Onset features and time to diagnosis in Friedreich´s Ataxia Article Swipe

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Ataxia Audiology Physical medicine and rehabilitation Medicine Psychology Neuroscience

Elisabetta Indelicato , Wolfgang Nachbauer , Andreas Eigentler , Matthias Amprosi , Raffaella Matteucci Gothe , Paola Giunti , Caterina Mariotti , Javier Arpa , Alexandra Dürr , Thomas Klopstock , Lüdger Schöls , Ilaria Giordano , Katrin Bürk , Massimo Pandolfo , Claire Didszdun , Jörg B. Schulz , Sylvia Boesch ·

YOU? · · 2020 · Open Access · · DOI: https://doi.org/10.21203/rs.3.rs-18562/v2 · OA: W4250249662

Background: In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich´s Ataxia (FRDA), a genetic disorder usually caused by homozygous GAA-repeat expansions. Methods: 611 genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov-Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit. Results: In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (n=57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR=2-9) years and it improved significantly after the introduction of genetic testing (2(IQR=1-5) years, p <0.001). Still, after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI[5.5,7.9] vs 4.5, [4.2,5] years in those with neurological presentation, p =0.001) as well as in b) patients with late-onset (3(IQR=1-7) vs 2(IQR=1-5) years compared to typical onset <25 years of age, p =0.03). Age at onset significantly correlated with the length of the shorter GAA repeat (GAA1) in case of neurological onset (r=-0,6; p <0,0001), but not in patients with non-neurological presentation (r=-0,1; p =0,4). Across 54 siblings’ pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r=-0,14, p =0,3). Conclusions: In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history.