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. 2020 Aug 3;15(1):198.
doi: 10.1186/s13023-020-01475-9.

Onset features and time to diagnosis in Friedreich's Ataxia

Elisabetta Indelicato  1 , Wolfgang Nachbauer  1 , Andreas Eigentler  1 , Matthias Amprosi  1 , Raffaella Matteucci Gothe  2 , Paola Giunti  3 , Caterina Mariotti  4 , Javier Arpa  5 , Alexandra Durr  6 , Thomas Klopstock  7   8 , Ludger Schöls  9   10 , Ilaria Giordano  11   12 , Katrin Bürk  13 , Massimo Pandolfo  14 , Claire Didszdun  15   16 , Jörg B Schulz  15   16 , Sylvia Boesch  17 ; EFACTS (European Friedreich’s Ataxia Consortium for Translational Studies)
Affiliations

Onset features and time to diagnosis in Friedreich's Ataxia

Elisabetta Indelicato et al. Orphanet J Rare Dis. .

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.

Keywords: Age at onset; Diagnostic delay; Friedreich’s Ataxia; Genetic testing; Natural history study.

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Conflict of interest statement

PG is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. CM reports grant from REATA Pharmaceuticals for phase 2 study in the treatment of Friedreich ataxia. TK discloses research funding in the last 12 months from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) for an investigator-initiated trial of nicotinamide in Friedreich ataxia, as well as (unrelated to this manuscript) research funding from the Bundesministerium für Bildung und Forschung (BMBF, Federal Ministry of Education and Research), and research funding, travel support and speaker/consultancy honoraria from Santhera Pharmaceuticals, Retrophin Inc. and ApoPharma Inc.. LS discloses research funding unrelated to this study from CureVac AG (Tübingen, Germany). MP reports grants from the Friedreich Ataxia Research Alliance, grants from FNRS (Belgium), grants and personal fees from Biomarin, grants and personal fees from Voyager Therapeutics, personal fees from Apopharma, personal fees from Vertex, personal fees from Pfizer, and grants from Euroataxia outside the submitted work. JBS serves on scientific advisory boards for Lundbeck Inc., TEVA, Novartis, ForwardPharma, and Lilly, received funding for travel and speaker honoraria from GlaxoSmithKline, Merz Pharmaceuticals, Medical Tribune, Lundbeck Inc., Pfizer Inc., Boehringer, Bayer, serves as Editor-in-Chief of the Journal of Neurochemistry, and is Associate Editor for eNeuro. SB reports funding from E-Rare-3 “Clinical research for new therapeutic uses of already existing molecules (repurposing) in rares diseases” (E_Rare-3JTC2016).

Figures

Fig. 1
Fig. 1
Relationship between age at onset and time to diagnosis, before and after 1996. Time to diagnosis (years) is plotted against age at onset (years). Cases with onset before 1996 are represented by black dots, while cases with onset after 1996 are represented by grey dots. A shortening in time to diagnosis after 1996 is evident as well as the presence of several very late onset cases (≥50 years old) detected only after 1996
Fig. 2
Fig. 2
Relationship between age at onset and GAA1-repeat length depending on onset symptoms. The length of the shorter GAA repeat (GAA1) is plotted against age at onset (years) in the groups with (a) neurological onset and (b) non-neurological onset. As evident in the graphics, a significant correlation between the GAA1 repeat length and age at onset is present in case of classical onset with neurological symptoms (r = − 0,6; p < 0,0001), while no correlation is found in the group with non-neurological onset (r = − 0,1; p = 0,4)
Fig. 3
Fig. 3
Relationship between age at onset and GAA1-repeat length in FRDA siblings. In 54 siblings’ pairs with FRDA, age at onset and GAA1-repeat length varied between the first sibling to become symptomatic and the latter one. In the graphic, difference in age at onset (in years) across the sibling pairs is plotted against difference in GAA1-repeat length. No correlation was found between the two variables (r = − 0,14, p = 0,3)
See this image and copyright information in PMC

References

    1. Vankan P. Prevalence gradients of Friedreich's ataxia and R1b haplotype in Europe co-localize, suggesting a common Palaeolithic origin in the Franco-Cantabrian ice age refuge. J Neurochem. 2013;126(Suppl 1):11–20. - PubMed
    1. Parkinson MH, Boesch S, Nachbauer W, Mariotti C, Giunti P. Clinical features of Friedreich’s ataxia: classical and atypical phenotypes. J Neurochem. 2013;126(Suppl 1):103–117. - PubMed
    1. Caruso G, Santoro L, Perretti A, Massini R, Pelosi L, Crisci C, et al. Friedreich’s ataxia: electrophysiologic and histologic findings in patients and relatives. Muscle Nerve. 1987;10(6):503–515. - PubMed
    1. Cossee M, Durr A, Schmitt M, Dahl N, Trouillas P, Allinson P, et al. Friedreich’s ataxia: point mutations and clinical presentation of compound heterozygotes. Ann Neurol. 1999;45(2):200–206. - PubMed
    1. Filla A, DeMichele G, Caruso G, Marconi R, Campanella G. Genetic data and natural history of Friedreich’s disease: a study of 80 Italian patients. J Neurol. 1990;237(6):345–351. - PubMed

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