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Lynch DR, Sharma S, Hearle P, Greeley N, Gunther K, Keita M, Strawser C, Hauser L, Park C, Schadt K, Lin KY. Characterization of clinical serum cardiac biomarker levels in individuals with Friedreich ataxia. J Neurol Sci 2024; 461:123053. [PMID: 38759249 DOI: 10.1016/j.jns.2024.123053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/18/2024] [Accepted: 05/13/2024] [Indexed: 05/19/2024]
Abstract
Friedreich ataxia is a progressive autosomal recessive neurodegenerative disorder characterized by ataxia, dyscoordination, and cardiomyopathy. A subset of patients with Friedreich ataxia have elevated levels of serum cardiac troponin I, but associations with disease outcomes and features of cardiomyopathy remain unclear. In this study, we characterized clinically obtained serum cardiac biomarker levels including troponin I, troponin T, and B-type natriuretic peptide in subjects with Friedreich ataxia and evaluated their association with markers of disease. While unprovoked troponin I levels were elevated in 36% of the cohort, cTnI levels associated with a cardiac event (provoked) were higher than unprovoked levels. In multivariate linear regression models, younger age predicted increased troponin I values, and in logistic regression models younger age, female sex, and marginally longer GAA repeat length predicted abnormal troponin I levels. In subjects with multiple assessments, mean unprovoked troponin I levels decreased slightly over time. The presence of abnormal troponin I values and their levels were predicted by echocardiographic measures of hypertrophy. In addition, troponin I levels predicted long-term markers of clinical cardiac dysfunction over time to a modest degree. Consequently, troponin I values provide a marker of hypertrophy but only a minimally predictive biomarker for later cardiac manifestations of disease such as systolic dysfunction or arrhythmia.
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Affiliation(s)
- David R Lynch
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America.
| | - Sonal Sharma
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Patrick Hearle
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Nathaniel Greeley
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Katherine Gunther
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Medina Keita
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Cassandra Strawser
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Lauren Hauser
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Courtney Park
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Kimberly Schadt
- Divisions of Neurology Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
| | - Kimberly Y Lin
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America; Divisions of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States of America
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Edzeamey FJ, Ramchunder Z, Pourzand C, Anjomani Virmouni S. Emerging antioxidant therapies in Friedreich's ataxia. Front Pharmacol 2024; 15:1359618. [PMID: 38379897 PMCID: PMC10876797 DOI: 10.3389/fphar.2024.1359618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 01/25/2024] [Indexed: 02/22/2024] Open
Abstract
Friedreich's ataxia (FRDA) is a rare childhood neurologic disorder, affecting 1 in 50,000 Caucasians. The disease is caused by the abnormal expansion of the GAA repeat sequence in intron 1 of the FXN gene, leading to the reduced expression of the mitochondrial protein frataxin. The disease is characterised by progressive neurodegeneration, hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. The reduced expression of frataxin has been suggested to result in the downregulation of endogenous antioxidant defence mechanisms and mitochondrial bioenergetics, and the increase in mitochondrial iron accumulation thereby leading to oxidative stress. The confirmation of oxidative stress as one of the pathological signatures of FRDA led to the search for antioxidants which can be used as therapeutic modality. Based on this observation, antioxidants with different mechanisms of action have been explored for FRDA therapy since the last two decades. In this review, we bring forth all antioxidants which have been investigated for FRDA therapy and have been signed off for clinical trials. We summarise their various target points in FRDA disease pathway, their performances during clinical trials and possible factors which might have accounted for their failure or otherwise during clinical trials. We also discuss the limitation of the studies completed and propose possible strategies for combinatorial therapy of antioxidants to generate synergistic effect in FRDA patients.
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Affiliation(s)
- Fred Jonathan Edzeamey
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health, Medicine, and Life Sciences (CHMLS), Brunel University London, Uxbridge, United Kingdom
| | - Zenouska Ramchunder
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health, Medicine, and Life Sciences (CHMLS), Brunel University London, Uxbridge, United Kingdom
| | - Charareh Pourzand
- Department of Life Sciences, University of Bath, Bath, United Kingdom
- Centre for Therapeutic Innovation, University of Bath, Bath, United Kingdom
| | - Sara Anjomani Virmouni
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health, Medicine, and Life Sciences (CHMLS), Brunel University London, Uxbridge, United Kingdom
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Baban A, Cicenia M, Travaglini L, Calì F, Vasco G, Francalanci P, Novelli A, Adorisio R, Amodeo A, Dallapiccola B, Bertini E, Drago F. Remember Friedreich ataxia even in a toddler with apparently isolated dilated (not hypertrophic!) cardiomyopathy. Revisited. Minerva Pediatr (Torino) 2023; 75:117-123. [PMID: 33820410 DOI: 10.23736/s2724-5276.21.05969-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Friedreich ataxia (FRDA) is the most common form of ataxia in late childhood. Neurological manifestations often precede cardiac involvement, presenting mainly as hypertrophic cardiomyopathy. We describe a toddler with apparently isolated severe heart failure, successfully managed with heart transplant (HT). Although well described in adolescents and adults, onset of FRDA is very uncommon in toddlers and neurological ataxic features are predominant. The presenting symptom of cardiomyopathy is very rare. Similar history is rarely reported in literature, that we described, including an aggressive cardiomyopathy in children younger than 5 years-old. RESULTS: Our patient was diagnosed with FRDA at a postoperative stage due to minimal neurological manifestations. Moreover, the novelty of this study lies in demonstrating a major DNA triplet repeat expansion in skeletal muscle compared to DNA from peripheral blood leukocytes. These results support the concept that triplet repeat expansion is variable among different tissues in FRDA, and in our case it was more expanded in the post mitotic muscular tissue than in blood cells. We believe on the importance of taking in consideration this rare condition even in a toddler with apparently isolated cardiomyopathy and especially when conventional investigations give negative results. We discuss potential trigger effect of HT as a precipitating factor in manifesting neurological symptoms. This observation corresponds to our experience and relates to three patients described so far (the third patient died suddenly). Early onset cardiomyopathy with FRDA should increase awareness of this rare condition and we highlight HT successful outcome. Further reports are needed to delineate this rare condition in youngsters.
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Affiliation(s)
- Anwar Baban
- European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart - ERN GUARD-Heart HCP, Unit of Pediatric Cardiology and Arrhythmia/Syncope, Bambino Gesù Children Hospital and Research Institute, Rome, Italy
| | - Marianna Cicenia
- European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart - ERN GUARD-Heart HCP, Unit of Pediatric Cardiology and Arrhythmia/Syncope, Bambino Gesù Children Hospital and Research Institute, Rome, Italy
| | - Lorena Travaglini
- European Reference Network for Rare Neurological Disorders HCP, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children Research Hospital IRCCS, Rome, Italy
| | - Federica Calì
- European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart - ERN GUARD-Heart HCP, Unit of Pediatric Cardiology and Arrhythmia/Syncope, Bambino Gesù Children Hospital and Research Institute, Rome, Italy
| | - Gessica Vasco
- Department of Neurosciences, Bambino Gesù Children Hospital and Research Institute, Rome, Italy
| | - Paola Francalanci
- Department of Pathology, Bambino Gesù Children Hospital and Research Institute, Rome, Italy
| | - Antonio Novelli
- Laboratory of Medical Genetics, Bambino Gesù Children Hospital and Research Institute, Rome, Italy
| | - Rachele Adorisio
- European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart - ERN GUARD-Heart HCP, Unit of Pediatric Cardiology and Arrhythmia/Syncope, Bambino Gesù Children Hospital and Research Institute, Rome, Italy
| | - Antonio Amodeo
- European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart - ERN GUARD-Heart HCP, Heart Failure and Transplant, Mechanical Circulatory Support Complex Unit, Bambino Gesù Research Hospital and Research Institute, Rome, Italy
| | - Bruno Dallapiccola
- European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart - ERN GUARD-Heart HCP, Unit of Pediatric Cardiology and Arrhythmia/Syncope, Bambino Gesù Children Hospital and Research Institute, Rome, Italy
| | - Enrico Bertini
- European Reference Network for Rare Neurological Disorders HCP, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children Research Hospital IRCCS, Rome, Italy
| | - Fabrizio Drago
- European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart - ERN GUARD-Heart HCP, Unit of Pediatric Cardiology and Arrhythmia/Syncope, Bambino Gesù Children Hospital and Research Institute, Rome, Italy -
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Payne RM. Cardiovascular Research in Friedreich Ataxia: Unmet Needs and Opportunities. JACC Basic Transl Sci 2022; 7:1267-1283. [PMID: 36644283 PMCID: PMC9831864 DOI: 10.1016/j.jacbts.2022.04.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/18/2022] [Accepted: 04/18/2022] [Indexed: 01/18/2023]
Abstract
Friedreich Ataxia (FRDA) is an autosomal recessive disease in which a mitochondrial protein, frataxin, is severely decreased in its expression. In addition to progressive ataxia, patients with FRDA often develop a cardiomyopathy that can be hypertrophic. This cardiomyopathy is unlike the sarcomeric hypertrophic cardiomyopathies in that the hypertrophy is associated with massive mitochondrial proliferation within the cardiomyocyte rather than contractile protein overexpression. This is associated with atrial arrhythmias, apoptosis, and fibrosis over time, and patients often develop heart failure leading to premature death. The differences between this mitochondrial cardiomyopathy and the more common contractile protein hypertrophic cardiomyopathies can be a source of misunderstanding in the management of these patients. Although imaging studies have revealed much about the structure and function of the heart in this disease, we still lack an understanding of many important clinical and fundamental molecular events that determine outcome of the heart in FRDA. This review will describe the current basic and clinical understanding of the FRDA heart, and most importantly, identify major gaps in our knowledge that represent new directions and opportunities for research.
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Affiliation(s)
- R. Mark Payne
- Address for correspondence: Dr R. Mark Payne, Division of Pediatric Cardiology, Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 West Walnut, R4 302b, Indianapolis, Indiana 46202, USA.
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Norrish G, Rance T, Montanes E, Field E, Brown E, Bhole V, Stuart G, Uzun O, McLeod KA, Ilina M, Adwani S, Daubeney P, Delle Donne G, Linter K, Jones CB, Bharucha T, Cervi E, Kaski JP. Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study. Arch Dis Child 2022; 107:450-455. [PMID: 34610949 PMCID: PMC9046745 DOI: 10.1136/archdischild-2021-322455] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 09/17/2021] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Hypertrophic cardiomyopathy (HCM) is an important predictor of long-term outcomes in Friedreich's ataxia (FA), but the clinical spectrum and survival in childhood is poorly described. This study aimed to describe the clinical characteristics of children with FA-HCM. DESIGN AND SETTING Retrospective, longitudinal cohort study of children with FA-HCM from the UK. PATIENTS 78 children (<18 years) with FA-HCM diagnosed over four decades. INTERVENTION Anonymised retrospective demographic and clinical data were collected from baseline evaluation and follow-up. MAIN OUTCOME MEASURES The primary study end-point was all-cause mortality (sudden cardiac death, atrial arrhythmia-related death, heart failure-related death, non-cardiac death) or cardiac transplantation. RESULTS The mean age at diagnosis of FA-HCM was 10.9 (±3.1) years. Diagnosis was within 1 year of cardiac referral in 34 (65.0%) patients, but preceded the diagnosis of FA in 4 (5.3%). At baseline, 65 (90.3%) had concentric left ventricular hypertrophy and 6 (12.5%) had systolic impairment. Over a median follow-up of 5.1 years (IQR 2.4-7.3), 8 (10.5%) had documented supraventricular arrhythmias and 8 (10.5%) died (atrial arrhythmia-related n=2; heart failure-related n=1; non-cardiac n=2; or unknown cause n=3), but there were no sudden cardiac deaths. Freedom from death or transplantation at 10 years was 80.8% (95% CI 62.5 to 90.8). CONCLUSIONS This is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly.
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Affiliation(s)
- Gabrielle Norrish
- Centre for Inherited Cardiovascular Disease, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK,Institute of Cardiovascular Science, University College London, London, UK
| | - Thomas Rance
- Centre for Inherited Cardiovascular Disease, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK
| | - Elena Montanes
- Centre for Inherited Cardiovascular Disease, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK
| | - Ella Field
- Centre for Inherited Cardiovascular Disease, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK
| | - Elspeth Brown
- Paediatric Cardiology, Leeds General Infirmary, Leeds, UK
| | - Vinay Bhole
- Paediatric Cardiology, Birmingham Women and Children’s NHS Foundation Trust, Birmingham, UK
| | - Graham Stuart
- Bristol Congenital Heart Centre, Bristol Heart Institute, Bristol, UK
| | - Orhan Uzun
- Paediatric cardiology, University Hospital of Wales, Cardiff, UK
| | - Karen A McLeod
- Paediatric cardiology, Royal Hospital for Sick Children, Glasgow, UK
| | - Maria Ilina
- Paediatric cardiology, Royal Hospital for Children, Glasgow, UK
| | - Satish Adwani
- Paediatric Cardiology, John Radcliffe Hospital, Oxford, UK
| | - Piers Daubeney
- Paediatric cardiology, Royal Brompton and Harefield NHS Trust and National Heart and Lung Institute, London, UK
| | - Grazia Delle Donne
- Paediatric cardiology, Royal Brompton and Harefield NHS Trust and National Heart and Lung Institute, London, UK
| | - Katie Linter
- Paediatric cardiology, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Caroline B Jones
- Paediatric cardiology, Alder Hey Children’s Hospital, Liverpool, UK
| | - Tara Bharucha
- Department of Congenital Cardiology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Elena Cervi
- Centre for Inherited Cardiovascular Disease, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK
| | - Juan Pablo Kaski
- Centre for Inherited Cardiovascular Disease, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK .,Institute of Cardiovascular Science, University College London, London, UK
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6
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Lodato V, Parlapiano G, Calì F, Silvetti MS, Adorisio R, Armando M, El Hachem M, Romanzo A, Dionisi-Vici C, Digilio MC, Novelli A, Drago F, Raponi M, Baban A. Cardiomyopathies in Children and Systemic Disorders When Is It Useful to Look beyond the Heart? J Cardiovasc Dev Dis 2022; 9:47. [PMID: 35200700 PMCID: PMC8877723 DOI: 10.3390/jcdd9020047] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 11/16/2022] Open
Abstract
Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely heterogenous. These two factors play a major role in the difficulties of establishing standard diagnostic and therapeutic protocols. Isolated CMP in children is a frequent finding, mainly caused by sarcomeric gene variants with a detection rate that can reach up to 50% of analyzed cohorts. Complex multisystemic forms of pediatric CMP are even more heterogenous. Few studies in literature take into consideration this topic as the main core since it represents a rarity (systemic CMP) within a rarity (pediatric population CMP). Identifying etiology in this cohort is essential for understanding prognosis, risk stratification, eligibility to heart transplantation and/or mechanical-assisted procedures, preventing multiorgan complications, and relatives' recurrence risk calculation. The previous points represent a cornerstone in patients' empowerment and personalized medical care approach. The aim of this work is to propose a new approach for an algorithm in the setting of the diagnostic framework of systemic pediatric CMP. On the other hand, during the literature review, we noticed a relatively common etiologic pattern in some forms of complex/multisystem CMP. In other words, certain syndromes such as Danon, Vici, Alström, Barth, and Myhre syndrome share a common pathway of directly or indirectly defective "autophagy" process, which appears to be a possible initiating/triggering factor for CMPs. This conjoint aspect could be important for possible prognostic/therapeutic implications in this category of patients. However, multicentric studies detailed functional and experimental models are needed prior to deriving conclusions.
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Affiliation(s)
- Valentina Lodato
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (V.L.); (G.P.); (F.C.); (M.S.S.); (F.D.)
| | - Giovanni Parlapiano
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (V.L.); (G.P.); (F.C.); (M.S.S.); (F.D.)
- Laboratory of Medical Genetics, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy;
| | - Federica Calì
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (V.L.); (G.P.); (F.C.); (M.S.S.); (F.D.)
| | - Massimo Stefano Silvetti
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (V.L.); (G.P.); (F.C.); (M.S.S.); (F.D.)
| | - Rachele Adorisio
- Heart Failure Clinic-Heart Failure, Heart Transplant, Mechanical Circulatory Support Unit, Department of Pediatric Cardiology and Cardiac Surgery, Heart and Lung Transplant, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy;
| | - Michela Armando
- Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy;
| | - May El Hachem
- Dermatology and Genodermatosis Units, Genetics and Rare Disease Research Division, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy;
| | - Antonino Romanzo
- Ophtalmology Unit, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy;
| | - Carlo Dionisi-Vici
- Division of Metabolism, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy;
| | - Maria Cristina Digilio
- Genetics and Rare Diseases Research Division, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy;
| | - Antonio Novelli
- Laboratory of Medical Genetics, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy;
| | - Fabrizio Drago
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (V.L.); (G.P.); (F.C.); (M.S.S.); (F.D.)
| | - Massimiliano Raponi
- Medical Direction, Bambino Gesù Children Hospital, IRCCS, 00165 Rome, Italy;
| | - Anwar Baban
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (V.L.); (G.P.); (F.C.); (M.S.S.); (F.D.)
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7
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Lees JG, Napierala M, Pébay A, Dottori M, Lim SY. Cellular pathophysiology of Friedreich's ataxia cardiomyopathy. Int J Cardiol 2022; 346:71-78. [PMID: 34798207 DOI: 10.1016/j.ijcard.2021.11.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 11/01/2021] [Accepted: 11/12/2021] [Indexed: 12/17/2022]
Abstract
Friedreich's ataxia (FRDA) is a hereditary neuromuscular disorder. Cardiomyopathy is the leading cause of premature death in FRDA. FRDA cardiomyopathy is a complex and progressive disease with no cure or treatment to slow its progression. At the cellular level, cardiomyocyte hypertrophy, apoptosis and fibrosis contribute to the cardiac pathology. However, the heart is composed of multiple cell types and several clinical studies have reported the involvement of cardiac non-myocytes such as vascular cells, autonomic neurons, and inflammatory cells in the pathogenesis of FRDA cardiomyopathy. In fact, several of the cardiac pathologies associated with FRDA including cardiomyocyte necrosis, fibrosis, and arrhythmia, could be contributed to by a diseased vasculature and autonomic dysfunction. Here, we review available evidence regarding the current understanding of cellular mechanisms for, and the involvement of, cardiac non-myocytes in the pathogenesis of FRDA cardiomyopathy.
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Affiliation(s)
- Jarmon G Lees
- O'Brien Institute Department, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia; Department of Medicine, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Marek Napierala
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Alice Pébay
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, Victoria 3052, Australia; Department of Surgery, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Mirella Dottori
- Illawarra Health and Medical Research Institute, School of Medicine, Molecular Horizons, University of Wollongong, New South Wales 2522, Australia; Department of Biomedical Engineering, The University of Melbourne, Parkville, Victoria 3052, Australia
| | - Shiang Y Lim
- O'Brien Institute Department, St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia; Department of Surgery, The University of Melbourne, Parkville, Victoria 3010, Australia.
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8
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Cardiac Complications of Neuromuscular Disorders. Neuromuscul Disord 2022. [DOI: 10.1016/b978-0-323-71317-7.00003-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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9
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Seminotti B, Grings M, Tucci P, Leipnitz G, Saso L. Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders. Front Cell Neurosci 2021; 15:785057. [PMID: 34955754 PMCID: PMC8693715 DOI: 10.3389/fncel.2021.785057] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/05/2021] [Indexed: 01/14/2023] Open
Abstract
Inherited metabolic disorders (IMDs) are rare genetic conditions that affect multiple organs, predominantly the central nervous system. Since treatment for a large number of IMDs is limited, there is an urgent need to find novel therapeutical targets. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor that has a key role in controlling the intracellular redox environment by regulating the expression of antioxidant enzymes and several important genes related to redox homeostasis. Considering that oxidative stress along with antioxidant system alterations is a mechanism involved in the neuropathophysiology of many IMDs, this review focuses on the current knowledge about Nrf2 signaling dysregulation observed in this group of disorders characterized by neurological dysfunction. We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection.
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Affiliation(s)
- Bianca Seminotti
- Postgraduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Mateus Grings
- Postgraduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Paolo Tucci
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Guilhian Leipnitz
- Postgraduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Postgraduate Program in Biological Sciences: Physiology, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
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10
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Baban A, Lodato V, Parlapiano G, di Mambro C, Adorisio R, Bertini ES, Dionisi-Vici C, Drago F, Martinelli D. Myocardial and Arrhythmic Spectrum of Neuromuscular Disorders in Children. Biomolecules 2021; 11:1578. [PMID: 34827576 PMCID: PMC8615674 DOI: 10.3390/biom11111578] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/02/2021] [Accepted: 10/14/2021] [Indexed: 12/30/2022] Open
Abstract
Neuromuscular disorders (NMDs) are highly heterogenous from both an etiological and clinical point of view. Their signs and symptoms are often multisystemic, with frequent cardiac involvement. In fact, childhood onset forms can predispose a person to various progressive cardiac abnormalities including cardiomyopathies (CMPs), valvulopathies, atrioventricular conduction defects (AVCD), supraventricular tachycardia (SVT) and ventricular arrhythmias (VA). In this review, we selected and described five specific NMDs: Friedreich's Ataxia (FRDA), congenital and childhood forms of Myotonic Dystrophy type 1 (DM1), Kearns Sayre Syndrome (KSS), Ryanodine receptor type 1-related myopathies (RYR1-RM) and Laminopathies. These changes are widely investigated in adults but less researched in children. We focused on these specific topics due their relative frequency and their potential unexpected cardiac manifestations in children. Moreover these conditions present different inheritance patterns and mechanisms of action. We decided not to discuss Duchenne and Becker muscular dystrophies due to extensive work regarding the cardiac aspects in children. For each described NMD, we focused on the possible cardiac manifestations such as different types of CMPs (dilated-DCM, hypertrophic-HCM, restrictive-RCM or left ventricular non compaction-LVNC), structural heart abnormalities (including valvulopathies), and progressive heart rhythm changes (AVCD, SVT, VA). We describe the current management strategies for these conditions. We underline the importance, especially for children, of a serial multidisciplinary personalized approach and the need for periodic surveillance by a dedicated heart team. This is largely due to the fact that in children, the diagnosis of certain NMDs might be overlooked and the cardiac aspect can provide signs of their presence even prior to overt neurological diagnosis.
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Affiliation(s)
- Anwar Baban
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Department of Pediatric Cardiology and Cardiac Surgery, Heart and Lung Transplantation, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (V.L.); (C.d.M.); (R.A.); (F.D.)
| | - Valentina Lodato
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Department of Pediatric Cardiology and Cardiac Surgery, Heart and Lung Transplantation, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (V.L.); (C.d.M.); (R.A.); (F.D.)
| | - Giovanni Parlapiano
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy;
| | - Corrado di Mambro
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Department of Pediatric Cardiology and Cardiac Surgery, Heart and Lung Transplantation, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (V.L.); (C.d.M.); (R.A.); (F.D.)
| | - Rachele Adorisio
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Department of Pediatric Cardiology and Cardiac Surgery, Heart and Lung Transplantation, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (V.L.); (C.d.M.); (R.A.); (F.D.)
| | - Enrico Silvio Bertini
- The European Reference Network for Neuromuscular Disorders (ERN NMD), Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00146 Rome, Italy;
| | - Carlo Dionisi-Vici
- Division of Metabolism, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (C.D.-V.); (D.M.)
| | - Fabrizio Drago
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Department of Pediatric Cardiology and Cardiac Surgery, Heart and Lung Transplantation, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (V.L.); (C.d.M.); (R.A.); (F.D.)
| | - Diego Martinelli
- Division of Metabolism, Bambino Gesù Children Hospital and Research Institute, IRCCS, 00165 Rome, Italy; (C.D.-V.); (D.M.)
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11
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Vásquez-Trincado C, Patel M, Sivaramakrishnan A, Bekeová C, Anderson-Pullinger L, Wang N, Tang HY, Seifert EL. Adaptation of the heart to Frataxin depletion: Evidence that integrated stress response can predominate over mTORC1 activation. Hum Mol Genet 2021; 33:ddab216. [PMID: 34550363 PMCID: PMC11000666 DOI: 10.1093/hmg/ddab216] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 11/12/2022] Open
Abstract
Friedreich's ataxia (FRDA) is an inherited disorder caused by depletion of frataxin (FXN), a mitochondrial protein required for iron-sulfur cluster (ISC) biogenesis. Cardiac dysfunction is the main cause of death. Yet pathogenesis, and, more generally, how the heart adapts to FXN loss, remain poorly understood, though are expected to be linked to an energy deficit. We modified a transgenic (TG) mouse model of inducible FXN depletion that permits phenotypic evaluation of the heart at different FXN levels, and focused on substrate-specific bioenergetics and stress signaling. When FXN protein in the TG heart was 17% of normal, bioenergetics and signaling were not different from control. When, 8 weeks later, FXN was ~ 97% depleted in the heart, TG heart mass and cardiomyocyte cross-sectional area were less, without evidence of fibrosis or apoptosis. mTORC1 signaling was activated, as was the integrated stress response, evidenced by greater phosphorylation of eIF2α relative to total eIF2α, and decreased protein translation. We interpret these results to suggest that, in TG hearts, an anabolic stimulus was constrained by eIF2α phosphorylation. Cardiac contractility was maintained in the 97%-FXN-depleted hearts, possibly contributed by an unexpected preservation of β-oxidation, though pyruvate oxidation was lower. Bioenergetics alterations were matched by changes in the mitochondrial proteome, including a non-uniform decrease in abundance of ISC-containing proteins. Altogether, these findings suggest that the FXN depleted heart can suppress a major ATP demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term.
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Affiliation(s)
- César Vásquez-Trincado
- MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Monika Patel
- MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Aishwarya Sivaramakrishnan
- MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Carmen Bekeová
- MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Lauren Anderson-Pullinger
- MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Nadan Wang
- Center for Translational Medicine, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Hsin-Yao Tang
- Proteomics and Metabolomics Facility, The Wistar Institute, Philadelphia, PA 19104, United States
| | - Erin L Seifert
- MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, United States
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12
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Martinez HR, Beasley GS, Miller N, Goldberg JF, Jefferies JL. Clinical Insights Into Heritable Cardiomyopathies. Front Genet 2021; 12:663450. [PMID: 33995492 PMCID: PMC8113776 DOI: 10.3389/fgene.2021.663450] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/06/2021] [Indexed: 12/15/2022] Open
Abstract
Cardiomyopathies (CMs) encompass a heterogeneous group of structural and functional abnormalities of the myocardium. The phenotypic characteristics of these myocardial diseases range from silent to symptomatic heart failure, to sudden cardiac death due to malignant tachycardias. These diseases represent a leading cause of cardiovascular morbidity, cardiac transplantation, and death. Since the discovery of the first locus associated with hypertrophic cardiomyopathy 30 years ago, multiple loci and molecular mechanisms have been associated with these cardiomyopathy phenotypes. Conversely, the disparity between the ever-growing landscape of cardiovascular genetics and the lack of awareness in this field noticeably demonstrates the necessity to update training curricula and educational pathways. This review summarizes the current understanding of heritable CMs, including the most common pathogenic gene variants associated with the morpho-functional types of cardiomyopathies: dilated, hypertrophic, arrhythmogenic, non-compaction, and restrictive. Increased understanding of the genetic/phenotypic associations of these heritable diseases would facilitate risk stratification to leveraging appropriate surveillance and management, and it would additionally provide identification of family members at risk of avoidable cardiovascular morbidity and mortality.
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Affiliation(s)
- Hugo R. Martinez
- The Heart Institute, Le Bonheur Children’s Hospital, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Gary S. Beasley
- The Heart Institute, Le Bonheur Children’s Hospital, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Noah Miller
- The Heart Institute, Le Bonheur Children’s Hospital, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Jason F. Goldberg
- The Heart Institute, Le Bonheur Children’s Hospital, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - John L. Jefferies
- The Cardiovascular Institute, The University of Tennessee Health Science Center, Memphis, TN, United States
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13
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Mejia E, Lynch A, Hearle P, Okunowo O, Griffis H, Shah M, Lynch D, Lin KY. Ectopic Burden via Holter Monitors in Friedreich Ataxia. Pediatr Neurol 2021; 117:29-33. [PMID: 33652339 PMCID: PMC8085807 DOI: 10.1016/j.pediatrneurol.2021.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 01/09/2021] [Accepted: 01/17/2021] [Indexed: 01/24/2023]
Abstract
BACKGROUND Friedreich ataxia is the most commonly inherited ataxia; nearly 60% of deaths are cardiac in nature, with one in eight deaths due to arrhythmia. Additional or irregular heartbeats, measured as ectopy, can be quantified using portable heart rhythm monitoring. We sought to describe the ectopic burden in Friedreich ataxia. METHODS Using a natural history study of patients with Friedreich ataxia at a single center, we analyzed portable heart rhythm monitors (Holters). Ectopic burden was defined as the proportion of atrial or ventricular ectopic beats over total beats. RESULTS Of 456 patients, 131 had Holters. Sixty-eight (52.0%) were male, median age of symptom onset was 8.0 years (5.0 to 13.0, n = 111), median age at time of Holter was 17.3 years (interquartile range [IQR] 12.9 to 22.8, n = 129), and median duration of illness was 8.7 years (IQR 5.3 to 11.6, n = 110). Median GAA length on the shorter FXN allele was 706.0 (IQR 550.0 to 840.0, n = 112). Eight (7.8%, n = 103) had diminished cardiac function, and 74 (74.0%, n = 100) had ventricular hypertrophy. Ninety patients (83.0%) had atrial ectopy (supraventricular ectopy [SVE]): 85 (78.0%) with rare SVE (>0% to 5%) and five (5.0%) with frequent SVE (>10%). Twenty-five (19.0%) had supraventricular runs, and one (0.8%) had atrial fibrillation/flutter. Forty-five (41.0%) had ventricular ectopy (VE): 43 (39.0%) with rare VE (0% to 5%) and two (2.0%) with moderate VE (5% to 10%). Compared with patients with none and rare SVE, patients with frequent SVE had longer disease duration (18.3 versus 4.6 versus 9.0 years, P = 0.0005). CONCLUSION Patients with longer disease duration had higher rates of SVE. Heart rhythm monitoring may be considered for risk stratification; however, longitudinal analysis is needed.
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Affiliation(s)
- Erika Mejia
- Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
| | - Abigail Lynch
- Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Patrick Hearle
- Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Oluwatimilehin Okunowo
- Data Science & Biostatistics Unit, Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Heather Griffis
- Data Science & Biostatistics Unit, Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Maully Shah
- Division of Cardiology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - David Lynch
- Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Kimberly Y. Lin
- Division of Cardiology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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14
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Fomicheva EI, Myasnikov RP, Selivyorstov YA, Illarioshkin SN, Dadali EL, Drapkina OM. Cardiomyopathy of Friedreich's Disease. Modern Methods of Diagnostic. RATIONAL PHARMACOTHERAPY IN CARDIOLOGY 2021. [DOI: 10.20996/1819-6446-2021-01-05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Friedreich's disease is a hereditary neurodegenerative multiple organ disease, primarily affecting the most energy-dependent tissues (cells of the nervous system, myocardium, pancreas), the lesion of which is characterized by progressive ataxia, dysarthria, dysphagia, oculomotor disorders, loss of deep tendon reflexes, pyramid signs, diabetes mellitus, visual impairment. Friedreich's ataxia is the most common of all hereditary ataxias; nevertheless, this disease is considered orphan. By its pathogenesis, Friedreich's disease is mitochondrial ataxia, caused by a deficiency in the transcription of the FXN gene, leading to a decrease in the synthesis of the frataxin protein. Frataxin is a protein associated with the inner mitochondrial membrane, which in turn is involved in the formation of iron-sulfur clusters, the lack of which leads to a decrease in the production of mitochondrial ATP, an increase in the level of mitochondrial iron and oxidative stress. The basis of the clinical picture of Friedreich's disease is ataxia of a mixed (sensitive and cerebellar) nature. The steady and gradual progression of neurological symptoms significantly affects the quality of life of patients and is most often the leading reason for seeking medical attention. However, the prognosis is primarily due to the involvement of cardiac tissue in the pathological process. The main causes of death in patients with Friedreich's ataxia are severe heart failure and sudden cardiac death due to cardiomyopathy. The overwhelming majority of foreign and domestic publications on Friedreich's ataxia are devoted to the neurological manifestations of this disease, and little attention is paid to this problem in the cardiological scientific and practical society. The purpose of this review is to provide up-to-date information on modern methods of diagnosing myocardial damage at various stages of Friedreich's disease.
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Affiliation(s)
- E. I. Fomicheva
- National Medical Research Center for Therapy and Preventive Medicine
| | - R. P. Myasnikov
- National Medical Research Center for Therapy and Preventive Medicine
| | | | | | - E. L. Dadali
- National Medical Research Center for Therapy and Preventive Medicine
| | - O. M. Drapkina
- National Medical Research Center for Therapy and Preventive Medicine
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15
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Smith FM, Kosman DJ. Molecular Defects in Friedreich's Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities. Front Mol Biosci 2020; 7:569293. [PMID: 33263002 PMCID: PMC7686857 DOI: 10.3389/fmolb.2020.569293] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 09/10/2020] [Indexed: 01/18/2023] Open
Abstract
Friedreich’s ataxia (FRDA) is a multi-faceted disease characterized by progressive sensory–motor loss, neurodegeneration, brain iron accumulation, and eventual death by hypertrophic cardiomyopathy. FRDA follows loss of frataxin (FXN), a mitochondrial chaperone protein required for incorporation of iron into iron–sulfur cluster and heme precursors. After the discovery of the molecular basis of FRDA in 1996, over two decades of research have been dedicated to understanding the temporal manifestations of disease both at the whole body and molecular level. Early research indicated strong cellular iron dysregulation in both human and yeast models followed by onset of oxidative stress. Since then, the pathophysiology due to dysregulation of intracellular iron chaperoning has become central in FRDA relative to antioxidant defense and run-down in energy metabolism. At the same time, limited consideration has been given to changes in cytoskeletal organization, which was one of the first molecular defects noted. These alterations include both post-translational oxidative glutathionylation of actin monomers and differential DNA processing of a cytoskeletal regulator PIP5K1β. Currently unknown in respect to FRDA but well understood in the context of FXN-deficient cell physiology is the resulting impact on the cytoskeleton; this disassembly of actin filaments has a particularly profound effect on cell–cell junctions characteristic of barrier cells. With respect to a neurodegenerative disorder such as FRDA, this cytoskeletal and tight junction breakdown in the brain microvascular endothelial cells of the blood–brain barrier is likely a component of disease etiology. This review serves to outline a brief history of this research and hones in on pathway dysregulation downstream of iron-related pathology in FRDA related to actin dynamics. The review presented here was not written with the intent of being exhaustive, but to instead urge the reader to consider the essentiality of the cytoskeleton and appreciate the limited knowledge on FRDA-related cytoskeletal dysfunction as a result of oxidative stress. The review examines previous hypotheses of neurodegeneration with brain iron accumulation (NBIA) in FRDA with a specific biochemical focus.
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Affiliation(s)
- Frances M Smith
- Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, United States
| | - Daniel J Kosman
- Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, United States
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16
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Legrand L, Diallo A, Monin ML, Ewenczyk C, Charles P, Isnard R, Vicaut E, Montalescot G, Durr A, Pousset F. Predictors of Left Ventricular Dysfunction in Friedreich's Ataxia in a 16-Year Observational Study. Am J Cardiovasc Drugs 2020; 20:209-216. [PMID: 31650522 DOI: 10.1007/s40256-019-00375-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Friedreich's ataxia (FRDA) is a cerebellar ataxia due to GAA repeat expansions in the FXN gene, and in affected patients, lower left ventricular ejection fraction (LVEF) leads to poorer prognosis. We aimed to identify patients likely to develop worsening LVEF at an early stage. METHODS We included 115 FRDA patients aged 30 ± 10 years with 620 ± 238 GAA repeats on the shorter allele and disease onset of 15 ± 7 years. RESULTS At baseline, left ventricular (LV) hypertrophy was present in 53%, with LVEF 65 ± 7%, LV end diastolic diameter (LVEDD) 43 ± 5 mm, septal wall thickness (SWT) 11.8 ± 2.7 mm, and posterior wall thickness 11.1 ± 2.5 mm. After a mean follow-up of 13 ± 6 years, LVEF ≤ 50% was observed in 12 patients. The main determinants of LVEF ≤ 50% were GAA repeat number on the shorter allele (odds ratio [OR] 1.007, 95% confidence interval [CI] 1.003-1.012, p = 0.002), LVEDD (OR 1.217, 95% CI 1.058-1.399, p = 0.006), and SWT (OR 1.352, 95% CI 1.016-1.799, p = 0.04). High-risk patients were predicted 5 years before LVEF ≤ 50% occurred: area under the curve of 0.91, 95% CI 0.85-0.97. Patients with GAA repeats > 800 were categorized as high risk, patients with 500 < GAA < 800 were high risk if LVEDD was ≥ 52.6 mm and SWT was ≥ 13.3 mm, and patients with GAA < 500 were low risk if LVEDD was < 52.6 mm and SWT was < 13.3 mm. CONCLUSIONS Echocardiographic follow-up combined with size assessment of GAA repeat expansions is a powerful tool to identify patients at high risk of developing LV systolic dysfunction up to 5 years before clinical symptoms. Further studies are mandatory to investigate if these patients would benefit from cardiac interventions.
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Affiliation(s)
- Lise Legrand
- Cardiology Department, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France
- ICAN (Institute for Cardiometabolism and Nutrition), Pitié-Salpêtrière University Hospital, Paris, France
| | - Abdourahmane Diallo
- ACTION (Allies in Cardiovascular Trials Initiatives and Organized Networks) Group, URC Lariboisière University Hospital, Paris, France
| | - Marie-Lorraine Monin
- Cardiology Department, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France
- Genetics Department, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France
| | - Claire Ewenczyk
- Genetics Department, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France
| | - Perrine Charles
- Genetics Department, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France
| | - Richard Isnard
- Cardiology Department, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France
- ICAN (Institute for Cardiometabolism and Nutrition), Pitié-Salpêtrière University Hospital, Paris, France
- ACTION (Allies in Cardiovascular Trials Initiatives and Organized Networks) Group, URC Lariboisière University Hospital, Paris, France
| | - Eric Vicaut
- ACTION (Allies in Cardiovascular Trials Initiatives and Organized Networks) Group, URC Lariboisière University Hospital, Paris, France
| | - Gilles Montalescot
- Cardiology Department, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France
- ACTION (Allies in Cardiovascular Trials Initiatives and Organized Networks) Group, URC Lariboisière University Hospital, Paris, France
| | - Alexandra Durr
- Genetics Department, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France
- ICM (Brain and Spine Institute), INSERM, CNRS, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France
| | - Francoise Pousset
- Cardiology Department, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France.
- ICAN (Institute for Cardiometabolism and Nutrition), Pitié-Salpêtrière University Hospital, Paris, France.
- Département de Cardiologie, Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, 75651, Paris Cedex 13, France.
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17
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Arbustini E, Di Toro A, Giuliani L, Favalli V, Narula N, Grasso M. Cardiac Phenotypes in Hereditary Muscle Disorders: JACC State-of-the-Art Review. J Am Coll Cardiol 2019; 72:2485-2506. [PMID: 30442292 DOI: 10.1016/j.jacc.2018.08.2182] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 07/20/2018] [Accepted: 08/10/2018] [Indexed: 01/05/2023]
Abstract
Hereditary muscular diseases commonly involve the heart. Cardiac manifestations encompass a spectrum of phenotypes, including both cardiomyopathies and rhythm disorders. Common biomarkers suggesting cardiomuscular diseases include increased circulating creatine kinase and/or lactic acid levels or disease-specific metabolic indicators. Cardiac and extra-cardiac traits, imaging tests, family studies, and genetic testing provide precise diagnoses. Cardiac phenotypes are mainly dilated and hypokinetic in dystrophinopathies, Emery-Dreifuss muscular dystrophies, and limb girdle muscular dystrophies; hypertrophic in Friedreich ataxia, mitochondrial diseases, glycogen storage diseases, and fatty acid oxidation disorders; and restrictive in myofibrillar myopathies. Left ventricular noncompaction is variably associated with the different myopathies. Conduction defects and arrhythmias constitute a major phenotype in myotonic dystrophies and skeletal muscle channelopathies. Although the actual cardiac management is rarely based on the cause, the cardiac phenotypes need precise characterization because they are often the only or the predominant manifestations and the prognostic determinants of many hereditary muscle disorders.
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Affiliation(s)
- Eloisa Arbustini
- Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, University Hospital Policlinico San Matteo, Pavia, Italy.
| | - Alessandro Di Toro
- Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, University Hospital Policlinico San Matteo, Pavia, Italy
| | - Lorenzo Giuliani
- Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, University Hospital Policlinico San Matteo, Pavia, Italy
| | | | - Nupoor Narula
- Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, University Hospital Policlinico San Matteo, Pavia, Italy; Division of Cardiology, Department of Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, New York
| | - Maurizia Grasso
- Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, University Hospital Policlinico San Matteo, Pavia, Italy
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18
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Wong AOT, Wong G, Shen M, Chow MZY, Tse WW, Gurung B, Mak SY, Lieu DK, Costa KD, Chan CW, Martelli A, Nabhan JF, Li RA. Correlation between frataxin expression and contractility revealed by in vitro Friedreich's ataxia cardiac tissue models engineered from human pluripotent stem cells. Stem Cell Res Ther 2019; 10:203. [PMID: 31286988 PMCID: PMC6615274 DOI: 10.1186/s13287-019-1305-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/30/2019] [Accepted: 06/17/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Friedreich's ataxia (FRDA) is an autosomal recessive disease caused by a non-coding mutation in the first intron of the frataxin (FXN) gene that suppresses its expression. Compensatory hypertrophic cardiomyopathy, dilated cardiomyopathy, and conduction system abnormalities in FRDA lead to cardiomyocyte (CM) death and fibrosis, consequently resulting in heart failure and arrhythmias. Murine models have been developed to study disease pathology in the past two decades; however, differences between human and mouse physiology and metabolism have limited the relevance of animal studies in cardiac disease conditions. To bridge this gap, we aimed to generate species-specific, functional in vitro experimental models of FRDA using 2-dimensional (2D) and 3-dimensional (3D) engineered cardiac tissues from FXN-deficient human pluripotent stem cell-derived ventricular cardiomyocytes (hPSC-hvCMs) and to compare their contractile and electrophysiological properties with healthy tissue constructs. METHODS Healthy control and FRDA patient-specific hPSC-hvCMs were derived by directed differentiation using a small molecule-based protocol reported previously. We engineered the hvCMs into our established human ventricular cardiac tissue strip (hvCTS) and human ventricular cardiac anisotropic sheet (hvCAS) models, and functional assays were performed on days 7-17 post-tissue fabrication to assess the electrophysiology and contractility of FRDA patient-derived and FXN-knockdown engineered tissues, in comparison with healthy controls. To further validate the disease model, forced expression of FXN was induced in FXN-deficient tissues to test if disease phenotypes could be rescued. RESULTS Here, we report for the first time the generation of human engineered tissue models of FRDA cardiomyopathy from hPSCs: FXN-deficient hvCTS displayed attenuated developed forces (by 70-80%) compared to healthy controls. High-resolution optical mapping of hvCAS with reduced FXN expression also revealed electrophysiological defects consistent with clinical observations, including action potential duration prolongation and maximum capture frequency reduction. Interestingly, a clear positive correlation between FXN expression and contractility was observed (ρ > 0.9), and restoration of FXN protein levels by lentiviral transduction rescued contractility defects in FXN-deficient hvCTS. CONCLUSIONS We conclude that human-based in vitro cardiac tissue models of FRDA provide a translational, disease-relevant biomimetic platform for the evaluation of novel therapeutics and to provide insight into FRDA disease progression.
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Affiliation(s)
| | - Gabriel Wong
- Novoheart, Vancouver, British Columbia V6C 2V6 Canada
| | - Michael Shen
- Novoheart, Vancouver, British Columbia V6C 2V6 Canada
| | | | - Wan Wai Tse
- Novoheart, Vancouver, British Columbia V6C 2V6 Canada
| | - Bimal Gurung
- Novoheart, Vancouver, British Columbia V6C 2V6 Canada
| | - Suet Yee Mak
- Novoheart, Vancouver, British Columbia V6C 2V6 Canada
| | | | | | - Camie W. Chan
- Novoheart, Vancouver, British Columbia V6C 2V6 Canada
| | - Alain Martelli
- Current address: Astellas Innovation Management Astellas Pharma, 1030 Massachusetts Avenue, Cambridge, MA 02138 USA
| | - Joseph F. Nabhan
- Current address: Astellas Innovation Management Astellas Pharma, 1030 Massachusetts Avenue, Cambridge, MA 02138 USA
| | - Ronald A. Li
- Novoheart, Vancouver, British Columbia V6C 2V6 Canada
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Llorens JV, Soriano S, Calap-Quintana P, Gonzalez-Cabo P, Moltó MD. The Role of Iron in Friedreich's Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models. Front Neurosci 2019; 13:75. [PMID: 30833885 PMCID: PMC6387962 DOI: 10.3389/fnins.2019.00075] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 01/23/2019] [Indexed: 12/12/2022] Open
Abstract
Friedreich's ataxia (FRDA) is a rare early-onset degenerative disease that affects both the central and peripheral nervous systems, and other extraneural tissues, mainly the heart and endocrine pancreas. This disorder progresses as a mixed sensory and cerebellar ataxia, primarily disturbing the proprioceptive pathways in the spinal cord, peripheral nerves and nuclei of the cerebellum. FRDA is an inherited disease with an autosomal recessive pattern caused by an insufficient amount of the nuclear-encoded mitochondrial protein frataxin, which is an essential and highly evolutionary conserved protein whose deficit results in iron metabolism dysregulation and mitochondrial dysfunction. The first experimental evidence connecting frataxin with iron homeostasis came from Saccharomyces cerevisiae; iron accumulates in the mitochondria of yeast with deletion of the frataxin ortholog gene. This finding was soon linked to previous observations of iron deposits in the hearts of FRDA patients and was later reported in animal models of the disease. Despite advances made in the understanding of FRDA pathophysiology, the role of iron in this disease has not yet been completely clarified. Some of the questions still unresolved include the molecular mechanisms responsible for the iron accumulation and iron-mediated toxicity. Here, we review the contribution of the cellular and animal models of FRDA and relevance of the studies using FRDA patient samples to gain knowledge about these issues. Mechanisms of mitochondrial iron overload are discussed considering the potential roles of frataxin in the major mitochondrial metabolic pathways that use iron. We also analyzed the effect of iron toxicity on neuronal degeneration in FRDA by reactive oxygen species (ROS)-dependent and ROS-independent mechanisms. Finally, therapeutic strategies based on the control of iron toxicity are considered.
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Affiliation(s)
- José Vicente Llorens
- Department of Genetics, Faculty of Biological Sciences, University of Valencia, Valencia, Spain
- Unit for Psychiatry and Neurodegenerative Diseases, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Sirena Soriano
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, United States
| | - Pablo Calap-Quintana
- Department of Genetics, Faculty of Biological Sciences, University of Valencia, Valencia, Spain
- Unit for Psychiatry and Neurodegenerative Diseases, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Pilar Gonzalez-Cabo
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain
- Center of Biomedical Network Research on Rare Diseases CIBERER, Valencia, Spain
- Associated Unit for Rare Diseases INCLIVA-CIPF, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - María Dolores Moltó
- Department of Genetics, Faculty of Biological Sciences, University of Valencia, Valencia, Spain
- Unit for Psychiatry and Neurodegenerative Diseases, Biomedical Research Institute INCLIVA, Valencia, Spain
- Center of Biomedical Network Research on Mental Health CIBERSAM, Valencia, Spain
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20
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Hanson E, Sheldon M, Pacheco B, Alkubeysi M, Raizada V. Heart disease in Friedreich’s ataxia. World J Cardiol 2019; 11:1-12. [PMID: 30705738 PMCID: PMC6354072 DOI: 10.4330/wjc.v11.i1.1] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 12/11/2018] [Accepted: 01/06/2019] [Indexed: 02/06/2023] Open
Abstract
Friedreich’s ataxia (FRDA), which occurs in 1/50000 live births, is the most prevalent inherited neuromuscular disorder. Nearly all FRDA patients develop cardiomyopathy at some point in their lives. The clinical manifestations of FRDA include ataxia of the limbs and trunk, dysarthria, diabetes mellitus, and cardiac diseases. However, the broad clinical spectrum makes FRDA difficult to identify. The diagnosis of FRDA is based on the presence of suspicious clinical factors, the use of the Harding criteria and, more recently, the use of genetic testing for identifying the expansion of a triplet nucleotide sequence. FRDA is linked to a defect in the mitochondrial protein frataxin; an epigenetic alteration interferes with the folding of this protein, causing a relative deficiency of frataxin in affected patients. Frataxins are small essential proteins whose deficiency causes a range of metabolic disturbances, including oxidative stress, iron-sulfur cluster deficits, and defects in heme synthesis, sulfur amino acid metabolism, energy metabolism, stress responses, and mitochondrial function. The cardiac involvement seen in FRDA is a consequence of mitochondrial proliferation as well as the loss of contractile proteins and the subsequent development of myocardial fibrosis. The walls of the left ventricle become thickened, and different phenotypic manifestations are seen, including concentric or asymmetric hypertrophy and (less commonly) dilated cardiomyopathy. Dilated cardiomyopathy and arrhythmia are associated with mortality in patients with FRDA, whereas hypertrophic cardiomyopathy is not. Systolic function tends to be low-normal in FRDA patients, with an acute decline at the end of life. However, the literature includes only a few long-term prospective studies of cardiac progression in FRDA, and the cause of death is often attributed to heart failure and arrhythmia postmortem. Cardiomyopathy tends to be correlated with the clinical neurologic age of onset and the nucleotide triplet repeat length (i.e., markers of phenotypic disease severity) rather than the duration of disease or the severity of neurologic symptoms. As most patients are wheelchair-bound within 15 years of diagnosis, the clinical determination of cardiac involvement is often complicated by comorbidities. Researchers are currently testing targeted therapies for FRDA, and a centralized database, patient registry, and natural history study have been launched to support these clinical trials. The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in FRDA patients and then introduces gene-targeted and pathology-specific therapies as well as screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.
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Affiliation(s)
- Emily Hanson
- Department of Internal Medicine, Cardiology Section, University of New Mexico, Albuquerque, NM 87106, United States
| | - Mark Sheldon
- Department of Internal Medicine, Cardiology Section, University of New Mexico, Albuquerque, NM 87106, United States
| | - Brenda Pacheco
- Department of Internal Medicine, Cardiology Section, University of New Mexico, Albuquerque, NM 87106, United States
| | - Mohammed Alkubeysi
- Department of Internal Medicine, Cardiology Section, University of New Mexico, Albuquerque, NM 87106, United States
| | - Veena Raizada
- Department of Internal Medicine, Cardiology Section, University of New Mexico, Albuquerque, NM 87106, United States
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21
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22
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Cesar S. Neuromuscular diseases with hypertrophic cardiomyopathy. Glob Cardiol Sci Pract 2018; 2018:27. [PMID: 30393639 PMCID: PMC6209456 DOI: 10.21542/gcsp.2018.27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 06/15/2018] [Indexed: 12/12/2022] Open
Abstract
[first paragraph of article]Neuromuscular disorders are frequently associated with cardiac abnormalities, even in pediatric population. Cardiac involvement includes both structural changes and conduction disease. In general, HCM is a rare manifestation of neuromuscular diseases. Autosomal dominant inheritance with mutations in sarcomeric genes are described in about 60% of young adults and adult population with HCM. Other genetic disorders, such as inherited metabolic and neuromuscular diseases and other chromosome abnormalities are responsible of 5–10% of HCM in adults. We review the most frequent neuromuscular diseases related with HCM.
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Affiliation(s)
- Sergi Cesar
- Arrhythmia, Inherited Cardiac Diseases and Sudden Death Unit, Pediatric Cardiology Department, Sant Joan de Déu Hospital and Sant Joan de Déu Research Institute, University of Barcelona, Barcelona, Spain
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23
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Palandri A, Martin E, Russi M, Rera M, Tricoire H, Monnier V. Identification of cardioprotective drugs by medium-scale in vivo pharmacological screening on a Drosophila cardiac model of Friedreich's ataxia. Dis Model Mech 2018; 11:dmm033811. [PMID: 29898895 PMCID: PMC6078405 DOI: 10.1242/dmm.033811] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 06/06/2018] [Indexed: 12/30/2022] Open
Abstract
Friedreich's ataxia (FA) is caused by reduced levels of frataxin, a highly conserved mitochondrial protein. There is currently no effective treatment for this disease, which is characterized by progressive neurodegeneration and cardiomyopathy, the latter being the most common cause of death in patients. We previously developed a Drosophila melanogaster cardiac model of FA, in which the fly frataxin is inactivated specifically in the heart, leading to heart dilatation and impaired systolic function. Methylene Blue (MB) was highly efficient to prevent these cardiac dysfunctions. Here, we used this model to screen in vivo the Prestwick Chemical Library, comprising 1280 compounds. Eleven drugs significantly reduced the cardiac dilatation, some of which may possibly lead to therapeutic applications in the future. The one with the strongest protective effects was paclitaxel, a microtubule-stabilizing drug. In parallel, we characterized the histological defects induced by frataxin deficiency in cardiomyocytes and observed strong sarcomere alterations with loss of striation of actin fibers, along with full disruption of the microtubule network. Paclitaxel and MB both improved these structural defects. Therefore, we propose that frataxin inactivation induces cardiac dysfunction through impaired sarcomere assembly or renewal due to microtubule destabilization, without excluding additional mechanisms. This study is the first drug screening of this extent performed in vivo on a Drosophila model of cardiac disease. Thus, it also brings the proof of concept that cardiac functional imaging in adult Drosophila flies is usable for medium-scale in vivo pharmacological screening, with potent identification of cardioprotective drugs in various contexts of cardiac diseases.
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Affiliation(s)
- Amandine Palandri
- Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
| | - Elodie Martin
- Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
| | - Maria Russi
- Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
| | - Michael Rera
- Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
| | - Hervé Tricoire
- Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
| | - Véronique Monnier
- Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France
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Salman OF, El-Rayess HM, Abi Khalil C, Nemer G, Refaat MM. Inherited Cardiomyopathies and the Role of Mutations in Non-coding Regions of the Genome. Front Cardiovasc Med 2018; 5:77. [PMID: 29998127 PMCID: PMC6028572 DOI: 10.3389/fcvm.2018.00077] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 06/04/2018] [Indexed: 01/16/2023] Open
Abstract
Cardiomyopathies (CMs) are a group of cardiac pathologies caused by an intrinsic defect within the myocardium. The relative contribution of genetic mutations in the pathogenesis of certain CMs, such as hypertrophic cardiomyopathy (HCM), arrythmogenic right/left ventricular cardiomyopathy (ARVC) and left ventricular non-compacted cardiomyopathy (LVNC) has been established in comparison to dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM). The aim of this article is to review mutations in the non-coding parts of the genome, namely, microRNA, promoter elements, enhancer/silencer elements, 3′/5′UTRs and introns, that are involved in the pathogenesis CMs. Additionally, we will explore the role of some long non-coding RNAs in the pathogenesis of CMs.
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Affiliation(s)
- Oday F Salman
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Hebah M El-Rayess
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Charbel Abi Khalil
- Department of Genetic Medicine, Weill Cornell Medical College, Doha, Qatar
| | - Georges Nemer
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Marwan M Refaat
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.,Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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25
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Wang Q, Guo L, Strawser CJ, Hauser LA, Hwang WT, Snyder NW, Lynch DR, Mesaros C, Blair IA. Low apolipoprotein A-I levels in Friedreich's ataxia and in frataxin-deficient cells: Implications for therapy. PLoS One 2018; 13:e0192779. [PMID: 29447225 PMCID: PMC5813973 DOI: 10.1371/journal.pone.0192779] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 01/30/2018] [Indexed: 12/21/2022] Open
Abstract
Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure. However, the pathophysiology of heart disease in FA is non-vascular and there are conflicting data on HDL-cholesterol in FA. Two studies have shown a decrease in HDL-cholesterol compared with controls and two have shown there was no difference between FA and controls. One also showed that there was no difference in serum Apo-A-I levels in FA when compared with controls. Using a highly specific stable isotope dilution mass spectrometry-based assay, we demonstrated a 21.6% decrease in serum ApoA-I in FA patients (134.8 mg/dL, n = 95) compared with non-affected controls (172.1 mg/dL, n = 95). This is similar to the difference in serum ApoA-I levels between non-smokers and tobacco smokers. Knockdown of frataxin by > 70% in human hepatoma HepG2 cells caused a 20% reduction in secreted ApoA-I. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor caused a 200% increase in HMG-CoA in the control HepG2 cells with a similar increase in the frataxin knockdown HepG2 cells, back to levels found in the control cells. There was a concomitant 20% increase in secreted ApoA-I to levels found in the control cells that were treated with simvastatin. This study provides compelling evidence that ApoA-I levels are reduced in FA patients compared with controls and suggest that statin treatment would normalize the ApoA-I levels.
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Affiliation(s)
- QingQing Wang
- Penn/CHOP Center of Excellence in Friedreich’s Ataxia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Penn SRP Center and Center of Excellence in Environmental Toxicology Center, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Lili Guo
- Penn SRP Center and Center of Excellence in Environmental Toxicology Center, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Cassandra J. Strawser
- Penn/CHOP Center of Excellence in Friedreich’s Ataxia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Lauren A. Hauser
- Penn/CHOP Center of Excellence in Friedreich’s Ataxia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Wei-Ting Hwang
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Nathaniel W. Snyder
- AJ Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania, United States of America
| | - David R. Lynch
- Penn/CHOP Center of Excellence in Friedreich’s Ataxia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Clementina Mesaros
- Penn/CHOP Center of Excellence in Friedreich’s Ataxia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Penn SRP Center and Center of Excellence in Environmental Toxicology Center, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, Pennsylvania, United States of America
| | - Ian A. Blair
- Penn/CHOP Center of Excellence in Friedreich’s Ataxia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
- Penn SRP Center and Center of Excellence in Environmental Toxicology Center, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, Pennsylvania, United States of America
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26
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Plehn JF, Hasbani K, Ernst I, Horton KD, Drinkard BE, Di Prospero NA. The Subclinical Cardiomyopathy of Friedreich's Ataxia in a Pediatric Population. J Card Fail 2017; 24:672-679. [PMID: 28986271 DOI: 10.1016/j.cardfail.2017.09.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Revised: 08/10/2017] [Accepted: 09/25/2017] [Indexed: 10/18/2022]
Abstract
BACKGROUND Identification of a subclinical cardiomyopathy in pediatric patients with Friedreich's ataxia (FA) has not been well-described. METHODS We performed echocardiography (Echo), cardiac magnetic resonance imaging (cMRI), and neurologic assessment in a cross-sectional analysis of 48 genetically confirmed FA subjects aged 9-17 years with moderate neurologic impairment but without a cardiovascular history. Echo- and cMRI-determined left ventricular mass were indexed (LVMI) to height in grams/m2.7. LV remodeling was categorized as concentric remodeling (CR), concentric hypertrophy (CH), or eccentric hypertrophy based upon Echo- determined relative LV wall thickness. RESULTS Echo LVMI exceeded age-based normal values in 85% of subjects, and cMRI-determined LVMI correlated with depression of both diastolic and systolic tissue Doppler velocity (E': r = -0.65, P < .001, S': r = -0.46, P < .001) as well as increased early diastolic Doppler flow velocity/tissue velocity ratio (r= 0.55, P < .001), a marker of elevated LV filling pressure. Similar associations were found with echo-determined LV mass. Evidence of depressed LV relaxation and increased LV stiffness were observed in 88% and 71%, of subjects, respectively, despite a normal LV ejection fraction in almost all cases (mean = 60% + 7%). CR and CH were present in 40% and 44% of the study group, respectively, although significant depressions of E' and S' were observed only in subjects with CH (P < .005). CONCLUSIONS A subclinical hypertrophic cardiomyopathy is common in pediatric FA patients and CH is associated with both diastolic and systolic dysfunction.
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Affiliation(s)
- Jonathan F Plehn
- Translational Medicine Branch, National Heart, Lung and Blood Institute.
| | - Keren Hasbani
- Translational Medicine Branch, National Heart, Lung and Blood Institute
| | - Inez Ernst
- Translational Medicine Branch, National Heart, Lung and Blood Institute
| | | | - Bart E Drinkard
- Physical Rehabilitation Department, Clinical Research Center
| | - Nicholas A Di Prospero
- National Institute of Neurologic Diseases and Stroke, all of the National Institutes of Health, Bethesda, Maryland
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27
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Crombie DE, Curl CL, Raaijmakers AJA, Sivakumaran P, Kulkarni T, Wong RCB, Minami I, Evans-Galea MV, Lim SY, Delbridge L, Corben LA, Dottori M, Nakatsuji N, Trounce IA, Hewitt AW, Delatycki MB, Pera MF, Pébay A. Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency. Aging (Albany NY) 2017; 9:1440-1452. [PMID: 28562313 PMCID: PMC5472743 DOI: 10.18632/aging.101247] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 05/27/2017] [Indexed: 01/12/2023]
Abstract
We sought to identify the impacts of Friedreich's ataxia (FRDA) on cardiomyocytes. FRDA is an autosomal recessive degenerative condition with neuronal and non-neuronal manifestations, the latter including progressive cardiomyopathy of the left ventricle, the leading cause of death in FRDA. Little is known about the cellular pathogenesis of FRDA in cardiomyocytes. Induced pluripotent stem cells (iPSCs) were derived from three FRDA individuals with characterized GAA repeats. The cells were differentiated into cardiomyocytes to assess phenotypes. FRDA iPSC- cardiomyocytes retained low levels of FRATAXIN (FXN) mRNA and protein. Electrophysiology revealed an increased variation of FRDA- cardiomyocyte beating rates which was prevented by addition of nifedipine, suggestive of a calcium handling deficiency. Finally, calcium imaging was performed and we identified small amplitude, diastolic and systolic calcium transients confirming a deficiency in calcium handling. We defined a robust FRDA cardiac-specific electrophysiological profile in patient-derived iPSCs which could be used for high throughput compound screening. This cell-specific signature will contribute to the identification and screening of novel treatments for this life-threatening disease.
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Affiliation(s)
- Duncan E. Crombie
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
| | - Claire L. Curl
- Department of Physiology, the University of Melbourne, Melbourne, Australia
| | | | | | - Tejal Kulkarni
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
- Centre for Neural Engineering & Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia
| | - Raymond CB Wong
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
| | - Itsunari Minami
- Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan
| | - Marguerite V. Evans-Galea
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, and Department of Paediatrics, The University of Melbourne, Melbourne, Australia
| | - Shiang Y. Lim
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
- O'Brien Institute Department, St Vincent Institute of Medical Research, Fitzroy, Australia
| | - Lea Delbridge
- O'Brien Institute Department, St Vincent Institute of Medical Research, Fitzroy, Australia
| | - Louise A. Corben
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, and Department of Paediatrics, The University of Melbourne, Melbourne, Australia
- School of Psychological Sciences, Monash University, Frankston, Australia
| | - Mirella Dottori
- Centre for Neural Engineering & Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia
| | - Norio Nakatsuji
- Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan
| | - Ian A. Trounce
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
| | - Alex W. Hewitt
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
- Menzies Institute for Medical Research, School of Medicine, University of Tasmania, Hobart, Australia
| | - Martin B. Delatycki
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, and Department of Paediatrics, The University of Melbourne, Melbourne, Australia
- School of Psychological Sciences, Monash University, Frankston, Australia
- Victorian Clinical Genetics Services, Parkville, Australia
| | - Martin F. Pera
- Department of Anatomy and Neurosciences, the University of Melbourne, Florey Neuroscience & Mental Health Institute, Walter and Eliza Hall Institute of Medical Research, Australia
| | - Alice Pébay
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
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28
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Bürk K. Friedreich Ataxia: current status and future prospects. CEREBELLUM & ATAXIAS 2017; 4:4. [PMID: 28405347 PMCID: PMC5383992 DOI: 10.1186/s40673-017-0062-x] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 03/24/2017] [Indexed: 01/23/2023]
Abstract
Friedreich ataxia (FA) represents the most frequent type of inherited ataxia. Most patients carry homozygous GAA expansions in the first intron of the frataxin gene on chromosome 9. Due to epigenetic alterations, frataxin expression is significantly reduced. Frataxin is a mitochondrial protein. Its deficiency leads to mitochondrial iron overload, defective energy supply and generation of reactive oxygen species. This review gives an overview over clinical and genetic aspects of FA and discusses current concepts of frataxin biogenesis and function as well as new therapeutic strategies.
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Affiliation(s)
- Katrin Bürk
- University of Marburg, and Paracelsus-Elena Klinik, Klinikstr. 16, 34128 Kassel, Germany
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29
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Crombie DE, Pera MF, Delatycki MB, Pébay A. Using human pluripotent stem cells to study Friedreich ataxia cardiomyopathy. Int J Cardiol 2016; 212:37-43. [PMID: 27019046 DOI: 10.1016/j.ijcard.2016.03.040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Revised: 03/02/2016] [Accepted: 03/13/2016] [Indexed: 12/16/2022]
Abstract
Friedreich ataxia (FRDA) is the most common of the inherited ataxias. It is an autosomal recessive disease characterised by degeneration of peripheral sensory neurons, regions of the central nervous system and cardiomyopathy. FRDA is usually due to homozygosity for trinucleotide GAA repeat expansions found within first intron of the FRATAXIN (FXN) gene, which results in reduced levels of the mitochondrial protein FXN. Reduced FXN protein results in mitochondrial dysfunction and iron accumulation leading to increased oxidative stress and cell death in the nervous system and heart. Yet the precise functions of FXN and the underlying mechanisms leading to disease pathology remain elusive. This is particularly true of the cardiac aspect of FRDA, which remains largely uncharacterized at the cellular level. Here, we summarise current knowledge on experimental models in which to study FRDA cardiomyopathy, with a particular focus on the use of human pluripotent stem cells as a disease model.
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Affiliation(s)
- Duncan E Crombie
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Australia; Ophthalmology, Department of Surgery, The University of Melbourne, Australia
| | - Martin F Pera
- Department of Anatomy and Neurosciences, The University of Melbourne, Florey Neuroscience & Mental Health Institute, Walter and Eliza Hall Institute of Medical Research, Australia
| | - Martin B Delatycki
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Department of Paediatrics, The University of Melbourne, Australia; School of Psychology and Psychiatry, Monash University, Australia; Clinical Genetics, Austin Health, Australia
| | - Alice Pébay
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Australia; Ophthalmology, Department of Surgery, The University of Melbourne, Australia.
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30
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Abstract
Mitochondria of adult cardiomyocytes appear hypo-dynamic, lacking interconnected reticular networks and the continual fission and fusion observed in many other cell types. Nevertheless, proteins essential to mitochondrial network remodeling are abundant in adult hearts. Recent findings from cardiac-specific ablation of mitochondrial fission and fusion protein genes have revealed unexpected roles for mitochondrial dynamics factors in mitophagic mitochondrial quality control. This overview examines the clinical and experimental evidence for and against a meaningful role for the mitochondrial dynamism-quality control interactome in normal and diseased hearts. Newly discovered functions of mitochondrial dynamics factors in maintaining optimal cardiac mitochondrial fitness suggest that deep interrogation of clinical cardiomyopathy is likely to reveal genetic variants that cause or modify cardiac disease through their effects on mitochondrial fission, fusion, and mitophagy.
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Affiliation(s)
- Gerald W Dorn
- Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
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31
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Zipse MM, Aleong RG. Acquired Pulmonary Vein Isolation in a Patient with Friedreich Ataxia. Card Electrophysiol Clin 2016; 8:151-3. [PMID: 26920184 DOI: 10.1016/j.ccep.2015.10.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The electrophysiologic nature of atrial fibrillation (AF) and related atrial arrhythmias in Friedreich ataxia has not previously been characterized. In the presented case, dense atrial scar had progressed to the point of acquired pulmonary vein (PV) isolation before the delivery of a single radiofrequency lesion. AF was induced, and ultimately organized spontaneously into a microreentrant atrial tachycardia. Other atrial tachycardias were also identified near scar border zones; these potentially served as triggers for AF in this patient, independent of the PVs. This case emphasizes the need to address non-PV substrate in some patients undergoing catheter ablation of AF.
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Affiliation(s)
- Matthew M Zipse
- Cardiac Electrophysiology, Cardiology Division, University of Colorado, Denver, Anschutz Medical Campus, 12401 East 17th Avenue, B-132, Aurora, CO 80045, USA.
| | - Ryan G Aleong
- Cardiac Electrophysiology, Cardiology Division, University of Colorado, Denver, Anschutz Medical Campus, 12401 East 17th Avenue, B-132, Aurora, CO 80045, USA.
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32
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Abstract
Hypertrophic cardiomyopathy associated with Friedreich's ataxia is progressive, and there are few, if any, effective treatments available at present. This case report describes a Friedreich's ataxia patient who had a septal myectomy for the management of hypertrophic cardiomyopathy with improved symptoms over a 7-year period. This suggests that septal myectomy may be a viable option to relieve symptoms and interrupt progression of heart disease in appropriately selected Friedreich's ataxia patients.
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33
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Peverill RE. Staging of cardiomyopathy in Friedreich ataxia. Int J Cardiol 2016; 202:574-5. [PMID: 26451786 DOI: 10.1016/j.ijcard.2015.09.047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 09/19/2015] [Indexed: 12/01/2022]
Affiliation(s)
- Roger E Peverill
- Monash Cardiovascular Research Centre, MonashHeart and Department of Medicine (School of Clinical Sciences at Monash Medical Centre), Monash University and Monash Health, Clayton, VIC, Australia.
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34
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Lee YK, Ho PWL, Schick R, Lau YM, Lai WH, Zhou T, Li Y, Ng KM, Ho SL, Esteban MA, Binah O, Tse HF, Siu CW. Modeling of Friedreich ataxia-related iron overloading cardiomyopathy using patient-specific-induced pluripotent stem cells. Pflugers Arch 2014; 466:1831-44. [PMID: 24327207 DOI: 10.1007/s00424-013-1414-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 11/07/2013] [Accepted: 11/28/2013] [Indexed: 11/24/2022]
Abstract
Friedreich ataxia (FRDA), a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy, is due to GAA repeat expansions within the first intron of the frataxin (FXN) gene encoding the mitochondrial protein involved in iron-sulfur cluster biosynthesis. The triplet codon repeats lead to heterochromatin-mediated gene silencing and loss of frataxin. Nevertheless, inadequacy of existing FRDA-cardiac cellular models limited cardiomyopathy studies. We tested the hypothesis that iron homeostasis deregulation accelerates reduction in energy synthesis dynamics which contributes to impaired cardiac calcium homeostasis and contractile force. Silencing of FXN expressions occurred both in somatic FRDA-skin fibroblasts and two of the induced pluripotent stem cells (iPSC) clones; a sign of stress condition was shown in FRDA-iPSC cardiomyocytes with disorganized mitochondrial network and mitochondrial DNA (mtDNA) depletion; hypertrophic cardiac stress responses were observed by an increase in α-actinin-positive cell sizes revealed by FACS analysis as well as elevation in brain natriuretic peptide (BNP) gene expression; the intracellular iron accumulated in FRDA cardiomyocytes might be due to attenuated negative feedback response of transferring receptor (TSFR) expression and positive feedback response of ferritin (FTH1); energy synthesis dynamics, in terms of ATP production rate, was impaired in FRDA-iPSC cardiomyocytes, which were prone to iron overload condition. Energetic insufficiency determined slower Ca(2+) transients by retarding calcium reuptake to sarcoplasmic reticulum (SR) and impaired the positive inotropic and chronotropic responses to adrenergic stimulation. Our data showed for the first time that FRDA-iPSCs cardiac derivatives represent promising models to study cardiac stress response due to impaired iron homeostasis condition and mitochondrial damages. The cardiomyopathy phenotype was accelerated in an iron-overloaded condition early in calcium homeostasis aspect.
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Affiliation(s)
- Yee-Ki Lee
- Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China
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35
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Tricoire H, Palandri A, Bourdais A, Camadro JM, Monnier V. Methylene blue rescues heart defects in a Drosophila model of Friedreich's ataxia. Hum Mol Genet 2014; 23:968-79. [PMID: 24105471 DOI: 10.1093/hmg/ddt493] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Friedreich's ataxia (FRDA), the most common hereditary ataxia, is characterized by progressive degeneration of the central and peripheral nervous system, hypertrophic cardiomyopathy and a high risk of diabetes. FRDA is caused by abnormally low levels of frataxin, a highly conserved mitochondrial protein. Drosophila has been previously successfully used to model FRDA in various cell types, including neurons and glial cells. Here, we report the development of a Drosophila cardiac model of FRDA. In vivo heart imaging revealed profound impairments in heart function in frataxin-depleted Drosophila, including a strong increase in end-systolic and end-diastolic diameters and a decrease in fractional shortening (FS). These features, reminiscent of pathological phenotypes in humans, are fully rescued by complementation with human frataxin, suggesting conserved cardiac functions of frataxin between the two organisms. Oxidative stress is not a major factor of heart impairment in frataxin-depleted flies, suggesting the involvement of other pathological mechanisms notably mitochondrial respiratory chain (MRC) dysfunction. Accordingly, we report that methylene blue (MB), a compound known to act as an alternative electron carrier that bypasses mitochondrial complexes I-III, was able to prevent heart dysfunction. MB also partially rescued the phenotype when administered post-symptomatically. Analysis of MB derivatives demonstrates that only compounds with electron carrier properties are able to prevent the heart phenotype. Thus MB, a compound already used for several clinical applications, appears promising for the treatment of the heart dysfunctions that are a major cause of death of FRDA patients. This work provides the grounds for further evaluation of MB action in mammals.
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Affiliation(s)
- Hervé Tricoire
- Unité de Biologie Fonctionnelle et Adaptative (BFA) EAC4413 CNRS, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
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36
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Lynch DR, Regner SR, Schadt KA, Friedman LS, Lin KY, Sutton MGSJ. Management and therapy for cardiomyopathy in Friedreich’s ataxia. Expert Rev Cardiovasc Ther 2014; 10:767-77. [DOI: 10.1586/erc.12.57] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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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 1:103-17. [PMID: 23859346 DOI: 10.1111/jnc.12317] [Citation(s) in RCA: 168] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Revised: 05/15/2013] [Accepted: 05/15/2013] [Indexed: 11/27/2022]
Abstract
One hundred and fifty years since Nikolaus Friedreich's first description of the degenerative ataxic syndrome which bears his name, his description remains at the core of the classical clinical phenotype of gait and limb ataxia, poor balance and coordination, leg weakness, sensory loss, areflexia, impaired walking, dysarthria, dysphagia, eye movement abnormalities, scoliosis, foot deformities, cardiomyopathy and diabetes. Onset is typically around puberty with slow progression and shortened life-span often related to cardiac complications. Inheritance is autosomal recessive with the vast majority of cases showing an unstable intronic GAA expansion in both alleles of the frataxin gene on chromosome 9q13. A small number of cases are caused by a compound heterozygous expansion with a point mutation or deletion. Understanding of the underlying molecular biology has enabled identification of atypical phenotypes with late onset, or atypical features such as retained reflexes. Late-onset cases tend to have slower progression and are associated with smaller GAA expansions. Early-onset cases tend to have more rapid progression and a higher frequency of non-neurological features such as diabetes, cardiomyopathy, scoliosis and pes cavus. Compound heterozygotes, including those with large deletions, often have atypical features. In this paper, we review the classical and atypical clinical phenotypes of Friedreich's ataxia.
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Affiliation(s)
- Michael H Parkinson
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
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38
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Lane DJR, Huang MLH, Ting S, Sivagurunathan S, Richardson DR. Biochemistry of cardiomyopathy in the mitochondrial disease Friedreich's ataxia. Biochem J 2013; 453:321-36. [PMID: 23849057 DOI: 10.1042/bj20130079] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
FRDA (Friedreich's ataxia) is a debilitating mitochondrial disorder leading to neural and cardiac degeneration, which is caused by a mutation in the frataxin gene that leads to decreased frataxin expression. The most common cause of death in FRDA patients is heart failure, although it is not known how the deficiency in frataxin potentiates the observed cardiomyopathy. The major proposed biochemical mechanisms for disease pathogenesis and the origins of heart failure in FRDA involve metabolic perturbations caused by decreased frataxin expression. Additionally, recent data suggest that low frataxin expression in heart muscle of conditional frataxin knockout mice activates an integrated stress response that contributes to and/or exacerbates cardiac hypertrophy and the loss of cardiomyocytes. The elucidation of these potential mechanisms will lead to a more comprehensive understanding of the pathogenesis of FRDA, and will contribute to the development of better treatments and therapeutics.
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Affiliation(s)
- Darius J R Lane
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building, D06, University of Sydney, Sydney, NSW 2006, Australia
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39
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Yoon G, Soman T, Wilson J, George K, Mital S, Dipchand AI, McCabe J, Logan W, Kantor P. Cardiac transplantation in Friedreich ataxia. J Child Neurol 2012; 27:1193-6. [PMID: 22752490 PMCID: PMC3671892 DOI: 10.1177/0883073812448229] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
In this article, we describe a 14-year-old boy with a confirmed diagnosis of Friedreich ataxia who underwent cardiac transplantation for left ventricular failure secondary to dilated cardiomyopathy with restrictive physiology. His neurological status prior to transplantation reflected early signs of neurological disease, with evidence of dysarthria, weakness, mild gait impairment, and limb ataxia. We review the ethical issues considered during the process leading to the decision to offer cardiac transplantation.
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Affiliation(s)
- Grace Yoon
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
| | - Teesta Soman
- Department of Pediatrics, Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Judith Wilson
- Department of Pediatrics, Division of Cardiology, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Kristen George
- Department of Pediatrics, Division of Cardiology, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Seema Mital
- Department of Pediatrics, Division of Cardiology, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Anne I. Dipchand
- Department of Pediatrics, Division of Cardiology, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Jane McCabe
- Department of Pediatrics, Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - William Logan
- Department of Pediatrics, Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Paul Kantor
- Department of Pediatrics, Division of Cardiology, The Hospital for Sick Children, University of Toronto, Toronto, Canada
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40
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Schadt KA, Friedman LS, Regner SR, Mark GE, Lynch DR, Lin KY. Cross-sectional analysis of electrocardiograms in a large heterogeneous cohort of Friedreich ataxia subjects. J Child Neurol 2012; 27:1187-92. [PMID: 22752487 PMCID: PMC3674639 DOI: 10.1177/0883073812448461] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Electrocardiographic (ECG) findings in Friedreich ataxia and their relation to disease characteristics have not been well described. In this retrospective cross-sectional study, the authors reviewed baseline ECGs from 239 children and adults with Friedreich ataxia. ECG abnormalities--assessed in relation to participant age, sex, shorter guanine-adenine-adenine triplet repeat length, age of disease onset, and functional disability score--were found in 90% of subjects, including nonspecific ST-T wave changes (53%), right axis deviation (32%), left ventricular hypertrophy (19%), and right ventricular hypertrophy (13%). Female sex and shorter guanine-adenine-adenine repeat lengths were associated with a normal ECG (P = .004 and P = .003). Males and those of younger age were more likely to show ventricular hypertrophy (P = .006 and P = .026 for left ventricular hypertrophy and P < .001 and P = .001 for right). Neurologic status as measured by the functional disability score did not predict ECG abnormalities.
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Affiliation(s)
- Kimberly A. Schadt
- Department of Pediatrics, Division of Neurology, Children’s Hospital of Philadelphia, Pennsylvania,Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lisa S. Friedman
- Department of Pediatrics, Division of Neurology, Children’s Hospital of Philadelphia, Pennsylvania,Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sean R. Regner
- Department of Pediatrics, Division of Neurology, Children’s Hospital of Philadelphia, Pennsylvania,Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - George E. Mark
- Department of Cardiology, Cooper University Hospital, Camden, New Jersey
| | - David R. Lynch
- Department of Pediatrics, Division of Neurology, Children’s Hospital of Philadelphia, Pennsylvania,Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kimberly Y. Lin
- Department of Pediatrics, Division of Cardiology, Children’s Hospital of Philadelphia, Pennsylvania
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41
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Abstract
Friedreich ataxia is the most common human ataxia and results from inadequate production of the frataxin protein, most often the result of a triplet expansion in the nuclear FXN gene. The gene cannot be transcribed to generate the messenger ribonucleic acid for frataxin. Frataxin is an iron-binding protein targeted to the mitochondrial matrix. In its absence, multiple iron-sulfur-dependent proteins in mitochondria and the cytosol lack proper assembly, destroying mitochondrial and nuclear function. Mitochondrial oxidant stress may also participate in ongoing cellular injury. Although progressive and debilitative ataxia is the most prominent clinical finding, hypertrophic cardiomyopathy with heart failure is the most common cause of early death in this disease. There is no cure. In this review the authors cover recent basic and clinical findings regarding the heart in Friedreich ataxia, offer recommendations for clinical management of the cardiomyopathy in this disease, and point out new research directions to advance the field.
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Affiliation(s)
- R Mark Payne
- Department of Medical & Molecular Genetics, Riley Heart Research Center, Wells Center for Pediatric Research, Indianapolis, IN 46202, USA.
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42
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Weidemann F, Rummey C, Bijnens B, Störk S, Jasaityte R, Dhooge J, Baltabaeva A, Sutherland G, Schulz JB, Meier T. The heart in Friedreich ataxia: definition of cardiomyopathy, disease severity, and correlation with neurological symptoms. Circulation 2012; 125:1626-34. [PMID: 22379112 DOI: 10.1161/circulationaha.111.059477] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND This cross-sectional study provides a practical approach for the clinical assessment of Friedreich ataxia (FA) cardiomyopathy (FA-CM). METHODS AND RESULTS A comprehensive cardiac assessment, including standard echocardiography, color Doppler myocardial imaging, cardiac magnetic resonance imaging, ECG, and exercise stress testing, was performed in 205 FA patients. To assess myocardial hypertrophy in FA-CM, the end-diastolic interventricular septal wall thickness (IVSTd) was found to be the best echocardiographic parameter compared with cardiac magnetic resonance imaging-determined left ventricular mass. With the use of this parameter, 4 groups of patients with FA-CM could be defined. Patients with normal values for IVSTd (31.7%) were classified as having no FA-CM. Patients with an IVSTd exceeding the predicted normal IVSTd were classified as having mild FA-CM (40%) if IVSTd exceeded the normal value by <18% or as having intermediate FA-CM (16.1%) if IVSTd exceeded the normal value by ≥18%. Patients with ejection fraction <50% were classified as having severe FA-CM (12.2%). In addition to increased myocardial mass, severe FA-CM was further characterized by dilatation of the left ventricle, reduced systolic strain rate of the posterior wall, and ECG abnormalities. Regional myocardial function correlated negatively with FA-CM groups. Younger patients had a tendency for more advanced FA-CM. Importantly, no clear correlation was found between FA-CM groups and neurological function. CONCLUSIONS We provide and describe a readily applicable clinical grouping of the cardiomyopathy associated with FA based on echocardiographic IVSTd and ejection fraction data. Because no distinct interrelations between FA-CM and neurological status could be determined, regular follow-up of potential cardiac involvement in FA patients is essential in clinical practice.
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Affiliation(s)
- Frank Weidemann
- Medizinische Klinik und Poliklinik I, Universitätsklinik Würzburg, Oberdürrbacherstrasse 6, Würzburg, Germany.
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43
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Silva LE, Prada LP, Páez H, Buitrago AF, Franco C, Sánchez R, Rendón I. Cardiopatía dilatada en ataxia de Friedreich: El punto sin retorno. REVISTA COLOMBIANA DE CARDIOLOGÍA 2012. [DOI: 10.1016/s0120-5633(12)70114-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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Regner SR, Lagedrost SJ, Plappert T, Paulsen EK, Friedman LS, Snyder ML, Perlman SL, Mathews KD, Wilmot GR, Schadt KA, Sutton MSJ, Lynch DR. Analysis of echocardiograms in a large heterogeneous cohort of patients with friedreich ataxia. Am J Cardiol 2012; 109:401-5. [PMID: 22078220 DOI: 10.1016/j.amjcard.2011.09.025] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Revised: 09/29/2011] [Accepted: 09/29/2011] [Indexed: 12/29/2022]
Abstract
Although Friedreich ataxia (FA) is associated with cardiomyopathy, the severity and evolution of cardiac disease is poorly understood. To identify factors predicting cardiomyopathy in FA, we assessed echocardiograms from a large heterogenous cohort and their relation to disease traits. The most recent echocardiograms from 173 subjects with FA were analyzed in a core laboratory to determine their relation to disease duration, subject age, age of onset, functional disability score, and GAA repeat length. Mean age of the cohort was 19.7 years, mean age of disease onset was 10.6 years, and mean shorter GAA length was 681 repeats. Echocardiograms collectively illustrated systolic dysfunction, diastolic dysfunction, and hypertrophy. Measurements of hypertrophy correlated moderately with each other (r = 0.39 to 0.79) but not with measurements of diastolic dysfunction (r <0.35). Diastolic measurements correlated poorly with each other, although 26% of the cohort had multiple diastolic abnormalities. The most common diastolic dysfunction classification was pseudonormalization. Classification of diastolic dysfunction was predicted by GAA repeat length but not by age or gender. Ejection fraction was below normal in 20% of the cohort. In linear regression analysis, increasing age predicted decreasing ejection fraction. Functional disability score, a measurement of neurologic ability, did not predict any echocardiographic measurements. In conclusion, hypertrophy and diastolic and systolic dysfunctions occur in FA and are substantially independent; diastolic dysfunction is the most common abnormality with most patients having an assigned diastolic dysfunction class of pseudonormalization.
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Affiliation(s)
- Sean R Regner
- Department of Neurology, University of Pennsylvania, Medical School, Philadelphia, Pennsylvania, USA
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45
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Abstract
Friedreich's Ataxia is the most common inherited ataxia in man. It is a mitochondrial disease caused by severely reduced expression of the iron binding protein, frataxin. A large GAA triplet expansion in the human FRDA gene encoding this protein inhibits expression of this gene. It is inherited in an autosomal recessive pattern and typically diagnosed in childhood. The primary symptoms include severe and progressive neuropathy, and a hypertrophic cardiomyopathy that may cause death. The cardiomyopathy is difficult to treat and is frequently associated with arrhythmias, heart failure, and intolerance of cardiovascular stress, such as surgeries. Innovative approaches to therapy, such as histone deacetylase inhibitors, and enzyme replacement with cell penetrant peptide fusion proteins, hold promise for this and other similar mitochondrial disorders. This review will focus on the basic findings of this disease, and the cardiomyopathy associated with its diagnosis.
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Affiliation(s)
- R Mark Payne
- Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202
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46
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Payne RM, Pride PM, Babbey CM. Cardiomyopathy of Friedreich's ataxia: use of mouse models to understand human disease and guide therapeutic development. Pediatr Cardiol 2011; 32:366-78. [PMID: 21360265 PMCID: PMC3097037 DOI: 10.1007/s00246-011-9943-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2011] [Accepted: 02/11/2011] [Indexed: 01/02/2023]
Abstract
Friedreich's ataxia is a multisystem disorder of mitochondrial function affecting primarily the heart and brain. Patients experience a severe cardiomyopathy that can progress to heart failure and death. Although the gene defect is known, the precise function of the deficient mitochondrial protein, frataxin, is not known and limits therapeutic development. Animal models have been valuable for understanding the basic events of this disease. A significant need exists to focus greater attention on the heart disease in Friedreich's ataxia, to understand its long-term outcome, and to develop new therapeutic strategies using existing medications and approaches. This review discusses some key features of the cardiomyopathy in Friedreich's ataxia and potential therapeutic developments.
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Affiliation(s)
- R Mark Payne
- Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 West Walnut, R4302, Indianapolis, IN 46202, USA.
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47
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Lagedrost SJ, Sutton MSJ, Cohen MS, Satou GM, Kaufman BD, Perlman SL, Rummey C, Meier T, Lynch DR. Idebenone in Friedreich ataxia cardiomyopathy-results from a 6-month phase III study (IONIA). Am Heart J 2011; 161:639-645.e1. [PMID: 21392622 DOI: 10.1016/j.ahj.2010.10.038] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2010] [Accepted: 10/29/2010] [Indexed: 11/30/2022]
Abstract
BACKGROUND Friedreich ataxia (FRDA) is commonly associated with hypertrophic cardiomyopathy, but little is known about its frequency, severity, or treatment. In this 6-month randomized, double-blind, controlled study, we sought to determine whether idebenone improves cardiac measures in FRDA. METHODS Seventy pediatric subjects were treated either with idebenone (450/900 mg/d or 1,350/2,250 mg/d) or with placebo. Electrocardiograms (ECGs) were assessed at each visit, and echocardiograms, at baseline and week 24. RESULTS We found ECG abnormalities in 90% of the subjects. On echocardiogram, 81.4% of the total cohort had left ventricular (LV) hypertrophy, as measured by increased LV mass index-Dubois, and the mean ejection fraction (EF) was 56.9%. In linear regression models, longer PR intervals at baseline were marginally associated with longer GAA repeat length (P = .011). Similarly, GAA repeat length did not clearly predict baseline EF (P = .086) and LV mass by M-mode (P = .045). Left ventricular mass index, posterior wall thickness, EF, and ECG parameters were not significantly improved by treatment with idebenone. Some changes in echocardiographic parameters during the treatment phase correlated with baseline status but not with treatment group. CONCLUSIONS Idebenone did not decrease LV hypertrophy or improve cardiac function in subjects with FRDA. The present study does not provide evidence of benefit in this cohort over a 6-month treatment period.
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Affiliation(s)
- Sarah J Lagedrost
- Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, USA
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48
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Mancuso M, Orsucci D, Choub A, Siciliano G. Current and emerging treatment options in the management of Friedreich ataxia. Neuropsychiatr Dis Treat 2010; 6:491-9. [PMID: 20856912 PMCID: PMC2938298 DOI: 10.2147/ndt.s6916] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia. Oxidative damage within the mitochondria seems to have a key role in the disease phenotype. Therefore, FRDA treatment options have been mostly directed at antioxidant protection against mitochondrial damage. Available evidence seems to suggest that patients with FRDA should be treated with idebenone, because it is well tolerated and may reduce cardiac hypertrophy and, at higher doses, also improve neurological function, but large controlled clinical trials are still needed. Alternatively, gene-based strategies for the treatment of FRDA may involve the development of small-molecules increasing frataxin gene transcription. Animal and human studies are strongly needed to assess whether any of the potential new treatment strategies, such as iron-chelating therapies or treatment with erythropoietin or histone deacetylase inhibitors and other gene-based strategies, may translate into an effective therapy for this devastating disorder. In this review, we try to provide an answer to some questions related to current and emerging treatment options in the management of FRDA.
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Affiliation(s)
- Michelangelo Mancuso
- Department of Neuroscience, Neurological Clinic, University of Pisa, Pisa, Italy
| | - Daniele Orsucci
- Department of Neuroscience, Neurological Clinic, University of Pisa, Pisa, Italy
| | - Anna Choub
- Department of Neuroscience, Neurological Clinic, University of Pisa, Pisa, Italy
| | - Gabriele Siciliano
- Department of Neuroscience, Neurological Clinic, University of Pisa, Pisa, Italy
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49
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Abstract
Cardiac abnormalities occur in association with many of the neuromuscular disorders that present in childhood. Genetic defects involving the cytoskeleton, nuclear membrane, and mitochondrial function have all been described in patients with skeletal myopathy and cardiac involvement. The most common classes of neuromuscular disorders with cardiac manifestations are the muscular dystrophies- Duchenne, Becker, limb-girdle and Emery Dreifuss. Friedreich Ataxia and myotonic dystrophy also have important cardiac involvement. The type and extent of cardiac manifestations are specific to the type of neuromuscular disorder. The most common cardiac findings include dilated or hypertrophic cardiomyopathy, atrioventricular conduction defects, atrial fibrillation and ventricular arrhythmias. Screening for cardiac involvement should be performed in all children with neuromuscular disorders that have the potential for cardiac involvement. This review discusses the cardiac findings associated with specific neuromuscular disorders and outlines the indications for evaluation and treatment.
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Affiliation(s)
- Daphne T Hsu
- Children's Hospital at Montefiore and the Albert Einstein College of Medicine, Bronx, New York 10467, USA.
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