Progression in Huntington’s linked to CAG repeat number

The progression, not just age of onset, of Huntington’s disease can be predicted by a measurable genetic factor, researchers have learned.

Huntington’s, an inherited neurodegenerative disease that affects motor function and cognition, is caused by an expansion of the CAG trinucleotide sequence on the huntingtin gene. Scientists have previously linked younger age at onset to a higher number of CAG repeats on the gene, but the association between these and the rate of progression after onset was poorly understood.

In research published online August 12 in JAMA Neurology, investigators linked the rate of progression – which, like age at onset, is highly variable in Huntington’s – to CAG repeat length. CAG repeat length was strongly associated with distinct patterns of brain damage, as well as clinical measures of cognitive and motor decline.

For their research, Douglas R. Langbehn, MD, PhD, of the University of Iowa, Iowa City, and colleagues used data from two longitudinal observational studies in gene carriers for Huntington’s and nonrelated controls. The researchers looked at data from 443 participants (56% female; mean age, 44.4 years) who were followed for a mean of 4 years, with more than 2,000 study visits across the multisite cohort. Neuropsychiatric testing and brain imaging were conducted annually, using composite scoring systems of the investigators’ design. These composite scores sought to be more sensitive by combining results from several validated clinical and imaging tests.

Age and speed of decline in total functional capacity tracked with more CAG repeats, the researchers found. For example, in people with 40 CAG repeats, the estimated mean age of initial motor-cognitive score change was 42.46 years; for those with 45 repeats, 26.65 years, and for people with 50 CAG repeats, 18.49 years. Higher repeats were seen significantly associated with accelerated, nonlinear decline on both clinical and brain-volume measures, except gray matter volume, according to principal component analyses conducted on the data.

“We derived a single summary measure capturing the motor-cognitive phenotype and showed that the accelerating progression of the phenotype with aging is highly CAG repeat length dependent (i.e., those with higher CAG decline earlier and faster). Contrary to some previous assertions, this CAG dependence continues well past the onset of clinical illness,” Dr. Langbehn and colleagues wrote in their analysis. “By characterizing these CAG repeat length–dependent disease trajectories, we provide insights into disease progression that may guide future therapeutic approaches and identify the most appropriate intervention ages to prevent clinical decline.”

Dr. Langbehn and colleagues acknowledged as a limitation of their study its likely exclusion of the sickest subjects because of the cohorts’ design. The CHDI Foundation funded the study. Of the 16 coauthors, 13 reported receiving funding from CHDI and/or from pharmaceutical manufacturers.

SOURCE: Langbehn et al. JAMA Neurol. 2019 Aug 12. doi: 10.1001/jamaneurol.2019.2328

The progression, not just age of onset, of Huntington’s disease can be predicted by a measurable genetic factor, researchers have learned.

Huntington’s, an inherited neurodegenerative disease that affects motor function and cognition, is caused by an expansion of the CAG trinucleotide sequence on the huntingtin gene. Scientists have previously linked younger age at onset to a higher number of CAG repeats on the gene, but the association between these and the rate of progression after onset was poorly understood.

In research published online August 12 in JAMA Neurology, investigators linked the rate of progression – which, like age at onset, is highly variable in Huntington’s – to CAG repeat length. CAG repeat length was strongly associated with distinct patterns of brain damage, as well as clinical measures of cognitive and motor decline.

For their research, Douglas R. Langbehn, MD, PhD, of the University of Iowa, Iowa City, and colleagues used data from two longitudinal observational studies in gene carriers for Huntington’s and nonrelated controls. The researchers looked at data from 443 participants (56% female; mean age, 44.4 years) who were followed for a mean of 4 years, with more than 2,000 study visits across the multisite cohort. Neuropsychiatric testing and brain imaging were conducted annually, using composite scoring systems of the investigators’ design. These composite scores sought to be more sensitive by combining results from several validated clinical and imaging tests.

Age and speed of decline in total functional capacity tracked with more CAG repeats, the researchers found. For example, in people with 40 CAG repeats, the estimated mean age of initial motor-cognitive score change was 42.46 years; for those with 45 repeats, 26.65 years, and for people with 50 CAG repeats, 18.49 years. Higher repeats were seen significantly associated with accelerated, nonlinear decline on both clinical and brain-volume measures, except gray matter volume, according to principal component analyses conducted on the data.

“We derived a single summary measure capturing the motor-cognitive phenotype and showed that the accelerating progression of the phenotype with aging is highly CAG repeat length dependent (i.e., those with higher CAG decline earlier and faster). Contrary to some previous assertions, this CAG dependence continues well past the onset of clinical illness,” Dr. Langbehn and colleagues wrote in their analysis. “By characterizing these CAG repeat length–dependent disease trajectories, we provide insights into disease progression that may guide future therapeutic approaches and identify the most appropriate intervention ages to prevent clinical decline.”

Dr. Langbehn and colleagues acknowledged as a limitation of their study its likely exclusion of the sickest subjects because of the cohorts’ design. The CHDI Foundation funded the study. Of the 16 coauthors, 13 reported receiving funding from CHDI and/or from pharmaceutical manufacturers.

SOURCE: Langbehn et al. JAMA Neurol. 2019 Aug 12. doi: 10.1001/jamaneurol.2019.2328

The progression, not just age of onset, of Huntington’s disease can be predicted by a measurable genetic factor, researchers have learned.

Huntington’s, an inherited neurodegenerative disease that affects motor function and cognition, is caused by an expansion of the CAG trinucleotide sequence on the huntingtin gene. Scientists have previously linked younger age at onset to a higher number of CAG repeats on the gene, but the association between these and the rate of progression after onset was poorly understood.

In research published online August 12 in JAMA Neurology, investigators linked the rate of progression – which, like age at onset, is highly variable in Huntington’s – to CAG repeat length. CAG repeat length was strongly associated with distinct patterns of brain damage, as well as clinical measures of cognitive and motor decline.

For their research, Douglas R. Langbehn, MD, PhD, of the University of Iowa, Iowa City, and colleagues used data from two longitudinal observational studies in gene carriers for Huntington’s and nonrelated controls. The researchers looked at data from 443 participants (56% female; mean age, 44.4 years) who were followed for a mean of 4 years, with more than 2,000 study visits across the multisite cohort. Neuropsychiatric testing and brain imaging were conducted annually, using composite scoring systems of the investigators’ design. These composite scores sought to be more sensitive by combining results from several validated clinical and imaging tests.

Age and speed of decline in total functional capacity tracked with more CAG repeats, the researchers found. For example, in people with 40 CAG repeats, the estimated mean age of initial motor-cognitive score change was 42.46 years; for those with 45 repeats, 26.65 years, and for people with 50 CAG repeats, 18.49 years. Higher repeats were seen significantly associated with accelerated, nonlinear decline on both clinical and brain-volume measures, except gray matter volume, according to principal component analyses conducted on the data.

“We derived a single summary measure capturing the motor-cognitive phenotype and showed that the accelerating progression of the phenotype with aging is highly CAG repeat length dependent (i.e., those with higher CAG decline earlier and faster). Contrary to some previous assertions, this CAG dependence continues well past the onset of clinical illness,” Dr. Langbehn and colleagues wrote in their analysis. “By characterizing these CAG repeat length–dependent disease trajectories, we provide insights into disease progression that may guide future therapeutic approaches and identify the most appropriate intervention ages to prevent clinical decline.”

Dr. Langbehn and colleagues acknowledged as a limitation of their study its likely exclusion of the sickest subjects because of the cohorts’ design. The CHDI Foundation funded the study. Of the 16 coauthors, 13 reported receiving funding from CHDI and/or from pharmaceutical manufacturers.

SOURCE: Langbehn et al. JAMA Neurol. 2019 Aug 12. doi: 10.1001/jamaneurol.2019.2328