Tuberous Sclerosis and relationship with LAM

Tuberous Sclerosis (TSC) is a genetic disorder in which there is an abnormal copy of a particular gene in every cell of the body. Something occurs to inactivate the normal copy in just some of the body tissues (such as lungs, kidneys, or brain) to cause various manifestations that can encompass the entire body. The diagnosis of TSC encompasses three elements : 1) mental retardation  2) skin growths on the face and 3) seizures.

It used to be believed that everyone with TSC experienced all three of these. It is now known that only 30-40% of those with TSC will have these three manifestations. Slides of the various skin lesions were shown: angiofibromas, Shagreen patches, and ash-leaf macules on the back.  Another sign to look for are pits in the enamel of the teeth where the enamel has not fully formed. Virtually all people with TSC have these pits and they can often be revealed by using dye tablets. There may also be fibromas in the gums and nails.

TSC is an autosomal dominant genetic disorder which means there is a 50% chance of passing it on to a child. About 1/3 of the cases are familial (or inherited) and the other 2/3 are a result of new mutations. The penetrance of the disease is 100% which means that everyone who has it has some sign or symptom of the disease. There may be some people who can go their entire lives and never know they have the disease. The disease is highly variable among individuals and within the same family. There are two genes that cause the disease, one on chromosome 9 and one on chromosome 16. There are some people who only have this abnormality of the gene in certain parts of their body - this is termed germline mosaicism. This may be what is occurring in some cases of sporadic LAM.

The gene involved in Polycystic Kidney Disease is very close to the TSC2 gene which produces tuberin. This is why some people with TSC may also have Polycystic Kidney Disease. The other gene involved in TSC is TSC1 which produces hamartin. Most people (80%) with TSC have problems with the TSC2 gene which is a much bigger gene than TSC1 and therefore can be subject to more mutations. Parents who have one child affected with TS have a 50% chance of having a second child affected with TS. Athena Diagnostics has developed a test that can detect some TSC mutations but it is quite expensive and insurance will not always pay for it.

Brain problems tend to first appear early in life, skin problems can also appear early and extend into adolescence and adulthood, kidney problems can be present in childhood and into the 30s and 40s. Heart lesions are present at birth and almost always resolve during the first few years of life. They rarely cause problems. Lung manifestations usually first appear in the 20s, 30s, and 40s. The reasons for these differences in the time of first appearance for various TSC associated problems are not known. Brain disorders can include seizures, learning disorders, behavioral problems, sleeping disorders and autism. TSC is one of the leading causes of autism. The cortical tuber is the hallmark of brain lesions. Nodules can occur in the ventricles or spaces in the brain. It appears that they become dormant after age 18. Only about 5% of these will grow and do not necessarily have to be removed. A better understanding of how TSC behaves is important in avoiding unnecessary surgery. The number of cortical tubers that a person has is not necessarily predictive of the types or severity of the symptoms that will occur. Brain aneurysms are rare but if they do occur they are usually seen in children.

Angiomyolipomas (AMLs) typically appear after 1 year of age. At the most, about 5% of TSC patients will have polycystic kidney disease because of involvement of the PKD gene which is adjacent to the TSC gene. Those with TSC tend to have larger AMLs than those with sporadic LAM leading to bleeding, high blood pressure or kidney failure in extreme cases. AMLs are sometimes confused with polycystic kidney disease. AMLs are one of the main problems in those with TSC along with brain disorders. There is a suspicion on the part of some that those having larger AMLs have more biologically active AMLs and that they are more likely to spread to the lungs and cause LAM but this is not proven. If there are abnormal blood vessels they can burst causing bleeding and pain. If this is the case they can be embolized to get rid of the tumor and prevent bleeding. AMLs can occur in other places such as the liver but don’t cause issues in this location.

Eye involvement in TSC rarely causes problems. There may be white patches on the retina (achromic patches) or hamartomas but they rarely affect vision or cause problems. If you have been diagnosed with probable TS and are concerned about the disease occurring in your children or grandchildren then it might be worth having further diagnostic tests for TSC disease including a genetic test.