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New hearts for Friedreich patients

Published:January 13, 2017DOI:https://doi.org/10.1016/j.jns.2017.01.035
      Most individuals with Friedreich ataxia (FRDA) have an abnormal electrocardiogram and elevated serum concentrations of cardiac troponin 1. Many eventually develop cardiac hypertrophy, and heart failure is a frequent cause for their death. Histological evaluation of the heart shows enlarged cardiomyocytes encircled by fibrotic endomysium. Some of the enlarged cardiac myocytes, and also some macrophages that have accumulated in endomysium, contain iron-positive inclusions, but total cardiac iron content is not increased. Molecular studies have shown that frataxin deficiency impairs assembly of mitochondrial iron-sulfur cluster-containing subunits, thereby impeding mitochondrial electron transport and diminishing cardiac energy production [
      • Friedman L.S.
      • Schadt K.A.
      • Regner S.R.
      • Mark G.E.
      • Lin K.Y.
      • Sciascia T.
      • St John Sutton M.
      • Willi S.
      • Lynch D.R.
      Elevation of serum cardiac troponin I in a cross-sectional cohort of asymptomatic subjects with Friedreich ataxia.
      ,
      • Weidmann F.
      • Liu D.
      • Hu K.
      • Florescu C.
      • Niemann M.
      • Herrmann S.
      • Kramer B.
      • Klebe S.
      • Doppler K.
      • Uceyler N.
      • Ritter C.O.
      • Ertl G.
      • Stork S.
      The cardiomyopathy in Friedreich's ataxia – new biomarker for staging cardiac involvement.
      ,
      • Kruger P.C.
      • Yang K.X.
      • Parsons P.J.
      • Becker A.B.
      • Feustel P.J.
      • Koeppen A.H.
      Abundance and significance of iron, zinc, copper, and calcium in the hearts of patients with Friedrech ataxia.
      ,
      • Bunse M.
      • Bit-Avragim N.
      • Riefflin A.
      • Perrot A.
      • Schmidt O.
      • Kreuz F.R.
      • Dietz R.
      • Jung W.-I.
      • Osterziel J.K.
      Cardiac energetics correlates to myocardial hypertrophy in Friedreich's ataxia.
      ].
      Analysis of large North American and European FRDA cohorts has helped to clarify the evolution of cardiomyopathy in this disorder. In general, the onset of cardiac dysfunction occurs earliest in patients with the longest FXN GAA repeats and lowest tissue frataxin levels. However, cardiomyopathy tends to be less severe in the small proportion of FRDA patients who are double heterozygous for an expanded FXN GAA repeat and a null FXN mutation, despite the generally very low levels of frataxin in these patients [
      • Lazaropoulos M.
      • Dong Y.
      • Clark E.
      • Greeley N.R.
      • Seyer L.A.
      • Brigatti K.W.
      • Christie C.
      • Perlman S.L.
      • Wilmot G.R.
      • Gomez C.M.
      • Mathews K.D.
      • Yoon G.
      • Zesiewicz T.
      • Hoyle C.
      • Subramony S.H.
      • Brocht A.F.
      • Farmer J.M.
      • Wilson R.B.
      • Deutsch E.C.
      • Lynch D.R.
      Frataxin levels in peripheral tissue in Friedreich ataxia.
      ,
      • Galea C.A.
      • Huq A.
      • Lockhart P.J.
      • Tai G.
      • Corben L.A.
      • Yiu E.M.
      • Gurrin L.C.
      • Lynch D.R.
      • Gelbard S.
      • Durr A.
      • Pousset F.
      • Parkinson M.
      • Labrum R.
      • Giunti P.
      • Perlman S.L.
      • Delatycki M.B.
      • Evans-Galea M.V.
      Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia.
      ].
      Trials of anti-oxidants (vitamin E or idebenone), of a mitochondrial respiratory chain electron transport facilitator (coenzyme Q10), or of an iron chelator (deferiprone) to prevent or slow progression of FRDA cardiomyopathy have thus far yielded minor or equivocal benefits. Combined therapy with coenzyme Q10 and vitamin E was initially reported to improve FRDA cardiac function, but this was not confirmed in a later double blind study. Both idebenone and deferiprone were reported to slow progress of cardiac hypertrophy in FRDA, but the favorable response to idebenone has not been consistently documented, and attempts to enhance the benefits of deferiprone by dose escalation appeared to worsen FRDA-associated neurological deficits [
      • Kearney M.
      • Orrell R.W.
      • Fahey M.
      • Brassington R.
      • Pandolfo M.
      Pharmacological treatments for Friedreich ataxia.
      ,
      • Pandolfo M.
      • Arpa J.
      • Delatycki M.B.
      • Le Quan Sang K.H.
      • Mariotti C.
      • Munnich A.
      • Sanz-Gallego I.
      • Tai G.
      • Tarnopolsky M.A.
      • Taroni F.
      • Spino M.
      • Tricta F.
      Deferiprone in Friedreich ataxia: a 6-month randomized controlled trial.
      ].
      What, then, can be done for FRDA patients with life-threatening cardiomyopathy, and in particular for those FRDA patients in whom neurological dysfunction has not yet become disabling? Counting the present series of 3 patients by McCormick et al. [
      • McCormick A.
      • Shinnick J.
      • Schadt K.
      • Rodriguez R.
      • Addonizio L.
      • Hirano M.
      • Perlman S.
      • Lin K.Y.
      • Lynch D.R.
      Cardiac transplantation in Friedreich ataxia: extended follow up.
      ], a total of 7 FRDA patients with end-stage cardiomyopathy have undergone successful cardiac transplantation. Notably, the transplanted hearts showed no signs of cardiomyopathy during decades-long post-transplantation followup, providing strong evidence that FRDA cardiomyopathy develops independently of other manifestations of this systemic disease. The impact of the transplanted hearts on quality of life was large, even though there was no consistent evidence that the transplants themselves, or the immunosuppressive drugs administered thereafter to prevent graft rejection, slowed the progress of neurological dysfunction in these patients.
      Can we hope for effective future interventions, other than cardiac transplantation, to ameliorate FRDA cardiomyopathy? Studies in FRDA patient-derived cell lines indicate that small molecule approaches to augmenting cardiac FXN transcription and frataxin expression might be possible [
      • Chutake Y.K.
      • Lam C.C.
      • Costello W.N.
      • Anderson M.P.
      • Bidichandani S.I.
      Reversal of epigenetic promoter silencing in Friedreich ataxia by a class I histone deacetylase inhibitor.
      ]. It may also be possible to augment cardiac frataxin expression in FRDA patients by viral transduction [
      • Perdomini M.
      • Belbellaa B.
      • Monassier L.
      • Reutenauer L.
      • Messaddeq N.
      • Cartier N.
      • Crystal R.G.
      • Aubourg P.
      • Puccio H.
      Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia.
      ], or, as in vivo gene editing techniques improve, by direct excision of the expanded FXN GAA repeat [

      Li Y, Polak U, Bhalla AD, Rozwadowska N, Butler JS, Lynch DR, Dent SYR, Napienala M. Excision of expanded GAA repeats alleviates the molecular phenotype of Friedreich's ataxia. Mol. Ther. 23(6)1055–1065.

      ].

      Conflicts of interest

      None.

      Acknowledgements

      None.

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