The mutation responsible for Huntington’s disease (HD) ultimately leads to a severe brain disorder in adults. However, a recent study has revealed that children with this HD mutation actually exhibit larger brain sizes and higher IQs compared to their peers without the mutation.
The genetic alteration that triggers Huntington’s disease (HD) — a debilitating brain condition that impairs movement and cognitive functions — may also promote earlier brain development and contribute to increased human intelligence.
This insight emerges from over a decade of research involving brain imaging and brain function assessments, including measures of motor skills, cognition, and behavior, gathered from a distinct group of individuals — children and young adults who possess the HD gene. Although the HD mutation leads to a fatal brain condition in adulthood, findings indicate that during early childhood, those with the mutation show both larger brains and elevated IQs compared to those without it.
“Our findings imply that the gene mutation may confer advantages for brain development in early life, but that these advantages could turn into drawbacks later on,” remarks Peg Nopoulos, MD, who leads the psychiatry department at the UI Carver College of Medicine and is the senior author of the paper published in The Annals of Neurology.
These findings may also guide the development of effective treatments for HD. If the gene’s early effects are advantageous, removing or suppressing it entirely might negate these developmental benefits. It might be more beneficial to design therapies that lessen the gene’s activity as patients age.
Moreover, Nopoulos is excited about the new evidence indicating the gene’s advantageous role in early brain development.
“This suggests the gene could be linked to higher IQ levels,” she notes. “Previous studies have not identified any genes significantly influencing IQ, even though intelligence is known to be hereditary.”
HD gene associated with enhanced brain development in youth
Huntington’s disease arises from a mutation in the huntingtin (HTT) gene. The protein that the HTT gene produces is crucial for normal development, yet variations within this protein segment greatly impact brain function.
The specific segment involves a long repetition of the amino acid glutamine. An increased number of repeats correlates with larger, more intricate brains. For instance, species like sea urchins or simple fish have no repeats, while more complex organisms such as rodents and apes possess a few, and humans feature the highest counts.
Typical individuals have between 10-26 repeats, but having 40 or more leads to the development of HD. Although the gene expansion is present from birth, symptoms of HD only surface in middle age. Nopoulos’s research group at the University of Iowa has extensively examined how the expansion of the HTT gene influences brain development decades prior to the onset of the disease.
“We know the expanded gene is responsible for a devastating degenerative disease in later life, but it’s also essential for overall development,” she comments. “We were surprised to discover it positively impacts brain development in early stages. Children with the gene expansion have larger cerebrum volumes and higher IQs compared to those without it.”
Particularly, the research indicated that well before experiencing HD symptoms, those with the gene expansion demonstrated improved cognitive, behavioral, and motor functioning relative to children with a normal range of repeats. Furthermore, these children had larger cerebral volumes and more extensive cortical areas. Following this initial peak, a gradual decline in brain function and structure was observed.
The study gathered data from nearly 200 participants involved in the Kids-HD study, the sole longitudinal study tracking children and young adults at risk of HD due to family history.
Evolutionary advantages come with drawbacks
While the results may be unexpected, they align with findings from evolutionary biologists who propose that genes like HTT might have been ‘favorably selected’ during human brain evolution. This idea, known as antagonistic pleiotropy, suggests some genes can have positive effects early in life but lead to negative consequences later on.
The results also challenge the notion that the protein from the HD gene is just a harmful substance causing brain degeneration.
“Overall, our study indicates that we should reconsider the concept of the toxic protein theory,” asserts Nopoulos, a member of the Iowa Neuroscience Institute. “Instead, we should explore antagonistic pleiotropy, which proposes that genes like HTT may enhance early brain development at the expense of longevity, leading to potential premature aging.”
“This suggests that rather than simply targeting the gene for therapies, medications aimed at slowing the aging process could prove more beneficial.”
Future directions
Nopoulos’s team is advancing research beyond the Kids-HD initiative. With significant funding obtained in 2019, she has launched the Children to Adult Neurodevelopment in Gene-Expanded Huntington’s Disease (ChANGE-HD) project, a multi-center study aiming to recruit hundreds of participants for over 1,200 assessments, validating key insights from the Kids-HD study and advancing future research on HD.
A primary focus will be on uncovering how an enlarged brain might later suffer from degeneration. One hypothesis that Nopoulos and her team intend to explore is that an expanded cortex may lead to excessive production of glutamate (a crucial neurotransmitter), which benefits early brain development but could subsequently cause neurotoxicity and brain deterioration.
Alongside Nopoulos, the UI team comprises Mohit Neema, MD, UI research scientist and first author of the study; Jordan Schultz, PharmD; Douglas Langbehn, MD, PhD; Amy Conrad, PhD; Eric Epping, MD, PhD; and Vincent Magnotta, PhD.
The research received partial funding from the National Institute of Neurological Disorders and Stroke and the CHDI Foundation.
