Onset features and time to diagnosis in Friedreich’s Ataxia

Elisabetta Indelicato, Wolfgang Nachbauer, Andreas Eigentler, Matthias Amprosi, Raffaella Matteucci Gothe, Paola Giunti, Caterina Mariotti, Javier Arpa, Alexandra Durr, Thomas Klopstock, Ludger Schöls, Ilaria Giordano, Katrin Bürk, Massimo Pandolfo, Claire Didszdun, Jörg B. Schulz, Sylvia Boesch & on behalf of the EFACTS (European Friedreich’s Ataxia Consortium for Translational Studies); Orphanet J Rare Dis 15, 198 (2020). doi:10.1186/s13023-020-01475-9

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.
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.

A Drosophila model of Friedreich Ataxia with CRISPR/Cas9 insertion of GAA repeats in the frataxin gene reveals in vivo protection by N-acetyl cysteine

Maria Russi, Elodie Martin, Benoit D’Autréaux, Laura Tixier, Hervé Tricoire, Véronique Monnier; Human Molecular Genetics, ddaa170, doi:10.1093/hmg/ddaa170 

 Friedreich Ataxia (FA) is caused by GAA repeat expansions in the first intron of FXN, the gene encoding frataxin, which results in decreased gene expression. Thanks to the high degree of frataxin conservation, the Drosophila melanogaster fruitfly appears as an adequate animal model to study this disease and to evaluate therapeutic interventions. Here, we generated a Drosophila model of FA with CRISPR/Cas9 insertion of approximately 200 GAA in the intron of the fly frataxin gene fh. These flies exhibit a developmental delay and lethality associated with decreased frataxin expression. We were able to by-pass preadult lethality using genetic tools to overexpress frataxin only during the developmental period. These frataxin-deficient adults are short-lived and present strong locomotor defects. RNA-Seq analysis identified deregulation of genes involved in amino-acid metabolism and transcriptomic signatures of oxidative stress. In particular, we observed a progressive increase of Tspo expression, fully rescued by adult frataxin expression. Thus, Tspo expression constitutes a molecular marker of the disease progression in our fly model and might be of interest in other animal models or in patients. Finally, in a candidate drug screening, we observed that N-acetyl cysteine improved the survival, locomotor function, resistance to oxidative stress and aconitase activity of frataxin-deficient flies. Therefore, our model provides the opportunity to elucidate in vivo the protective mechanisms of this molecule of therapeutic potential. This study also highlights the strength of the CRISPR/Cas9 technology to introduce human mutations in endogenous orthologous genes, leading to Drosophila models of human diseases with improved physiological relevance.