Genetic Mechanism of Conserved Ancestral Haplotype in SCA10

Study Overview
=================
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.

Official Title
-----------------
Genetic Mechanism of Conserved Ancestral Haplotype in SCA10

Conditions
-----------------
Spinocerebellar Ataxia Type 10

Intervention / Treatment
-----------------
* Other: Non-interventional study


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Presence of symptomatic ataxic disease<br>Presence of symptomatic ataxic disease with definite molecular diagnosis of SCA10 or whose first-degree relative has a molecular diagnosis of SCA10. | Other: Non-interventional study<br>* 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.<br>|
| Premanifest for SCA10<br>Asymptomatic participants of either sex aged ≥18 with definite molecular diagnosis of SCA10 (Premanifest carriers) | Other: Non-interventional study<br>* 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.<br>|
| At risk for SCA10<br>Asymptomatic participants of either sex, aged ≥18 whose first-degree relative has a molecular diagnosis of SCA10 (50%-at-risk relatives*). | Other: Non-interventional study<br>* 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.<br>|
| Non-carrier for SCA10 (Control)<br>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. | Other: Non-interventional study<br>* 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.<br>|

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 | 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 | The Spinocerebellar Ataxia Functional Index (SCAFI) is composed of: 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). 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. 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. | 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 | 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). | Baseline visit 1, Follow up visit (12-18 months after visit 1) | 
| 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. | 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 | 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. | Baseline visit 1, Follow up visit (12-18 months after visit 1) | 
| 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). | 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 | 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). | Baseline visit 1, Follow up visit (12-18 months after visit 1) | 
| 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. | Baseline visit 2 (within 6 weeks of visit 1) | 
| 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. | Baseline visit 2 (within 6 weeks of visit 1) | 
| 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. | Baseline visit 2 (within 6 weeks of visit 1) | 
| 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. | Baseline visit 2 (within 6 weeks of visit 1) | 
| 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. | Baseline visit 2 (within 6 weeks of visit 1) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SCA10, genotype, spinocerebellar, ataxia, type 10, cerebellum, G allele, haplotype