 2/3 of diagnoses occur due to spontaneous mutation (we donât know why). […] If a parent is affected, his or her children have a 50% chance of inheriting the TSC gene. […] If parents are unaffected, the chance of a sibling of someone diagnosed with TSC also having TSC is 1-2%.
#22 Tuberous Sclerosis Complex: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/1177711-overview
Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder affecting cellular differentiation, proliferation, and migration early in development, resulting in a variety of hamartomatous lesions that may affect virtually every organ system of the body. It is associated with two genetic loci: TSC1, located on chromosome 9q34, and TSC2, located on chromosome 16p13. Mutations in either of these genes can lead to the clinical phenotype. […] Clinically, tuberous sclerosis complex (TSC) exhibits an autosomal-dominant inheritance pattern, with a high spontaneous mutation rate. Two distinct genetic loci responsible for TSC have been identified: one on chromosome band 9q34 (also referred to as TSC1) and another on chromosome band 16p13 (TSC2). […] The high incidence of sporadic TSC, coupled with a probable „second hit” phenomenon, seems a likely explanation for the marked phenotypic variability observed. The second hit hypothesis suggests that in addition to an inherited or sporadic autosomal mutation in one allele of either TSC1 or TSC2, clinical signs and/or symptoms manifest only after a further mutation or inactivating event in the second, unaffected allele (second hit).
#23 Tuberous sclerosis complex: MedlinePlus GeneticsLock
https://medlineplus.gov/genetics/condition/tuberous-sclerosis-complex/
Tuberous sclerosis complex is a genetic disorder characterized by the growth of numerous noncancerous (benign) tumors in many parts of the body. […] Variants (also known as mutations) in the TSC1 or TSC2 gene can cause tuberous sclerosis complex. […] People with tuberous sclerosis complex are born with one altered copy of the TSC1 gene or the TSC2 gene in each cell. […] For tumors to develop in tuberous sclerosis complex, a second change involving the other copy of the TSC1 or TSC2 gene must occur in cells during a person’s lifetime. […] In people with tuberous sclerosis complex, a second variant in the TSC1 or TSC2 gene typically occurs in multiple cells over an affected person’s lifetime. […] Tuberous sclerosis complex has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing tumors and other problems with development. […] Rarely, individuals with tuberous sclerosis complex do not have an identified variant in the TSC1 or TSC2 gene.
#24 Genetics of Tuberous Sclerosis: Practice Essentials, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/951002-overview
More than 450 different disease-causing mutations are known for TSC1, and more than 1300 for TSC2, with most of TSC1 mutations being truncating comprising frameshift, nonsense, and splice mutations. […] Molecular studies suggest that tumor development relies on second-hit events, ie, a storm of them, to produce multifocal renal cell carcinoma in tuberous sclerosis complex. […] Angiofibromas may result from ultraviolet ray-induced mutations.
#25 2013 Tuberous Sclerosis Complex Highlight – Understanding the Etiology of Tuberous Sclerosis Complex, Tuberous Sclerosis Complex Research Program, Congressionally Directed Medical Research Programs
https://cdmrp.health.mil/tscrp/research_highlights/14bordey_highlight
Tuberous sclerosis complex (TSC) is a genetic disorder resulting from mutations in TSC1 or TSC2 genes. […] Currently, there is no cure for TSC, and the mechanisms leading to TSC brain lesions and the subsequent development of neurological symptoms are not well defined. […] Dr. Bordey demonstrated that the knockout of Tsc1 in select groups of neurons in embryonic mice already carrying a mutant Tsc1 allele (Tsc1flox/mutant) led to the development of cortical tuber-like lesions that share many characteristics with the cortical lesions seen in the human disease. […] Using this mouse model, Dr. Bordey and her research team have identified several proteins, such as hypoxia inducible factor 1 (Hif1a), which are abnormally regulated in TSC. […] These results suggest that Hif1a may play an important role in the formation of lesions in TSC. […] Future research by Dr. Bordey and her team will attempt to identify additional proteins that are abnormally regulated in TSC and also determine whether or not restoring Hif1a or other molecules to normal levels can prevent the formation of lesions in TSC.
#26 2013 Tuberous Sclerosis Complex Highlight – Understanding the Etiology of Tuberous Sclerosis Complex, Tuberous Sclerosis Complex Research Program, Congressionally Directed Medical Research Programs
https://cdmrp.health.mil/tscrp/research_highlights/14bordey_highlight
Tuberous sclerosis complex (TSC) is a genetic disorder resulting from mutations in TSC1 or TSC2 genes. […] Currently, there is no cure for TSC, and the mechanisms leading to TSC brain lesions and the subsequent development of neurological symptoms are not well defined. […] Dr. Bordey demonstrated that the knockout of Tsc1 in select groups of neurons in embryonic mice already carrying a mutant Tsc1 allele (Tsc1flox/mutant) led to the development of cortical tuber-like lesions that share many characteristics with the cortical lesions seen in the human disease. […] Using this mouse model, Dr. Bordey and her research team have identified several proteins, such as hypoxia inducible factor 1 (Hif1a), which are abnormally regulated in TSC. […] These results suggest that Hif1a may play an important role in the formation of lesions in TSC. […] Future research by Dr. Bordey and her team will attempt to identify additional proteins that are abnormally regulated in TSC and also determine whether or not restoring Hif1a or other molecules to normal levels can prevent the formation of lesions in TSC.
#27 Understanding the Etiology of Tuberous Sclerosis Complex
https://apps.dtic.mil/sti/html/tr/ADA566455/index.html
Tuberous Sclerosis Complex TSC is a genetic multisystem disorder characterized by severe neurological symptoms e.g. seizures, which are the most significant causes of disability and morbidity. Presently, there are no known cures for TSC and the etiology of the disease is not well understood, perhaps due to the lack of model system to study this disorder. […] In TSC patients, mutations in Tsc1 or Tsc2, result in the formation of lesions. The mechanisms leading to TSC lesions and associated seizure generation during perinatal life remain unclear in the absence of an animal model of TSC lesions. […] Using a novel technical approach i.e. in vivo electroporation in mice with conditional and mutant alleles we generated the first TSC animal model that replicates the discrete cortical lesions seen in humans. We have gathered information on the mechanisms of lesion formation and cortical hyperexcitability.
#28 Tuberous sclerosis – Wikipedia
https://en.wikipedia.org/wiki/Tuberous_sclerosis
Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. […] TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin, respectively, with TSC2 mutations accounting for the majority and tending to cause more severe symptoms. […] TSC is a genetic disorder with an autosomal dominant pattern of inheritance, variable expressivity, and incomplete penetrance. […] Two-thirds of TSC cases result from sporadic genetic mutations, not inheritance, but their offspring may inherit it from them. […] Current genetic tests have difficulty locating the mutation in roughly 20% of individuals diagnosed with the disease.
#29 Tuberous sclerosis complex — Knowledge Hub
https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/tuberous-sclerosis-complex/
Tuberous sclerosis complex (TSC) is a rare, highly variable genetic condition characterised by the growth of benign tumours in the skin, brain, heart, kidneys, lungs and bones. […] It is caused by constitutional pathogenic variants in either of the tumour suppressor genes: TSC1 or TSC2. […] TSC is caused by heterozygous loss-of-function pathogenic variants in either the TSC2 or TSC1 gene, which result in constitutive activation of the mTOR pathway and cause benign tumour growth in multiple organs and neuropsychiatric symptoms. […] Pathogenic variants in the TSC2 gene are the cause of most cases of TSC, and typically result in a more severe phenotype. […] Incomplete penetrance can occur when not everyone who has the variant develops the disease.
#30 Orphanet: Tuberous sclerosis complex
https://www.orpha.net/en/disease/detail/805
TSC is due to mutations in either TSC1(9q34) or TSC2 (16p13.3) which encode proteins that indirectly inhibit the mTOR pathway. […] Expressivity of TSC is variable due to mosaicism and to genetic-epigenetic modifiers.
#31 Tuberous Sclerosis Complex: Understanding Symptoms, Causes, and Treatments â¢ Yesil Health
https://yesilhealth.com/your-health/tuberous-sclerosis-complex-understanding-symptoms-causes-and-treatments/
While TSC is primarily a genetic disorder, some researchers are exploring potential environmental factors that may contribute to the severity of symptoms or the likelihood of developing TSC-related complications. Factors such as prenatal exposure to certain medications or toxins may play a role, although more research is needed to establish definitive links. […] Understanding these causes is essential for managing Tuberous Sclerosis Complex effectively. Early intervention can help mitigate some of the complications associated with the disorder.
#32 Tubular Sclerosis Complex – Causes & Symptoms
https://lonestarneurology.net/blog/tubular-sclerosis-complex/
Tuberous Sclerosis Complex (TSC) is a rare genetic illness. […] Mutations in either the TSC1 or TSC2 genes cause it. […] In approximately 70-80% of cases, Tuberous Sclerosis is an inheritance from a parent with the illness. […] In around 20-30% of cases, TSC disease arises from a spontaneous mutation in either the TSC1 or TSC2 gene. […] In rare cases, the condition can arise from a genetic mutation early in fetal development. […] In some cases, other genetic factors may change the expression of the TSC1 or TSC2 gene. […] The specific causes of Tuberous Sclerosis may vary from person to person. […] It is important to note that environmental factors, such as diet or exposure to toxins, are not causes of Tuberous Sclerosis. […] Tuberous Sclerosis Complex occurs due to mutations in the TSC1 or TSC2 genes.
#33 tuberous sclerosis symptoms
https://www.medicalnewstoday.com/articles/tuberous-sclerosis-symptoms
Tuberous sclerosis, or tuberous sclerosis complex (TSC), causes noncancerous tumor growth. […] TSC is a genetic disease that is present at birth. It causes benign tumors to develop in the brain and spinal cord, as well as several organs, including the kidneys and eyes. […] A mutation in the TSC1 or TSC2 gene causes TSC. […] The TSC1 gene produces hamartin, a protein, and the TSC2 gene produces another protein, tuberin. […] Doctors do not fully understand how these proteins work, but they think they may undermine the activation of the protein mTOR, which causes cell changes during development. […] If a parent has TSC, their child has a 50% chance of inheriting the mutation. […] There is no evidence of specific lifestyle or environmental factors that lead to the genetic mutation. […] Rarely, a child may inherit TSC even if their parent does not have it because of mutations in the egg or sperm.
#34 Tuberous Sclerosis Complex (TSC): ERKNet Patsientidele
https://www.erknet.org/patients/et/your-kidney-disease/tsc/disease-information
Tuberous sclerosis complex (TSC), also known as tuberous sclerosis, is a rare genetic disease that causes non-cancerous (benign) tumors to grow in the brain and several areas of the body, including the spinal cord, nerves, eyes, lung, heart, kidneys, and skin. […] Identifying mutations in the TSC1 or TSC2 genes confirms the diagnosis. […] Treatment plans for TSC should be individualized based on the specific symptoms and complications experienced by each patient. […] Drugs like everolimus and sirolimus, which are mTOR inhibitors, have been approved for the treatment of specific TSC-related complications, such as kidney angiomyolipomas (AMLs) and brain subependymal giant cell astrocytomas (SEGA). […] Angiomyolipomas are the most common kidney lesions in TSC and can be found in people without TSC.
#35 New Understanding of What Causes Tuberous Sclerosis Could Improve Treatment â Patient Worthy
https://patientworthy.com/2019/02/14/new-understanding-what-causes-tuberous-sclerosis-could-improve-treatment/
Tuberous sclerosis complex (TSC) is a rare condition which results in the buildup of tumors in the skin, kidneys, brain, as well as other organs. […] TSC is caused by mutations in TSC1 and TSC2. […] It has long been understood that the mutations in the TSC genes affect mTORC1, making it hyperactive and resulting in progression of disease. […] However, we now understand that these TSC mutations manifest in different ways which means they may affect mTORC1 or they may not. […] TSC mutations are still clearly the cause of this condition.
#36 Tuberous sclerosis: MedlinePlus Medical EncyclopediaLock
https://medlineplus.gov/ency/article/000787.htm
Tuberous sclerosis is a genetic condition. Changes (non-working gene variants or mutations) in one of two genes, TSC1 and TSC2, are responsible for most cases. […] Only one parent needs to pass on the non-working gene for the child to get the disease. However, two-thirds of cases are due to new gene changes. In most cases, there is no family history of tuberous sclerosis. […] There are no known risk factors, other than having a parent with tuberous sclerosis. In that case, each child has a 50% chance of inheriting the disease. […] DNA testing for the two genes that can cause this disease (TSC1 or TSC2) is available. […] Genetic counseling is recommended for couples who have a personal or family history of tuberous sclerosis and who want to have children. Prenatal diagnosis is available for families with a known gene variant or history of this condition. However, tuberous sclerosis often appears as a new DNA mutation. These cases are not preventable.
#37 Tuberous sclerosis Information | Mount Sinai – New York
https://www.mountsinai.org/health-library/diseases-conditions/tuberous-sclerosis
Tuberous sclerosis is a genetic disorder that affects the skin, brain/nervous system, kidneys, heart, and lungs. The condition can also cause tumors to grow in the brain. These tumors have a tuber or root-shaped appearance. […] Tuberous sclerosis is a genetic condition. Changes (non-working gene variants or mutations) in one of two genes, TSC1 and TSC2, are responsible for most cases. […] Only one parent needs to pass on the non-working gene for the child to get the disease. However, two-thirds of cases are due to new gene changes. In most cases, there is no family history of tuberous sclerosis. […] There are no known risk factors, other than having a parent with tuberous sclerosis. In that case, each child has a 50% chance of inheriting the disease. […] Prenatal diagnosis is available for families with a known gene variant or history of this condition. However, tuberous sclerosis often appears as a new DNA mutation. These cases are not preventable.
#38 Tuberous Sclerosis – MD Searchlight
https://mdsearchlight.com/genetic-disorders/tuberous-sclerosis/
They can deactivate a protein complex that regulates cell growth and metabolism. […] If this complex is not working correctly, it can lead to uncontrolled cell growth and the formation of solid tumors. […] Tuberous sclerosis has also been linked to a protein called vascular epithelial growth factor D (VEGF-D), most notably in conditions like lymphangioleiomyomatosis and kidney tumors known as angiomyolipomas. […] Tuberous sclerosis affects around 1 in 6,000 to 1 in 10,000 newborns, making its overall occurrence approximately 1 in 20,000 people. […] Tuberous sclerosis complex (TSC) is a genetic condition characterized by a higher likelihood of forming benign tumors called hamartomas. […] It is caused by flaws in the TSC1 and TSC2 genes and can lead to neurological problems, such as epilepsy and intellectual disability, as well as affecting other body systems like the lungs, kidneys, skin, and heart.
#39 Research team investigates causes of tuberous sclerosis
https://phys.org/news/2021-05-team-tuberous-sclerosis.html
Tuberous Sclerosis Complex (TSC) affects between one and two of every 10,000 new-born babies. This genetic disease leads to the formation of benign tumors which can massively impair the proper functioning of vital organs such as the kidneys, the liver and the brain. […] The disease affects different patients to varying degrees and is triggered by mutations in one of two genes, the TSC1 or TSC2 gene. […] The researchers have now found out that one part of the TSC1 protein, a so-called domain, can bind to the surfaces of lysosomal membranes. […] Mutations occur particularly frequently in the membrane binding domain. […] We assume that some of the pathogenic effects can now be explained by a loss of the correct localization of the TSC complex.
#40 Tuberous Sclerosis Complex
https://practicalneurology.com/articles/2022-oct/tuberous-sclerosis-complex
Tuberous sclerosis complex represents the opportunity of targeted treatment resulting from identifying pathogenic gene variants for long-recognized syndromes. […] TSC is an autosomal dominant neurocutaneous epilepsy syndrome that was well defined before a specific causative gene variant was discovered. […] In the 1990s, multilinkage analysis of families that had multiple generations of people with TSC led to the identification of the TSC2 and TSC1 genes, which respectively encode the proteins hamartin and tuberin. These proteins form the tumor suppressor complex mTORC1. […] Pathogenic variants of TSC1 are more likely to be familial (ie, germline mutations), whereas pathogenic variants of TSC2 are more sporadic. […] Genetic testing of individuals and their family members, when available, may lead to further understanding of genotype-phenotype correlations and disease mechanisms. […] Often there is a family history, but TSC can arise from a de novo mutation. […] Understanding the genetic pathogenesis of TSC has led to improved diagnosis and characterization of the syndrome.
#41 Tuberous sclerosis complex — Knowledge Hub
https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/tuberous-sclerosis-complex/
Tuberous sclerosis complex (TSC) is a rare, highly variable genetic condition characterised by the growth of benign tumours in the skin, brain, heart, kidneys, lungs and bones. […] It is caused by constitutional pathogenic variants in either of the tumour suppressor genes: TSC1 or TSC2. […] TSC is caused by heterozygous loss-of-function pathogenic variants in either the TSC2 or TSC1 gene, which result in constitutive activation of the mTOR pathway and cause benign tumour growth in multiple organs and neuropsychiatric symptoms. […] Pathogenic variants in the TSC2 gene are the cause of most cases of TSC, and typically result in a more severe phenotype. […] Incomplete penetrance can occur when not everyone who has the variant develops the disease.
#42 2013 Tuberous Sclerosis Complex Highlight – Understanding the Etiology of Tuberous Sclerosis Complex, Tuberous Sclerosis Complex Research Program, Congressionally Directed Medical Research Programs
https://cdmrp.health.mil/tscrp/research_highlights/14bordey_highlight
Tuberous sclerosis complex (TSC) is a genetic disorder resulting from mutations in TSC1 or TSC2 genes. […] Currently, there is no cure for TSC, and the mechanisms leading to TSC brain lesions and the subsequent development of neurological symptoms are not well defined. […] Dr. Bordey demonstrated that the knockout of Tsc1 in select groups of neurons in embryonic mice already carrying a mutant Tsc1 allele (Tsc1flox/mutant) led to the development of cortical tuber-like lesions that share many characteristics with the cortical lesions seen in the human disease. […] Using this mouse model, Dr. Bordey and her research team have identified several proteins, such as hypoxia inducible factor 1 (Hif1a), which are abnormally regulated in TSC. […] These results suggest that Hif1a may play an important role in the formation of lesions in TSC. […] Future research by Dr. Bordey and her team will attempt to identify additional proteins that are abnormally regulated in TSC and also determine whether or not restoring Hif1a or other molecules to normal levels can prevent the formation of lesions in TSC.
#43 New Understanding of What Causes Tuberous Sclerosis Could Improve Treatment â Patient Worthy
https://patientworthy.com/2019/02/14/new-understanding-what-causes-tuberous-sclerosis-could-improve-treatment/
Tuberous sclerosis complex (TSC) is a rare condition which results in the buildup of tumors in the skin, kidneys, brain, as well as other organs. […] TSC is caused by mutations in TSC1 and TSC2. […] It has long been understood that the mutations in the TSC genes affect mTORC1, making it hyperactive and resulting in progression of disease. […] However, we now understand that these TSC mutations manifest in different ways which means they may affect mTORC1 or they may not. […] TSC mutations are still clearly the cause of this condition.