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Is Ataxia an Underestimated Symptom of Huntington's Disease?

ABSTRACT: Background: Huntington's disease (HD) is a progressive disorder characterized by motor, cognitive and psychiatric features. Cerebellar ataxia is classically considered as uncommon in HD clinical spectrum. Objective: To determine the prevalence of cerebellar ataxia in patients with HD, both in the early and in the late stages of HD. Methods: Seventy-two individuals considered eligible were assessed by two trained doctors, applying the Scale for Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) for ataxia, the Unified Huntington's Disease Rating Scale (UHDRS) and also, Barthel Index (BI), in order to evaluate functional capacity. Results: Fifty-one patients (70.8%) presented with clinical ataxia at the time of examination (mean time of disease was 9.1 years). Six (8.33%) patients presented with cerebellar ataxia as first symptom. When stratified according to time of disease, a decline in the presence of chorea (p = 0.032) and an increase in cognitive deficit (p = 0.023) were observed in the patients as the disease progressed. The presence of ataxia was associated with longer duration of illness and severity of illness (UHDRS) (p < 0.0001), and shorter Barthel (less functionality) (p = 0.001). Conclusions: Cerebellar involvement may play an important role in natural history of brain degeneration in HD. The presence of cerebellar ataxia in HD is relevant and it may occur even in early stages, and should be included as part of the motor features of the disease.

SUBMITTER: Franklin GL

PROVIDER: S-EPMC7689004 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Is Ataxia an Underestimated Symptom of Huntington's Disease?

Franklin Gustavo L GL Camargo Carlos Henrique F CHF Meira Alex T AT Pavanelli Giovana M GM Milano Sibele S SS Germiniani Francisco B FB Lima Nayra S C NSC Raskin Salmo S Barsottini Orlando Graziani Povoas OGP Pedroso José Luiz JL Maggi Fernanda Aparecida FA Tumas Vitor V de Carvalho Pedro Manzke PM de Oliveira Ana Carolina AC Braga Bárbara B Souza Laura Cristina LC Guimarães Rachel Paes RP Piovesana Luiza Gonzaga LG Lopes-Cendes Íscia Teresinha ÍT de Azevedo Paula Christina PC França Marcondes Cavalcante MC Martinez Alberto Rolim Muro ARM Teive Hélio A G HAG

Frontiers in neurology 20201112

Background: Huntington's disease (HD) is a progressive disorder characterized by motor, cognitive and psychiatric features. Cerebellar ataxia is classically considered as uncommon in HD clinical spectrum. Objective: To determine the prevalence of cerebellar ataxia in patients with HD, both in the early and in the late stages of HD. Methods: Seventy-two individuals considered eligible were assessed by two trained doctors, applying the Scale for Assessment and Rating of Ataxia ...[more]

PMID: 33281707

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Project description:Huntington's disease is caused by the expansion of a CAG repeat within exon 1 of the HTT gene, which is unstable, leading to further expansion, the extent of which is brain region and peripheral tissue specific. The identification of DNA repair genes as genetic modifiers of Huntington's disease, that were known to abrogate somatic instability in Huntington's disease mouse models, demonstrated that somatic CAG expansion is central to disease pathogenesis, and that the CAG repeat threshold for pathogenesis in specific brain cells might not be known. We have previously shown that the HTT gene is incompletely spliced generating a small transcript that encodes the highly pathogenic exon 1 HTT protein. The longer the CAG repeat, the more of this toxic fragment is generated, providing a pathogenic consequence for somatic expansion. Here, we have used the R6/2 mouse model to investigate the molecular and behavioural consequences of expressing exon 1 HTT with 90 CAGs, a mutation that causes juvenile Huntington's disease, compared to R6/2 mice carrying ?200 CAGs, a repeat expansion of a size rarely found in Huntington's disease patient's blood, but which has been detected in post-mortem brains as a consequence of somatic CAG repeat expansion. We show that nuclear aggregation occurred earlier in R6/2(CAG)90 mice and that this correlated with the onset of transcriptional dysregulation. Whereas in R6/2(CAG)200 mice, cytoplasmic aggregates accumulated rapidly and closely tracked with the progression of behavioural phenotypes and with end-stage disease. We find that aggregate species formed in the R6/2(CAG)90 brains have different properties to those in the R6/2(CAG)200 mice. Within the nucleus, they retain a diffuse punctate appearance throughout the course of the disease, can be partially solubilized by detergents and have a greater seeding potential in young mice. In contrast, aggregates from R6/2(CAG)200 brains polymerize into larger structures that appear as inclusion bodies. These data emphasize that a subcellular analysis, using multiple complementary approaches, must be undertaken in order to draw any conclusions about the relationship between HTT aggregation and the onset and progression of disease phenotypes.

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Is Ataxia an Underestimated Symptom of Huntington's Disease?

Publications

Is Ataxia an Underestimated Symptom of Huntington's Disease?

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