High prevalence of carriers of intermediate and pathological range polyglutamine disease-associated alleles in the general population

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)

Novel genetic modifiers of Alzheimer disease phenotype

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.

Determinants of age-at-onset and disease progression largely overlap in Huntington disease

Huntington’s disease breakthrough!

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!

Interactions between polyglutamine-disease associated genes…

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.

Global warming, brown fat and diabetes

In 2009 three influential back-to-back papers appeared in the renowned New England Journal of Medicine which conclusively demonstrated that even mild cold exposure could activate brown adipose tissue, thereby dramatically increasing resting energy expenditure in humans:

  1. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009; 360(15):1509-1517.
  2. Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009; 360(15):1500-1508.
  3. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009; 360(15):1518-1525.

This fascinating finding immediately prompted me to write a letter, together with my colleague Hanno Pijl, in response in which I postulated that based on these findings global warming might actually worsen the obesity pandemic (bearing in mind Newton’s law of cooling). However, our letter was unfortunately rejected without peer-review. Seven years later (!) another study was published by Hanssen et al. which prompted me again to contact Hanno Pijl, who brought me into contact with Patrick Rensen and Lisanne Blauw, and together we finally managed to conduct a more thorough examination of the relation between rising global temperatures and the incidence of diabetes in the United States, as well as the prevalence of glucose intolerance worldwide. And the results were fascinating indeed as you can read here.  The article was widely covered in the international media and has already been downloaded more than 13500 times!  So a happy end after all you might think, but unfortunately I don’t think so as long as some lunatic ‘world leaders’ are just flatly denying the very concept of global warming (very, very, very sad…)