No abstract

Huntington disease (HD) is a devastating monogenic autosomal dominant disorder. HD is caused by a CAG expansion in exon 1 of the gene coding for huntingtin, placed in the short arm of chromosome 4. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unraveling mechanisms are still unknown. This practical and brief review summarizes some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis.

Background and purpose Despite enormous advances in identifying genetic variants responsible for many neurological diseases, access to genetic testing may be limited in clinical practice. The objective of this study was to assess worldwide access to genetic tests for movement disorders and factors impacting their utilization. Methods The Rare Movement Disorders Study Group of the International Parkinson and Movement Disorder Society designed an online survey electronically mailed to all 7815 members. Results Survey data completed by 1269 participants from 109 countries were analysed. Limited access to geneticists and genetic counsellors was reported in many world regions compared to Europe and North America. Availability of genetic testing was limited, with rates of access lower than 50%. Genetic testing for chorea was the most commonly available. For parkinsonism, dystonia, ataxia, hereditary spastic paraplegias and metabolic disorders, there was limited access to genetic testing in all countries compared to Europe and North America, with significant differences found for Africa, Central/South America, Asia. In many regions, genetic testing was supported by either private or public funding. Genetic testing was free of charge in Europe according to 63.5% of respondents. In North America, Africa, Central/South America, Asia and the Middle East access to free of charge genetic testing was by far significantly lower compared to Europe. Conclusions This survey highlights difficulties in accessing genetic testing and individuals with expertise in genetics at the worldwide level. In addition, major disparities in genetic testing amongst world regions are highlighted, probably due to a variety of factors including financial barriers.

Our results contribute to support that timing functions are impaired in HD in correlation with clinical deterioration. Recordings of cognitive performance related to timing could be a potential useful tool to measure the neurodegenerative progression of movement disorder-related pathologies.

Heterozygous mutations in the glucocerebrosidase (GBA) gene have been reported as a common risk factor for the development of Parkinson's disease (PD) in Gaucher disease (GD) patients and in heterozygous GBA mutation positive carriers. In this study, we analyzed the occurrence of prodromal markers of PD in an Argentinean cohort with type 1 GD. After signed informed consent, we evaluated 26 patients with type 1 GD under enzymatic replacement therapy from a cohort of the Hospital Ricardo Gutierrez GD Study Group in Buenos Aires City, Argentina. We performed an extensive neurological examination, including cognitive assessment by Montreal Cognitive Assessment (MoCA) and a questionnaire performed ad hoc, to identify non-motor PD symptoms. Parasomnias were reported by 7 patients (26.92%), rapid eye movement behavior disorders in 2 (7.69%), constipation in 2 (7.69%), hyposmia in 1 (3.84%), tremor in 1 (3.84%), and depression in 3 cases (11.53%). MoCA assessment was abnormal in 44.44% of patients. No patient fulfilled PD diagnostic criteria (Queen Square Brain Bank criteria). The identification of prodromal markers of PD in type 1 GD suggests that this population represents a very interesting cohort for identifying potential biomarkers and neuroprotective therapies for PD.