Onset features and time to diagnosis in Friedreich's Ataxia
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 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 and
... oms at onset as well as age at suspicion of FRDA 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, p =0.001) as well as in b) patients with late-onset (3(IQR=1-7) vs 2(IQR=1-5) years compared to early onset <25 years of age, p =0.03). Age at onset significantly correlated with GAA-repeat length 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 GAA and disease milestones are not valid in case of atypical presentations or positive family history.