Autosomal Recessive Cerebellar Ataxia
Conditions
Keywords
autosomal recessive cerebellar ataxia, algorithm, genetic diagnosis
Brief summary
RADIAL is an algorithm which has been developed following a review of the literature on 67 autosomal recessive cerebellar ataxias (ARCA) and personal clinical experience. Frequency and specificity of each feature were defined for each autosomal recessive cerebellar ataxia, and corresponding prediction scores were assigned. Clinical and paraclinical features of patients are entered into the algorithm, and a patient's total score for each ARCA is calculated, producing a ranking of possible diagnoses. Sensitivity and specificity of the algorithm were assessed by blinded analysis of a multinational cohort of 834 patients with molecularly confirmed autosomal recessive cerebellar ataxia. The performance of the algorithm was assessed versus a blinded panel of autosomal recessive cerebellar ataxia experts. The correct diagnosis was ranked within the top 3 highest-scoring diagnoses at a sensitivity and specificity of \>90% for 84% and 91% of the evaluated genes, respectively. Mean sensitivity and specificity of the top 3 highest-scoring diagnoses were 92% and 95%, respectively. Our aim is now to validate in a prospective cohort of ARCA, the performance of RADIAL to predict the correct genetic diagnosis.
Interventions
GENETICGenetic diagnosis (PMDA panel)
Blood samples for DNA study
DIAGNOSTIC_TESTUse of RADIAL algorithm
RADIAL card filling (contains clinical and biological data)
Sponsors
University Hospital, Strasbourg, France
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
\- For patients: 1. Patient, male or female, over 5 years old (no upper age limit) 2. Patient with cerebellar ataxia who started before the age of 40 3. Patient with a family history compatible with autosomal recessive inheritance (sporadic case, consanguinity, several cases in siblings) 4. Patient in which an acquired cause of cerebellar ataxia has been excluded 5. Patient whose genetic diagnosis is unknown (NB: patients with a known negative result for the Friedreich's disease gene are eligible for inclusion)) 6. For patients over 18 years old: patient speaking and reading French, able to give a signed and dated informed consent to participate in the study. Patients who have reached the age of majority and whose DNA has been banked and who have signed a consent form authorizing the subsequent use of this DNA for research purposes, including genetic analysis of cerebellar ataxias or associated pathologies, and for whom the RADIAL information sheet can be completed in full, are eligible for inclusion. 7. For patient under 18 years old: Tutor or person with parental authority must speak French and be able to give a signed and dated informed consent for the minor patient. Patients who are minors, whose DNA has been banked and for whom the parental authority has signed a consent form authorizing the subsequent use of this DNA for research purposes, including genetic analysis of cerebellar ataxias or associated pathologies, and for whom the RADIAL information sheet can be completed, are eligible. 8. Patient affiliated to the French national health insurance \- For relatives: 9. Male or female, over 18 years old (no upper age limit) 10. Biological father or mother of a patient included in RADIAL-VALID research protocol 11. (for prospective inclusion only) To be available for a visit to the participating center where the child is being followed 12. Speaking and reading French, able to give a signed and dated informed consent to participate in the study 13. Subject affiliated to the French national health insurance
Exclusion criteria
\- For patients: 14. Patient in whom targeted sequencing of a panel of PMDA genes and/or exome/genome sequencing have already been performed. * For patients and related: 15. Subject of a legal protection measure 16. Subject in exclusion period (determined by previous or current study)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of patients for whom the final genetic diagnosis is in the top 3 of the diagnoses proposed by the RADIAL algorithm (corresponding to the diseases with the 3 highest score given by the algorithm). | At final visit (depending of genetic results from 2 to 24 month maximum after inclusion visit) | The final diagnosis will be established after a genetic analysis and a medical interpretation of the results by geneticists. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of patients for whom the final genetic diagnosis is the first diagnosis proposed by the RADIAL algorithm (corresponding to the disease with the highest score given by the algorithm). | At final visit (depending of genetic results from 2 to 24 month maximum after inclusion visit) | — |
| Comparison of interpretation times by the clinical-genetic team (genetic and clinical data) with and without the help of the RADIAL algorithm | At final visit (depending of genetic results from 2 to 24 month maximum after inclusion visit) | Randomization is a methodological refinement that is only useful for this secondary endpoint (does not relate to the primary endpoint). The clinical and paraclinical data of all patients will be treated in the same way, and randomization concerns only the use of RADIAL made by the data biologist in sample processing. There is therefore no randomization of subjects but only of genetic results. At the genetic study stage (Panel PMDA panel), for the patient group randomized with RADIAL results, the interpretation of genetic data (and in particular of the different variants found) will be done aware of the results given by RADIAL, and in the randomized group without results RADIAL , the analysis of the genetic data will be done in the absence of knowledge of the results provided by RADIAL. |
| Comparison of the satisfaction score given by the clinical-genetic team in the interpretation of data with and without the help of the RADIAL algorithm | At final visit (depending of genetic results from 2 to 24 month maximum after inclusion visit) | Randomization is a methodological refinement that is only useful for this secondary endpoint (does not relate to the primary endpoint). The clinical and paraclinical data of all patients will be treated in the same way, and randomization concerns only the use of RADIAL made by the data biologist in sample processing. There is therefore no randomization of subjects but only of genetic results. At the genetic study stage (Panel PMDA panel), for the patient group randomized with RADIAL results, the interpretation of genetic data (and in particular of the different variants found) will be done aware of the results given by RADIAL, and in the randomized group without results RADIAL , the analysis of the genetic data will be done in the absence of knowledge of the results provided by RADIAL. |
| Influence of RADIAL on genetic diagnosis: percentage of patients whose diagnosis has been reviewed after the clinical-genetic team has learned of the results proposed by RADIAL | At final visit (depending of genetic results from 2 to 24 month maximum after inclusion visit) | Randomization is a methodological refinement that is only useful for this secondary endpoint (does not relate to the primary endpoint). The clinical and paraclinical data of all patients will be treated in the same way, and randomization concerns only the use of RADIAL made by the data biologist in sample processing. There is therefore no randomization of subjects but only of genetic results. At the genetic study stage (Panel PMDA panel), for the patient group randomized with RADIAL results, the interpretation of genetic data (and in particular of the different variants found) will be done aware of the results given by RADIAL, and in the randomized group without results RADIAL , the analysis of the genetic data will be done in the absence of knowledge of the results provided by RADIAL. |
| Percentage of patients for whom the genome analysis will have detected a new gene. | At final visit (depending of genetic results from 2 to 24 month maximum after inclusion visit) | If no diagnosis is established after the PMDA + RADIAL analyzes, additional genetic analyzes will be carried out for patient and for relatives (genome). These new analyzes should help to define the diagnosis of the patient. |
Countries
France
Contacts
Primary ContactTranchant Christine, MD
Outcome results
None listed