- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04495426
Genetic Mechanism of Conserved Ancestral Haplotype in SCA10 (CAHSCA10)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Spinocerebellar ataxia type 10 (SCA10) is a rare ataxic disorder due to a large expansion of intronic (ATTCT)n repeat in ATXN10. SCA10 afflicts primarily Latin American (LA) populations of Native American Ancestry; recent discoveries of two East Asian (EA) SCA10 families suggests an Asian origin. SCA10 families from LA and EA share an ancestral haplotype that includes the G allele (allele frequency: 2-4% in EA and LA populations but 0% elsewhere) of a C/G/T single nucleotide polymorphism (SNP) at rs41524745 (https://www.ncbi.nlm.nih.gov/snp/rs41524547#frequency_tab). Two characteristics suggest that rs41524745 has a functional role over the expansion: this SNP resides in the sequence encoding miR4762; and total linkage between the SNP and the SCA10 repeat, although they are ~35kb apart, a distance sufficient for multiple recombination events within the 15,000-20,000 years since human migration across Bering landmass. We studied DNA samples with G allele at rs41524547 from the 1000 Genomes repository and our own samples from general populations and surprisingly found 0-25% of these G(+) samples have SCA10 repeat expansions. Since our genotype-phenotype data suggest that SCA10 expansions with (ATTCC)n or (ATCCT)n(ATCCC)n repeat insertion in the 3' end of (ATTCT)n expansion exhibit full penetrance while pure (ATTCT)n expansion has reduced penetrance, the last one can be more common than previously expected. Hypotheses: (1) the G allele at rs41524547 predisposes the SCA10 (ATTCT)n repeat for expansion (Type A expansion), that remains mostly non-penetrant, and (2) the (ATTCT)n-(ATTCC)n (Type B) or (ATTCT)n(ATCCT)n-(ATCCC)n (Type C) repeat drives the SCA10 pathogenicity. To test the hypothesis, we propose three Aims in close collaborations between US and Brazilian SCA10 consortia:
Aim 1. To determine the relationship between SCA10 and the G allele at rs41524547.
Aim 2. To confirm that Type B and Type C expansions are pathogenic, but Type A expansions have significantly reduced pathogenicity.
Aim 3. To determine if the G allele at rs41524547 reduces downstream recombination rates, protects against the toxicity of SCA10 RNA expansions, or promote expanded states of the SCA10 repeat.
This effort will enable long term goals to: (1) identify people at risk for SCA10 by high-throughput screening of general populations for the G allele at rs41524547 in Brazil, (2) determine the frequency of non-penetrant SCA10 expansion alleles in Brazil, and (3) develop treatments of SCA10 based on results of this project.
The proposed project requires complimentary expertise in multiple areas, including coordination of the clinical studies, along with recruitment plans and executions, management of tissue repository, maintenance and expansion of the clinical database, clinical MR technology and data analyses, which will be ongoing in both the US and Brazil.
Study Type
Enrollment (Anticipated)
Contacts and Locations
Study Contact
- Name: Tetsuo Ashizawa, MD
- Phone Number: 713-441-8224
- Email: tashizawa@houstonmethodist.org
Study Contact Backup
- Name: Titilayo Olubajo, CCRP
- Phone Number: 713-363-9803
- Email: tolubajo@houstonmethodist.org
Study Locations
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Porto Alegre, Brazil, 90.035-903
- Recruiting
- Hospital de Clinicas de Porto Alegre
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Contact:
- Laura Bannach Jardim, MD, PhD
- Phone Number: +(51) 3359-8011
- Email: ljardim@hcpa.edu.br
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Contact:
- Maria Luiza Saraiva Pereira, PhD
- Phone Number: +(51) 3359-8011
- Email: mlpereira@hcpa.edu.br
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Curibita
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Paraná, Curibita, Brazil, 80250-210
- Recruiting
- Universidade Federal do Parana
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Contact:
- Helio AG Teive
- Phone Number: +55 41 3019-5060
- Email: teiveads@mps.com.br
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-
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Texas
-
Houston, Texas, United States, 77030
- Recruiting
- Houston Methodist Hospital
-
Contact:
- Tetsuo Ashizawa, MD
- Phone Number: 713-441-8224
- Email: tashizawa@houstonmethodist.org
-
Contact:
- Titilayo Olubajo, CCRP
- Phone Number: 713-363-9803
- Email: tolubajo@houstonmethodist.org
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Description
Inclusion Criteria:
- Signed informed consent (no study-related procedures may be performed before the subject has signed the consent form).
- Participants of either sex aged ≥18 with presence of symptomatic ataxic disease with definite molecular diagnosis of SCA10 or whose first-degree relative has a molecular diagnosis of SCA10.
- Asymptomatic participants of either sex aged ≥18 with definite molecular diagnosis of SCA10 (Premanifest carriers) or those whose first-degree relative has a molecular diagnosis of SCA10 (50%-at-risk relatives*).
- Participants capable of understanding and complying with protocol requirements.
Exclusion Criteria:
- Known genotype consistent with other inherited ataxias.
- Concomitant disorder(s) or condition(s) that affects assessment of ataxia or severity of ataxia during this study.
- Unwillingness to provide a DNA sample at study entry.
- Inability to undergo MRI scanning, Weight over 300lbs, Presence of structural abnormalities such as subdural hematoma or primary or metastatic neoplasms, concurrent illnesses or treatment interfering with cognitive function such as stroke or normal pressure hydrocephalus.
Study Plan
How is the study designed?
Design Details
- Observational Models: Cohort
- Time Perspectives: Cross-Sectional
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
Presence of symptomatic ataxic disease
Presence of symptomatic ataxic disease with definite molecular diagnosis of SCA10 or whose first-degree relative has a molecular diagnosis of SCA10.
|
There are no treatments to stop or even slow down the progression of this disease although there are treatments that temporarily improve the symptoms, such as anti-seizure medications.
|
Premanifest for SCA10
Asymptomatic participants of either sex aged ≥18 with definite molecular diagnosis of SCA10 (Premanifest carriers)
|
There are no treatments to stop or even slow down the progression of this disease although there are treatments that temporarily improve the symptoms, such as anti-seizure medications.
|
At risk for SCA10
Asymptomatic participants of either sex, aged ≥18 whose first-degree relative has a molecular diagnosis of SCA10 (50%-at-risk relatives*).
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There are no treatments to stop or even slow down the progression of this disease although there are treatments that temporarily improve the symptoms, such as anti-seizure medications.
|
Non-carrier for SCA10 (Control)
At risk participants who test negative for the SCA10 mutation will serve as non-carriers.
Exclusion criteria described above also applies to non-carrier subjects.
If the number of non-carriers were less than 10, we will recruit additional participants from normal population to supplement the controls.
|
There are no treatments to stop or even slow down the progression of this disease although there are treatments that temporarily improve the symptoms, such as anti-seizure medications.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Examine the disease progression in SCA10 as determined by change in the scale for the assessment and rating of ataxia score compared to healthy controls
Time Frame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
|
Scale for the assessment and rating of ataxia (SARA) was evaluated in two large validation trials performed by the EUROSCA clinical group and was found to be easy to use, reliable and valid.
SARA has eight categories with accumulative score ranging from 0 (no ataxia) to 40 (most severe ataxia).
|
Baseline visit 1, Follow up visit (12-18 months after visit 1)
|
Examine the disease progression in SCA10 as determined by change in Spinocerebellar Ataxia Functional Index score compared to healthy controls
Time Frame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
|
The Spinocerebellar Ataxia Functional Index (SCAFI) is composed of:
|
Baseline visit 1, Follow up visit (12-18 months after visit 1)
|
Examine the disease progression in SCA10 as determined by change in Composite Cerebellar Functional Severity Score compared to healthy controls
Time Frame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
|
The Composite Cerebellar Functional Severity (CCFS) score is a quantitative tool to measure cerebellar severity independently from age.
It is an assessment in addition to a clinical examination and has demonstrated its usefulness in epidemiological studies, clinical trials, and patient follow-up that only take 5 minutes to be administrated.
The CCFS is a combination of the time to perform 2 tasks; a 9-hole pegboard and a click test.
It was validated in adults and children.
CCFS scores range from 0.50 (normal/no ataxia) to 1.80 (more severe ataxia).
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Baseline visit 1, Follow up visit (12-18 months after visit 1)
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Examine the disease progression in SCA10 as determined by change in Neurological Examination Score for Spinocerebellar Ataxia compared to healthy controls
Time Frame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
|
The Neurological Examination Score for Spinocerebellar Ataxia (NESSCA) scale is based on the standardized neurological examination, and consists of 18 items that yield a total score ranging from 0 (no ataxia) to 40 (most severe ataxia).
The NESSCA is a comprehensive measure of disease severity that was shown to be both clinically useful and scientifically valid.
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Baseline visit 1, Follow up visit (12-18 months after visit 1)
|
Examine the disease progression in SCA10 as determined by change in Inventory of Non-ataxia Symptoms score compared to healthy controls
Time Frame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
|
The Inventory of Non-ataxia Symptoms (INAS) is a scale utilized in recording the occurrence of accompanying non-ataxia symptoms.
In the SARA validation trials, INAS was applied to a large number of SCA patients.
For a semiquantitative assessment of non-ataxia signs, the number of non-ataxia signs is counted yielding the INAS count, a dimensionless value with a range from 0 (no ataxia) to 16 (most severe ataxia).
To determine the INAS count, only the presence or absence of one of the 16 signs is considered.
Statistical evaluation showed good reliability.
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Baseline visit 1, Follow up visit (12-18 months after visit 1)
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Examine the disease progression in SCA10 as determined by change in Beck Depression Inventory score compared to healthy controls
Time Frame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
|
The Beck Depression Inventory (BDI) is a 21-item, self-report rating inventory that measures characteristic attitudes and symptoms of depression.
Answers can range from 0 to 3 for each item.
The total score will range from 0 (considered normal) to 40 (extreme depression).
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Baseline visit 1, Follow up visit (12-18 months after visit 1)
|
Examine the disease progression in SCA10 as determined by change in Europe Quality of Life-5 Dimension score compared to healthy controls
Time Frame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
|
The Europe Quality of Life-5 Dimension (Euro Qol-5D or EQ-5D), is a measure developed by the EuroQol Group that generates a single index value for health status with considerable potential for use in health care evaluation.The EQ-5D descriptive system is a preference-based HRQL measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
The answers given to ED-5D permit to find 243 unique health states or can be converted into EQ-5D index an utility scores anchored at 0 for death and 1 for perfect health.
The EQ-5D questionnaire also includes a Visual Analog Scale (VAS), by which respondents can report their perceived health status with a grade ranging from 0 (the worst possible health status) to 100 (the best possible health status).
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Baseline visit 1, Follow up visit (12-18 months after visit 1)
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Number of participants with Electroencephalography changes that may be distinctive for SCA10
Time Frame: Baseline visit 2 (within 6 weeks of visit 1)
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Electroencephalography (EEG) will be obtained and analyzed for changes that may be distinctive for SCA10: seizure spikes and/or sharp waves during and, sometimes, between seizure episodes.
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Baseline visit 2 (within 6 weeks of visit 1)
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Examine the level of disease activity based on change in cerebellar and brainstem volumes compared to healthy controls
Time Frame: Baseline visit 2 (within 6 weeks of visit 1)
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Magnetic Resonance Imaging (MRI) using a 3T scanner will be used to measure cerebellar and brainstem volumes.
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Baseline visit 2 (within 6 weeks of visit 1)
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Examine the level of disease activity based on change in grey matter and white matter loss metrics from voxel-based morphometry compared to healthy controls
Time Frame: Baseline visit 2 (within 6 weeks of visit 1)
|
Magnetic Resonance Imaging (MRI) will be used to measure change in grey matter volume and white matter volume from voxel-based morphometric data.
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Baseline visit 2 (within 6 weeks of visit 1)
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Examine the level of disease activity based on change in mean diffusivity compared to healthy controls
Time Frame: Baseline visit 2 (within 6 weeks of visit 1)
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Magnetic Resonance Imaging (MRI) will be used to measure change in mean diffusivity.
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Baseline visit 2 (within 6 weeks of visit 1)
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Examine the level of disease activity based on change in radial and axial diffusivity compared to healthy controls
Time Frame: Baseline visit 2 (within 6 weeks of visit 1)
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Magnetic Resonance Imaging (MRI) will be used to measure change in radial and axial diffusivity.
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Baseline visit 2 (within 6 weeks of visit 1)
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Tetsuo A, MD, National Institute of Neurological Diseases
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Neurologic Manifestations
- Genetic Diseases, Inborn
- Neurodegenerative Diseases
- Dyskinesias
- Spinal Cord Diseases
- Heredodegenerative Disorders, Nervous System
- Cerebellar Diseases
- Cerebellar Ataxia
- Ataxia
- Spinocerebellar Ataxias
- Spinocerebellar Degenerations
Other Study ID Numbers
- Pro00022772
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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