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Spinocerebellar Ataxia Type 10CAHSCA10NCT04495426

Genetic Mechanism of Conserved Ancestral Haplotype in SCA10

An observational study of Spinocerebellar Ataxia Type 10, run by The Methodist Hospital Research Institute at 3 sites in 2 countries.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

Spinocerebellar ataxia type 10 (SCA10) is a hereditary ataxia whose ancestral mutation occurred in East Asia. The mutation is likely to have migrated during peopling of American continents from East Asia. We found a specific rare DNA variation associated with SCA10. Read more about this study

Who is it for?
Ages 18 years and olderHealthy volunteers can take part
Conditions the study is for
Spinocerebellar Ataxia Type 10
What is being tested?
Non-interventional study
How many people
100 participants
Where
3 sitesin 2 countries
Study dates
15 Sep 2020to 31 Dec 2023
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Study population: We will recruit symptomatic participants, premanifest carriers and related non-carriers (at-risk siblings without a SCA10 expansion) members of SCA10 families who have been diagnosed with Spinocerebellar ataxia type 10 (SCA10) or those whose first-degree relative has a molecular diagnosis or SCA10.

Who may be able to join

  • 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.

Who cannot join

  • 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.

Trial locations and contacts

3 sites in 2 countries.

Titilayo Olubajo, CCRP contact

713-363-9803

tolubajo@houstonmethodist.org

3 sites in 2 countries

Brazil2 sites, 2 recruiting
  • Universidade Federal do Paraná

    Paraná, Curibita, 80250-210

    Helio AG Teive, +55 41 3019-5060, teiveads@mps.com.br

    Recruiting
  • Hospital de Clinicas de Porto Alegre

    Porto Alegre, 90.035-903

    Laura Bannach Jardim, MD, PhD, +(51) 3359-8011, ljardim@hcpa.edu.br

    Maria Luiza Saraiva Pereira, PhD, +(51) 3359-8011, mlpereira@hcpa.edu.br

    Recruiting

Other trials in Brazil

United States1 site, 1 recruiting
  • Houston Methodist Hospital

    Houston, Texas, 77030

    Tetsuo Ashizawa, MD, 713-441-8224, tashizawa@houstonmethodist.org

    Titilayo Olubajo, CCRP, 713-363-9803, tolubajo@houstonmethodist.org

    Recruiting

Other trials in United States

About this study

Spinocerebellar ataxia type 10 (SCA10) is a hereditary ataxia whose ancestral mutation occurred in East Asia. The mutation is likely to have migrated during peopling of American continents from East Asia. We found a specific rare DNA variation associated with SCA10. We test whether this variation played a key role in the birth and subsequent spreading of SCA10 mutation.

Read the 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.

Being tested
Non-interventional study
Keywords
SCA10, genotype, spinocerebellar, ataxia, type 10, cerebellum, G allele, haplotype
Medical subject headings
Spinocerebellar Ataxia 10, Ataxia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Non-interventional studyOther

    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.

Study groups in NCT04495426
Study groupRoleWhat they receive
Presence of symptomatic ataxic diseasePresence of symptomatic ataxic disease with definite molecular diagnosis of SCA10 or whose first-degree relative has a molecular diagnosis of SCA10.
Receives: Other: Non-interventional study
Premanifest for SCA10Asymptomatic participants of either sex aged ≥18 with definite molecular diagnosis of SCA10 (Premanifest carriers)
Receives: Other: Non-interventional study
At risk for SCA10Asymptomatic participants of either sex, aged ≥18 whose first-degree relative has a molecular diagnosis of SCA10 (50%-at-risk relatives*).
Receives: Other: Non-interventional study
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.
Receives: Other: Non-interventional study

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    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).

    Measured: Baseline visit 1, Follow up visit (12-18 months after visit 1)

  2. Examine the disease progression in SCA10 as determined by change in Spinocerebellar Ataxia Functional Index score compared to healthy controls

    The Spinocerebellar Ataxia Functional Index (SCAFI) is composed of:

    1. Timed 8 meter walk at maximum speed (8MW). Times are only given for two successfully completed trials. Discontinue the test if participant cannot complete trial in 3 minutes (more severe ataxia).
    2. Timed dexterity test: 9-hole peg test (9HPT). Times are only given for two successfully completed trials for each hand. If participant cannot complete one trial in 5 minutes (more severe ataxia) discontinue 9-hole-peg test.
    3. Timed speech test: PATA rate, a measure of speech performance. The participant is asked to repeat "PATA" as quickly and distinctly as possible for 10 seconds until told to stop. As soon as the participant begins speaking, start timer and begin counting the number of PATA repeats. Higher number (less dysarthria), lower number (more dysarthria). Discontinue if PATA articulation is too difficult to distinguish for counting or if participant cannot complete 10 seconds for two consecutive trials.

    Measured: Baseline visit 1, Follow up visit (12-18 months after visit 1)

  3. Examine the disease progression in SCA10 as determined by change in Composite Cerebellar Functional Severity Score compared to healthy controls

    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).

    Measured: Baseline visit 1, Follow up visit (12-18 months after visit 1)

  4. Examine the disease progression in SCA10 as determined by change in Neurological Examination Score for Spinocerebellar Ataxia compared to healthy controls

    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.

    Measured: Baseline visit 1, Follow up visit (12-18 months after visit 1)

  5. Examine the disease progression in SCA10 as determined by change in Inventory of Non-ataxia Symptoms score compared to healthy controls

    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.

    Measured: Baseline visit 1, Follow up visit (12-18 months after visit 1)

  6. Examine the disease progression in SCA10 as determined by change in Beck Depression Inventory score compared to healthy controls

    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).

    Measured: Baseline visit 1, Follow up visit (12-18 months after visit 1)

  7. Examine the disease progression in SCA10 as determined by change in Europe Quality of Life-5 Dimension score compared to healthy controls

    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).

    Measured: Baseline visit 1, Follow up visit (12-18 months after visit 1)

  8. Number of participants with Electroencephalography changes that may be distinctive for SCA10

    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.

    Measured: Baseline visit 2 (within 6 weeks of visit 1)

  9. Examine the level of disease activity based on change in cerebellar and brainstem volumes compared to healthy controls

    Magnetic Resonance Imaging (MRI) using a 3T scanner will be used to measure cerebellar and brainstem volumes.

    Measured: Baseline visit 2 (within 6 weeks of visit 1)

  10. 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

    Magnetic Resonance Imaging (MRI) will be used to measure change in grey matter volume and white matter volume from voxel-based morphometric data.

    Measured: Baseline visit 2 (within 6 weeks of visit 1)

  11. Examine the level of disease activity based on change in mean diffusivity compared to healthy controls

    Magnetic Resonance Imaging (MRI) will be used to measure change in mean diffusivity.

    Measured: Baseline visit 2 (within 6 weeks of visit 1)

  12. Examine the level of disease activity based on change in radial and axial diffusivity compared to healthy controls

    Magnetic Resonance Imaging (MRI) will be used to measure change in radial and axial diffusivity.

    Measured: Baseline visit 2 (within 6 weeks of visit 1)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Jul 2020
  2. Study start15 Sep 2020
  3. Primary completion31 Dec 2023 (estimated)
  4. Study completion31 Dec 2023 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Cross-sectional
Enrolment
100 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04495426
Sponsor's protocol ID
Pro00022772
Acronym
CAHSCA10
Status last verified
Aug 2021
First submitted
13 Jul 2020
Last updated
1 Sep 2021
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

An observational study of Spinocerebellar Ataxia Type 10, run by The Methodist Hospital Research Institute at 3 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 1 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Brazil, United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Tetsuo Ashizawa, MD (713-441-8224, tashizawa@houstonmethodist.org), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). The study lists 12 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Sep 2021.

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