Leukocyte telomere lenght in Huntington's Disease. A study in fully penetrant and reduced penetrant alleles

Introduction. Huntington's Disease (HD), an autosomal dominant neurodegenerative disease, is caused by an expanded CAG repeat in the first exon of HTT gene. The disease is fully penetrant in individuals with 40 or more CAG repeats, and reduced penetrance in the range of 36-39 repeats. Overall the age at onset, usually at midlife, inversely correlates with the number of CAG repeats, and severity of symptoms vary widely between individuals. In the present study, we investigated the relationship between Leukocyte Telomere Length (LTL) and disease progression. Methods. LTL (T/S ratio) was measured in manifest HD patients (HD, n=62) and pre-manifest HD patients (pre-HD, n=38) with fully penetrant alleles, in subjects with reduced penetrant alleles (rp-HD, n=23), and age-matched controls (n= 76). Results. Mean LTL values of controls, pre-HD and HD patients were significantly different (p< 0.0001), in the order: HD (0.58 ± 0.07) <pre-HD (0.78 ± 0.16) <controls (0.92 ± 0.09). Mean LTL values of rp-HD subjects (0.82± 0.16) were significantly lower than controls (p=0.003), but similar to pre- HD patients. An inverse relationship between mean LTL and CAG repeat number was found in the pre-HD (p=0.03). Conclusion. In pre-HD patients, LTL shorten gradually according to advancing age and CAG number, up to the low values observed in HD patients. A similar LTL shortening seems to be present in rp-HD, but at more advanced age. The possible use of LTL as biomarker of disease progression is discussed. Supported by: grant EHDN 0942 to LV; grants 2017/2018 La Sapienza University to RMC