Monday, 23 September 2013

Huntington's Disease

Huntington's disease (HD) is a rare, hereditary, fatal (death usually occurs 10-25 years after the first symptoms appear) neurodegenerative disorder (i.e. a neurological [pertaining to the brain, spinal cord and/or nerve cells] yet progressive disorder) that can strike persons at any time in life. It causes a progressive decline in motor function (your ability to control your normally, voluntary movements), cognitive function (memory, learning, etc.), emotional stability, connection with reality (in the later stages people with the disorder can become psychotic with many of the classic symptoms of paranoid schizophrenia) and various other neurological functions. The first symptom is usually chorea (an abnormal involuntary movement disorder that often presents with involuntary flailing movements) hence the previous name of the condition, Huntington's chorea.1

It is due to the build-up of a faulty (or mutated) huntingtin protein (mHtt) which is due to a mutation in the huntingtin gene (HTT). This gene is used to create the huntingtin protein which plays a key role in various cellular processes in the brain and testes. The gene is inherited in an autosomal dominant fashion (i.e. it is inherited in a manner that is totally independent of the sex of the parent and the child. This is because we all get two autosomes [the type of chromosome on which the huntingtin gene is found; these are the non-sex chromosomes] of each variety [there's 21 different autosomes], one from our father, one from our mother. It takes just one autosome that contains a faulty huntingtin gene to cause Huntington's disease). The faulty huntingtin protein builds up and this leads to neuronal (electrically-signalling brain, spinal cord and nerve cell [in this case mostly just brain cell]) dysfunction and death (although we're not sure exactly how).1

At this point in time there are limited treatment options for people with Huntington's disease. Most treatments are aimed at making the patient as comfortable as possible as they die. Treatments that are designed to do this include neuroleptics (antidopaminergic drugs; drugs that counteract the actions of the neurotransmitter, dopamine, throughout the nervous system [brain, spinal cord and nerves] particularly in the basal ganglia -- the part of the brain that takes the biggest hit in Huntington's disease. It plays a key role in controlling our voluntary movements. Neuroleptics are basically the older antipsychotic medications [the so called "typical" antipsychotics] and some of the older antiemetics [anti-nausea and vomiting]), benzodiazepines (e.g. diazepam [VALIUM], clonazepam [RIVOTRIL]), dopamine-depleting agents (e.g. reserpine, tetrabenazine) and valproate (EPILIM, DEPAKENE, DEPAKOTE) which are designed to help with the choreas typical of HD. Likewise if symptoms include muscle rigidity and slowed movements then dopamine agonists (receptor activators; compounds that mimic dopamine's effects in the body) or levodopa (a compound the body uses to synthesise dopamine) are preferred. Depression is also common in patients with HD and is often treated standard antidepressants such as sertraline (ZOLOFT), fluoxetine (PROZAC), etc. None of these treatments are believed to be disease-modifying i.e. treatments that actually slow (or "modify") the course of the disease.1

I theorise that valproate may have disease-modifying effects in HD seeing how it is a known histone deacetylase (HDAC) inhibitor (which alter the generation of proteins from genes) and HDAC inhibitors are known to slow the progression of HD in animal models of the disease.2

Coenzyme Q10 is an enzyme that participates in the electron-transport chain that provides a significant portion of a cell's energy. Consequently it plays a pivotal role in mitochondrial (the "power house" of cells) function. When it's supplemented with dietary supplements it provides antioxidant, anti-inflammatory and neuroprotectant (neuron-protecting) effects. In animal models of HD it was found to possess diseases-modifying effects.3

Creatine, another naturally-occurring antioxidant, has been found to possess protective effects in animal models of HD.3,4

Reference List:

  1. Revilla FJ. Huntington Disease. 2013 May 14 [cited 2013 Sep 23]; Available from:
  2. Sadri-Vakili G, Cha J-H. Histone Deacetylase Inhibitors: A Novel Therapeutic Approach to Huntingtons Disease (Complex Mechanism of Neuronal Death). Current Alzheimer Research [Internet]. 2006 Sep 1 [cited 2013 Sep 23];3(4):403–8. Available from:
  3. Yang L, Calingasan NY, Wille EJ, Cormier K, Smith K, Ferrante RJ, et al. Combination therapy with Coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson’s and Huntington’s Diseases. Journal of Neurochemistry [Internet]. 2009 [cited 2013 Sep 23];109(5):1427–39. Available from:
  4. Dedeoglu A, Kubilus JK, Yang L, Ferrante KL, Hersch SM, Beal MF, et al. Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington’s disease transgenic mice. J Neurochem. 2003 Jun;85(6):1359–67. 

Monday, 9 September 2013

The Tuberous Sclerosis Complex

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: