Pathogenic Insights and Search for Biomarkers in RFC1-ataxia/CANVAS: a Model to a Deeper Understanding of Molecular Mechanisms Underlying Late-onset Neurodegeneration
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 4
- 主要终点
- Scale for the Assessment and Rating of Ataxia (SARA) scale
研究概览
简要总结
CANVAS (Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome), also referred to as RFC1-ataxia, is a recently molecularly characterized neurodegenerative disorder caused by a biallelic expansion of an AAGGG pentanucleotide repeat in intron 2 of the Replication Factor C subunit 1 (RFC1) gene.
This adult-onset condition presents with a variable combination of cerebellar ataxia, peripheral neuropathy, and vestibular dysfunction. Currently, limited data are available regarding its natural history and the molecular mechanisms by which this dynamic mutation leads to neurodegeneration of selective neuronal populations.
Given that recent literature identifies RFC1/CANVAS as a relatively common genetic cause of late-onset ataxia, elucidation of its underlying pathogenic mechanisms may offer insights into the molecular pathways implicated in more prevalent late-onset neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease.
详细描述
The research proposal recognizes as the primary aim to evaluate and compare the sensitivity of individual validated clinical rating scales in assessing global disease severity and/or progression in a cohort of RFC1-ataxia patients Secondary aims are i) to identify novel potential circulating biomarkers in RFC1-ataxia by testing a cohort of RFC1-ataxia patients vs controls and ii) to establish and study patient-derived cell models to get insight about pathogenesis of RFC1-ataxia, particularly concerning mitochondrial function.
For these purposes, a longitudinal assessment of a study cohort of genetically determined RFC1- ataxia patients ( intention to treat 25 pts) will be carried out.
Based on the involvement of cerebellar and proprioceptive systems in RFC1-ataxia, the following clinical rating scales have been selected: Scale for the Assessment and Rating of Ataxia (SARA) , International Cooperative Ataxia Rating Scale (ICARS), SEnsory Ataxia Rating Scale (SEARS) , Berg Balance Scale (BBS) , and Tinetti Assessment Tool . Vestibular symptoms will be assessed by Dizziness Handicap Inventory questionnaire (DHI).
For statistical analysis regarding clinical severity, at T0 (baseline) RFC1- patients will also undergo:
1) neurophysiological studies: EMG and nerve studies, motor and sensory evoked potentials recorded at the four limbs; 2) vestibular function assessment by video head-impulse-test. Collected data will also include: age at onset (AAO) of symptoms, age at enrollment (AAE), disease duration (DD); presence of unexplained cough and/or swallowing disturbances; 3T brain and spinal cord MRI. Statistical analysis will be performed by Pearson's correlation tests . Global and item scores for each scale will be also correlated with DD, disability stage estimated by the SPATAX disability score (0: no functional handicap, 1: no functional handicap but signs at examination, 2: mild, able to run, unlimited walking, 3: moderate, unable to run, limited walking without aid, 4: severe, walking with one stick, 5: walking with two sticks, 6: unable to walk, requiring a wheelchair, 7: confined to a bed), and other major diagnostic findings individually contributing to motor disability ( i.e. neuropathy, vestibulopathy, cerebellar atrophy) .
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Molecular diagnosis of RFC1-ataxia
- •age >18 years and <80 years
- •ability to sign informed consent
排除标准
- •Diagnosis of other degenerative and/or non-degenerative neurological diseases
- •Not signed informed consent
结局指标
主要结局
Scale for the Assessment and Rating of Ataxia (SARA) scale
时间窗: 1 year
SARA is a clinical scale validated in degenerative ataxias, which assesses a range of different impairments related to cerebellar dysfunction. The scale is made up of 8 items related to gait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements and heel-shin test ; Each item scores from 0 ( no impairment) to 4 ( maximum impairment) Global SARA score ranges from 0 (no cerebellar ataxia ) to 40 (maximal severity of ataxia )
INTERNATIONAL CO-OPERATIVE ATAXIA RATING SCALE (ICARS)
时间窗: 1 year
ICARS is another, recommended outcome scale for cerebellar ataxias, including 19 items and 4 subscales evaluating postural and gait disturbances, limb ataxia, dysarthria, and oculomotor disorders (14); Each subscale has an ordinal scale with 0 indicating normal and the higher score indicating greatest impairment or that the patient is unable to complete the task. Global score ranges from 0 to 100 : higher score indicates greater impairment
SENSORY ATAXIA RATING SCALE (SEARS)
时间窗: 1 year
SEARS is a 10-item functional scale developed and validated to cover the clinical spectrum of manifestations in patients with sensory neuronopathies. It has been validated for any forms of sensory ataxia, including 10-meter walking test (10mWT) to assess gait speed. Scores range from 0 (no impairment) to 41 (maximal impairment)
Berg Balance Scale (BBS)
时间窗: 1 year
BBS for balance assessment is an ordinal scale ranging from 0 to 56, consisting of 13 items with a score from 0 to 4 where 0 is the minimum performance and 4 is the maximum performance regarding the item required. This scale mainly evaluates the static balance and minimally the dynamic
Tinetti scale
时间窗: 1 year
The Tinetti Assessment Tool is a simple test that measures both gait and balance abilities based on performing specific tasks. Scoring of the Tinetti Assessment Tool is done on a 3-point ordinal scale with a range of 0 to 2, where 0 represents the most impairment, while 2 represents independence. The individual scores are then combined to form three measures: an overall gait assessment score (maximum score 12), overall balance assessment score (maximum score 16), combined gait and balance score (maximum total score is 28). Scores below 19 indicate high risk for falls
Dizziness Handicap Inventory Scale (DHI)
时间窗: 1 year
The DHI evaluates the self-perception of the incapacitating effects, on the quality of life, caused by dizziness. It comprises 25 items with a total score ranging between 0 and 100 points. DHI can be further subdivided into physical (DHI-P, 28 points), functional (DHI-F 36 points) and emotional (DHI-E 36 points) sub scores. A higher score indicates a more severe handicap.
次要结局
未报告次要终点