This first article will be dedicated to understanding the hereditary nature of HD.
It is common to have questions such as: Why, in some families, all the siblings inherit the disease if there’s a 50% chance of inheritance? Why do symptoms start later in life if the affected individual is already born with the mutation? Why can symptoms be different in people who have the same CAG expansion? My family has been battling with HD for more than two decades – why isn’t there a cure yet?
In order to answer most of these questions we have to take a deep dive into two main concepts that describe HD, it is a genetically inherited and neurodegenerative disease. Although some questions are still unanswered, these two concepts and what they imply will describe and explain most of the processes that happen in HD leading to the vastly varied and complex realities lived by affected families. In this first article we will focus on the genetic aspect of HD.Â
When a disease is hereditary, it mainly means it is carried in our DNA, which is the genetic material inside each cell. DNA not only helps differentiate species but also contains the unique instructions that make us who we are.Â
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It works like an instructions manual, guiding how we develop, grow, and reproduce. It also contains information about traits like our hair and eye color. As you can imagine, since it carries so much information, DNA needs to have a very specific and organized structure in order for the body to function properly.Â
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DNA is found within the nucleus of each cell inside our body, and is packed into structures called chromosomes, which contain genes. Humans have 46 chromosomes, arranged in 23 pairs, and thousands of genes in total.
To understand HD we need to focus on chromosome 4, one of the 23 pairs in the human body. This chromosome is estimated to have between 1,000 and 1,100 genes, each providing instructions to make proteins that perform different functions in the body.Â
In HD, a specific gene on chromosome 4 is altered. When there’s a change (also called a mutation) in a gene, the resulting protein may not function as intended. In the case of HD, the mutation causes a section of the gene to expand.Â
This expansion leads to the production of an abnormally long protein that becomes toxic, known as huntingtin. The section of the gene where this mutation happens is made up of smaller building blocks identified by the letters CAG, which is the sequence analyzed in the genetic test that can determine if someone has inherited the disease.Â
This expansion leads to the production of an abnormally long protein that becomes toxic, known as huntingtin. The section of the gene where this mutation happens is made up of smaller building blocks identified by the letters CAG, which is the sequence analyzed in the genetic test that can determine if someone has inherited the disease.Â
Everyone has a pair of chromosome 4, so everyone has the gene where the HD expansion can happen. The difference between healthy individuals and those who develop the disease lies in how many CAG repeats each person carries.
 It is worth mentioning that HD is an autosomal dominant disease, which means a person only needs one of the two chromosomes to have the expanded gene for the disease to show.Â
This also means that every child of someone who carries the disease has a 50% chance of inheriting the disease, each time a baby is conceived. It’s similar to having a boy or a girl: some families have three girls, others have three boys, but the chance doesn’t change based on previous children.Â
In the following image you can observe the different ranges of CAG repeats and what they imply for the genetic status.Â
The normal range of repeats is between 10 and 26, which is what healthy individuals typically have on both chromosomes.Â
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Repeats in the range of 27 to 35 are considered asymptomatic carriers. Individuals in this range will not develop the disease during their lifetime, but the gene is already altered in a way that can make the gene unstable, and increase the risk of a greater expansion in future generations.Â
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A repeat range from 36 to 39 is referred to as reduced penetrance. Most individuals in this range typically develop symptoms in late stages of life. However, the 50% chance of passing it on to offspring begins in this range, along with the risk that the mutation may expand further in future generations.Â
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When the number of repeats is 40 or higher, the gene is said to have full penetrance, meaning that symptoms will develop at some point during the individual’s lifetime—most often between the ages of 35 and 50. The chance of passing it on to offspring remains 50%.
This is a question scientists have been trying to answer for the past couple of decades. Earlier this year, new research helped shed light on this topic. The answer lies mostly in a phenomenon called somatic expansion, which means that the CAG repeat keeps expanding throughout a person’s lifetime in different cells of the body and becomes longer, with some cells reaching up to 1,000 CAG repeats.Â
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This also helps explain why some people with the same number of CAG repeats can have different ages of onset. Somatic expansion can happen at different times and rates between people.Â
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In addition, a combination of other genetic and environmental factors, which are still being studied, may also play a role in how early or late symptoms appear.
Not every cell in our body is the same. They vary according to their function, and it is estimated that there are around 200 types of cells in the human body. As they vary in function, they also vary in vulnerability or susceptibility to changes in DNA.Â
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Some cells are especially vulnerable to the effects of expanded CAG repeats. This is the case for medium spiny neurons, which are a specific type of cell found in the brain. A recent study showed that once the CAG repeats within a cell reaches 150 or more, the cell appears to turn on genes that cause cell death, a process known as neurodegeneration.Â
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We hope this information explains well most of the aspects of the genetic and hereditary nature of HD. Stay tuned because in our next article we will keep simplifying science and taking a closer look at the neurodegenerative process!
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If you have any questions or suggestions feel free to reach out to jarelys@eurohuntington.org
– Article written by Jarelys López