by Stefano Torti
With this post, we welcome Stefano as our guest blogger. We invite others to join our roster of bloggers. Please feel free to contact CheckOrphan about writing your own rare disease stories.
In his thesis work, our guest blogger analyzed the psychosocial impact of predictive medicine. Generally the diagnostic process for rare diseases is already available, but the treatment is not yet optimized. This gap impacts patients’ private and professional lives as well as their future reproductive choices. Please Stefano go ahead, the floor is yours!
How Stefano knew about HD
Thank you, Assunta!
I heard of Huntington’s disease for the first time about two years ago. It was a spring night. I was idly zapping when I landed on a local TV station. A woman was talking about a nasty illness that had struck first her estranged husband, then their eldest son, a young man in his late-20s, who had inherited the disease from his father.
This condition had left the both of them physically and mentally incapacitated in a few years’ time; to make matters worse, the youngest son had also inherited the genetic mutation responsible for the disease, and although healthy now, he knew he would have through the same ordeal as his father and brother, which was a source of excruciating anguish for him.
Her expression was very sad and tired, but full of dignity; her voice was calm as she described the hell on earth she and her loved ones were enduring: a severe neurodegenerative disease.
Impressed by her story, I decided to keep watching, but unfortunately the program ended a few minutes later. Wanting to learn more about that disease I have never heard of before, I decided to do some research on the web the following day. So I did, and that’s what I found out about HD in the following days.
Huntington’s Disease: The Facts
Huntington’s disease (HD) is a genetic, neurodegenerative illness, named after the physician who described its signs and symptoms for the first time in 1872. It involves virtually any aspect of the affected person’s functioning, leading to an irreversible decline of motor and cognitive abilities and to behavioural disorders, up to paralysis and dementia.
It usually reduces life expectancy to 15-20 years from the onset of the first symptoms; pneumonia, choking and physical injury from falls are the most common causes of death.
The onset of HD generally occurs in adult age (35-44 years old), although the disease may develop earlier in life (juvenile HD).
HD is caused by an autosomal dominant genetic mutation, i.e. each child of an affected parent has a 50% chance of inheriting it, regardless of sex.
As a result, the illness can be diagnosed even before the onset of the first symptoms through genetic testing (pre-symptomatic testing). The test for HD is able to detect the presence of the mutation with extremely high accuracy (virtually 100%).
As the penetrance of the mutation is complete, a positive test result means that the individual will surely develop HD at some point in life.
Researchers are still looking for a cure for HD. Treatment is merely symptomatic and mostly pharmacological, although physical therapy and cognitive rehabilitation have proven to be useful in improving patients’ quality of life as well. These are the facts about HD, which I found more and more appalling as I read and learned.
A test can detect the mutation involved in the disease: if positive, it results in the testee living from that moment on with a Damocles’s sword on his head. How could they endure this?
But before focusing on that, I wanted to understand how a genetic mutation could bring such a disease. It was not an easy task, since I had not (and have not yet) any serious background in genetics, but I’ll try my best to explain it without going too technical.
From Genes to Macroscopic
Huntington’s disease is caused by a mutation of the HTT gene, which is located on the short arm of chromosome 4. The HTT gene contains several repeats of the so-called CAG triplet (from the names of the three DNA bases – cytosine-adenine-guanine – that compose it), that codes for a protein called huntingtin (HTT).
Depending on the number of CAG repeats, the following outcomes are possible:
- < 26: this is the number of CAG repeats in the wild-type HTT gene, resulting in a normal form of huntingtin protein, with no risk of developing the disease for both the person and their offspring;
- 27-35: the individual will not develop HD; however, as CAG repeats are unstable during meiosis, (the form of cell division that produces reproductive cells) a larger number of repeats can be passed to offspring (de novo mutations), posing some risk of them developing HD;
- 36-39: result in a reduced penetrance of the mutation, with a much later onset and a very slow progression of symptoms; some individuals may even die before experiencing them; however, the risk of developing HD is higher for their offspring.
- > 40: the mutation has full penetrance and the disease will certainly occur at some point in the individual’s life; offspring have a 50% chance of inheriting it.
The higher the number of CAG repeats, the earlier the onset of the disease and the more severe the symptoms.
The processes through which the mutated gene leads to the irreversible decay of cells in the brain are still a matter of research.
An interesting aspect is that the role played by huntingtin protein in neuronal growth and functioning is still unknown, although it is agreed that it probably acts in both processes. This shows us that investing in rare disease means not only finding a cure for affected people, but also, in a broader sense, better understanding how our body works.
The mutated huntingtin protein has proven to have a toxic effects on the whole brain, yet the earliest and most severe effects are in the medium-sized spiny neurons (MSN), which are found in the striatum, a part of the basal ganglia responsible for movement and behaviour control whose malfunction is involved in several other neurological conditions, for example in PANDAS, which we wrote about some weeks ago
As the illness progresses, virtually all areas of the brain are affected, and this explains the wide range of motor, cognitive and behavioral symptoms found in HD. Thanks to neuroimaging, the earliest macroscopic brain modifications in pre-symptomatic HD carriers can be detected as early as 15 years before the onset of the disease.
After getting more acquainted with the genetics of HD, I then wanted to know what the disease is actually about. What are the first symptoms? Is the progress the same for all people affected?
I felt it was going to be somewhat painful, but I also wanted to better understand this condition, so I kept searching the web for some info.
HD Symptoms: More Than Chorea
However, HD is not just about chorea and motor disturbances. It entails a wide range of behavioral and cognitive symptoms which affect not only the sufferers, but their families as well.
It is basically a time stealer, both in quantity and quality.
While searching the web for information about HD, what impressed me the most was “La Pieuvre” (The Octopus), a feature-length film by Laetitia Carton which chronicles her journey towards genetic testing while taking care of her mother, already affected by the disease. It is a bit long, but I really think it gives the big picture of HD and what it really means to families. It made me realize that HD is a true “family business”: shared beliefs, fears and frustrations, but also hardiness, cohesion, mutual support and love.
While HD is obviously a nasty disease, I was somewhat relieved to learn that it may be a brighter side to it.
The complex interaction between the mutated HTT gene, the tumor suppressor gene TP5, and their respective protein products might improve the activity of the immunity system, resulting in a lower cancer incidence among mutation carriers, a silver lining in a difficult situation.
Since I had never heard of Huntington’s disease before, I regarded it as a rare disease. It is indeed, but not as rare as I thought, it has just to be diagnosed properly!
The worldwide prevalence of HD is 2.71 per 100,000 persons, although it greatly varies among ethnic groups, with a higher incidence among Caucasians in Europe, North America and Oceania (for example, the incidence in the U.K. is 12.3/100,000) and a far lower prevalence in Africa and Asia.
Some areas have a much higher prevalence than their regional average, a notable one being the region of the Lake Maracaibo in Venezuela, with a prevalence of 700 per 100,000 persons. This abnormally high prevalence is due to the so-called founder effect, a migration of carriers in isolated areas, where inbreeding leads to an unusually high prevalence of the mutation among locals.
As said, treatment for HD is symptomatic and relies on drugs such as:
- tetrabenazine (approved by FDA in 2008), ataractic anticonvulsants like valproic acid and typical (haloperidole) and atypical (olanzapine) neurolectics are used to suppress chorea;
- antidepressants (e.g. fluoxetine), neurolectics and mood stabilizers (lithium compounds) are used to treat psychiatric and behavioural symptoms
I already knew a completely effective treatment for Huntington’s disease is still to be found, as upsetting as it can be; yet I hoped the available treatments were effective in bringing some relief.
This is not always the case, because due to the wide range of symptoms and related medication, treatment of HD is riddled with important side effects, mainly due to unwarranted drug interactions and to the progressive nature of the disease, which requires a flexible therapeutic approach. A drug which is effective in the first stages of HD often does not work for later stages, and vice versa.
A striking paradox is that most drugs used to treat HD are not specific to it, but rather borrowed from treatment for other neurodegenerative diseases with similar symptoms, such as Parkinson’s disease and Alzheimer’s disease.
So, clinical trials to verify the safety and efficacy of drugs that have been routinely used to treat HD for decades have been run only in recent years. A fairly obvious gap between medical practice and actual evidence from trials, isn’t it?
Besides, in the earlier stages of HD non-pharmacological treatment such as physical, speech and occupational therapy has proven to be useful in delaying the decay of motor and speech abilities, helping patients in keeping up with their daily routine, probably the biggest source of a much sought-after “normality”.
Individual and family psychotherapy can also be useful in supporting compliance with therapy and easing acceptance of the impact HD has both on daily life and future projects.
If current treatment options for HD can be somewhat disappointing, the search for an effective cure has been underway for at least two decades, with many research directions being explored.
Pharmacological-wise, the most promising approaches currently are:
- pridopidine: a modulator of dopamine (the neurotransmitter involved in movement control, mood and motivation). Several clinical trials has showed a positive effect of pridopidine on motor abilities;
- PBT2: this drug promotes metal homeostasis in neurons, preventing their decay. It has also been proposed as a possible treatment for Alzheimer’s disease;
- selisistat: a selective inhibitor of the SirT1 protein, which in turn is supposed to modulate the expression of the HTT gene.
Among non-pharmacological approaches the following are worth noting:
- stem-cell therapy: it aims at replacing damaged neurons by transplanting stem cells in the brain. Results have been mixed in animal models, yet it is still a valuable approach for studying HD in a laboratory setting;
- gene silencing: this technique aims at reducing the production of the mutant huntingtin protein form by targeting the mutant HTT allele responsible for its production with specifically-designed drugs;
- designing drugs able to prevent the transfer of the misfolded (mutant) huntingtin protein from cell to cell (which likely happens in a similar way to infections) and its aggregation in clumps which lead to neurodegenerative processes;
- non-steroidal anti-inflammatory drugs (NSAIDs): since inflammation is characteristic of a broad spectrum of neurodegenerative diseases, the sparing effect this class of drugs has on neuronal cells (already tested for Alzheimer’s and Parkinson’s disease) could be a valid treatment option for HD also.
In general, clinical research on HD is riddled with several pitfalls:
- limited follow-up: on average, from 6 months to 3 years;
- the small number of participants enrolled (usually < 100 people); the difficulties in enrolling HD patients are being addressed by platforms such as ENROLL-HD, aimed at integrating the existing patient registries in the world, providing the basis for a worldwide network of patients, researchers and hospitals;
- the need for a multidisciplinary approach, involving all the professionals (physicians, geneticists, biologists, physical therapist, psychiatrists, psychologists and so on) whose contribution is essential to both treat and find new paths for research on HD. So, an open minded attitude among professionals is much needed to give the HD community a hope.
I was really happy to learn about the amazing work done by researchers from all over the world! Surely it will take much effort and time, but I am really confident that we will hear of important steps forward in the next few years.