Huntington’s Disease
Huntington’s Disease, short HD, is a devastating genetic disorder that affects about 10-15 out of 100,000 people in western European countries. Pretty much everywhere else in the world, the prevalence is very low with the exception of Venezuela. Interestingly, the high HD prevalence in Venezuela can be traced back to a single ancestor with the disease.
Huntington’s Disease is an autosomal dominant disorder, which means that only one parent needs to carry the mutated gene and pass it on to their child for the disease to develop. The chances for that to happen are 50%. If both parents carry the mutated gene, the risk of their child to develop HD increases to 75% and if at least one parent carries two copies of the mutated gene, there is a 100% certainty of passing on the disease.
HD is also a monogenic disease, which means that only one gene is affected and responsible for the symptoms of the disease.
Huntington’s Disease is a neurodegenerative disorder that starts to present at varying ages of life. For many people, first symptoms appear between the ages of 30 and 50. Disease onset for people under 20 years old is also known, in which case experts speak of juvenile HD.
Symptoms of HD can be categorized in three groups: motor symptoms, cognitive symptoms and psychiatric symptoms. The first symptoms to manifest are usually cognitive and psychiatric ones. This often happens multiple years before the first motor symptoms appear. Cognitive symptoms in the beginning include impaired emotional recognition, reduction in processing speed, reduced ability to concentrate and retain newly acquired information, as well as declines in language skills. Common psychiatric symptoms include apathy, anxiety, irritability, depression and suicidal tendencies. At later stages of the disease, patients often suffer from dementia as well.
Motor symptoms usually start with a symptom called chorea. People often describe chorea as bizarre looking dance-like movements. Signs of chorea are not automatically proof of Huntington’s Disease though. Other neurodegenerative diseases also present with chorea. To diagnose HD, doctors will ask for a family history of the disease and perform a genetic screen. With the disease progressing, common motor symptoms include dyskinesia, which is the difficulty or distortion of performing voluntary movements, bradykinesia, which describes slow movements, dystonia, which is the involuntary contraction of muscles, and ultimately rigidity.
So what exactly happens in patients with HD? Let's start by looking at some biology background first.
Our bodies consist of trillions of cells. Each cell contains a chemical code that carries all the information necessary for our cells and in turn our bodies to operate properly. This chemical code is called DNA and it is located within the nucleus of cells. The building blocks of DNA are called nucleotides and there are 4 different nucleotides, A T C and G. Just like languages use letters to build words to communicate information, DNA also builds words. Different to language though, DNA words all consist of 3 letters only, like for example CAG. Each 3 letter word is called codon. Now what happens from here? DNA alone does not really execute functions. It simply carries information. The molecules that execute most of our cells’ and bodies’ functions are called proteins. Proteins consist of building blocks called amino acids and there are 21 amino acids that are commonly found in proteins. The 3 letter DNA codons each translate into specific amino acids. And just like codons are on a string of DNA, amino acids are connected to a string that makes up the protein. Depending on the composition of amino acids, proteins form into different shapes and exert different functions.
The region of DNA carrying information for a specific protein is called gene. Each cell carries two copies of the same gene, one inherited from the father and one from the mother. Sometimes the information coded in a gene is incorrect. That’s when we speak of a mutation. Incorrect information also leads to incorrect proteins that depending on the mutation can’t carry out their function anymore, or gain a new function.
So, back to Huntington’s disease. What’s different here?
The mutated gene in Huntington’s disease is called HTT gene. It is located on the short arm of chromosome 4 and carries the information for the huntingtin protein. In non-mutated genes, also called wild-type genes, one part of HTT consists of multiple repetitions of the 3 letter word CAG. The number of repeats varies from person to person and also between ethnicities. Depending on the literature resources you look at, the numbers considered normal and abnormal differ slightly but roughly it is said that less than 27 CAG repeats is considered normal, or healthy. Less than 36 CAG repeats leads to the development of HD with reduced penetrance. This means not all people develop the disease or they die of other causes before HD could start to manifest. With 36 or more CAG repeats the mutated HTT gene is fully penetrant which means that all carriers will for sure develop HD unless they die prematurely for other reasons.
The codon CAG translates into the amino acid called glutamine. This means that patients with HD have an extended chain of glutamine amino acids in their huntingtin protein. This changes the shape and function of the protein. When a protein just loses its function and is basically useless, we speak of a loss-of-function mutation. In the case of the huntingtin protein, however, the mutated protein exerts functions that are different from the wild-type protein. In this case, we speak of a gain-of-function mutation.
Although researchers have been studying the huntingtin protein for decades now, it is still not entirely clear what the exact functions of the wild-type and mutated huntingtin proteins are and how they contribute to the development of HD symptoms. What is known is that either directly or indirectly many functional pathways are affected which ultimately leads to cell death. It is also pretty clear that the mutated huntingtin protein gains toxic functions that harm cells.
While the huntingtin protein is expressed throughout our entire body, it has its most important functions in neurons, brain cells. That’s why patients with HD present with a loss of brain mass and all the neurological symptoms described earlier.
We also know that the mutated huntingtin protein gets degraded into smaller pieces and the pieces containing the extended glutamine chain form aggregates. It is not clear however, if these aggregates are harmful or protective. Both hypotheses circulate the scientific field and more research needs to be done to answer this question.
Furthermore, it was observed that the mutated huntingtin protein interacts with other proteins it is not supposed to interact with, which is most likely a big contributor to pathway dysregulations and malfunctions.
The multifaceted functions of the wild-type protein in combination with the gained toxic functions of the mutated huntingtin protein make it very complicated to fully understand and develop effective drugs for HD. A lot of research is invested into developing different methods to eliminate the mutated huntingtin gene and multiple clinical trials are currently ongoing. Available treatments to date are scarce and aim to manage symptoms rather than treat the core problem. There is also no internationally recognized treatment regime and unfortunately no cure.
What does a prognosis for patients with Huntington’s disease look like? The short answer is devastating. HD is not a hidden disease because it is inherited in a dominant way which means if you have one copy of the mutated gene, you’ll develop the disease. This means many patients know that when Huntington’s disease runs in their family they have a 50 percent chance of carrying the gene. Not everyone decides to get tested before the onset of symptoms. It was long discussed if it is ethical to screen for HD and what the appropriate age restrictions would be. Nowadays, if a family history is known, adults can request to be tested for the mutated HTT gene.
The age of disease onset differs and is inversely correlated with the number of CAG repeats, meaning the more CAG repeats, the earlier the disease onset. Although there are other genetic and environmental factors influencing the age of disease onset as well as disease progression the number of CAG repeats is still a major indicator of what can be expected.
After first motor symptoms manifest, life expectancy is about 20 years. HD itself is actually not fatal but it leads to many other complications that ultimately result in death. The most common cause of death in HD is pneumonia developed from aspirated food and fluids. The more progressed the disease is, the less control patients have over their muscles and problems with swallowing become more problematic. Swallowed foods and fluids then lead to infections that patients often don’t recover from. Another common and very tragic cause of death in HD is suicide.
Fertility is not affected in patients with Huntington’s Disease, however, it is noteworthy that the disease tends to develop earlier and earlier in life with ongoing generations. This is because when cells replicate, DNA needs to be replicated as well and regions that are made up of CAG repeats are very prone to replication mistakes. Unfortunately, those mistakes mostly lead to extensions of the CAG repeats and not deletions. This is especially true for sperm in men. That’s why children of fathers with HD often inherit more CAG repeats than children of mothers with HD.
Literature used
https://pubmed.ncbi.nlm.nih.gov/28817209/
https://pubmed.ncbi.nlm.nih.gov/21171977/
