The analysis of C9orf72 mutation in Huntington disease patients with excluded HTT dynamic mutation

Dynamic mutation act as an unstable heritable element where the probability of a mutant phenotype expression is a function of the number of the repeats within. These mutations, typically short sequences repeated many times, give rise to numerous known diseases. A repeat expansion in the C9orf72 gene has recently been identified as a major cause of familial and sporadic frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). Moreover, Huntington disease-like (HDL) syndrome due to C9ORF72 expansions is observed as a rare, genetic neurodegenerative disease characterized by movement disorders, including dystonia, chorea, myoclonus, tremor and rigidity. Associated features are also cognitive and memory impairment, early psychiatric disturbances and behavioral problems. In many cases where Huntington disease (HD) is suspected, the genetic test for HD is negative: these are known as HD phenocopies. In this study, we aim to assess the frequency of C9orf72 expansions in a cohort of HD phenocopies patients. The mutation of C9orf72 is a hexanucleotide repeat expansion of the six nucleotides (GGGGCC)n. In a healthy person, there are few repeats of this hexanucleotide, typically less than 20-30, but in people with the mutation, the repeat can occur in the order of hundreds. A cohort of 1046 HD patients with excluded HTT mutations where analyzed for the C9orf72 expansion using repeat primed PCR. We identified three cases that had hexanucleotide (GGGGCC)n repeat expansion within C9orf72 gene. In these patients the first symptoms appeared at a young age and mainly problems with muscle coordination and control. These findings suggest that C9orf72 repeat expansion is a rare cause of clinical symptoms in patients with HTT repeat expansion excluded.