Objective: We present an overview of patients seen by our Neurogenetic Clinic since 2019, focusing on the cerebellar ataxia (CA) cohort.

Background: Diagnostic yield of rare neurological disease is increasing as next-generation sequencing (NGS) and advanced molecular testing are incorporated in routine clinical work-up. The advent of tailored disease-modifying therapy and prenatal genetic diagnosis optimize care for diagnosed patients. Yet disease rarity, phenotype-genotype variability and complex inheritance patterns continue to hinder diagnosis.

Method: We conducted a retrospective study of patients with CA from the Neurogenetic Clinic between the years of 2019-2021, including analysis of demographic and clinical data, and genetic workup yield.

Results: We report 74 patients (44 female) diagnosed at ages 23-84 years, with juvenile till late adulthood onset of disease. Of the newly referred 52 symptomatic patients, we reached a genetic diagnosis in 11 patients (21%) in accordance with current reported diagnostic yield in CA cohorts (20-30%). Of these newly diagnosed patients, 3 (27%) were diagnosed using repeat expansion analysis and 8 (73%) were diagnosed using NGS testing.  Five patients remain undiagnosed following completion of both repeat expansion and NGS analysis. Workup is pending amongst remaining 36 cases due to financial limitations. Our center’s diagnostic yield was attained by tailoring repeat expansion and transcript analysis and routine in-house database and NGS revisions. One example that demonstrates the importance of attaining a genetic diagnosis is of a young woman with bi-allelic CYP27A1 mutations. Her diagnosis of Cerebrotendinous xanthomatosis (CTX) prompted disease modifying treatment and enabled prenatal recurrence risk assessment.

Conclusion: Referral to designated Neurogenetic clinics optimizes diagnostic yield of rare diseases including CA. Lessons learnt from the CA cohort apply to workup of all patients with rare neurological diseases. We provide advice to overcome current diagnostic pitfalls and increase awareness of withstanding challenges, based on our single-center experience. Incorporating tailored updated molecular workup in routine clinical practice and maintaining a patient-centered approach will ensure timely diagnosis, prevention of recurrence and increase access to developing personalized therapy.

References: Poster:
Israel Neurology Association Annual meeting, December 2021
Israeli Medical Genetic Association, December 2021

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MDS Abstracts - https://www.mdsabstracts.org/abstract/expanding-the-services-of-neurogenetic-clinic-lessons-learnt-from-cerebellar-ataxia-cohort/