mtor signalling, part of the growth factor (insulin) signalling pathway. thus, mutations at the tsc1 and tsc2 loci result in a loss of control of cell growth and cell division, and therefore a predisposition to forming tumors. tsc affects tissues from different germ layers. cutaneous and visceral lesions may occur, including angiofibroma, cardiac rhabdomyomas, and renal angiomyolipomas. the central nervous system lesions seen in this disorder include hamartomas of the cortex, hamartomas of the ventricular walls, and subependymal giant cell tumors, which typically develop in the vicinity of the foramina of monro. molecular genetic studies have defined at least two loci for tsc. in tsc1, the abnormality is localized on chromosome 9q34, but the nature of the gene protein, called hamartin, remains unclear. no missense mutations occur in tsc1. in tsc2, the gene abnormalities are on chromosome 16p13. this gene encodes tuberin, a guanosine triphosphatase–activating protein. the specific function of this protein is unknown. in tsc2, all types of mutations have been reported; new mutations occur frequently. few differences have yet been observed in the clinical phenotypes of patients with mutation of one gene or the other. cells from individuals with pathogenic mutations in the tsc2 gene display abnormal accumulation of glycogen that is associated with depletion of lysosomes and autophagic impairment. the defective degradation of glycogen by the autophagy-lysosome pathway is, at least in part, independent of impaired regulation of mtorc1 and is restored, in cultured cells, by the combined use of pkb/akt and mtorc1 pharmacological inhibitors. diagnosis tuberous sclerosis complex is diagnosed with clinical and genetic tests. there are many different mutations in the tsc1 and tsc2 genes that have been identified in individuals with tsc. a pathogenic mutation in the gene prevents the proteins from being made or inactivates the proteins. if such a pathogenic mutation is found then this alone is sufficient to diagnose tsc. however, some mutations are less clear in their effect, and so not sufficient alone for diagnosis. between 1 in 10 and 1 in 4 of individuals with tsc have no mutation that can be identified. once a particular mutation is identified in someone with tsc, this mutation can be used to make confident diagnoses in other family members. for clinical diagnosis, there isn't one sign that is unique (pathognomonic) to tsc, nor are all signs seen in all individuals. therefore, several signs are considered together, classed as either major or minor features. an individual with two major features, or one major feature and at least two minor features can be given a definite diagnosis of tsc. if only one major feature or at least two minor features are present, the diagnosis is only regarded as possibly tsc. diagnostic criteria for tuberous sclerosis complex major features location sign onset note 1 skin hypomelanotic macules infant – child at least three, at least 5 mm in diameter. 2 head facial angiofibromas or fibrous cephalic plaque infant – adult at least three angiofibromas 3 fingers and toes ungual fibroma adolescent – adult at least two 4 skin shagreen patch (connective tissue nevus) child 5 eyes multiple retinal nodular hamartomas infant 6 brain cortical dysplasias fetus (includes tubers and cerebral white matter radial migration lines) 7 brain subependymal nodule child – adolescent 8 brain subependymal giant cell astrocytoma child – adolescent 9 heart cardiac rhabdomyoma fetus 10 lungs lymphangioleiomyomatosis adolescent – adult 11 kidneys renal angiomyolipoma child – adult at least two. together, 10 and 11 count as one major feature. minor features location sign note 1 skin "confetti" skin lesions 2 teeth dental enamel pits at least three 3 gums intraoral fibromas at least two 4 eyes retinal achromic patch 5 kidneys multiple renal cysts 6 liver, spleen and other organs nonrenal hamartoma tsc can be first diagnosed at any stage of life. prenatal diagnosis is possible by chance if heart tumours are discovered during routine ultrasound. in infancy, epilepsy, particularly infantile spasms, or developmental delay may lead to neurological tests. the white patches on the skin may also first become noticed. in childhood, behavioural problems and autism spectrum disorder may provoke a diagnosis. during adolescence, the skin problems appear. in adulthood, kidney and lung problems may develop. an individual may also be diagnosed at any time as a result of genetic testing of family members of another affected person. management tuberous sclerosis complex affects multiple organ systems so a multidisciplinary team of medical professionals is required. in suspected or newly diagnosed tsc, the following tests and procedures are recommended by 2012 international tuberous sclerosis complex consensus conference. take a personal and family history covering three generations. genetic counselling and tests determine if other individuals are at risk. a magnetic resonance imaging (mri) of the brain to identify tubers, subependymal nodules (sen) and sub-ependymal giant cell astrocytomas (sega). children undergo a baseline electroencephalograph (eeg) and family educated to identify seizures if/when they occur. assess children for behavioural issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems. scan the abdomen for tumours in various organs, but most importantly angiomyolipomata in the kidneys. mri is superior to ct or ultrasound. take blood pressure and test renal function. in adult women, test pulmonary function and perform a high-resolution computed tomography (hrct) of the chest. examine the skin under a wood's lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas). in infants under three, perform an echocardiogram to spot rhabdomyomas, and electrocardiogram (ecg) for any arrhythmia. use a fundoscope to spot retinal hamartomas or achromic patches. the various symptoms and complications from tsc may appear throughout life, requiring continued surveillance and adjustment to treatments. the following ongoing tests and procedures are recommended by 2012 international tuberous sclerosis complex consensus conference. in children and adults younger than 25 years, a magnetic resonance imaging (mri) of the brain is performed every one to three years to monitor for subependymal giant cell astrocytoma (sega). if a sega is large, growing or interfering with ventricles, the mri is performed more frequently. after 25 years, if there are no segas then periodic scans may no longer be required. a sega causing acute symptoms are removed with surgery, otherwise either surgery or drug treatment with an mtor inhibitor may be indicated. repeat screening for tsc-associated neuropsychiatric disorders (tand) at least annually. sudden behavioural changes may indicate a new physical problem (for example with the kidneys, epilepsy or a sega). routine eeg determined by clinical need. infantile spasms are best treated with vigabatrin and adrenocorticotropic hormone used as a second-line therapy. other seizure types have no tsc-specific recommendation, though epilepsy in tsc is typically difficult to treat (medically refractory). repeat mri of abdomen every one to three years throughout life. check renal (kidney) function annually. should angiomyolipoma bleed, this is best treated with embolisation and then corticosteroids. removal of the kidney (nephrectomy) is strongly to be avoided. an asymptomatic angiomyolipoma that is growing larger than 3 cm is best treated with an mtor inhibitor drug. other renal complications spotted by imaging include polycystic kidney disease and renal cell carcinoma. repeat chest hrct in adult women every five to 10 years. evidence of lymphangioleiomyomatosis (lam) indicates more frequent testing. an mtor inhibitor drug can help, though a lung transplant may be required. a 12-lead ecg should be performed every three to five years. the mtor inhibitor everolimus was approved in the us for treatment of tsc-related tumors in the brain (subependymal giant cell astrocytoma) in 2010 and in the kidneys (renal angiomyolipoma) in 2012. oral everolimus (rapalog) reduces tumour size, is effective in terms of response to skin lesions and does not increase the risk of adverse events. everolimus also showed evidence of effectiveness at treating epilepsy in some people with tsc. in 2017, the european commission approved everolimus for treatment of refractory partial-onset seizures associated with tsc. neurosurgical intervention may reduce the severity and frequency of seizures in tsc patients. embolization and other surgical interventions can be used to treat renal angiomyolipoma with acute hemorrhage. surgical treatments for symptoms of lymphangioleiomyomatosis (lam) in adult tsc patients include pleurodesis to prevent pneumothorax and lung transplantation in the case of irreversible lung failure. other treatments that have been used to treat tsc manifestations and symptoms include a ketogenic diet for intractable epilepsy and pulmonary rehabilitation for lam. facial angiofibromas can be reduced with laser treatment and the effectiveness of mtor inhibitor topical treatment is being investigated. laser therapy is painful, requires anaesthesia, and has risks of scarring and dyspigmentation. prognosis the prognosis for individuals with tsc depends on the severity of symptoms, which range from mild skin abnormalities to varying degrees of learning disabilities and epilepsy to severe intellectual disability, uncontrollable seizures, and kidney failure. those individuals with mild symptoms generally do well and live long, productive lives, while individuals with the more severe form may have serious disabilities. however, with appropriate medical care, most individuals with the disorder can look forward to normal life expectancy. a study of 30 tsc patients in egypt found, "...earlier age of seizures commencement (<6 months) is associated with poor seizure outcome and poor intellectual capabilities. infantile spasms and severely epileptogenic eeg patterns are related to the poor seizure outcome, poor intellectual capabilities and autistic behavior. higher tubers numbers is associated with poor seizure outcome and autistic behavior. left-sided tuber burden is associated with poor intellect, while frontal location is more encountered in asd . so, close follow up for the mental development and early control of seizures are recommended in a trial to reduce the risk factors of poor outcome. also early diagnosis of autism will allow for earlier treatment and the potential for better outcome for children with tsc." leading causes of death include renal disease, brain tumour, lymphangioleiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe intellectual disability. cardiac failure due to rhabdomyomas is a risk in the fetus or neonate but is rarely a problem subsequently. kidney complications such as angiomyolipoma and cysts are common and more frequent in females than males and in tsc2 than tsc1. renal cell carcinoma is uncommon. lymphangioleiomyomatosis is only a risk for females with angiomyolipomas. in the brain, the subependymal nodules occasionally degenerate to subependymal giant cell astrocytomas. these may block the circulation of cerebrospinal fluid around the brain, leading to hydrocephalus. detection of the disease should be followed by genetic counselling. it is also important to realise that though the disease does not have a cure, symptoms can be treated symptomatically. hence, awareness regarding different organ manifestations of tsc is important. epidemiology tsc occurs in all races and ethnic groups, and in both genders. the live-birth prevalence is estimated to be between 10 and 16 cases per 100,000. a 1998 study estimated total population prevalence between about 7 and 12 cases per 100,000, with more than half of these cases undetected. prior to the invention of ct scanning to identify the nodules and tubers in the brain, the prevalence was thought to be much lower, and the disease associated with those people diagnosed clinically with learning disability, seizures and facial angiofibroma. whilst still regarded as a rare disease, tsc is common when compared to many other genetic diseases, with at least 1 million individuals affected worldwide. history main article: timeline of tuberous sclerosis désiré-magloire bourneville tsc first came to medical attention when dermatologists described the distinctive facial rash (1835 and 1850). a more complete case was presented by von recklinghausen (1862), who identified heart and brain tumours in a newborn who had only briefly lived. however, bourneville (1880) is credited with having first characterized the disease, coining the name "tuberous sclerosis", thus earning the eponym bourneville's disease. the neurologist vogt (1908) established a diagnostic triad of epilepsy, idiocy, and adenoma sebaceum (an obsolete term for facial angiofibroma). symptoms were periodically added to the clinical picture. the disease as presently understood was first fully described by gomez (1979). the invention of medical ultrasound, ct and mri has allowed physicians to examine the internal organs of live patients and greatly improved diagnostic ability. in 2002, treatment with rapamycin was found to be effective at shrinking tumours in animals. this has led to human trials of rapamycin as a drug to treat several of the tumors associated with tsc.