Lifestyle May Influence Age of Onset of Huntington’s, Analysis Says

Younger age at disease onset linked to suicidal behavior and substance abuse

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Beyond genetic factors, the onset of Huntington’s disease later in life was related to being in a stable partnership, living in large cities, and having lower education levels, a large-scale analysis suggests.

In comparison, a younger age at disease onset was associated with suicidal behavior and the use of alcohol, drugs, and tobacco.

Because psychiatric symptoms can precede motor impairment by many years, the researchers noted that “suicide risk must be monitored in all individuals and particularly in younger patients.”

The analysis was published in the Journal of Neurology, in the study “Beyond the CAG triplet number: exploring potential predictors of delayed age of onset in Huntington’s disease.”

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Huntington’s disease is caused by an expansion of the CAG repeat in the huntingtin (HTT) gene, in which C stands for cytosine, A for adenine, and G for guanine — all building blocks of DNA. CAG is typically repeated 10 to 35 times in this gene, whereas people with 40 or more repeats develop Huntington’s.

Onset of symptoms typically occurs in the fourth or fifth decade of life but can range from childhood to late adulthood.

The length of CAG repeats is the most significant factor that determines the age of onset and accounts for about 70% of the variability in onset age. In some cases, a CAG repeat range from 40 to 42 can be related to typical mid-adult onset as well as late-onset after 60 years of age.

What non-genetic factors did researchers investigate?

To identify non-genetic factors that may influence the age of Huntington’s onset, researchers based at the Università Cattolica del Sacro Cuore in Italy collected demographic, behavioral, and socio-environmental data from participants in Enroll-HD — a global, observational study of Huntington’s disease families.

The team analyzed data from 5,053 European Caucasian people with a confirmed Huntington’s diagnosis, who carry at least 36 CAG repeats. A subgroup of 593 patients who all shared 41 CAG repeats was also investigated alongside a group of 630 individuals with an absent or unknown family history.

Across all participants, the mean age of onset was 46.18 years. In this group, predictors of onset age included the number of CAG triplets, family inheritance, marital status, level of education, place of residence, suicidal behavior, alcohol abuse, drug use, and smoking habits in their past medical history.

Specifically, older age of onset was related to a lower number of CAG repeats, family history, living in stable, lifelong partnerships (married or widowed), a lower educational level, and living in larger cities. Younger onset age was associated with suicidal behavior and the use of alcohol, drugs, and tobacco.

The mean age of onset of 56.80 years in patients with 41 CAG repeats was older than the whole sample. Individuals with older age of onset were more likely to be in a stable partnership, have less frequent suicidal behaviors and drug use and abuse, and have unknown/missing family history. Factors predicting an earlier onset included inheritance, being single, and drug use. The team detected no difference across genders.

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Among patients with no known family history of Huntington’s, the mean age of onset was 53.78 years. Here, significant predictors of a younger onset included suicidal behaviors, depression, tobacco habits, and drug use.

“There is substantial variation in [age of onset] that is not explained by the [Huntington’s] gene pathological mutation, and our results demonstrate that non-genetic factors might also modulate its impact,” the researchers concluded.

“These data set the stage for reasoning about which determinants beyond CAG repeats may be involved in [age of onset] and provide potentially valuable information to guide disease-modifying therapeutic strategies and future clinical trial designs,” they added.