The Phenotype of Huntington’s disease like 2

Abstract

Background: Huntington’s disease like 2 (HDL2) is described as the disease with the greatest resemblance to Huntington’s disease (HD). Both disorders clinically comprise a movement disorder, dementia and psychiatric symptoms. HDL2 has been reported exclusively in people of African ancestry, with the highest frequency in South Africa. Anecdotally, HDL2 has been associated with acanthocytes on blood smears, less oculomotor dysfunction and greater parkinsonism, potentially differentiating it from HD. Aim: To describe systematically the HDL2 phenotype and compare it to that of HD. Method: A systematic review of published HDL2 clinical descriptions was conducted to establish the extant HDL2 phenotype. Subsequently, a blinded cross-sectional observational study compared African ancestry subjects. HDL2 (n=15) study participants were compared to subjects with HD (n=13); these two groups were concurrently compared to an unaffected control group. Data collected included a standardised history, general and neurological examination results, blood samples and MRI scans. Motor rating scales were used to assess the movement disorder of affected subjects which was video-recorded. The data were analysed with respect to clinical phenotypes, quantitative radiological volumes and erythrocyte features. Results: The literature generally described the HDL2 phenotype as similar to HD, however, HDL2 subjects were reported to have less oculomotor dysfunction, dystonia, dysarthria and greater parkinsonism. Only four HDL2 cases had reported acanthocytes. The current study found no acanthocytes in HDL2 or any other participants. The MRI intracerebral volumes of subjects with HDL2 and HD showed similar cortical and subcortical atrophy but the thalamic volumes in subjects with HDL2 were smaller than those of the HD groups. Blinded raters could not distinguish between HDL2 and HD after analysing individual subjects. The two affected groups had similar overall Unified Huntington’s Disease Rating Scale (UHDRS) motor scores, with worse scores for some of the motor and cognitive components in the HDL2 group. Conclusion: This research suggests that HDL2 and HD cannot be differentiated based on the presence of acanthocytes or by examining individual patients. The study shows that there is a predominant clinical similarity between HDL2 and HD, however, there are additional findings that suggest HDL2 has clinical and radiological features that are more severe. This finding may have implications for the pathogenic mechanisms of both diseases. Furthermore, this research has found potential clinical and neuroimaging biomarkers for HDL2 that may give reference for future research into the pathogenesis and treatment of HDL2