The Tuberous Sclerosis Complex

Source:  The Tuberous Sclerosis Complex    Tag:  tuberous sclerosis symptoms
Tuberous sclerosis complex (TSC) is a disease that I learnt of today in my studies of the drug rapamycin (Sirolimus; RAPAMUNE) that's quite frankly rather sad. It is a genetic disease that causes benign (i.e. non-cancerous) tumours to arise in any and, often, every organ of the body. The way how this presents in terms of symptoms greatly depends, of course, on the location of the tumour(s). Epilepsy is common in patients with TSC and status epilepticus is not an uncommon cause of death in patients with TSC. Status epilepticus is basically either singular long, sustained seizures or a series of small seizures that occurs in short succession. Mental retardation and autism is not uncommon in patients with TSC which can result from episodes of status epilepticus or directly from the growth of tumours in the brain and the pressure this can exert on brain tissue. Many patients with TSC are also born with heart defects, many also have vision impairments.1

It is inherited in an autosomal dominant fashion, that is, there is no gender influence on how the gene is inherited and it takes just one copy (as opposed to two copies if the gene was recessive) of the gene to cause the disease. What this means is that if one parent has the disease there's a 1/4 chance one of their kids will develop the disease and if both parents have the disease then there's a 3/4 chance that their kids will inherit the disease and if one parent has two copies of the gene as opposed to the minimum of one copy that is needed to cause the disease then all their kids will have TSC.1

There are two distinct genes that, when mutated, can lead to TSC: TSC1 and TSC2. These genes are both what's known as tumour suppressor genes – (note: what follows is not the definition of a tumour suppressor gene, it's the term tumour suppressor gene applies to this case; in general it just means a gene that appears to severe as a safe-guard against cancer) they encode (used as instructions per say for the production of) proteins that in turn regulate the activity of the mammalian target of rapamycin (mTOR) and if the activity of these genes is impaired, by say a mutation (like is the case in TSC), mTOR activity increases leading to an increased propensity for uncontrolled cell growth like that seen in cancer. The place where rapamycin, the popular immunosuppressant (immune system-suppressing drug), comes in is that it inhibits mTOR, which is, as you can probably guess, the drug after which mTOR is named.1

Ironically not long ago I was reading up about the ketogenic diet (the diet that aims to induce ketogenesis [the formation of ketone bodies from dietary fats and their utilisation as an energy source of the body] by depriving the body of other energy sources like carbohydrates and, to a lesser extent, proteins) and I learnt that one of its potential mechanisms in the treatment of epilepsy (most often from non-TSC courses) is that it inhibits mTOR.2 mTOR appears to play a key role in longevity too and lately a novel class of drugs known as sirtuin activators have been in development and the way they work is by activating the sirtuin family of enzymes which includes SIRT1, an enzyme that in turn, by interacting with TSC1/2 inhibits mTOR.3 Resveratrol is a compound that occurs naturally in grapeskins and other plant sources that activates SIRT1. Hence it is conceivable that drugs like resveratrol may be of therapeutic benefit in patients with TSC. Resveratrol, however, is not exactly suited for this indication due to the fact that it has poor oral bioavailability, that is, very little of the original drug reaches circulation (in the blood) in the body after it is taken orally.3

Reference List:
  1. Franz DN. Tuberous Sclerosis [Internet]. 2013 [cited 2013 Sep 10]. Available from:
  2. Danial NN, Hartman AL, Stafstrom CE, Thio LL. How Does the Ketogenic Diet Work? Four Potential Mechanisms. J Child Neurol [Internet]. 2013 Aug 1 [cited 2013 Sep 10];28(8):1027–33. Available from:
  3. Ghosh HS, McBurney M, Robbins PD. SIRT1 Negatively Regulates the Mammalian Target of Rapamycin. PLoS ONE [Internet]. 2010 Feb 15 [cited 2013 Sep 10];5(2):e9199. Available from: