K10 Is there Convincing Evidence that Intermediate Repeats in the HTT Gene Cause Huntington’s Disease?

Background Huntington’s disease (HD) is a neurodegenerative disease associated with a CAG repeat expansion in the Huntingtin (HTT) gene. A trinucleotide size between 27 and 35 is considered ‘intermediate’ and not to cause symptoms and signs of HD. There are articles claiming otherwise. Aims Our objective is to determine if there is convincing evidence that intermediate repeats (IA) cause HD. Methods Previously published case reports on HTT intermediate repeat sizes and all cases from the Netherlands with an IA were reviewed for clinical symptoms. Results Two patients had a clinical presentation of Huntington’s disease and an IA out of ten reported cases in literature. Between 2001 and 2012, 1,690 patients were tested for HD in the Netherlands. One case out of 60 with an IA had a phenotype resembling HD, but had already been published in a case report. Conclusion The frequency of IAs in the general population is high and therefore it is likely that the combination of an IA and symptoms resembling HD is based on coincidence. With evolving genetic insight and the finding of new genetic causes for HD like syndromes, it is more likely that the symptoms are caused by a yet unknown or recently discovered HD mimic, like C9orf72. Consequently, we find that it is premature to claim that IA can cause HD. We recommend systematic follow up of this group of individuals and if possible brain pathology for confirmation or exclusion of HD.