Timeline of tuberous sclerosis

Timeline of tuberous sclerosis

The timeline of tuberous sclerosis discovery and research spans less than 200 years. Tuberous sclerosis (TSC) is a rare, multi-system genetic disease that causes benign tumours to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioural problems and skin abnormalities, as well as lung and kidney disease. TSC is caused by mutations on either of two genes, TSC1 and TSC2, which encode for the proteins hamartin and tuberin respectively. These proteins act as tumour growth suppressors and regulate cell proliferation and differentiation.cite web
url = http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm
title = Tuberous Sclerosis Fact Sheet
accessdate = 2007-01-09
date = 2006-04-11
publisher = NINDS
] Originally regarded as a rare pathological curiosity, it is now an important focus of research into tumour formation and suppression.

There are four chapters to the story of tuberous sclerosis.Rott (2005), page 2 - Introduction.] In the late 19th century, notable physicians working in the great European teaching hospitals first described the cortical and dermatological manifestations; these early researchers have been awarded with eponyms such as "Bourneville's disease"cite web
author = Enersen, Ole Daniel
authorlink = Ole Daniel Enersen
url = http://www.whonamedit.com/doctor.cfm/2408.html
title = Désiré-Magloire Bourneville
publisher = Who Named It?
accessdate = 2007-04-30
] and "Pringle's adenoma sebaceum".cite web
author = Enersen, Ole Daniel
url = http://www.whonamedit.com/doctor.cfm/2409.html
title = John James Pringle
publisher = Who Named It?
accessdate = 2007-04-30
] At the start of the 20th century, these symptoms were recognised as belonging to a single medical condition. Further organ involvement was discovered, along with a realisation that the condition was highly variable in its severity. The late 20th century saw great improvements in cranial imaging techniques and the discovery of the two genes. Finally, the start of the 21st century saw the beginning of a molecular understanding of the illness, along with possible non-surgical therapeutic treatments.

19th century

;1835: French dermatologist Pierre François Olive Rayer published an atlas of skin diseases. It contains 22 large coloured plates with 400 figures presented in a systematic order. On page 20, fig. 1 is a drawing that is regarded as the earliest description of tuberous sclerosis.Curatolo (2003), chapter: "Hisorical Background".] Entitled "végétations vasculaires", Rayer noted these were "small vascular, of papulous appearance, widespread growths distributed on the nose and around the mouth".cite book
author = Rayer, Pierre François
title = Traité des maladies de la peau / atlas
url = http://web2.bium.univ-paris5.fr/livanc/?cote=00584
accessdate = 2006-12-09
year = 1835
publisher = J.B. Baillière
location = Paris
language = French
pages = 20
] No mention was made of any medical condition associated with the skin disorder.

;1850: English dermatologists Thomas Addison and William Gull described, in "Guy's Hospital Reports", the case of a four-year-old girl with a "peculiar eruption extending across the nose and slightly affecting both cheeks", which they called "vitiligoidea tuberosa".cite journal
author = Jay V
year = 2004
title = Historical contributions to pediatric pathology: Tuberous Sclerosis
journal = Pediatric and Developmental Pathology
volume = 2
issue = 2
pages = 197–8
pmid = 9949228
doi = 10.1007/s100249900110

;1862: German physician Friedrich Daniel von Recklinghausen, who was working as an assistant to Rudolf Virchow in the Institute for Pathological Anatomy in Berlin,cite web
author = Enersen, Ole Daniel
url = http://www.whonamedit.com/doctor.cfm/1174.html
title = Friedrich Daniel von Recklinghausen
publisher = Who Named It?
accessdate = 2006-12-10
] presented a case to the city's Obstetrical Society.cite journal
last = von Recklinghausen
first = F
year = 1862
title = Ein Herz von einem Neugeborene welches mehrere theils nach aussen, theils nach den Höhlen prominirende Tumoren (Myomen) trug
journal = Monatschr Geburtsheilkd
volume = 20
pages = 1–2
language = German
(As cited in Curatolo (2003))] The heart of an infant who "died after taking a few breaths" had several tumours. He called these tumours "myomata", one of which was the "size of a pigeon's egg". He also noted the brain had "a great number of scleroses". These were almost certainly the cardiac rhabdomyomas and cortical tubers of tuberous sclerosis. He failed to recognise a distinct disease, regarding it as a pathological-anatomical curiosity.cite journal
author = Jansen F, van Nieuwenhuizen O, van Huffelen A
title = Tuberous sclerosis complex and its founders
journal = Journal of Neurology, Neurosurgery and Psychiatry
volume = 75
issue = 5
pages = 770
year = 2004
pmid = 15090576
url = http://jnnp.bmj.com/cgi/content/full/75/5/770
doi = 10.1136/jnnp.2003.027524
] Von Recklinghausen's name would instead become associated with neurofibromatosis after a classic paper in 1881.

;1864: German pathologist Rudolf Virchow published a three-volume work on tumours that described a child with cerebral tuberous sclerosis and rhabdomyoma of the heart. His description contained the first hint that this may be an inherited disease: the child's sister had died of a cerebral tumour.cite book
last = Virchow R
year = 1863–7
title = Die Krankhaften Geschwülste. Vol II
publisher = August Hirschwald
location = Berlin
pages = 148
(As cited in Acierno (1994))]

;1880: French neurologist Désiré-Magloire Bourneville had a chance encounter with the disease that would bear his name. He was working as an unofficial assistant to Jean Martin Charcot at La Salpêtrière. While substituting for his teacher, Louis J.F. Delasiauve,cite book
last = Wilkins, Robert H (ed); Brody, Irwin A (ed)
title = Neurological Classics
year = 1997
publisher = American Association of Neurological Surgeons
isbn = 1879284499
chapter = XXXI Tuberous Sclerosis
pages = 149-52
(contains an abridged translation of Bourneville's 1880 paper)] he attended to Marie, a 15-year-old girl with psychomotor retardation, epilepsy and a "confluent vascular-papulous eruption of the nose, the cheeks and forehead". She had a history of seizures since infancy and was taken to the children's hospital aged three and declared a hopeless case. She had learning difficulties and could neither walk nor talk. While under Bourneville's care, Marie had an ever increasing number of seizures, which came in clusters. She was treated with quinquina, bromide of camphor, amyl nitrite, and the application of leeches behind the ears. On 1879-05-07 Marie died in her hospital bed. The post-mortem examination disclosed hard, dense tubers in the cerebral convolutions, which Bourneville named "Sclérose tubéreuse des circonvolutions cérébrales". He concluded they were the source (focus) of her seizures. In addition, whitish hard masses, one "the size of a walnut", were found in both kidneys.cite journal
author = Bourneville D
year = 1880
title = Sclérose tubéreuse des circonvolutions cérébrales: Idiotie et épilepsie hemiplégique
journal = Archives de neurologie, Paris
volume = 1
pages = 81–9l
url = http://www.bium.univ-paris5.fr/histmed/medica/cote?epo0073
language = French
accessdate = 2006-12-10

;1881: German physician Hartdegen described the case of a two-day-old baby who died in status epilepticus. Post-mortem examination revealed small tumours in the lateral ventricles of the brain and areas of cortical sclerosis, which he called "glioma gangliocellulare cerebri congenitum".cite book
last = Sancak
first = Özgür
title = Tuberous Sclerosis Complex: Mutations, Functions and Phenotypes
year = 2005
publisher = Stichting Tubereuze Sclerose Nederland
isbn = 9090201939
pages = 11–2
] cite journal
author = Hartdegen A
year = 1881
month = February
title = Ein Fall von multipler Verhärtung des Grosshirns nebst histologisch eigenartigen harten Geschwülsten der Seitenventrikel ("Glioma gangliocellulare") bei einem Neugeborenen
journal = European Archives of Psychiatry and Clinical Neuroscience
volume = 11
issue = 1
pages = 117–31
doi = 10.1007/BF02054825
] ;1881: Bourneville and Édouard Brissaud examined a four-year-old boy at "La Bicétre". As before, this patient had cortical tubers, epilepsy and learning difficulties. In addition he had a heart murmur and, on post-mortem examination, had tiny hard tumours in the ventricle walls in the brain (subependymal nodules) and small tumours in the kidneys (angiomyolipomas).cite journal
author = Bourneville D, Brissaud É
year = 1881
title = Encéphalite ou sclérose tubéreuse des circonvolutions cérébrales
journal = Archives de neurologie, Paris
volume = 1
pages = 390–412
(As cited in Curatolo (2003))]

;1885: French physicians Félix Balzer and Pierre Eugène Ménétrier reported a case of "adénomes sébacés de la face et du cuir" (adenoma of the sebaceous glands of the face and scalp).cite journal
author = Balzer F, Ménétrier P
year = 1885
title = Étude sur un cas d’adénomes sébacés de la face et du cuir
journal = Archives de Physiologie normale et pathologique (série III)
volume = 6
pages = 564–76
(As cited in Curatolo (2003))] The term has since proved to be incorrect as they are neither adenoma nor derived from sebaceous glands. The papular rash is now known as facial angiofibroma.cite journal
author = Sanchez N, Wick M, Perry H
title = Adenoma sebaceum of Pringle: a clinicopathologic review, with a discussion of related pathologic entities
journal = Journal of Cutaneous Pathology
volume = 8
issue = 6
pages = 395–403
year = 1981
pmid = 6278000
doi = 10.1111/j.1600-0560.1981.tb01028.x

;1885: French dermatologists François Henri Hallopeau and Émile Leredde published a case of adenoma sebaceum that was of a hard and fibrous nature. They first described the shagreen plaques and later would note an association between the facial rash and epilepsy.cite journal
author = Hallopeau F
coauthors = Leredde É
year = 1885
title = Sur un cas d'adenomes sébacés à forme sclereuse
journal = Ann Dermatol Syph
volume = 6
pages = 473–9
(As cited in Curatolo (2003))] ;1890: Scottish dermatologist John James Pringle, working in London, described a 25-year-old woman with subnormal intelligence, rough lesions on the arms and legs, and a papular facial rash. Pringle brought attention to five previous reports, two of which were unpublished.cite journal
author = Pringle, JJ
year = 1890
title = A case of congenital adenoma sebaceum
journal = British Journal of Dermatology, Oxford
volume = 2
pages = 1–14
url = http://www.bium.univ-paris5.fr/histmed/medica/cote?epo0074
] Pringle's adenoma sebaceum would become a common eponym for the facial rash.

Early 20th century

;1901: Italian physician GB Pellizzi studied the pathology of the cerebral lesions. He noted their dysplastic nature, the cortical heterotopia and defective myelination. Pellizzi classified the tubers into type 1 (smooth surface) and type 2 (with central depressions).cite journal
author = Pellizzi GB
title = Contributo allo studio dell'idiozia: rivisita sperimentale di freniatria e medicina legale delle alienazioni mentali
journal = Riv Sper Freniat
year = 1901
volume = 27
pages = 265–9
(As cited in Curatolo (2003))] cite journal
author = Braffman BH, Bilaniuk LT, Naidich TP, Altman NR, Post MJ, Quencer RM, Zimmerman RA, Brody BA
title = MR imaging of tuberous sclerosis: pathogenesis of this phakomatosis, use of gadopentetate dimeglumine, and literature review
journal = Radiology
volume = 183
issue = 1
pages = 227–38
year = 1992
pmid = 1549677
url = http://radiology.rsnajnls.org/cgi/reprint/183/1/227

;1903: German physician Richard Kothe described periungual fibromas, which were later rediscovered by the Dutch physician Johannes Koenen in 1932 (known as Koenen's tumours).cite journal
author = Kothe R
title = Zur Lehre der Talgdrüsengeschwülste
year = 1903
journal = Archives of Dermatology and Syphilis
volume = 68
pages = 273–8
language = German
(As cited in Rott (2005))]

;1906: Australian neurologist Alfred Walter Campbell, working in England, considered the lesions in the brain, skin, heart and kidney to be caused by one disease. He also first described the pathology in the eye. His review of 20 reported cases led him to suggest a diagnostic triad of symptoms that is more commonly attributed to Vogt.cite journal
last = Campbell
first = AW
year = 1906
title = Cerebral sclerosis
journal = Brain
volume = 28
pages = 382–96
doi = 10.1093/brain/28.3-4.367

;1908: German paediatric neurologist Heinrich Vogt established the diagnostic criteria for TSC, firmly associating the facial rash with the neurological consequences of the cortical tubers.cite web
author = Enersen, Ole Daniel
url = http://www.whonamedit.com/doctor.cfm/1050.html
title = Heinrich Vogt
publisher = Who Named It?
accessdate = 2006-12-11
] cite journal
author = Vogt H
year = 1908
title = Zur Diagnostik der tuberösen Sklerose
journal = Zeitschrift für die Erforschung und Behandlung des jugendlichen Schwachsinns auf wissenschaftlicher Grundlage, Jena
volume = 2
pages = 1–16
(As cited in Curatolo (2003) and fully cited by Who Named It?)] Vogt's triad of epilepsy, idiocy, and adenoma sebaceum held for 60 years until research by Manuel Gómez discovered that fewer than a third of patients with TSC had all three symptoms.

;1910: J. Kirpicznick was first to recognise that TSC was a genetic condition. He described cases of identical and fraternal twins and also one family with three successive generations affected.cite journal
author = Kirpicznik J
year = 1910
title = Ein Fall von Tuberoser Sklerose und gleichzeitigen multiplen Nierengeschwùlsten
journal = Virchow's Archiv für pathologische Anatomie und Physiologie und für klinische Medicin
volume = 202
issue = 3
pages = 258
language = German
url = http://www.springerlink.com/content/q1g5757047p30583/fulltext.pdf
doi = 10.1007/BF01993975
(As cited in Curatolo (2003))]

;1911: Edward Sherlock, barrister-at-law and lecturer in biology, reported nine cases in his book on the "feeble-minded". He coined the term "epiloia", a portmanteau of epilepsy and anoia (mindless).cite book
last = Sherlock
first = Edward Birchall
title = The Feeble-minded, A Guide to Study and Practice.
year = 1911
publisher = Macmillan & Co
(As cited in Jay (2004))] The word is no longer widely used as a synonym for TSC. The geneticist Robert James Gorlin suggested in 1981 that it could be a useful acronymn for epilepsy, low intelligence, and adenoma sebaceum.OMIM|191100|Tuberous Sclerosis]

;1913: H. Berg is credited with first stating that TSC was a hereditary disorder, noting its transmission through two or three generations.cite journal
author = Berg H
year = 1913
title = Vererbung der tuberösen Sklerose durch zwei bzw. drei Generationen.
journal = Z ges Neurol Psychiatr
volume = 19
pages = 528–39
language = German
doi = 10.1007/BF02909909
(As cited in Curatolo (2003))]

;1914: P. Schuster described a patient with adenoma sebaceum and epilepsy but of normal intelligence. This reduced phenotypic expression is called a "forme fruste".cite journal
author = Schuster P
year = 1914
title = Beiträge zur Klinik der tuberösen Sklerose des Gehirns
journal = Dtsch Z Nervenheilk
volume = 50
pages = 96–133
language = German
(As cited in Curatolo (2003))]

;1918: French physician René Lutembacher published the first report of cystic lung disease in a patient with TSC. The 36-year-old woman died from bilateral pneumothoraces. Lutembacher believed the cysts and nodules to be metastases from a renal fibrosarcoma. This complication, which only affects women, is now known as lymphangioleiomyomatosis (LAM).cite journal
author = Lutembacher R
year = 1918
title = Dysembryomes métatypique des reins. Carcinose submiliaire aigue du poumon avec emphysème généralisé et double pneumothorax
journal = Ann Med
volume = 5
pages = 435–50
language = French
(As cited in Curatolo (2003))] cite journal
author = Abbott GF, Rosado-de-Christenson ML, Frazier AA, Franks TJ, Pugatch RD, Galvin JR.
title = From the archives of the AFIP: lymphangioleiomyomatosis: radiologic-pathologic correlation
journal = Radiographics
volume = 25
issue = 3
pages = 803–28
year = 2005
pmid = 15888627
url = http://radiographics.rsnajnls.org/cgi/content/full/25/3/803
doi = 10.1148/rg.253055006

;1920: Dutch ophthalmologist Jan van der Hoeve described the retinal hamartomas (phakoma). He grouped both TSC and neurofibromatosis together as "phakomatoses" (later called neurocutaneous syndromes).cite journal
author = Van der Hoeve J
year = 1920
title = Eye symptoms in tuberous sclerosis of the brain
journal = Trans Ophthalmol Soc UK
volume = 40
pages = 329–34
(As cited in Curatolo (2003))]

;1924: H. Marcus noted that characteristic features of TSC such as intracranial calcifications were visible on x-ray.cite book
author = Marcus H
year = 1924
title = Svenska Làk Sallsk Forth
(As cited by cite journal
author = Dickerson WW
year = 1945
title = Characteristic roentgenographic changes associated with tuberous sclerosis
journal = Archives of Neurology and Psychiatry
pages = 199–204
volume = 53
, as cited in Curatolo (2003) and Gómez (1995))]

Mid-20th century

;1932: MacDonald Critchley and Charles J.C. Earl studied 29 patients with TSC who were in mental institutions. They described behaviour—unusual hand movements, bizarre attitudes and repetitive movements (stereotypies)—that today would be recognised as autistic. However it would be 11 years before Leo Kanner suggested the term "autism". They also noticed the associated white spots on the skin (hypomelanic macules).cite journal
author = Critchley M, Earl CJC
year = 1932
title = Tuberose sclerosis and allied conditions
journal = Brain
volume = 55
pages = 311–46
doi = 10.1093/brain/55.3.311

;1934: N.J. Berkwitz and L.G. Rigler showed it was possible to diagnose tuberous sclerosis using pneumoencephalography to highlight non-calcified subependymal nodules. These resembed "the wax drippings of a burning candle" on the lateral ventricles.cite journal
author = Berkwitz NJ, Rigler LG
title = Tuberous sclerosis diagnosed with cerebral pneumography
journal = Archives of Neurology and Psychiatry
volume = 35
pages = 833–8
year = 1934
(As cited in Gómez (1995))]

;1942: Sylvan E. Moolten proposed "the tuberous sclerosis complex", which is now the preferred name. This recognises the multi-organ nature of the disease. Moolten introduced three words to describe its pathology: "the basic lesion is "hamartial", becoming in turn tumor-like ("hamartoma") or truly neoplastic ("hamartoblastoma")."cite journal
author = Moolten SE
year = 1942
title = Hamartial nature of tuberous sclerosis complex and its bearings on the tumor problem: report of a case with tumor anomaly of the kidney and adenoma sebaceum.
journal = Arch Intern Med
volume = 69
pages = 589–623

;1954: Norwegian pathologist Reidar Eker bred a line of Wistar rats predisposed to renal adenomas. The Eker rat became an important model of dominantly inherited cancer.cite journal
author = Eker R
title = Familial renal adenomas in Wistar rats; a preliminary report
journal = Acta Pathologica et Microbiologica Scandinavica
volume = 34
issue = 6
pages = 554–62
year = 1954
pmid = 13206757
(As cited in Yeung (1994))]

;1966: Phanor Perot and Bryce Weir pioneered surgical intervention for epilepsy in TSC. Of the seven patients who underwent cortical tuber resection, two became seizure-free. Prior to this, only four patients had ever been surgically treated for epilepsy in TSC. cite journal
author = Perot P, Weir B, Rasmussen T
title = Tuberous sclerosis. Surgical therapy for seizures
journal = Archives of Neurology
volume = 15
issue = 5
pages = 498–506
year = 1966
pmid = 5955139
(As cited in cite journal
author = Bebin EM, Kelly PJ, Gómez MR
title = Surgical treatment for epilepsy in cerebral tuberous sclerosis
journal = Epilepsia
volume = 34
issue = 4
pages = 651–7
year = 1993
pmid = 8330575
doi = 10.1111/j.1528-1157.1993.tb00442.x

;1967: J.C. Lagos and Manuel Rodríguez Gómez reviewed 71 TSC cases and found that 38% of patients have normal intelligence.cite journal
author = Lagos JC, Gómez MR
title = Tuberous sclerosis: reappraisal of a clinical entity
journal = Mayo Clinic Proceedings
volume = 42
issue = 1
pages = 26–49
year = 1967
pmid = 5297238
(As cited in Curatolo (2003))]

;1971: American geneticist Alfred Knudson developed his "two hit" hypothesis to explain the formation of retinoblastoma in both children and adults. The children had a congenital germline mutation which was combined with an early lifetime somatic mutation to cause a tumour. This model applies to many conditions involving tumour suppressor genes such as TSC.cite journal
author = Knudson AG
title = Mutation and cancer: statistical study of retinoblastoma
journal = Proceedings of the National Academy of Sciences of the USA
volume = 68
issue = 4
pages = 820–3
year = 1971
pmid = 5279523
url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=5279523
doi = 10.1073/pnas.68.4.820
(As cited in Rott (2005))] In the 1980s, Knudson's studies on the Eker rat strengthened this hypothesis.cite journal
author = Yeung R
title = Lessons from the Eker rat model: from cage to bedside
journal = Current Molecular Medicine
volume = 4
issue = 8
pages = 799–806
year = 2004
pmid = 15579026
doi = 10.2174/1566524043359791

;1975: Giuseppe Pampiglione and E. Pugh, in a letter to "The Lancet", noted that up to 69% of patients presented with infantile spasms.cite journal
author = Pampiglione G, Pugh E
title = Letter: Infantile spasms and subsequent appearance of tuberous sclerosis syndrome
journal = Lancet
volume = 2
issue = 7943
pages = 1046
year = 1975
pmid = 53537
doi = 10.1016/S0140-6736(75)90343-8

;1975: Riemann first used ultrasound to examine TSC-affected kidneys in the case of a 35-year-old woman with chronic renal failure.cite journal
author = Riemann JF, Mörl M, Rott HD
title = Chronische Niereninsuffizienz bei Morbus Bourneville-Pringle (Chronic renal failure in bourneville-pringle's disease)
journal = Medizinische Klinik
volume = 70
issue = 26
pages = 1128–32
year = 1975
pmid = 1223616
language = German
(As cited in Rott (2005))]

Late 20th century

;1976: Cranial computed tomography (CT, invented 1972) proved to be an excellent tool for diagnosing cerebral neoplasms in children, including those found in tuberous sclerosis.cite journal
author = Berger PE, Kirks DR, Gilday DL, Fitz CR, Harwood-Nash DC
title = Computed tomography in infants and children: intracranial neoplasms
journal = American Journal of Roentgenology
volume = 127
issue = 1
pages = 129–37
year = 1976
pmid = 180824

;1979: Manuel Gómez published a monograph: "Tuberous Sclerosis" that remained the standard textbook for three editions over two decades. The book described the full clinical spectrum of TSC for the first time and established a new set of diagnostic criteria to replace the Vogt triad.cite book
last = Gómez
first = Manuel R
title = Tuberous Sclerosis
edition = 1st Ed
year = 1979
publisher = Raven Press
location = New York
isbn = 0890043132
(As cited in Özgür (2005))]

;1982: Kenneth Arndt successfully treated facial angiofibroma with an argon laser.cite journal
author = Arndt KA
year = 1982
title = Adenoma sebaceum: successful treatment with the argon laser
journal = Plastic Reconstructive Surgery
volume = 70
pages = 91–3
pmid = 7089113
(As cited in Rott (2005))]

;1983: Positron emission tomography (PET, invented 1981) was compared to electroencephalography (EEG) and CT. It was found to be capable of locating epileptogenic cortical tubers that would otherwise have been missed.cite journal
author = Szelies B, Herholz K, Heiss W, "et al"
title = Hypometabolic cortical lesions in tuberous sclerosis with epilepsy: demonstration by positron emission tomography
journal = Journal of Computer Assisted Tomography
volume = 7
issue = 6
pages = 946–53
year = 1983
pmid = 6415136
(As cited in Rott (2005))]

;1984: The cluster of infantile spasms in TSC was discovered to be preceded by a focal EEG discharge.cite journal
author = Dulac O, Lemaitre A, Plouin P
year = 1984
title = The Bourneville syndrome: clinical and EEG features of epilepsy in the first year of life
journal = Boll Lega Ital Epil
volume = 45/46
pages = 39–42
(As cited in Curatolo (2003))]

;1985: Magnetic resonance imaging (MRI, invented 1980) was first used in TSC to identify affected regions in the brain of a girl with tuberous sclerosis.cite journal
author = Kandt RS, Gebarski SS, Goetting MG
title = Tuberous sclerosis with cardiogenic cerebral embolism: magnetic resonance imaging
journal = Neurology
volume = 35
issue = 8
pages = 1223–5
year = 1985
pmid = 4022361
(As cited in Rott (2005))]

;1987: MR was judged superior to CT imaging for both sensitivity and specificity. In a study of fifteen patients, it identified subependymal nodules projecting into the lateral ventricles in twelve patients, distortion of the normal cortical architecture in ten patients (corresponding to cortical tubers), dilated ventricles in five patients, and distinguished a known astrocytoma from benign subependymal nodules in one patient.cite journal
author = McMurdo SK Jr, Moore SG, "et al"
title = MR imaging of intracranial tuberous sclerosis
journal = AJR Am J Roentgenol
volume = 148
issue = 4
pages = 791–6
year = 1987
pmid = 3493666

;1987: MR imaging was found to be capable of predicting the clinical severity of the disease (epilepsy and developmental delay). A study of 25 patients found a correlation with the number of cortical tubers identified. In contrast, CT was not a useful predictor, but was superior at identifying calcified lesions.cite journal
author = Roach ES, Williams DP, Laster DW
title = Magnetic resonance imaging in tuberous sclerosis
journal = Arch Neurol
volume = 44
issue = 3
pages = 301–3
year = 1987
pmid = 3827681
(As cited in Curatolo (2003))]

;1987: Linkage analysis on 19 families with TSC located a probable gene on chromosome 9.cite journal
author = Fryer AE, Chalmers A, Connor JM, "et al"
title = Evidence that the gene for tuberous sclerosis is on chromosome 9
journal = Lancet
volume = 1
issue = 8534
pages = 659–61
year = 1987
pmid = 2882085
doi = 10.1016/S0140-6736(87)90416-8

;1988: Cortical tubers found on MR imaging corresponded exactly to the location of persistent EEG foci, in a study of six children with TSC. In particular, frontal cortical tubers were associated with more intractable seizures.cite journal
author = Curatolo P, Cusmai R
title = Imagerie par résonance magnétique nucléaire dans la maladie de Bourneville: relation avec les données électroencéphalographiques (Magnetic resonance imaging in the Bourneville syndrome: relations with EEG)
journal = Neurophysiologie clinique
volume = 18
issue = 5
pages = 459–67
year = 1988
pmid = 3185465
language = French
(As cited in Curatolo (2003))]

;1990: Vigabatrin was found to be a highly effective antiepileptic treatment for infantile spasms, particularly in children with TSC.cite journal
author = Chiron C, Dulac O, Luna D, "et al"
title = Vigabatrin in infantile spasms
journal = Lancet
volume = 335
issue = 8685
pages = 363–4
year = 1990
pmid = 1967808
doi = 10.1016/0140-6736(90)90660-W
] Following the discovery in 1997 of severe persistent visual field constriction as a possible side-effect, vigabatrin monotherapy is now largely restricted to this patient group.cite journal
author = Vigabatrin Paediatric Advisory Group
title = Guideline for prescribing vigabatrin in children has been revised.
journal = BMJ
volume = 320
issue = 7246
pages = 1404–5
year = 2000
pmid = 10858057
doi = 10.1136/bmj.320.7246.1404

;1992: Linkage analysis located a second gene to chromosome 16p13.3, close to the polycystic kidney disease type 1 (PKD1) gene. [cite journal
author = Kandt RS, Haines JL, Smith M, "et al"
title = Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease
journal = Nature Genetics
volume = 2
issue = 1
pages = 37–41
year = 1992
pmid = 1303246
doi = 10.1038/ng0992-37

;1993: The European Chromosome 16 Tuberous Sclerosis Consortium announced the cloning of TSC2; its product is called tuberin.cite journal
author = European Chromosome 16 Tuberous Sclerosis Consortium
title = Identification and characterization of the tuberous sclerosis gene on chromosome 16
journal = Cell
volume = 75
issue = 7
pages = 1305–15
year = 1993
pmid = 8269512
(As cited in Rott (2005))]

;1994: The Eker rat was discovered to be an animal model for tuberous sclerosis; it has a mutation in the rat-equivalent of the TSC2 gene.cite journal
author = Yeung R, Xiao G, Jin F, "et all"
title = Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene
journal = Proc Natl Acad Sci USA
volume = 91
issue = 24
pages = 11413–6
year = 1994
pmid = 7972075
url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=7972075
doi = 10.1073/pnas.91.24.11413

;1995: MRI with fluid attenuated inversion recovery (FLAIR) sequences was reported to be significantly better than standard T2-weighted images at highlighting small tubers, especially subcortical ones.cite journal
author = Maeda M, Tartaro A, Matsuda T, Ishii Y
title = Cortical and subcortical tubers in tuberous sclerosis and FLAIR sequence
journal = Journal of Computer Assisted Tomography
volume = 19
issue = 4
pages = 660–1
year = 1995
pmid = 7622707
doi = 10.1097/00004728-199507000-00033
] cite journal
author = Takanashi J, Sugita K, Fujii K, Niimi H
title = MR evaluation of tuberous sclerosis: increased sensitivity with fluid-attenuated inversion recovery and relation to severity of seizures and mental retardation
journal = AJNR American Journal of Neuroradiology
volume = 16
issue = 9
pages = 1923–8
year = 1995
pmid = 8693996
url = http://www.ajnr.org/cgi/reprint/16/9/1923

;1997: The TSC1 Consortium announced the cloning of TSC1; its product is called hamartin.cite journal
author = van Slegtenhorst M, de Hoogt R, Hermans C, "et al"
title = Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34
journal = Science
volume = 277
issue = 5327
pages = 805–8
year = 1997
pmid = 9242607
doi = 10.1126/science.277.5327.805

;1997: The PKD1 gene, which leads to autosomal dominant polycystic kidney disease (ADPKD), and the TSC2 gene were discovered to be adjacent on chromosome 16p13.3. A team based at the Institute of Medical Genetics in Wales studied 27 unrelated patients with TSC and renal cystic disease. They concluded that serious renal disease in those with TSC is usually due to contiguous gene deletions of TSC2 and PKD1. They also noted that the disease was different (earlier and more severe) than ADPKD and that patients with TSC1 did not suffer significant cystic disease.cite journal
author = Sampson JR, Maheshwar MM, Aspinwall R, "et al"
title = Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene
journal = American Journal of Human Genetics
volume = 61
issue = 4
pages = 843–51
year = 1997
pmid = 9382094
url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=9382094
doi = 10.1086/514888

;1997: Patrick Bolton and Paul Griffiths examined 18 patients with TSC, half of whom had some form of autism. They found a strong association between tubers in the temporal lobes and the patients with autism.cite journal
author = Bolton PF, Griffiths PD
title = Association of tuberous sclerosis of temporal lobes with autism and atypical autism
journal = Lancet
volume = 349
issue = 9049
pages = 392–5
year = 1997
pmid = 9033466
doi = 10.1016/S0140-6736(97)80012-8

;1998: The Tuberous Sclerosis Consensus Conference issued revised diagnosic criteria, which is the current standard.cite journal
author = Roach ES, Gómez MR, Northrup H
title = Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria
journal = Journal of Child Neurology
volume = 13
issue = 12
pages = 624–8
year = 1998
pmid = 9881533

;1998: An Italian team used magnetoencephalography (MEG) to study three patients with TSC and partial epilepsy. Combined with MRI, they were able to study the association between tuberous areas of the brain, neuronal malfunctioning and epileptogenic areas.cite journal
author = Peresson M, Lopez L, Narici L, Curatolo P
title = Magnetic source imaging and reactivity to rhythmical stimulation in tuberous sclerosis
journal = Brain Dev
volume = 20
issue = 7
pages = 512–8
year = 1998
pmid = 9840671
doi = 10.1016/S0387-7604(98)00034-5
] Later studies would confirm that MEG is superior to EEG in identifying the eliptogenic tuber, which may be a candidate for surgical resection.cite journal
author = Jansen F, Huiskamp G, van Huffelen A, Bourez-Swart M, Boere E, Gebbink T, Vincken K, van Nieuwenhuizen O
title = Identification of the epileptogenic tuber in patients with tuberous sclerosis: a comparison of high-resolution EEG and MEG
journal = Epilepsia
volume = 47
issue = 1
pages = 108–14
year = 2006
pmid = 16417538
url = http://www.blackwell-synergy.com/doi/full/10.1111/j.1528-1167.2006.00373.x
doi = 10.1111/j.1528-1167.2006.00373.x

21st century

;2001: A multi-centre cohort of 224 patients were examined for mutations and disease severity. Those with TSC2 were less severely affected than those with TSC1. They had fewer seizures and less mental impairment. Some symptoms of TSC were rare or absent in those with TSC1. A conclusion is that "both germline and somatic mutations appear to be less common in TSC1 than in TSC2". title = Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs
journal = The American Jounal of Human Genetics
volume = 68
issue = 1
pages = 64–80
year = 2001
pmid = 11112665
url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=11112665
doi = 10.1086/316951]

;2002: Several research groups investigated how the TSC1 and TSC2 gene products (tuberin and hamartin) work together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signalling. This important pathway regulates cell proliferation and tumour suppression.cite journal
author = Tee A, Fingar D, Manning B, Kwiatkowski D, Cantley L, Blenis J
title = Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling
journal = Proc Natl Acad Sci USA
volume = 99
issue = 21
pages = 13571–6
date = 2005-10-15
pmid = 12271141
url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12271141
doi = 10.1073/pnas.202476899

;2002: Treatment with rapamycin (sirolimus) was found to shrink tumours in the Eker rat (TSC2)cite journal
author = Kenerson H, Aicher L, True L, Yeung R
title = Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors
journal = Cancer Res
volume = 62
issue = 20
pages = 5645–50
year = 2002
pmid = 12384518
url = http://cancerres.aacrjournals.org/cgi/content/full/62/20/5645
] and mouse (TSC1)cite journal
author = Kwiatkowski D, Zhang H, Bandura J, "et al"
title = A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells
journal = Hum Mol Genet
volume = 11
issue = 5
pages = 525–34
year = 2002
pmid = 11875047
url = http://hmg.oxfordjournals.org/cgi/content/full/11/5/525
doi = 10.1093/hmg/11.5.525
] models of tuberous sclerosis.

;2006: Small trials showed promising results in the use of rapamycin to shrink angiomyolipomacite journal
author = Wienecke R, Fackler I, Linsenmaier U, Mayer K, Licht T, Kretzler M
title = Antitumoral activity of rapamycin in renal angiomyolipoma associated with tuberous sclerosis complex
journal = American Journal of Kidney Diseases
volume = 48
issue = 3
pages = e27–9
year = 2006
month = Sep
pmid = 16931204
doi = 10.1053/j.ajkd.2006.05.018
] and astrocytomas.cite journal
author = Franz DN, Leonard J, Tudor C, "et al"
title = Rapamycin causes regression of astrocytomas in tuberous sclerosis complex
journal = Ann Neurol
volume = 59
issue = 3
pages = 490–8
year = 2006
pmid = 16453317
url = http://www3.interscience.wiley.com/cgi-bin/fulltext/112394625/PDFSTART
doi = 10.1002/ana.20784
] Several larger multicentre clinical trials began: lymphangioleiomyomatosis (LAM)cite web
url = http://www.clinicaltrials.gov/ct/show/NCT00411619
title = Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus Trial (The MILES Trial)
accessdate = 2007-01-10
date = 2007-01-06
publisher = ClinicalTrials.gov (NIH)
] and kidney angiomyolipoma (AML)cite web
url = http://www.clinicaltrials.gov/show/NCT00126672
title = Sirolimus in Treating Patients With Angiomyolipoma of the Kidney
accessdate = 2007-01-10
date = 2006-11-21
publisher = ClinicalTrials.gov (NIH)
] were treated with rapamycin; giant cell atrocytomas were treated with the rapamycin derivative everolimus.cite web
url = http://www.clinicaltrials.gov/ct/gui/show/NCT00408343
title = Everolimus (RAD001) Therapy of Giant Cell Astrocytoma in Patients With Tuberous Sclerosis Complex
accessdate = 2007-01-10
date = 2006-12-13
publisher = ClinicalTrials.gov (NIH)



* cite book
author = Acierno, Louis J
title = The History of Cardiology
accessdate = 2007-01-11
date= 1994
publisher = Taylor & Francis
isbn = 1850703396
pages = 427

* cite book
author=Curatolo, Paolo (Editor)
title=Tuberous Sclerosis Complex : From Basic Science to Clinical Phenotypes
publisher=MacKeith Press
isbn = 1-898683-39-5

* cite journal
author = Gómez MR
year = 1995
title = History of the tuberous sclerosis complex
journal = Brain & Development
volume = 17
issue = suppl
pages = 55–7 |pmid=8882573
doi = 10.1016/0387-7604(94)00130-8

* cite web
url = http://www.tsdev.de/92001/Uploaded/hhehn%7Cgeschichte_der_tsc2005.pdf
title = Zur Geschichte der Tuberösen Sklerose (The History of Tuberous Sclerosis)
accessdate = 2007-01-08
author = Rott HD, Mayer K, Walther B, Wienecke R
date = 2005
publisher = Tuberöse Sklerose Deutschland e.V
language = German
format = PDF

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