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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 usually caused by homozygous GAA-repeat expansions. METHODS: Six hundred eleven genet...

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Autores principales: Indelicato, Elisabetta, Nachbauer, Wolfgang, Eigentler, Andreas, Amprosi, Matthias, Matteucci Gothe, Raffaella, Giunti, Paola, Mariotti, Caterina, Arpa, Javier, Durr, Alexandra, Klopstock, Thomas, Schöls, Ludger, Giordano, Ilaria, Bürk, Katrin, Pandolfo, Massimo, Didszdun, Claire, Schulz, Jörg B., Boesch, Sylvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397644/
https://www.ncbi.nlm.nih.gov/pubmed/32746884
http://dx.doi.org/10.1186/s13023-020-01475-9
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author Indelicato, Elisabetta
Nachbauer, Wolfgang
Eigentler, Andreas
Amprosi, Matthias
Matteucci Gothe, Raffaella
Giunti, Paola
Mariotti, Caterina
Arpa, Javier
Durr, Alexandra
Klopstock, Thomas
Schöls, Ludger
Giordano, Ilaria
Bürk, Katrin
Pandolfo, Massimo
Didszdun, Claire
Schulz, Jörg B.
Boesch, Sylvia
author_facet Indelicato, Elisabetta
Nachbauer, Wolfgang
Eigentler, Andreas
Amprosi, Matthias
Matteucci Gothe, Raffaella
Giunti, Paola
Mariotti, Caterina
Arpa, Javier
Durr, Alexandra
Klopstock, Thomas
Schöls, Ludger
Giordano, Ilaria
Bürk, Katrin
Pandolfo, Massimo
Didszdun, Claire
Schulz, Jörg B.
Boesch, Sylvia
author_sort Indelicato, Elisabetta
collection PubMed
description 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.
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spelling pubmed-73976442020-08-06 Onset features and time to diagnosis in Friedreich’s Ataxia Indelicato, Elisabetta Nachbauer, Wolfgang Eigentler, Andreas Amprosi, Matthias Matteucci Gothe, Raffaella Giunti, Paola Mariotti, Caterina Arpa, Javier Durr, Alexandra Klopstock, Thomas Schöls, Ludger Giordano, Ilaria Bürk, Katrin Pandolfo, Massimo Didszdun, Claire Schulz, Jörg B. Boesch, Sylvia Orphanet J Rare Dis Research 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. BioMed Central 2020-08-03 /pmc/articles/PMC7397644/ /pubmed/32746884 http://dx.doi.org/10.1186/s13023-020-01475-9 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Indelicato, Elisabetta
Nachbauer, Wolfgang
Eigentler, Andreas
Amprosi, Matthias
Matteucci Gothe, Raffaella
Giunti, Paola
Mariotti, Caterina
Arpa, Javier
Durr, Alexandra
Klopstock, Thomas
Schöls, Ludger
Giordano, Ilaria
Bürk, Katrin
Pandolfo, Massimo
Didszdun, Claire
Schulz, Jörg B.
Boesch, Sylvia
Onset features and time to diagnosis in Friedreich’s Ataxia
title Onset features and time to diagnosis in Friedreich’s Ataxia
title_full Onset features and time to diagnosis in Friedreich’s Ataxia
title_fullStr Onset features and time to diagnosis in Friedreich’s Ataxia
title_full_unstemmed Onset features and time to diagnosis in Friedreich’s Ataxia
title_short Onset features and time to diagnosis in Friedreich’s Ataxia
title_sort onset features and time to diagnosis in friedreich’s ataxia
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397644/
https://www.ncbi.nlm.nih.gov/pubmed/32746884
http://dx.doi.org/10.1186/s13023-020-01475-9
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