Understanding Your Risk: How Huntington’s Disease is Inherited

Huntington's disease (HD) is a rare, inherited brain disorder that gradually affects a person's movements, thinking ability, and behavior. Receiving an HD diagnosis, or having a family member affected by it, can bring many questions, especially about the risk for other family members. Understanding how HD is passed down through families is a crucial step for those living with or at risk of the disease.

This article aims to explain the genetic basis of Huntington's disease, how it is inherited, and what this means for families.

What Causes Huntington's Disease?

Huntington's disease is caused by a change, or mutation, in a single gene called the huntingtin gene (HTT). This gene is responsible for making a protein necessary for nerve cells (neurons) in the brain.

Within the HTT gene, there is a section where a specific DNA sequence, called CAG, is repeated many times. In most people, the CAG sequence is repeated a relatively small number of times. However, in people with Huntington's disease, this CAG repeat is significantly longer than usual. This expanded CAG repeat leads to the production of an abnormal huntingtin protein that doesn't function correctly and is toxic to certain brain cells, particularly in areas like the striatum (Raymund A C Roos, 2010; P McColgan & S J Tabrizi, 2018).

The length of the CAG repeat is key. While the exact threshold can vary slightly, an expansion of 36 or more CAG repeats is considered to cause Huntington's disease. Generally, a longer CAG repeat length is associated with an earlier age when symptoms begin (onset) (Raymund A C Roos, 2010). For instance, in cases of Juvenile Huntington's disease (onset before age 20), the repeat length often exceeds 55 (Mayke Oosterloo et al., 2024).

How is Huntington's Disease Inherited?

Huntington's disease follows an autosomal dominant inheritance pattern. This means that a person only needs to inherit one copy of the altered HTT gene from either parent to be at risk of developing the disease.

We all inherit two copies of most genes – one from our mother and one from our father. If a parent has Huntington's disease, they have one typical copy of the HTT gene and one altered copy with the expanded CAG repeat. For each child they have, there is a:

• 50% chance of inheriting the altered HTT gene and therefore being at risk of developing HD.
• 50% chance of inheriting the typical HTT gene and therefore not being at risk of developing HD (Nicholas S Caron et al., 1993).

This inheritance pattern is the same for both male and female children. If a child inherits the typical gene copy, they will not develop Huntington's disease and cannot pass the altered gene on to their own children.

Understanding Anticipation

A notable feature of Huntington's disease is a phenomenon called anticipation. This refers to the tendency for symptoms to appear at a younger age and sometimes be more severe in successive generations within a family (Garrett Rossi & Joan C Oh, 2020).

Anticipation is linked to the CAG repeat expansion. The expanded CAG repeat in the HTT gene can sometimes get even longer when it is passed down from parent to child. This expansion in repeat length from one generation to the next often leads to an earlier age of onset in the child compared to the parent (Mayke Oosterloo et al., 2024).

Anticipation is particularly pronounced when the altered gene is inherited from the father (paternal transmission). Studies have shown that the CAG repeat is more likely to expand significantly when passed through the male germline, leading to more noticeable anticipation in paternal inheritance compared to maternal inheritance (Anastasia Vishnevetsky et al., 2022).

Genetic Testing and Counseling

For individuals who have a family history of Huntington's disease but do not show symptoms, predictive genetic testing is available to determine if they have inherited the expanded CAG repeat (Nicholas S Caron et al., 1993). This test is typically performed using a blood sample.

For individuals who are already showing symptoms suggestive of HD, diagnostic genetic testing can confirm the diagnosis by identifying the expanded CAG repeat (Thomas B Stoker et al., 2022).

Genetic testing for HD, especially predictive testing, is a deeply personal decision with significant implications. It is strongly recommended that individuals considering testing undergo comprehensive genetic counseling both before and after the test. Genetic counselors can provide information about the disease, inheritance patterns, the testing process, potential results, and help individuals explore the emotional and social impact of knowing their genetic status (Martha A Nance, 2017). Predictive testing is generally not recommended for asymptomatic individuals under the age of 18 (Nicholas S Caron et al., 1993).

Reproductive Options

For families affected by Huntington's disease who are planning to have children, several reproductive options are available to reduce the risk of passing the altered gene to future generations. These options include:

• Prenatal testing: Testing the fetus during pregnancy through procedures like chorionic villus sampling or amniocentesis (Raymund A C Roos, 2010).
• Preimplantation genetic testing (PGT): Used in conjunction with in vitro fertilization (IVF), PGT allows embryos to be tested for the HD-causing gene expansion before they are implanted (Nicholas S Caron et al., 1993).

Decision-making about these options can be complex and emotionally challenging, and genetic counseling is vital to explore the choices available and their implications (Neil Fahy et al., 2023).

Conclusion

Understanding the genetic risks and inheritance patterns of Huntington's disease is a critical part of navigating this condition for individuals and families. HD is an autosomal dominant disorder caused by an expanded CAG repeat in the HTT gene, typically leading to a 50% risk for children of an affected parent. The phenomenon of anticipation, often more pronounced with paternal inheritance, can lead to earlier onset in younger generations. Genetic testing and counseling provide valuable tools for diagnosis and risk assessment, and reproductive options are available for family planning. Open communication within families and support from healthcare professionals and patient organizations are essential resources for those facing the complexities of Huntington's disease inheritance.

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