Validation of the RADIAL Algorithm for Diagnosis of Autosomal Recessive Cerebellar Ataxia

Validation of the RADIAL Algorithm for Diagnosis of Autosomal Recessive Cerebellar Ataxia

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.

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)