de Oliveira Camila Maria, Leotti Vanessa Bielefeldt, Cappelli Amanda Henz, Rocha Anastacia Guimarães, Ecco Gabriela, Bolzan Gabriela, Kersting Nathalia, Saraiva-Pereira Maria-Luiza, Jardim Laura Bannach
Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Centros de Pesquisa Clínica e Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
Mov Disord. 2023 Jan;38(1):26-34. doi: 10.1002/mds.29226. Epub 2022 Sep 21.
Little is known about preclinical stages of Machado-Joseph disease, a polyglutamine disorder characterized by progressive adult-onset ataxia.
We aimed to describe the longitudinal progression of clinical and oculomotor variables in the preataxic phase of disease.
Carriers and noncarriers were assessed at three visits. Preataxic carriers (Scale for Assessment and Rating of Ataxia score < 3) expected to start ataxia in ≤4 years were considered near onset (PAN). Progressions of ataxic and preataxic carriers, considering status at the end of the study, were described according to the start (or its prediction) of gait ataxia (TimeToAfterOnset) and according to the study time.
A total of 35 ataxics, 38 preataxics, and 22 noncarriers were included. The "TimeToAfterOnset" timeline showed that Neurological Examination Scale for Spinocerebellar Ataxias (NESSCA; effect size, 0.09), Inventory of Non-Ataxia Symptoms (INAS0.07), and the vestibulo-ocular reflex gain (0.12) progressed in preataxic carriers, and that most slopes accelerate in PAN, turning similar to those of ataxics. In the study time, NESSCA (1.36) and vertical pursuit gain (1.17) significantly worsened in PAN, and 6 of 11 PANs converted to ataxia. For a clinical trial with 80% power and 2-year duration, 57 PANs are needed in each study arm to detect a 50% reduction in the conversion rate.
NESSCA, INAS, vestibulo-ocular reflex, and vertical pursuit gains significantly worsened in the preataxic phase. The "TimeToAfterOnset" timeline unveiled that slopes of most variables are small in preataxics but increase and reach the ataxic slopes from 4 years before the onset of ataxia. For future trials in preataxic carriers, we recommend recruiting PANs and using the conversion rate as the primary outcome. © 2022 International Parkinson and Movement Disorder Society.
Machado-Joseph病是一种多聚谷氨酰胺疾病，其特征为成人起病的进行性共济失调，目前对其临床前期阶段了解甚少。
我们旨在描述疾病共济失调前期临床和动眼变量的纵向进展。
对携带者和非携带者进行了三次访视评估。预计在≤4年内开始出现共济失调的共济失调前期携带者（共济失调评估和分级量表评分<3）被视为接近发病（PAN）。根据步态共济失调开始（或其预测）时间（发病后时间）和研究时间，描述了共济失调携带者和共济失调前期携带者在研究结束时的进展情况。
共纳入35例共济失调患者、38例共济失调前期患者和22例非携带者。“发病后时间”时间线显示，在共济失调前期携带者中，脊髓小脑共济失调神经学检查量表（NESSCA；效应量，0.09）、非共济失调症状量表（INAS；效应量，0.07）和前庭眼反射增益（0.12）有所进展，且大多数斜率在PAN中加速，变得与共济失调患者相似。在研究期间，PAN组的NESSCA（1.36）和垂直跟踪增益（1.17）显著恶化，11例PAN中有6例转变为共济失调。对于一项效能为80%、持续时间为2年的临床试验，每个研究组需要57例PAN才能检测到转化率降低50%。
在共济失调前期阶段，NESSCA、INAS、前庭眼反射和垂直跟踪增益显著恶化。“发病后时间”时间线显示，大多数变量在共济失调前期携带者中的斜率较小，但在共济失调发病前4年开始增加并达到共济失调患者的斜率。对于未来在共济失调前期携带者中进行的试验，我们建议招募PAN患者并将转化率作为主要结局指标。©2022国际帕金森病和运动障碍协会
