Timeline of tuberous sclerosis
Encyclopedia
Tuberous sclerosis
Tuberous sclerosis or tuberous sclerosis complex is a rare multi-system genetic disease that causes non-malignant tumors 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, behavioral...
(TSC) is a rare, multi-system genetic disease
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that can cause benign tumours to grow on the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
or other vital organs such as the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s, heart
Human heart
The human heart is a muscular organ that provides a continuous blood circulation through the cardiac cycle and is one of the most vital organs in the human body...
, eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
s, lung
Human lung
The human lungs are the organs of respiration in humans. Humans have two lungs, with the left being divided into two lobes and the right into three lobes. Together, the lungs contain approximately of airways and 300 to 500 million alveoli, having a total surface area of about in...
s, and skin
Human skin
The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has multiple layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to that of most other mammals,...
. A combination of symptoms may include seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, developmental delay
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, behavioural problems and skin abnormalities, as well as lung and kidney disease. TSC is caused by mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s on either of two gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, TSC1
TSC1
Tuberous sclerosis protein 1, also known as TSC1 or hamartin, is a human protein and gene.- Function :This peripheral membrane protein was implicated as a tumor suppressor...
and TSC2
TSC2
Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and gene.-Interactions:TSC2 has been shown to interact with FOXO1, GSK3B, Peptidylglycine alpha-amidating monooxygenase, RAP1A, MAPK1, AKT1, AXIN1, TSC1, PTK2, Protein kinase, AMP-activated, alpha 1, YWHAZ, RPS6KA1,...
, which encode for the protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s hamartin and tuberin respectively. These proteins act as tumour growth suppressors
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
and regulate cell proliferation and differentiation. 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. In the late 19th century, notable physician
Physician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...
s working in the great European teaching hospital
Teaching hospital
A teaching hospital is a hospital that provides clinical education and training to future and current doctors, nurses, and other health professionals, in addition to delivering medical care to patients...
s first described the cortical
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
and dermatological
Dermatology
Dermatology is the branch of medicine dealing with the skin and its diseases, a unique specialty with both medical and surgical aspects. A dermatologist takes care of diseases, in the widest sense, and some cosmetic problems of the skin, scalp, hair, and nails....
manifestation
Medical sign
A medical sign is an objective indication of some medical fact or characteristic that may be detected by a physician during a physical examination of a patient....
s; these early researchers have been awarded with eponym
Eponym
An eponym is the name of a person or thing, whether real or fictitious, after which a particular place, tribe, era, discovery, or other item is named or thought to be named...
s such as "Bourneville's disease" and "Pringle's adenoma sebaceum". 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
Neuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...
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 RayerPierre François Olive Rayer
Pierre François Olive Rayer was a French physician who was a native of Saint Sylvain. He made important contributions in the fields of pathological anatomy, physiology, comparative pathology and parasitology....
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. Entitled "végétations vasculaires", Rayer noted these were "small vascular
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
, of papulous
Papule
A papule is a circumscribed, solid elevation of skin with no visible fluid, varying in size from a pinhead to 1 cm.With regard to the quote "...varying in size from a pinhead to 1cm," depending on which text is referenced, some authors state the cutoff between a papule and a plaque as 0.5cm,...
appearance, widespread growths distributed on the nose and around the mouth". No mention was made of any medical condition associated with the skin disorder.
1850: English dermatologists Thomas Addison
Thomas Addison
Thomas Addison was a renowned 19th-century English physician and scientist. He is traditionally regarded as one of the "great men" of Guy's Hospital in London....
and William Gull described, in Guy's Hospital
Guy's Hospital
Guy's Hospital is a large NHS hospital in the borough of Southwark in south east London, England. It is administratively a part of Guy's and St Thomas' NHS Foundation Trust. It is a large teaching hospital and is home to the King's College London School of Medicine...
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".
1862: German physician Friedrich Daniel von Recklinghausen
Friedrich Daniel von Recklinghausen
Friedrich Daniel von Recklinghausen was a German pathologist who practiced medicine in Würzburg and Strassburg . Born in Gütersloh, Westphalia, he was the father of physiologist Heinrich von Recklinghausen ....
, who was working as an assistant to Rudolf Virchow
Rudolf Virchow
Rudolph Carl Virchow was a German doctor, anthropologist, pathologist, prehistorian, biologist and politician, known for his advancement of public health...
in the Institute for Pathological Anatomy in Berlin, presented a case to the city's Obstetrical Society. 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 rhabdomyoma
Rhabdomyoma
A rhabdomyoma is a benign tumor of striated muscle. Rhabdomyomas may be either "cardiac" or "extracardiac" . Extracardiac forms of rhabdomyoma are subclassified into three distinct types: Adult type, Fetal type, and Genital type.Cardiac rhabdomyomas are the most common primary tumor of the heart...
s and cortical
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
tubers of tuberous sclerosis. He failed to recognise a distinct disease, regarding it as a pathological-anatomical curiosity. Von Recklinghausen's name would instead become associated with neurofibromatosis
Neurofibromatosis
Neurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors that may be benign or may cause serious damage by compressing nerves and other tissues...
after a classic paper in 1881.
1864: German pathologist Rudolf Virchow
Rudolf Virchow
Rudolph Carl Virchow was a German doctor, anthropologist, pathologist, prehistorian, biologist and politician, known for his advancement of public health...
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.
1880: French neurologist Désiré-Magloire Bourneville
Désiré-Magloire Bourneville
Désiré-Magloire Bourneville was a French neurologist born in Garencières. He studied medicine in Paris, and was an intern at the Salpêtrière and Bicêtre Hospitals....
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
Pitié-Salpêtrière Hospital
The Pitié-Salpêtrière Hospital is a teaching hospital located in Paris, France. Part of the Assistance publique - Hôpitaux de Paris, it is one of Europe's largest hospitals...
. While substituting for his teacher, Louis J.F. Delasiauve
Louis Delasiauve
Louis Jean Francois Delasiauve was a French psychiatrist who was a native of Garennes-sur-Eure. In 1830 he earned his doctorate in Paris, and for the next eight years practiced medicine in Ivry. Afterwards he worked at the Bicêtre Hospital, and later became a director at the Salpêtrière, where he...
, he attended to Marie, a 15-year-old girl with psychomotor retardation
Psychomotor retardation
Psychomotor retardation involves a slowing-down of thought and a reduction of physical movements in an individual. Psychomotor retardation can cause a visible slowing of physical and emotional reactions, including speech and affect...
, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
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
Quinquina
In France, quinquina is a collective name for bitters having quinine as one of their main ingredients. Quinquina is also known as Peruvian Bark.It originates from South America...
, bromide
Bromide
A bromide is a chemical compound containing bromide ion, that is bromine atom with effective charge of −1. The class name can include ionic compounds such as caesium bromide or covalent compounds such as sulfur dibromide.-Natural occurrence:...
of camphor
Camphor
Camphor is a waxy, white or transparent solid with a strong, aromatic odor. It is a terpenoid with the chemical formula C10H16O. It is found in wood of the camphor laurel , a large evergreen tree found in Asia and also of Dryobalanops aromatica, a giant of the Bornean forests...
, amyl nitrite
Amyl nitrite
Amyl nitrite is the chemical compound with the formula C5H11ONO. A variety of isomers are known, but they all feature an amyl group attached to the nitrito functional group. The alkyl group is unreactive and the chemical and biological properties are mainly due to the nitrite group...
, and the application of leech
Leech
Leeches are segmented worms that belong to the phylum Annelida and comprise the subclass Hirudinea. Like other oligochaetes such as earthworms, leeches share a clitellum and are hermaphrodites. Nevertheless, they differ from other oligochaetes in significant ways...
es behind the ears. On 7 May 1879 Marie died in her hospital bed. The post-mortem
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
examination disclosed hard, dense tubers in the cerebral
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
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.
1881: German physician Hartdegen described the case of a two-day-old baby who died in status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
. Post-mortem examination revealed small tumours in the lateral ventricles
Lateral ventricles
The lateral ventricles are part of the ventricular system of the brain. Classified as part of the telencephalon, they are the largest of the ventricles....
of the brain and areas of cortical sclerosis
Sclerosis (medicine)
In medicine, sclerosis refers to the stiffening of a structure, usually caused by a replacement of the normal organ-specific tissue with connective tissue.Types include:...
, which he called "glioma gangliocellulare cerebri congenitum".
1881: Bourneville and Édouard Brissaud
Édouard Brissaud
-See also:*Timeline of tuberous sclerosis*History of Tourette syndrome...
examined a four-year-old boy at La Bicétre
Bicêtre Hospital
The Bicêtre Hospital is located in Le Kremlin-Bicêtre, which is a commune in the southern suburbs of Paris, France. It lies 4.5 km from the center of Paris. The Bicêtre Hospital was originally planned as a military hospital, with construction begun in 1634. With the help of Vincent de Paul, it was...
. As before, this patient had cortical tubers, epilepsy and learning difficulties. In addition he had a heart murmur
Heart murmur
Murmurs are extra heart sounds that are produced as a result of turbulent blood flow that is sufficient to produce audible noise. Most murmurs can only be heard with the assistance of a stethoscope ....
and, on post-mortem examination, had tiny hard tumours in the ventricle
Ventricular system
The ventricular system is a set of structures containing cerebrospinal fluid in the brain. It is continuous with the central canal of the spinal cord.-Components:The system comprises four ventricles:* right and left lateral ventricles* third ventricle...
walls in the brain (subependymal nodules) and small tumours in the kidneys (angiomyolipoma
Angiomyolipoma
Angiomyolipoma are the most common benign tumour of the kidney and are composed of blood vessels, smooth muscle cells and fat cells. Angiomyolipoma are strongly associated with the genetic disease tuberous sclerosis, in which most individuals will have several angiomyolipoma affecting both kidneys...
s).
1885: French physicians Félix Balzer
Félix Balzer
Félix Balzer was a French physician, specialising in dermatology and pathology.Balzer gave an early description of pseudoxanthoma elasticum in 1884. He used the term "xanthome elastique" but subsequently it was found not to be a form of xanthomatosis...
and Pierre Eugène Ménétrier
Pierre Eugène Ménétrier
Pierre Eugène Ménétrier was a French pathologist from Paris. He is remembered for his description of a rare gastric disorder that was later to become known as Ménétrier's disease....
reported a case of "adénomes sébacés de la face et du cuir" (adenoma of the sebaceous glands of the face and scalp). The term has since proved to be incorrect as they are neither adenoma
Adenoma
An adenoma is a benign tumor of glandular origin. Adenomas can grow from many organs including the colon, adrenal glands, pituitary gland, thyroid, prostate, etc. Although these growths are benign, over time they may progress to become malignant, at which point they are called adenocarcinomas...
nor derived from sebaceous glands. The papular rash is now known as facial angiofibroma.
1885: French dermatologists François Henri Hallopeau
François Henri Hallopeau
François Henri Hallopeau was a French dermatologist. He studied medicine under Alfred Vulpian and Sigismond Jaccoud. He co-founded and was secretary general of the Société Française de dermatologie et de syphiligraphie. He became a member of the Académie de Médecine in 1893.He coined the medical...
and Émile Leredde
Émile Leredde
Émile Leredde was a French physician, specialising in dermatology. In 1885, Leredde published with François Henri Hallopeau a report on the papular facial rash of tuberous sclerosis, then known as "adénomes sébacés" . The report also noticed the frequent association of epilepsy with the...
published a case of adenoma sebaceum that was of a hard and fibrous nature. They first described the shagreen
Shagreen
Shagreen is a type of leather or rawhide consisting of rough untanned skin, formerly made from a horse's back or that of an onager . Shagreen is now commonly made of the skins of sharks and rays....
plaques and later would note an association between the facial rash and epilepsy.
1890: Scottish dermatologist John James Pringle
John James Pringle
John James Pringle was a Scottish dermatologist. He was born in Borgue, Kirkcudbrightshire and educated at Merchiston Castle school. He graduated in medicine from Edinburgh University in 1876...
, 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. Pringle's adenoma sebaceum would become a common eponym
Eponym
An eponym is the name of a person or thing, whether real or fictitious, after which a particular place, tribe, era, discovery, or other item is named or thought to be named...
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 heterotopiaHeterotopia (medicine)
In medicine, "heterotopia" refers to normal tissue present at an abnormal site or the displacement of an organ or part of an organ from its normal position. For example, gray matter heterotopia, the displacement of gray matter into the cerebral white matter or ventricles...
and defective myelination. Pellizzi classified the tubers into type 1 (smooth surface) and type 2 (with central depressions).
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).
1906: Australian neurologist Alfred Walter Campbell
Alfred Walter Campbell
-Further reading:...
, 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
Heinrich Vogt
Heinrich Vogt was a German neurologist. He published papers on tuberous sclerosis and Batten disease. Later he became a professor of psychiatry and published a handbook on the treatment of nervous diseases...
.
1908: German paediatric neurologist Heinrich Vogt
Heinrich Vogt
Heinrich Vogt was a German neurologist. He published papers on tuberous sclerosis and Batten disease. Later he became a professor of psychiatry and published a handbook on the treatment of nervous diseases...
established the diagnostic criteria for TSC, firmly associating the facial rash with the neurological consequences of the cortical tubers. Vogt's triad of epilepsy, idiocy, and adenoma sebaceum held for 60 years until research by Manuel Gómez
Manuel Rodríguez Gómez
Manuel Rodríguez Gómez was an American neurologist most noted for his work on tuberous sclerosis, a rare genetic disorder.-Life:...
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.
1911: Edward Sherlock, barrister-at-law
Barrister
A barrister is a member of one of the two classes of lawyer found in many common law jurisdictions with split legal professions. Barristers specialise in courtroom advocacy, drafting legal pleadings and giving expert legal opinions...
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). 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 acronym for epilepsy, low intelligence, and adenoma sebaceum.
1913: H. Berg is credited with first stating that TSC was a hereditary disorder, noting its transmission through two or three generations.
1914: P. Schuster described a patient with adenoma sebaceum and epilepsy but of normal intelligence. This reduced phenotypic
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
expression is called a forme fruste.
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
Pneumothorax
Pneumothorax is a collection of air or gas in the pleural cavity of the chest between the lung and the chest wall. It may occur spontaneously in people without chronic lung conditions as well as in those with lung disease , and many pneumothoraces occur after physical trauma to the chest, blast...
. Lutembacher believed the cysts and nodules to be metastases from a renal fibrosarcoma
Fibrosarcoma
Fibrosarcoma is a malignant tumor derived from fibrous connective tissue and characterized by immature proliferating fibroblasts or undifferentiated anaplastic spindle cells.Usually in males ages 30 to 40. Originates in fibrous tissues of the bone. Invades long or flat bones such as femur, tibia,...
. This complication, which only affects women, is now known as lymphangioleiomyomatosis
Lymphangioleiomyomatosis
Lymphangioleiomyomatosis is a rare lung disease that results in a proliferation of disorderly smooth muscle growth throughout the lungs, in the bronchioles, alveolar septa, perivascular spaces, and lymphatics, resulting in the obstruction of small airways and lymphatics...
(LAM).
1920: Dutch ophthalmologist Jan van der Hoeve
Jan van der Hoeve
Jan van der Hoeve was a Dutch ophthalmologist. He is recognised for his concept of the phakomatoses, often called neurocutaneous syndromes....
described the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
l hamartomas (phakoma). He grouped both TSC and neurofibromatosis
Neurofibromatosis
Neurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors that may be benign or may cause serious damage by compressing nerves and other tissues...
together as "phakomatoses
Phakomatoses
Phakomatoses are disorders of central nervous system that additionally result in lesions on the skin and the eye.These tissues have a common ectodermal origin...
" (later called neurocutaneous syndromes).
1924: H. Marcus noted that characteristic features of TSC such as intracranial calcifications were visible on x-ray
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...
.
Mid-20th century
1932: MacDonald CritchleyMacDonald Critchley
Macdonald Critchley CBE was a British neurologist. He was former president of the World Federation of Neurology, and the author of over 200 published articles on neurology and 20 books, including The Parietal Lobes , Aphasiology, and biographies of James Parkinson and Sir William Gowers.Macdonald...
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
Leo Kanner
Leo Kanner was a Jewish American psychiatrist and physician known for his work related to autism. Kanner's work formed the foundation of child and adolescent psychiatry in the U.S. and worldwide....
suggested the term "autism". They also noticed the associated white spots on the skin (hypomelanic macules).
1934: N.J. Berkwitz and L.G. Rigler showed it was possible to diagnose tuberous sclerosis using pneumoencephalography
Pneumoencephalography
Pneumoencephalography is a medical procedure in which most of the cerebrospinal fluid is drained from around the brain and replaced with air, oxygen, or helium to allow the structure of the brain to show up more clearly on an X-ray image...
to highlight non-calcified subependymal nodules. These resembled "the wax drippings of a burning candle" on the lateral ventricles.
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)."
1954: Norwegian pathologist Reidar Eker bred a line of Wistar rats predisposed to renal adenoma
Adenoma
An adenoma is a benign tumor of glandular origin. Adenomas can grow from many organs including the colon, adrenal glands, pituitary gland, thyroid, prostate, etc. Although these growths are benign, over time they may progress to become malignant, at which point they are called adenocarcinomas...
s. The Eker rat became an important model of dominantly inherited cancer.
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.
1967: J.C. Lagos and Manuel Rodríguez Gómez
Manuel Rodríguez Gómez
Manuel Rodríguez Gómez was an American neurologist most noted for his work on tuberous sclerosis, a rare genetic disorder.-Life:...
reviewed 71 TSC cases and found that 38% of patients have normal intelligence.
1971: American geneticist Alfred Knudson
Alfred G. Knudson
Alfred George Knudson, Jr. M.D., Ph.D. is a geneticist specializing in cancer genetics. Among his many contributions to the field was the formulation of the Knudson hypothesis in 1971, which explains the effects of mutation on carcinogenesis .Born in Los Angeles in 1922, Knudson received his B.S...
developed his "two hit" hypothesis
Knudson hypothesis
The Knudson hypothesis is the hypothesis that cancer is the result of accumulated mutations to a cell's DNA. It was first proposed by Carl O. Nordling in 1953, and later formulated by Alfred G. Knudson in 1971. Knudson's work led indirectly to the identification of cancer-related genes...
to explain the formation of retinoblastoma
Retinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
in both children and adults. The children had a congenital germline mutation
Germline mutation
A germline mutation is any detectable and heritable variation in the lineage of germ cells. Mutations in these cells are transmitted to offspring, while, on the other hand, those in somatic cells are not. A germline mutation gives rise to a constitutional mutation in the offspring, that is, a...
which was combined with an early lifetime somatic
Somatic cell
A somatic cell is any biological cell forming the body of an organism; that is, in a multicellular organism, any cell other than a gamete, germ cell, gametocyte or undifferentiated stem cell...
mutation to cause a tumour. This model applies to many conditions involving tumour suppressor genes
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
such as TSC. In the 1980s, Knudson's studies on the Eker rat strengthened this hypothesis.
1975: Giuseppe Pampiglione and E. Pugh, in a letter to The Lancet
The Lancet
The Lancet is a weekly peer-reviewed general medical journal. It is one of the world's best known, oldest, and most respected general medical journals...
, noted that up to 69% of patients presented with infantile spasms.
1975: Riemann first used ultrasound
Medical ultrasonography
Diagnostic sonography is an ultrasound-based diagnostic imaging technique used for visualizing subcutaneous body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions...
to examine TSC-affected kidneys in the case of a 35-year-old woman with chronic renal failure.
Late 20th century
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
(CT, invented 1972) proved to be an excellent tool for diagnosing cerebral neoplasms in children, including those found in tuberous sclerosis.
1979: Manuel Gómez published a monograph
Monograph
A monograph is a work of writing upon a single subject, usually by a single author.It is often a scholarly essay or learned treatise, and may be released in the manner of a book or journal article. It is by definition a single document that forms a complete text in itself...
: "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.
1982: Kenneth Arndt successfully treated facial angiofibroma with an argon laser.
1983: Positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
(PET, invented 1981) was compared to electroencephalography
Electroencephalography
Electroencephalography is the recording of electrical activity along the scalp. EEG measures voltage fluctuations resulting from ionic current flows within the neurons of the brain...
(EEG) and CT. It was found to be capable of locating epileptogenic cortical tubers that would otherwise have been missed.
1984: The cluster of infantile spasms in TSC was discovered to be preceded by a focal EEG discharge.
1985: Magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(MRI, invented 1980) was first used in TSC to identify affected regions in the brain of a girl with tuberous sclerosis.
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
Astrocytoma
Astrocytomas are a type of neoplasm of the brain. They originate in a particular kind of glial-cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usually affect other organs...
from benign subependymal nodules in one patient.
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.
1987: Linkage analysis on 19 families with TSC located a probable gene on chromosome 9.
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.
1990: Vigabatrin
Vigabatrin
Vigabatrin is an antiepileptic drug that inhibits the catabolism of gamma-aminobutyric acid by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist...
was found to be a highly effective antiepileptic treatment for infantile spasms, particularly in children with TSC. Following the discovery in 1997 of severe persistent visual field
Visual field
The term visual field is sometimes used as a synonym to field of view, though they do not designate the same thing. The visual field is the "spatial array of visual sensations available to observation in introspectionist psychological experiments", while 'field of view' "refers to the physical...
constriction as a possible side-effect, vigabatrin monotherapy is now largely restricted to this patient group.
1992: Linkage analysis located a second gene to chromosome 16p13.3, close to the polycystic kidney disease
Polycystic kidney disease
Autosomal dominant polycystic kidney disease is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels...
type 1 (PKD1) gene.
1993: The European Chromosome 16 Tuberous Sclerosis Consortium announced the cloning of TSC2
TSC2
Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and gene.-Interactions:TSC2 has been shown to interact with FOXO1, GSK3B, Peptidylglycine alpha-amidating monooxygenase, RAP1A, MAPK1, AKT1, AXIN1, TSC1, PTK2, Protein kinase, AMP-activated, alpha 1, YWHAZ, RPS6KA1,...
; its product is called tuberin.
1994: The Eker rat was discovered to be an animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
for tuberous sclerosis; it has a mutation in the rat-equivalent of the TSC2 gene.
1995: MRI with fluid attenuated inversion recovery
Fluid attenuated inversion recovery
Fluid attenuated inversion recovery is a pulse sequence used in magnetic resonance imaging which was invented by Dr. Graeme Bydder. FLAIR can be used with both three dimensional imaging or two dimensional imaging ....
(FLAIR) sequences was reported to be significantly better than standard T2-weighted images at highlighting small tubers, especially subcortical ones.
1997: The TSC1 Consortium announced the cloning of TSC1; its product is called hamartin.
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.
1997: Patrick Bolton and Paul Griffiths examined 18 patients with TSC, half of whom had some form of autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
. They found a strong association between tubers in the temporal lobes and the patients with autism.
1998: The Tuberous Sclerosis Consensus Conference issued revised diagnosic criteria, which is the current standard.
1998: An Italian team used magnetoencephalography
Magnetoencephalography
Magnetoencephalography is a technique for mapping brain activity by recording magnetic fields produced by electrical currents occurring naturally in the brain, using arrays of SQUIDs...
(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. Later studies would confirm that MEG is superior to EEG in identifying the eliptogenic tuber, which may be a candidate for surgical resection.
21st century
2001: A multi-centre cohortCohort study
A cohort study or panel study is a form of longitudinal study used in medicine, social science, actuarial science, and ecology. It is an analysis of risk factors and follows a group of people who do not have the disease, and uses correlations to determine the absolute risk of subject contraction...
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".
2002: Several research groups investigated how the TSC1 and TSC2 gene products (tuberin and hamartin) work together to inhibit mammalian target of rapamycin
Mammalian target of rapamycin
The mammalian target of rapamycin also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 is a protein which in humans is encoded by the FRAP1 gene...
(mTOR)-mediated downstream signalling. This important pathway regulates cell proliferation and tumour suppression.
2002: Treatment with rapamycin (sirolimus) was found to shrink tumours in the Eker rat (TSC2) and mouse (TSC1) models of tuberous sclerosis.
2006: Small trials showed promising results in the use of rapamycin to shrink angiomyolipoma and astrocytomas. Several larger multicentre clinical trials began: lymphangioleiomyomatosis (LAM) and kidney angiomyolipoma (AML) were treated with rapamycin; giant cell astrocytomas were treated with the rapamycin derivative everolimus
Everolimus
Everolimus is the 40-O- derivative of sirolimus and works similarly to sirolimus as an mTOR inhibitor....
.