Genetic Mechanism of Conserved Ancestral Haplotype in SCA10

NCT ID: NCT04495426

Last Updated: 2021-09-01

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 100 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2020-09-15
• Study Completion Date: 2023-12-31

Brief 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. We test whether this variation played a key role in the birth and subsequent spreading of SCA10 mutation.

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.

Conditions

Spinocerebellar Ataxia Type 10

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

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.

Non-interventional study

Intervention Type: OTHER

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)

Non-interventional study

Intervention Type: OTHER

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\*).

Non-interventional study

Intervention Type: OTHER

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.

Non-interventional study

Intervention Type: OTHER

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.

Interventions

Non-interventional study

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.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. Signed informed consent (no study-related procedures may be performed before the subject has signed the consent form).

2. 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.

3. 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*).

4. Participants capable of understanding and complying with protocol requirements.

Exclusion Criteria

1. Known genotype consistent with other inherited ataxias.

2. Concomitant disorder(s) or condition(s) that affects assessment of ataxia or severity of ataxia during this study.

3. Unwillingness to provide a DNA sample at study entry.

4. 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Hospital de Clinicas de Porto Alegre

OTHER

Sponsor Role: collaborator

The Methodist Hospital Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Tetsuo Ashizawa, MD

Neurosciences Research Program, Director

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Tetsuo A, MD

Role: PRINCIPAL_INVESTIGATOR

National Institute of Neurological Diseases

Locations

Houston Methodist Hospital

Houston, Texas, United States

Site Status: RECRUITING

Universidade Federal do Paraná

Paraná, Curibita, Brazil

Site Status: RECRUITING

Hospital de Clinicas de Porto Alegre

Porto Alegre, , Brazil

Site Status: RECRUITING

Countries

United States; Brazil

Central Contacts

Tetsuo Ashizawa, MD

Role: CONTACT

tashizawa@houstonmethodist.org

713-441-8224

Titilayo Olubajo, CCRP

Role: CONTACT

tolubajo@houstonmethodist.org

713-363-9803

Facility Contacts

Tetsuo Ashizawa, MD

Role: primary

tashizawa@houstonmethodist.org

713-441-8224

Titilayo Olubajo, CCRP

Role: backup

tolubajo@houstonmethodist.org

713-363-9803

Helio AG Teive

Role: primary

teiveads@mps.com.br

+55 41 3019-5060

Laura Bannach Jardim, MD, PhD

Role: primary

ljardim@hcpa.edu.br

+(51) 3359-8011

Maria Luiza Saraiva Pereira, PhD

Role: backup

mlpereira@hcpa.edu.br

+(51) 3359-8011

Other Identifiers

Pro00022772

Identifier Type: -

Identifier Source: org_study_id