Onset features and time to diagnosis in Friedreich's Ataxia

Indelicato, Elisabetta; Nachbauer, Wolfgang; Eigentler, Andreas; Amprosi, Matthias; Gothe, Raffaella Matteucci; Giunti, Paola; Mariotti, Caterina; Arpa, Javier; Durr, Alexandra; Klopstock, Thomas; Schoels, Ludger; Giordano, Ilaria; Bürk, Katrin; Pandolfo, Massimo; Didszdun, Claire; Schulz, Jörg B. und Bösch, Sylvia (2020): Onset features and time to diagnosis in Friedreich's Ataxia. In: Orphanet Journal of Rare Diseases, Bd. 15, Nr. 1, 198

Abstract

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: Six hundred eleven 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch