Genetic Mechanism of Conserved Ancestral Haplotype in SCA10

NCT04495426 | Unknown

• 1 other identifier: Pro00022772
• Study Type: observational
• Target: 100
• Locations: 2 countries
• Sites: 3

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.

Conditions

Spinocerebellar Ataxia Type 10

Keywords

SCA10; genotype; spinocerebellar; ataxia; type 10; cerebellum; G allele; haplotype

Outcome Measures

Primary Outcomes (12)

• 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: 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.

  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)

Study Arms (4)

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.

Other: Non-interventional study

Premanifest for SCA10

Asymptomatic participants of either sex aged ≥18 with definite molecular diagnosis of SCA10 (Premanifest carriers)

Other: Non-interventional study

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\*).

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.

Other: Non-interventional study

Interventions

Non-interventional study 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; Non-carrier for SCA10 (Control); Premanifest for SCA10; Presence of symptomatic ataxic disease

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead
• Hospital de Clinicas de Porto Alegre: collaborator

Study Sites (3)

Houston Methodist Hospital

Houston, Texas, 77030, United States

RECRUITING

Universidade Federal do Paraná

Paraná, Curibita, 80250-210, Brazil

RECRUITING

Hospital de Clinicas de Porto Alegre

Porto Alegre, 90.035-903, Brazil

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

Blood samples will be stored with new ID for de-identification and used for DNA analysis and RNA repository. Sperm samples will be obtained by ejaculating semen into a condom or directly into a urine specimen collection container during a sexual activity. A subset of symptomatic (up to 5) and at-risk individuals (up to 10) will be invited to a follow-up visit to collect a skin biopsy. PIs will choose candidates for this invitation, based on their SCA10 haplotypes and type of expansions. In order to preserve genetic status blinding of at-risk subjects, for each premanifest carrier chosen, a non-carrier will be also invited to be a donor of a skin biopsy. A fibroblast culture will be established and stored in a bio-repository for further analysis.

MeSH Terms

Conditions

Spinocerebellar Ataxia 10; Ataxia

Condition Hierarchy (Ancestors)

Dyskinesias; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Tetsuo A, MD

  National Institute of Neurological Diseases

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tetsuo Ashizawa, MD

CONTACT

713-441-8224; tashizawa@houstonmethodist.org

Titilayo Olubajo, CCRP

CONTACT

713-363-9803; tolubajo@houstonmethodist.org

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Neurosciences Research Program, Director

Study Record Dates

• First Submitted: July 13, 2020
• First Posted: July 31, 2020
• Study Start: September 15, 2020
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: September 1, 2021

Record last verified: 2021-08

Locations

BR (2); US (1)