Gene expansion drives Huntington's disease development

Subtle changes in the brain can be identified decades before a diagnosis of Huntington's disease, two major new studies that shed light on what drives the disease have shown.

In the first study, published in Cell, scientists at the Broad Institute, Harvard Medical School and McLean Hospital, all in Massachusetts, identified that the disease-causing mutation in the huntingtin (HTT) gene slowly transforms from a latent to a toxic form, leading to the death of brain cells and symptom onset.

'These experiments have changed how we think about how Huntington's develops,' said Professor Steve McCarroll, director of genomic neurobiology at the Broad Institute and co-senior author of the study. 'This is a really different way of thinking about how a mutation brings about a disease, and we think that it will apply in DNA-repeat disorders beyond Huntington's disease.'

A mutant DNA triplet (CAG) repeat expansion, known as a type of somatic expansion, in the HTT gene is the cause of Huntington's disease. While healthy individuals have a repeat size of 15-35 CAGs those with Huntington's disease have 36 or more, with longer repeats leading to an earlier onset of cognitive, psychiatric and motor symptoms. However, although the cause of Huntington's disease has long been known, it has remained unclear why symptoms take decades to manifest, with the average age of clinical onset being 40-50 years.

The scientists measured the CAG repeat length in brain cells taken from 50 people with Huntington's disease and 53 controls. They found that the repeat expands over time and only occurs in the specific brain cells that die in the brains of people with Huntington's disease – and only when reaching approximately 150 repeats do the cells rapidly degenerate and die.

Professor McCarroll and his team suggest that developing therapies to slow this type of somatic expansion may be more effective than other approaches and could substantially postpone symptom onset.

'It's going to take much scientific work by many people to get to treatments that slow the expansion of DNA repeats,' Professor McCarroll said. 'But we're hopeful that understanding this as the central disease-driving process leads to deep focus and new options.'

In a second study, published in Nature Medicine, researchers at University College London have also found that subtle changes in the brain, detectable through advanced imaging, blood and spinal fluid analysis, occur in Huntington's disease patients up to two decades before a clinical motor diagnosis.

Over a 4.5-year period, the researchers compared 57 people with the Huntington's disease somatic expansion, who were on average 23 years from a predicted clinical diagnosis, with 46 closely matched controls. They discovered that people with the Huntington's disease somatic expansion showed no decline in any clinical function, when compared to the controls.

However, changes in spinal fluid biomarkers were discovered in people with the Huntington's disease somatic expansion. They specifically found elevated levels of neurofilament light chain (a marker for neuronal injury) and reduced levels of proenkephalin (a marker of healthy brain cells), both of which indicate that the neurodegenerative process begins long before symptoms are evident and before a clinical diagnosis.

In addition, brain scans revealed atrophy in people with the Huntington's disease somatic expansion, which was not seen in the healthy controls.

'Our study underpins the importance of somatic CAG repeat expansion driving the earliest neuropathological changes of the disease in living humans with the Huntington's disease gene expansion,' said Professor Sarah Tabrizi, joint head of department of neurodegenerative disease and lead author of the study.

Both teams conclude that somatic expansion of the Huntington's disease gene, which can be measured in blood samples, is an early indicator of Huntington's disease.