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      Prevalence of Non-psychiatric Comorbidities in Pre-symptomatic and Symptomatic Huntington's Disease Gene Carriers in Poland

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          Abstract

          Huntington's disease (HD) is monogenic neurodegenerative disorder caused by CAG expansions within the Huntingtin gene ( Htt); it has a prevalence of 1 in 10,000 worldwide and is invariably fatal. Typically, healthy individuals have fewer than 35 CAG repeats, while the CAG expansions range from 36 to ~200 in HD patients. The hallmark of HD is neurodegeneration, especially in the striatal nuclei, basal ganglia and cerebral cortex, leading to neurological symptoms that involve motor, cognitive, and psychiatric events. However, HD is a complex disorder that may also affect peripheral organs, so it is possible that HD patients could be affected by comorbidities. Hence, we investigated the prevalence of comorbid conditions in HD patients (pre-symptomatic and symptomatic groups) and compared the frequency of those conditions to a control group. Our groups represent 65% of HD gene carriers registered in Poland. We identified 8 clusters of comorbid conditions in both HD groups, namely: musculoskeletal, allergies, cardiovascular, neurological, gastrointestinal, thyroid, psychiatric, and ophthalmologic. We found that HD patients have a significantly higher percentage of co-existing conditions in comparison to the control group. Among the 8 clusters of diseases, musculoskeletal, psychiatric, and cardiovascular events were significantly more frequent in both pre- and symptomatic HD patients, while neurological and gastrointestinal clusters showed significantly higher occurrence in the HD symptomatic group. A greater recognition of comorbidity in HD might help to better understand health outcomes and improve clinical management.

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          Most cited references28

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          Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue.

          The expansion of CAG triplet repeats in the translated region of the human HD gene, encoding a protein (huntingtin) of unknown function, is a dominant mutation leading to manifestation of Huntington's disease. Targeted disruption of the homologous mouse gene (Hdh), to examine the normal role of huntingtin, shows that this protein is functionally indispensable, since nullizygous embryos become developmentally retarded and disorganized, and die between days 8.5 and 10.5 of gestation. Based on the observation that the level of the regionalized apoptotic cell death in the embryonic ectoderm, a layer expressing the Hdh gene, is much higher than normal in the null mutants, we propose that huntingtin is involved in processes counterbalancing the operation of an apoptotic pathway.
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            Huntingtin-protein interactions and the pathogenesis of Huntington's disease.

            At least nine inherited neurodegenerative diseases share a polyglutamine expansion in their respective disease proteins. These diseases show distinct neuropathological changes, suggesting that protein environment and protein-protein interactions play an important role in the specific neuropathology. A gain of toxic function as a result of an expanded polyglutamine tract can cause the protein huntingtin to interact abnormally with a variety of proteins, resulting in the complex of neuropathological changes seen in Huntington's disease. Recent studies have identified several huntingtin-interacting proteins that might be associated with the normal function of huntingtin and/or involved in the pathology of Huntington's disease. In this article, we focus on the potential roles of huntingtin-protein interactions in the pathogenesis of Huntington's disease.
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              Cognitive impairment in Huntington disease: diagnosis and treatment.

              Cognition has been well characterized in the various stages of Huntington disease (HD) as well as in the prodrome before the motor diagnosis is given. Although the clinical diagnosis of HD relies on the manifestation of motor abnormalities, the associated impairments have been growing in prominence for several reasons. First, research to understand the most debilitating aspects of HD has suggested that cognitive and behavioral changes place the greatest burden on families, are most highly associated with functional decline, and can be predictive of institutionalization. Second, cognitive impairments are evident at least 15 years prior to the time at which motor diagnosis is given. Finally, cognitive decline is associated with biological markers such as brain atrophy, circulating levels of brain-derived neurotrophic factors, and insulin-like growth factor 1. Efforts are now underway to develop valid and reliable measures of cognition in the prodrome as well as in all stages of HD so that clinical trials can be conducted using cognitive outcomes.
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                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                11 March 2020
                2020
                : 7
                : 79
                Affiliations
                [1] 1Department of Public Health, Poznan University of Medical Sciences , Poznan, Poland
                [2] 2First Department of Neurology, Institute of Psychiatry and Neurology , Warsaw, Poland
                [3] 3Department of Human Evolutionary Biology, Adam Mickiewicz University , Poznan, Poland
                [4] 4Department of Histology and Embryology, Poznan University of Medical Sciences , Poznan, Poland
                [5] 5Department of Life Sciences, Imperial College London , London, United Kingdom
                [6] 6Imperial College Centre for Synthetic Biology, Imperial College London , London, United Kingdom
                Author notes

                Edited by: Giovanni Tarantino, University of Naples Federico II, Italy

                Reviewed by: Shihua Li, Jinan University, China; Anthony Hannan, The University of Melbourne, Australia; Phyllis May-Ling Chua, Monash University, Australia

                This article was submitted to Translational Medicine, a section of the journal Frontiers in Medicine

                †These authors have contributed equally to this work

                Article
                10.3389/fmed.2020.00079
                7078243
                32219094
                91296131-d1bf-44b0-8210-a786b20415d6
                Copyright © 2020 Zielonka, Witkowski, Puch, Lesniczak, Mazur-Michalek, Isalan and Mielcarek.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 06 December 2019
                : 25 February 2020
                Page count
                Figures: 1, Tables: 3, Equations: 0, References: 39, Pages: 7, Words: 5712
                Categories
                Medicine
                Original Research

                huntington's disease,peripheral pathology,comorbidities,multimorbidity,pre-symptomatic stage,symptomatic stage

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