Clinical trial NCT04495426: Genetic Mechanism of Conserved Ancestral Haplotype in SCA10
Official title: Genetic Mechanism of Conserved Ancestral Haplotype in SCA10
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Spinocerebellar Ataxia Type 10
Keywords: SCA10
genotype
spinocerebellar
ataxia
type 10
cerebellum
G allele
haplotype
Lead sponsor: The Methodist Hospital Research Institute
Sponsor class: OTHER
Collaborators: name: Hospital de Clinicas de Porto Alegre
First posted: 2020-07-31
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
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.

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.

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.

Primary outcomes:
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
timeFrame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
measure: Examine the disease progression in SCA10 as determined by change in Spinocerebellar Ataxia Functional Index score compared to healthy controls
timeFrame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
measure: Examine the disease progression in SCA10 as determined by change in Composite Cerebellar Functional Severity Score compared to healthy controls
timeFrame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
measure: Examine the disease progression in SCA10 as determined by change in Neurological Examination Score for Spinocerebellar Ataxia compared to healthy controls
timeFrame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
measure: Examine the disease progression in SCA10 as determined by change in Inventory of Non-ataxia Symptoms score compared to healthy controls
timeFrame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
measure: Examine the disease progression in SCA10 as determined by change in Beck Depression Inventory score compared to healthy controls
timeFrame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
measure: Examine the disease progression in SCA10 as determined by change in Europe Quality of Life-5 Dimension score compared to healthy controls
timeFrame: Baseline visit 1, Follow up visit (12-18 months after visit 1)
measure: Number of participants with Electroencephalography changes that may be distinctive for SCA10
timeFrame: Baseline visit 2 (within 6 weeks of visit 1)
measure: Examine the level of disease activity based on change in cerebellar and brainstem volumes compared to healthy controls
timeFrame: Baseline visit 2 (within 6 weeks of visit 1)
measure: 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
timeFrame: Baseline visit 2 (within 6 weeks of visit 1)
measure: Examine the level of disease activity based on change in mean diffusivity compared to healthy controls
timeFrame: Baseline visit 2 (within 6 weeks of visit 1)
measure: Examine the level of disease activity based on change in radial and axial diffusivity compared to healthy controls
timeFrame: Baseline visit 2 (within 6 weeks of visit 1)
Secondary outcomes:
Other outcomes:
Locations:
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Paraná
country: Brazil
facility: Universidade Federal do Paraná
state: Curibita
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
Study officials:
affiliation: National Institute of Neurological Diseases
name: Tetsuo A, MD
role: PRINCIPAL_INVESTIGATOR
References: