The prevalence of carriers of intermediate and pathological range polyglutamine disease-associated alleles is much higher in the general population than previously thought. So a substantially higher number of individuals may be at risk of developing a polyglutamine disease (including Huntington disease and spinocerebellar ataxias) later in life or bearing children with a de novo mutation (given the well-known germ-line instability of longer alleles) than previously assumed. See our study on this topic recently published in JAMA Neurology (https://lnkd.in/dU8Aehi) and the accompanying editorial (https://lnkd.in/dXkhFWk).
In close collaboration with colleagues from the Alzheimer Centre in Amsterdam, we recently made the intriguing observation that disease expression in Alzheimer disease is modulated by common CAG repeat length variations, especially those in ATXN1 and AR (link to the paper), providing further support for the notion that DNA repeat polymorphisms could be an under-appreciated class of genetic modifiers of brain structure and function in health and disease.
In case you have missed it: The results of the Ionis phase I huntingtin-lowering trial were announced on 11 December 2017 and appear very promising (BBC, The Guardian, CNN). The antisense oligonucleotide-based drug, IONIS-HTTRx, not only appeared to be safe and well-tolerated, but according to the company’s press-release, also dose-dependently decreased mutant huntingtin levels which “substantially exceeded expectations”. Grateful for having been able to make a small contribution to this major breakthrough as part of Professor Sarah Tabrizi’s clinical research team. We have now started the open lable extension study and I am very hopeful that we have taken a large step forward in finding a treatment for this devastating disease, although we are not there yet!
Using data from the Allen Human Brain Atlas and in collaboration with the Delft Bioinformatics Lab and we recently showed that co-expression patterns between the polyglutamine-disease associated genes ATN1 and ATXN2 coincide with brain regions affected in Huntington disease. The article is fully open acces and available here.
Our recent article provides yet further support for the role of DNA repeat polymorphisms as important, but still underappeciated, genetic modifiers of depression in the general population.