Introduction

 

We are parents of a child affected by Tuberous Sclerosis and have wished to gather practical information and make it accessible to all. Families are often lost facing this rare disease, whose symptoms and prognosis remain very different from one patient to another. 

We hope that this website can bring you a real support by sharing updated information, contacts or tips and will facilitate your everyday life and make you save time.

The information in this website and forum is free and open to all to grow communication related to Tuberous Sclerosis (such as disease knowledge and management, experience sharing between families or patients…).

First of all, do not remain alone facing TSC and do not hesitate to post your comments on the forum. Your input will be useful to all, whether you are directly or indirectly concerned by TSC. Patient (child, teenager, adult) or close relative (parent, grandparent, sister or brother, cousin), you can express yourselves and share your testimony. All areas in everyday life can be addressed here: work, school, leisure, social life, care, treatment … 

All initiatives, even small, put end to end, can improve the understanding of Tuberous Sclerosis and make us to control it better.

By definition, this website can be improved and can benefit from your comments. Do not hesitate to contact us through the forum or by email at the following address:

contact@sclerose-tubereuse.com

 

 

What to do at diagnosis ?

How to react to the announcement of TSC diagnosis ?

As early as the announcement of the diagnosis, it is essential to set up a medical follow-up in an hospital environment for optimal care. According to the symptoms (epilepsy, cutaneous problems, mental retardation, affected kidneys…), you will have to see frequently one or several specialized hospital departments.

Therefore, we recommend a thourough medical exam in a TSC Reference center.

Who should you contact?

You can join TSC patient associations. They can be found in many countries today (for example in the United Kingdom, Italy, France, Germany or in the United States). They contribute to inform about Tuberous Sclerosis, improve patient management and support research programs.

To help families at the announcement of the disease, a psychological help is advised, but only the parents can decide when it is appropriate.

Whether you are personally concerned by the diagnosis or the relative of a TSC child, you should know that you are not alone. We can all benefit from the experience of other families and to contribute to create a stronger mutual support.

 

TSC, a rare disease?

Tuberous Sclerosis is a genetic disease, generally with random distribution, with no parental age effect.

TSC is a rare disease, but it is not exceptional because its frequency is about 1 case in 6,000 births. About 60,000 people are affected by the disease in Europe, about as much in the United States and probably more than two millions worldwide. TSC is one of most wide-spread rare diseases. As a comparison, prevalence (number of patients) of cystic fibrosis or haemophilia is almost twice lower than that of TSC.

Tuberous Sclerosis Complex remains little known by the public and, regrettably, very often by the medical community in general. The main reasons are that it has a large diversity of expressions, but also little exposure to the media in many countries. Tuberous Sclerosis remains a disease with complex mechanisms and the symptoms may vary between the individuals and their age.

Some patients will be slightly affected and will live an almost normal life; others, more heavily affected, will need all the support of their family to develop their capacities at best. Each individual affected by TSC has his own story.

 

Symptoms

What is TSC ?

Tuberous Sclerosis Complex is a genetic disease, either with familial origin or due to a genetic de-novo mutation as none of the 2 parents were affected. It is considered that 70 % of TSC cases are due to new mutations.

The disease is a part of a group of diseases, known as neuro-ectodermoses or neuro-cutaneous syndromes. It is characterized by benign tumors which can affect various organs (brain, kidneys and skin primarily; heart, eyes, lungs, less frequently)

Why are there micro-tumors in organs?

The genetic disorders of the Tuberous Sclerosis result in an abnormal cell signal transduction which produces a chain reaction. The misleading signals cause an erratic growth of cells and vessels. The inflammatory reactions are then transformed into definitive and fibrosing lesions.

Mécanisme de la Sclérose Tubéreuse de Bourneville

Mécanisme de la Sclérose Tubéreuse de Bourneville

In-vitro studies have recently proved that some fibrosing lesions could be reversible. This gives hope for future medical advances (see the section  » Treatments and medical research  » on this site).

What are the symptoms of TSC ?

Tuberous Sclerosis has various symptoms with very variable aspects from a patient to an other. Some will be only slightly affected, others more severely. The patients can present one or several symptoms according to their age or to the evolution of the disease.

The Tuberous Sclerosis has a strong penetrance, this means that almost all patients will be affected by at least a symptom, but with very variable expressiveness.

Epilepsy

According to the scientific literature, 60 to 90 % of TSC patients will be affected by epilepsy during their life.

The onset of the disease is usually characterized by infantile spasms. The eyes roll upwards or sideswards, the child present spasms with flexions… The seizures may sometimes go unnoticed then become more frequent and intensify. We recommend you to react as quickly as possible. It is not harmless and patients need to see a neurologist as quickly as possible to avoid mental retardation. If necessary, do not hesitate to go to your hospital emergencies.

Infantile spasms in TSC usually appear around the 6th month of the life of the child. They are often associated with the « West Syndrome ». 

Epilepsy can also be present under other forms, or at the age of adolescence or adulthood, as partial or generalized seizures.

The epilepsy of the Tuberous Sclerosis is associated with the presence of tubers (where the name of the disease comes from) which are small benign tumors.

Tubers Corticaux dans la STB (Source irm-resonance.com)

Mental retardations, autistic disorders (autism) or behavior disorders in children or teenager may be directly due to Epilepsy. It is therefore important to control it as much as possible, whatever the seizures are.

At the cerebral level, sub-ependymal nodules sometimes develop and turn into giant cells, called Astrocytomas (or SEGA). Those can block the circulation  of the cerebrospinal fluid in brain and lead to hydrocephalus. A follow-up by a neurologist and regular MRIs are then of utmost importance. When necessary, the nodules can be removed by neurosurgery, in very specialized centers, because this intervention is delicate.

Cutaneous signs

Dermatologically, cutaneous achromic plaques are visible from the youngest age. Angiofibromas usually appear on the face during the teenage years. Angiofibromas can be more or less noticeable and sometimes come along with frontal plaques (shagreen plaque) or with other plaques in the lower back. The dermatological problems associated with TSC are very common in the adulthood and concern most of the patients.

Cardiac, renal and lung symptoms

In prenatal or neonatal periods, cardiac symptoms are known as  Rhabdomyomas (mild cardiac tumors). Those tumors spontaneously reduce after a few years. Echography allows an early diagnosis. Cardiac insufficiency due to Rhabdomyomas presents a risk for the foetus or the newborn child, but remain rarely a problem later on.

As far kidneys are concerned, AngioMyoLipomas (AML) develop generally in the teenage years. They require then a regular follow-up as they present variable degrees of risk. The objective is to measure their size and their change to protect the renal function. They are more frequent in girls than in boys.

The young adult women are sometimes affected by lung disorders. Lymphangio Leiomyo Matosis (LAM) is particularly observed in the case of female patients having AML. It is likely that LAM is introduced or strengthened by the production of estrogens or by the migration of TSC cells to other organs.

Symptômes Sclérose Tubéreuse de Bourneville

Symptômes Sclérose Tubéreuse de Bourneville

 

Dermatological symptoms

Dermatological symptoms are many and specific to TSC. They concern almost all patients at a point in their lives. In most cases, these affections are not dangerous per se, but they are often disgraceful and can be unpleasant for the affected person.

1- Face Angiofibromas are common in TSC patients and concern 90 % of them in the adulthood. These skin lesions appear from the age of 3 years. Those small tumefactions of reddish color are due to the erratic production of cutaneous micro-vessels or fibers on the face. These skin lesions can be reduced or eliminated by laser but they usually reappear after a few months. These laser treatments are only performed in specialized healthcare centers.

Angiofibromes

Angiofibromas / Hamartomas Tuberous Sclerosis Complex Source: dermatological deparment – CHU of Nantes, France

A recent publication in the ‘ Harvard School of Medicine ‘ review recommends to limit the exposure to sun and especially in summer. Sun exposure may favor proliferations of the cutaneous lesions and their severities.

2- Achromic spots (of white color) are also very frequent in TSC patients and are noticeable from the first months of life. They are situated on the whole body (members, back, belly), sometimes go unnoticed. An examination in the Wood light (ultraviolet light) performed by a dermatologist help localize them better.

3- « Shagreen » plaques are present in 30 % of TSC patients. They arise generally during the childhood and are mainly situated in the lower back. In some places, skin seems a little thickened and discolored.

4- A fibrous plaque at the forehead is less frequent but is very specific to  Tuberous Sclerosis, with a texture of thicker and not uniform skin of red color.

5- Fibro-nail keratomas appear generally in the adulthood and affect 50% of the patients. It is about outgrowths of flesh which appear on the edge of the nail of the hand or the foot. They can be more or less voluminous and sometimes painful when they are in contact. Minor interventions allow to reduce them or to eliminate them.

 

Treatments and medical research

Which medicine for this disease?

It does not exist, so to speak, a medicine or a drug to cure Tuberous Sclerosis. However, several therapeutic options are available to decrease the symptoms of the disease. For example, Vigabatrin (Sabril) has proven its efficacy in the treatment of the infantile spasms.

We insist on the necessity of getting closer, as soon as possible, to a specialized medical team to obtain the best possible treatments, according to the patient’s symptoms. It is imperative to address TSC symptoms very early, in particular neurological symptoms, to reserve to the patient the best possible cognitive development.

Care pathways

In case of a TSC diagnosis, families have to follow a care pathway, to which they are entitled:

· consult in an expert center as quickly as possible (for example, a TSC reference center); a rare disease is by definition less known by the general practionners;

· the expert center then gets in touch with your regular doctor and/or with the local specialist;

· there are different protocols according to the age and the symptoms of the patient;

· in case of new symptoms and/or resistance to treatment, the local doctors have to readdress the patients to the reference center; families can also address directly to the expert center;

· after every visit in the expert center, the local doctors are informed; these local doctors aim at renewing the treatment, verifying the absence of side effects and insuring the normal follow-up;

We recommend to follow this scheme to avoid any delay in diagnosis or treatment which would cause adverse events. In case of any new symptoms, do not hesitate to inform your regular doctor as soon as possible and, if necessary, request urgent support from the expert center.

An European database, TOSCA, is currently being elaborated to collect medical information about 2,000 TSC patients in Europe.

An International Consensus Conference, involving 79 specialists from 14 countries, was held in 2012. The experts made recommendations and presented guidelines relative to the medical follow-up of TSC patients (you can have access to those recommendations by clicking here. These recommendations concern all patients, from childhood to adulthood.

What follow-up for this disease?

The medical assessments that have to be made in the case of a TSC diagnosis are the following ones:

· electro-encephalogram ( EEG) if there is notion of seizures

· brain imaging (MRI determines the number of tubers and the presence of sub-ependimal nodules)

· renal echography

· electrocardiogram and, if it highlights arrhythmia, cardiac echography

· ophthalmological examination (fundus in search of retinal phacoma)

· neurodevelopmental test to estimate the cognitive functions

· complete clinical examination in particular a throurough dermatological exam.  

The implementation of a regular and multidisciplinary medical follow-up is necessary for TSC patients, and in particular neurological and renal follow-ups. From adolescence to adulthood, a neuropsychiatrist can also be of a big support to relieve families in the case of behavior disorders (routines, aggressiveness, depression).

Which Medical research for this disease?

These last years, medical research dedicated to TSC has developed in several specialities. It has brought new advances in the disease understanding and management.

The main advances concerning the disease are relatively recent: 

- The genes responsible for the disease (TSC 1 and TSC 2) were discovered in the 90s.

 - Vigabatrin ( Sabril) was approved in the 1990s for infantile spasms.

- Since 2005, several preclinical and clinical studies were conducted with rapamycine. Rapamycine is a molecule isolated by a team of Canadian researchers from a filamentous bacterium, Streptomyces hygroscopicus, coming from the ground of the Easter Island. It is known since the 80s to be a powerful immunosuppressor, used in the treatment of some cancers.

Clinical trials related to TSC were led in 2012 with rapamycine analogues. They were launched in the market and approved in the United States and in Europe, in precise indications (SEGA without possibility of surgical resection, angiomyolipomas of important size, refractory epilepsy). The results of these clinical trials seem encouraging but have to be confirmed; in particular two points are questionable: the long-term tolerance of these molecules and a better evaluation of potential side effects. Do not hesitate to speak about it with your doctors for more detailed information.

If you wish to know the list of the current clinical trials about TSC, you may go to www.clinicaltrials.org.

If you wish information on scientific publications relative to TSC, consult Pubmed, the online American Library of medicine.

Every year, an international TSC medical congress is organized in the United States or in Europe. A « Global Awareness Day » is taken place on May 15th, to raise awareness about the disease and develop scientific researches.

It is reassuring and promising to notice the large number of research projects relative to TSC. This should lead to the development of new treatments and steps forward to cure the disease.

Genetics and prognosis

Tubersous Sclerosis is an « autosomal dominant » disease. What does it mean? What are the transmission modes?

A genetic disease is said  » autosomal  » when the altered gene is not situated on a sexual chromosome (in this particular case, chromosome 9 or 16 for TSC1 or TSC2). The disease thus affects as much the boys as the girls.

We all have pairs of chromosomes in our cells, and consequently, two allels (or two versions of the same gene). When only one allel has to be affected so that the disease occurs, the allel is then « dominant »; this is the case for Tuberous Sclerosis which is thus called an  » autosomal dominant  » disease.

The Tuberous Sclerosis can be:

- of familial origin (30 % of the cases approximately) if one of the parents is affected

- the result of a neo-mutation (70 % of the cases approximately) when none of the parents is affected by the disease.

1-Family Transmission

When one of the two parents is a carrier of the disease, as the disease is  » autosomal dominant « , there is a 50/50 chance that the child be affected by Tuberous Sclerosis.

Family autosomal dominant transmission:

2-De-novo Transmission or neo-mutation

2a-The parents do not have the disease. A spontaneous mutation arises, randomly and for unknown reasons, in the egg or the sperm cell which will constitute the embryo. It is then a  » de-novo  » mutation, strictly speaking.

2b-In less frequent and particular cases, there is however a situation which is called « germline mosaicism « . The parents do not present the disease but one of the two is carrying a genetic abnormality in some of his reproductive cells (sperm cells or eggs). These disorders are not detectable. Testicles or ovaries present then a double population of cells, certain cells being carriers of the genetic disorder while others are no ; it is what is called  » germline  mosaicism « .

When a child is affected by the disease, and the parents are not, it is recommended to have a genetic advice for the rest of the family. When none of the parents are affected, the probability to have a second child affected by the disease is low, but is not zero. The probability is estimated by the scientific literature at 2 %.

Genetic diagnosis of Tuberous Sclerosis

voie-mtor-sclerose-tubereuse-soins-experts
Intracellular pathways – mTor 1 and 2 – in Tuberous Sclerosis 

Today, diagnosis is mainly based on the association of at least two symptoms  (cardiac, cutaneous, renal, intellectual, etc.).

It is also recommended to have a genetic diagnosis. This genetic diagnosis will  specify witch metabolic pathway is predominently affected.

Genetic studies in Tuberous Sclerosis highlight two genes at the origin of the disease, which are tumor suppressor genes: TSC1 (chromosome 9) and TSC2 (chromosome 16) coding respectively for hamartine and tuberine with consequences on mTORC1 and mTORC2 cell pathways.

What Prognosis for a child with TSC ­?

It is difficult to establish a reliable prognosis and anticipate the psychomotor and social development of a child with Tuberous Sclerosis. The prognosis  depends on the severity of symptoms, which go from slight abnormalities of the skin to diverse degrees of disorders (learning disabilities, epilepsy or  renal insufficiency). Besides, within the same family, each individual can be differently affected by the disease.

The people having mild symptoms will have a normal or quasi-normal life, whereas the individuals with more severe symptoms can have heavy handicaps. However, with appropriate medical care, most of the people with TSC have normal life expectancy.

A clinical trial concerning 30 patients STB asserted that  » the earlier the beginning of the epileptic seizures, the more mental retardations are likely to be important « .

The identification of mutation of TSC 1 (gene on the chromosome 9) is significantly more frequent in family cases than in sporadic cases. TSC 1 mutation is identified in only 20 % to 30 % of the patients.

The frequency of TSC 2 mutation (gene on the chromosome 16) is higher than that of TSC

1. TSC 2 is also associated with a more severe disorders than TSC 1.

TSC 2 may also cause larger genomic deletions. So, the patients affected by TSC 2 are susceptible to have more severe symptoms (largest number of cortical tubers, more severe epilepsy, autism, angiomyolipomas).

It is very likely that the patients with TSC 2 have more important renal impairment given the location of the defective gene close to that of the renal polykystosis.

Can I have children if I am affected by Tuberous Sclerosis ?

It is obviously possible to have children when you are affected by Tuberous Sclerosis. However, it is necessary to know, that according to genetics, there exists a 50/50 chance that your child be also affected, if your spouse is not.

For women affected by STB, it is always desirable that the pregnancy be anticipated and prepared at best to avoid some complications.

Learning and schooling

Which learning and education for my TSC child ?

It is difficult to determine which learning or education is the best adapted for a TSC child. Some children will have no or few difficulties but others can have mental retardation or even autism. So, some children can be in mainstream schooling. For other children, concerned by the epilepsy, behavioral or autistic disorders, schooling is sometimes difficult or is not possible.

Below, a graph which shows a wide spectrum of the capacities of a TSC child:

Source: Prather & de Vries, JCN 2004, de Vries & Prather, NEJM, 2007

Source(Spring): Prather and of Vries, JCN 2004, of Vries and Prather, NEJM, on 2007

Each child is unique and there is no universal rule. There are however possibilities to help children in their learning and schooling. It is, for example, recommended to have a neuro-psychological evaluation, to facilitate the choice of a school.

In the case of low or moderate retardations, dyslexia, dyscalculia or dysgraphia can frequently occur. Some of these difficulties can be addressed with orthophony or psychomotricity.

It is also necessary to note that a child can be bothered by the side effects of a medication (dizziness for example due to an anti-epileptic treatment) and it is necessary to mention it to his teachers, educators or therapists.

Behavior of a child or a teenager with TSC

Can also appear, in particular in the adolescence, anxiety, aggressiveness, attention deficits, hyper-activity, gestural routine, depression or even mutism. These disorders can aggravate in school. It is thus important that the parents remain alert and inform the people who supervise the child so that changes in behavior be quickly mentioned.

Educational options

Public, private or associative structures, are available to get information and support in case of doubt about the development of the child.

In the nursery or primary school, in case of difficulties of learning, we recommend the implementation of an Individual Adaptation Plan.

If your child does not adapt in an ordinary class, a solution may consist of schooling in small groups. These schools are particularly adapted if your child presents learning disabilities. However, these structures remain few and are generally expensive because of their specificities. They are intended for the children and the teenagers who have capacities of learning, without important behavioral disorders.

Some day-care hospitals also have facilities.

Patient Management

Patient healthcare coverage

Tuberous Sclerosis is classified as a « long term condition » and patients benefit generally from a 100% coverage of their care related to TSC, in many countries.

Financial support

A financial support is granted by the public authorities in some countries to compensate for expenditures due to the handicap (schooling, employment of a person, specific equipment…).

Some associations or public bodies (as city halls, houses of handicap) also propose financial supports accommodation for disabled people or the parents of an handicapped child.

Legal and patrimonial protection of the TSC patient

In case of handicap, TSC patients need an adapted protection as vulnerable individual. A mandate for future protection allows to organize with flexibility the protection on a daily basis and the management of the holdings.

On the patrimonial level, solutions specific to the handicap exist, in some countries, with tax advantages. We recommend you to get in touch with specialists to set up a strategy which could ensure the financial future of your child (generation of regular income, transmission of heritage…).

It is strongly recommended to inquire with people or with competent institutions to anticipate the situations where the vulnerable person could end up alone.

Reference Centers

Reference centers

You can find Tuberous Sclerosis Reference Centers in most of the countries.

Given the specificity of the disease and the rapid development of treatments and care, we recommend that you seek medical attention in one of these centers.

A simple search on the Internet will allow you to identify TSC Reference Centers.