Non-genetic Factors Can Play Great Role in Mortality Risk, Study Says
CAG repeats found not to be independent predictor of disease mortality
A greater number of CAG repeats within the HTT gene — the genetic cause of Huntington’s disease — is linked to earlier disease onset and death, but is not an independent predictor of mortality in people with the neurodegenerative disease, a study shows.
These findings suggest that “non-genetic factors contribute to mortality status and warrant further investigation,” the researchers wrote.
No significant differences were found in terms of sex, age at symptom onset, or functional and cognitive performances between living and deceased Huntington’s patients.
Larger studies are needed to confirm these findings and identify risk factors of mortality in people with Huntington’s — and especially for female patients, who were found in this study to have the highest risk of death.
The study, “Huntington’s disease: Mortality and risk factors in an Australian cohort,” was published in Journal of the Neurological Sciences.
More CAG repeats linked to earlier motor symptom onset and death
Huntington’s disease is a progressive neurodegenerative disorder characterized by symptoms such as uncontrolled movements, loss of cognitive function, and psychiatric problems. Patients also show progressive shrinkage, or atrophy, in a region of the brain known as the basal ganglia, which is responsible for movement coordination.
The disease is caused by excessive repeats of a portion of DNA, called CAG triplets, within the HTT gene. Healthy people normally have between 10 and 35 CAG repeats, but those with Huntington’s may have 36 to 120 repeats. A higher number of CAG repeats has been tied to earlier motor symptom onset and younger age at death.
“However, when potential confounding [influencing] factors, such as cardiovascular disease, are taken into consideration, the association between CAG repeat length and age at death has not found to be significant,” the researchers wrote.
Now, a team of researchers in Australia assessed whether CAG repeat length, age of disease onset, and basal ganglia atrophy would be risk factors of mortality in people with Huntington’s.
They retrospectively analyzed the medical records of 83 people (51 women and 32 men) diagnosed with Huntington’s who were admitted to the neuropsychiatry department in Royal Melbourne Hospital between 1992 and 2014. The records contained demographic, clinical, and brain imaging data.
non-genetic factors contribute to mortality status and warrant further investigation
Patients had a nearly six times higher risk of death than general population
Cognitive function was assessed with the Mini-Mental State Examination and Neuropsychiatry Unit Cognitive Assessment Tool, while function was evaluated with the Global Assessment of Functioning.
More than half of the patients (54.2%) had an Oceanic/Northern Western European ethnicity, and their median age was 41 years at symptom onset, and 48 years at admission. CAG repeat number was available for 73 patients, who had a median of 44 repeats.
Functional and cognitive impairment was moderate, and brain atrophy was present. Psychiatric/behavioral problems were the most common first symptoms (43.5% of patients), followed by motor symptoms (36.2%), and cognitive deficits (20.3%). More than half of the patients did not drink, smoke, or report heart disease risk factors.
A total of 44 patients (53%) died during the evaluated period, at a median age of 59 years. Huntington’s was the primary cause of death (83.7%), with respiratory symptoms listed as a common secondary cause.
Median survival after symptom onset was 18.8 years. Huntington’s patients had a nearly six times higher risk of death than the general population in Australia, with this risk being two times higher in female patients than male patients (8.3 vs. 4.2 increased risk).
Notably, patients between ages 50 and 69 years had a more than nine times higher risk of death compared with the general population.
While longer CAG repeat lengths were significantly associated with an earlier disease onset and death, no significant difference was found in CAG repeat lengths and age of symptom onset between living and deceased patients.
The researchers also found no significant differences in terms of sex, initial symptom, functional ability, cognitive function, cardiovascular risk factors, alcohol consumption, or tobacco use between these groups.
However, deceased patients had significantly more brain atrophy than living patients. In addition, patients living with Huntington’s were significantly more likely to have a personal and family history of psychiatric problems and a family history of dementia than deceased patients.
“These findings may be explained by earlier engagement with psychiatric and health services with ongoing support and care by individuals who are aware of their psychiatric and family history and that our sample was biased being a neuropsychiatry service compared to a neurology service,” the team wrote.
Further statistical analyses considering individual factors showed that CAG repeat length, age of disease onset, initial presenting symptom type, and brain atrophy were not predictors of mortality in patients.
Epigenetics and lifestyle may more prominently affect disease progression
These findings suggest that “while the CAG repeat length is strongly associated with age of symptomatic onset, there may be other factors that more prominently affect progression of symptoms and death such as epigenetics and lifestyle factors,” the team wrote.
Epigenetic factors refer to chemical modifications to DNA that influence the activity of genes without altering their underlying DNA sequence.
“The results of this study can be used to support healthcare services and future directions for research in this area,” the researchers wrote, adding that “the relatively long survival duration emphasizes that maintaining quality of life while being symptomatic with HD [Huntington’s disease] is crucial.”
The researchers highlighted some limitations to the study, including the small sample size and the retrospective nature. They also noted that participants were recruited from one specialist center and mostly had psychiatric or behavioral problems.
More studies are needed to confirm these findings and provide “a thorough understanding of risk factors for HD mortality beyond gene results,” the team wrote.
This may help Huntington’s patients “in adopting beneficial lifestyle changes to optimize their function and improve quality of life while living with this disease,” the researchers concluded.
About the Author
