What Is Tuberous Sclerosis?

Introduction 

Désiré‐Magloire Bourneville was the first person to describe Tuberous Sclerosis in the scientific literature in 1880. Tuberous Sclerosis (TS) is a genetic condition causing benign tumours in many of the organs of the body. Other names for this condition include Epiloia or Bourneville-Pringle disease. These tumours occur in a variety of different places, but the main areas that are affected are the head, kidneys and the skin. There are also patches of skin pigmentation changes due to a lack of melanin. TS is associated with developmental delay and seizures due to tumours in the brain.¹

Causes and genetics 

Genetic mutations responsible for TS are TSC1 and TSC2 genes. This is an autosomal dominant condition, which means that an affected parent has a 50% chance of passing the condition on to their children. The TSC1 gene is associated with the production of the protein hamartin. The TSC2 gene is associated with the protein tuberin. When there is a mutation in either TSC1 or TSC2, TS is the resulting clinical manifestation.¹ Sometimes, you can have unaffected parents (parents that don’t have TS), but a random mutation causes the condition in the child, which accounts for approximately 25% of cases of TS. There is also a type of mutation called mosaicism, which occurs when the patient has some genetic alterations and less severe symptoms. 

The prevalence in the UK is 0·7 per 100,000 people. The global prevalence and incidence rates are 1 in 5000 people. The prevalence has been underestimated due to the incomplete penetrance of the genes, giving intermediate phenotypes.⁴

Sometimes, people with mosaic TS have cortical tubers, but they do not have subependymal nodules (SEN). This is called a phenotype, or what the effect is on the patient’s body (How the condition presents) 

The TS does not appear to have a clear age or gender distribution, and it does not discriminate on either criterion. Symptoms are present at birth, however, if the symptoms are mild then they may go undiagnosed for a while.  81% of people diagnosed with TS are diagnosed before the age of 10⁸.

Clinical presentation 

Neurological manifestations 

• Cortical tubers are usually found on the outside edge of the brain, however, they can also be in other areas of the brain.³
• SEN are calcium-rich nodules that are found on an MRI on the walls of the cerebral ventricles which are filled with cerebral spinal fluid. This is a precursor to developing subependymal giant-cell astrocytomas. 
• Subependymal giant-cell astrocytomas are a benign tumour that usually occurs in childhood. They can cause problems for the individual as they can cause hydrocephalus (Increased fluid levels in the brain) and can also cause seizures that do not respond effectively to medication.
• Some of the main related conditions of TS are epilepsy and seizures. 
• Intellectual and developmental disabilities are also common in people with TS. 
• Autism 
• Dermatological symptoms can be present due to patches of skin that have less melanin.
• Facial angiofibromas. Facial angiofibromas are benign tumours that occur on the skin of the face. 
• Hypomelanotic macules 
• Problems with the kidneys. Such as renal angiomyolipomas and renal cysts. 
• Cardiac manifestations include Cardiac rhabdomyomas, and arrhythmias (irregular heart rhythm). 
• Pulmonary involvement 
• Ophthalmologic symptoms - these may include light or dark patches on the retina of the eye. This is the part of the eye that light hits after the light goes through the pupil. Damage to the retina can cause sight loss.⁹

Diagnosis and evaluation 

Diagnostic criteria

Imaging techniques will determine if a patient has benign tumours within the body. If TS is suspected, then further testing can be carried out to confirm the diagnosis, such as genetic testing. If a patient has a family member with the disorder, they may be more likely to arrange genetic testing due to the increased probability that they have it. 

Genetic testing determines if a patient has a mutation in either TSC1 or TSC2. Imaging techniques such as MRI and CT scans are also used to locate benign tumours. Ultrasonography is often used to image the kidneys or perform prenatal diagnosis before a baby is born. 

Hydrocephalus- this is a build-up of cerebrospinal fluid on the brain, which causes an increase in intracranial pressure. This in turn can lead to physical and neurological symptoms. Hydrocephalus can usually be seen on a prenatal ultrasound (before the baby is born).   

Genetic testing and counseling

Counselling is available for families and individuals with TS. The main reason TS diagnoses can be challenging sometimes is that it is hard to tell with any certainty what severity of symptoms will be associated with the diagnosis. This makes it hard for families to adjust and come up with a plan of treatment.⁵ Genetic testing can be offered to people who are planning their family, to determine if they carry the genes associated with TS so that they can make a decision on the probability of their children being affected with the disorder. 

Treatment and management

A multidisciplinary approach is required when managing the symptoms of TS. This is due to the fact that TS will affect lots of different organs in the body, producing a variety of different clinical problems. For example, problems with the skin will be addressed by the dermatology department whereas problems with the kidneys will be looked at by the renal specialists. 

Medications

Vigabatrin - This is a drug used to treat seizures associated with benign brain tumours. This drug works by inhibiting gamma-amino-butyric acid transaminase (GABA-T). GABA-T is an enzyme that breaks down GABA. If the breakdown of GABA is inhibited, then convulsions can be prevented¹¹. 

Rapamycin (Sirolimus)- Rapamycin is used to treat facial tumours called angiofibromas. The drug is also used to treat lymphangioleiomyomatosis which is a lung condition associated with TS. 

Everolimus - This is a type of chemotherapy that is used as a mTor blocker. It is also mainly used to help treat epilepsy that is caused by benign tumours in the brain. 

Surgical interventions

Brain tumours that are causing adverse side effects, such as problems with speech or memory, will need resection. This is when the whole tumour, or as much of the tumour that can be removed safely is taken away. This reduces pressure in the brain and will also help with the neurological symptoms. Renal embolisation- Surgery is required to remove blockages, which is called emboli, within the tubes within the kidney. 

Facial angiofibromas can cause distress to patients if they alter the appearance of the face. Surgery to remove angiofibroma may help patients who are suffering from depression or anxiety due to their facial angiofibroma.⁷

Management 

Management of seizures due to brain tumours is controlled with anti-seizure medication. Psychosocial support and education are required to help people with TS and their families deal with the associated symptoms, such as developmental delay and seizures. Whilst medication can reduce the amount of seizures, the medication will not cure the seizures. 

Occupational therapy may be offered to help with managing daily tasks such as brushing your teeth. Different levels of physical ability will require different interventions. Educational help (such as having a 1:1 teaching assistant or SENCO appointments) may be needed for people who have developmental delays due to brain tumours. This is because benign brain tumours may be associated with conditions such as autism and developmental delay.¹⁰ 

Current research and future directions 

Genetics and potential therapeutic targets, such as the TSC/mTOR Pathway and its association to kidney tumours, are currently being researched.. Whilst most of the tumours associated with TS are benign, people with TS have an increased risk of developing malignant kidney tumours (causing cancer). Clinical trials and experimental treatments are currently in the process of finding advances in early diagnosis and increasing the quality of life for affected individuals. 

Coping and support 

Knowrare is a website that helps to connect people with rare diseases like TS. Here you can find personal testimonials support and guidance that can help you with your diagnosis. Here you can connect with other people who are struggling with TS, and talk about any problems you are facing. A supportive community is vital in the management of any disease or disorder, as it enables you to ask other people who have experienced the same symptoms questions. 

Conclusion 

Tuberous Sclerosis is a multi-organ condition that can have a significant impact on the individuals affected due to tumours occurring in many different organs. Developmental delay is common due to the presence of brain tumours, as well as seizures and psychological side effects. Early diagnosis and comprehensive care are important to help give people a better quality of life. There is hope for the future due to advancements in research and treatment options. Rare diseases require further research to better aid in the treatment, management and diagnosis. An early diagnosis allows adequate provisions to be put in place to increase the quality of life for everyone affected.