Ir J Med Sci (2011) 180:799–805 DOI 10.1007/s11845-011-0744-y
REVIEW ARTICLE
Friedreich’s Ataxia: a review from a cardiology perspective T. Bourke • D. Keane
Received: 10 May 2010 / Accepted: 16 July 2011 / Published online: 7 August 2011 Ó Royal Academy of Medicine in Ireland 2011
Abstract Background Neuromuscular disorders are not among the common causes of cardiomyopathy in the general population; however, cardiomyopathy is known to occur in several neuromuscular disorders including Friedreich’s Ataxia (FA). In patients with neuromuscular disorders, concomitant cardiac involvement contributes significantly to morbidity and mortality and often leads to premature death. Methods An extensive literature search of Medline and Pubmed was conducted to include all published reports on cardiac involvement in FA. Secondary articles were identified from key paper reference listings. Conclusion Hypertrophic cardiomyopathy is a cardinal feature of FA; therefore all FA patients should be screened for cardiomyopathy. A cardiac examination, ECG and ECHO are advised at diagnosis, and also on the development of any cardiac symptoms. Treatment is determined by the presence of symptoms, the presence of left ventricular outflow gradient and the sudden death risk. Institution of aggressive medical therapy early in the course of the disease may help improve quality of life and provide survival benefit. Keywords Friedreich’s Ataxia Cardiomyopathy Congestive cardiac failure Sudden cardiac death Arrhythmias T. Bourke D. Keane Cardiac Arrhythmia Service, St Vincent’s University Hospital, Elm Park, Dublin, Ireland T. Bourke (&) UCLA Cardiac Arrhythmia Center, David Geffen School of Medicine at UCLA, A2-237 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA e-mail:
[email protected]
Introduction Friedreich’s Ataxia (FA) is a rare neuromuscular disorder. A referral to our service prompted a review of available data on cardiac involvement in this condition. The following is a brief summary of our findings.
Background FA is a progressive neurodegenerative disease and is the most common form of inherited ataxia; it accounts for at least 50% of cases of hereditary ataxias in most large series. The incidence of FA in Europe is 1:50,000 per year, with a carrier frequency of 1:70–100. Males and females are affected equally. FA is a recessively inherited trinucleotide repeat disorder and is most prevalent in Caucasians, with a prevalence of 1:29,000 in Europe. The locus of the genetic defect has been mapped to chromosome 9 [1]. The most common mutation, seen in more than 96% of the individuals, is a GAA triplet repeat expansion in intron 1 of the frataxin gene. Frataxin is a mitochondrial protein found in large amounts in the brain, heart, and pancreas. At increased repeat expansions, there is depressed transcription and expression of the frataxin protein. Its deficiency results in mitochondrial iron accumulation leading to cellular damage and death by production of toxic free radicals [2]. FA is most prevalent in white populations, most FA carriers and affected FA patients are believed to originate from a common European ancestor. Frataxin gene expansions are therefore almost nonexistent among black African and Asian populations. Cardiac involvement has been found in more than 90% of the subjects from a homogenous group of patients with FA who met strict neurologic and genetic criteria for the
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disease [3]. With longitudinal follow-up the incidence may be as high as 100% [4]. As cardiac involvement can be measured, it can be used to evaluate treatment efficacy. Currently no treatment can delay disease progression and in general survival is approximately 15–20 years after disease onset [5]. The clinical progression of FA is slow with an average time from onset to death of 36 years [6]. Initial therapies are likely to slow rather than reverse disease progression.
Clinical presentation Neurologic symptoms precede cardiac symptoms in most but not all patients. Initial presentation is with progressive ataxia, sensory loss and muscle weakness. The presence of hypertrophic cardiomyopathy, scoliosis and pes cavus is characteristic. Progressive ataxia of gait and limbs, dysarthria and decreased proprioception are results of increasing spinocerebellar degeneration secondary to their genetic defect. Generally FA begins between the 8th and 13th year of life [5, 7] and most patients become wheelchair bound before they are 20 years old. Heart disease is often clinically silent, as the neuromuscular disorder curtails physical activity. A search for cardiomyopathy at initial diagnosis is essential as cardiac symptoms often only manifest themselves in advanced disease and early identification of cardiac involvement allows institution of measures to alleviate heart failure symptoms and to decrease or prevent sudden death.
Cardiac involvement Cardiomyopathy Cardiomyopathy occurs in two-thirds of patients with FA and is a frequent cause of death. Cardiomyopathy, usually in its hypertrophic form, is a cardinal feature of FA. Its presence decreases life expectancy explicitly despite moderate clinical symptoms. The pathogenesis of myocardial involvement is unclear. There appears to be no relationship between the degree of neurological deficit (such as ataxia or muscle weakness) and the degree of cardiac involvement [3]. An asymmetric septal hypertrophy or a dilated cardiomyopathy may also occur but these are less common. It is thought that dilated cardiomyopathy in FA represents disease progression from the hypertrophic form [8, 9]. The extent of left ventricular hypertrophy increases in proportion to the size of the GAA expansion [10, 11]. In a series by Hewer et al. all hearts of FA patients were abnormal, most frequent histological findings being muscle fibre hypertrophy and interstitial fibrosis [12].
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Arrhythmias Arrhythmias may occur but are rarer than expected on the basis of the high prevalence of cardiac involvement. Atrial and ventricular arrhythmias are common features of the dilated form of cardiomyopathy. The presence of atrial dysrythmias in FA is a marker of left ventricular dysfunction and has negative prognostic implications. Despite being common in most forms of hypertrophic cardiomyopathy, ventricular arrhythmias in FA patients with left ventricular hypertrophy have not been reported. A case report published recently described recurrent ventricular tachycardia (VT) and also atrial fibrillation in a patient with FA in the absence of myocardial disease. The patient underwent ICD insertion and subsequently received three appropriate therapies for VT [13]. Sudden death may occur in FA patients, the mechanism of which is not well characterised. Clinically relevant disorders of impulse formation or conduction have not been reported in FA despite histological evidence of conduction system fibrosis. Mitral valve prolapse has been reported in up to 15% of the patients. The occurrence of cardiomyopathies, bradyarrhythmias, tachyarrhythmias and sudden death varies greatly between different forms of neuromuscular disorders [14]. Table 1 provides a summary of cardiac involvement in several neuromuscular disorders. Chest pain Although angina has been reported, the role of coronary artery disease is often underestimated and dismissed in this young patient population. Chest pains may occur often without correlation to coronary disease. Myocardial ischemia may occur due to abnormal coronary vasculature and/or a mismatch between the thickened LV wall and coronary blood flow; however, premature occlusive coronary artery disease has been reported [15]. Chest pain should therefore be fully investigated especially in patients with co-existing cardiovascular risk factors. Ten percent of patients are known to develop diabetes. Early diagnosis of coronary lesions may permit aggressive management and prevent development of an ischaemic cardiomyopathy.
Identifying cardiac involvement Clinically, an ejection systolic murmur at the left sternal margin (consistent with dynamic left ventricular outflow tract obstruction), third or fourth heart sound or an ECG suggesting LVH may give clues to the presence of cardiac involvement. There may be an associated mitral
801 Table 1 Cardiac involvement in neuromuscular disorders Neuromuscular disorder
Cardiac involvement
Bradyarrhythmias
Ventricular arrhythmias
Sudden cardiac death
SCD prevention
Friedreich’s Ataxia
Often associated with concentric HCM, DCM may occur
No clinically relevant disorders of impulse formation or conduction reported
VT reported in DCM patients
SCD may occur, mechanism not well characterized
No specific antiarrhythmic therapy indicated, interventions needed to decrease SCD are unclear
Duchenne Muscular Dystrophy
Virtually all develop CM, clinically apparent by age 10
Conduction abnormalities occur, complete heart block not reported
Substrate for ventricular arrhythmias present, occur in 30% of those with severe muscle disease
SCD reported especially in severe disease, 1 in 4 die of a cardiac cause, divided equally between HF and SCD
Treatment of arrhythmia does not improve survival
Becker Muscular Dystrophy
CM may develop, does not correlate with degree of skeletal muscle involvement
Poorly characterized, complete heart block reported
Prevalence not well documented, bundle branch reentry VT recognised
Not reported
Not reported
Myotonic Dystrophy
CM is rare, cardiac involvement is primarily arrhythmic
Conduction system disease is common, may progress to complete heart block requiring pacing
VT reported, prone to bundle branch reentry VT, successful radiofrequency ablation reported
Up to 1 in 3 die suddenly, Ventricular arrhythmias thought to be responsible for a portion of sudden deaths
Arrhythmia management not well established, trials to evaluate same are recommended
Emery Dreifuss Muscular Dystrophy
Cardiac involvement is primarily arrhythmic DCM is recognised
Impulse generation and conduction abnormalities are common, ventricular pacing by 30 years of age is typical
VT and VF reported
SCD is common even among pacemaker recipients
Benefits of ICD over pacemaker therapy has not been established
Limbgirdle Muscular Dystrophy
Cardiac involvement in specific genetic subtypes only, usually arrhythmic CM may occur
Progressive AV block commonly requires pacing
Specific arrhythmias not reported
SCD occurs even in paced patients
Interventions needed to decrease SCD are unclear
HCM hypertrophic cardiomyopathy, DCM dilated cardiomyopathy, CM cardiomyopathy, VT ventricular tachycardia, VF ventricular fibrillation, SCD sudden cardiac death
regurgitation murmur due to systolic anterior motion of the anterior mitral valve leaflet. The soft pan-systolic murmur of mitral regurgitation may also be found in the presence of left ventricular dilatation due to a dilated cardiomyopathy. Wide spectrums of electrographic and echocardiographic findings have been reported [16, 17]. Electrocardiography is abnormal in the vast majority of patients with T wave inversion, left axis deviation and repolarisation abnormalities being most frequently seen (Fig. 1). The most common echocardiography finding is concentric thickening of the left ventricle with preserved left ventricular systolic function (Fig. 2). Asymmetrical hypertrophy may also be seen, and left ventricular dilatation in association with left ventricular dysfunction is seen in the setting of dilated cardiomyopathy.
Prognosis Cardiac involvement is the most frequent cause of death [18]. Left ventricular hypertrophy is the principal determinant of survival, mean life expectancy between 27 and 38 years is determined not by central nervous degeneration but by concomitant cardiac disease [1, 10]. Individuals who develop a dilated cardiomyopathy have a poor prognosis with progressive cardiac deterioration leading to refractory cardiac decompensation and death.
Cardiac treatment While the approach to the treatment of any cardiac condition is an individualised one, current guidelines on the
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802 Fig. 1 Electrocardiogram from a patient with Friedreich’s Ataxia shows marked bradycardia (secondary to beta blockade), widespread T wave changes and small QRS voltages in leads V4 to V6
Fig. 2 Two-dimensional echocardiographic still frames from a patient with Friedreich’s Ataxia. a Parasternal long axis view showing thickening of the interventricular septum and posterior wall. b Apical four-chamber view showing dilatation of left ventricular
cavity. IVS interventricular septum, PW posterior wall, LV left ventricle, LA left atrium, MV mitral valve, AV aortic valve, LVOT left ventricular outflow tract
treatment of hypertrophic cardiomyopathy [19] and heart failure [20] should be followed. A fundamental goal in the treatment of HCM is the alleviation of symptoms related to heart failure. The main therapeutic approach has been pharmacological. Treatment options in HCM depend on the presence or absence of a left ventricular outflow tract (LVOT) gradient and the presence or absence of symptoms. Symptoms in patients with hypertrophic cardiomyopathy and obstruction are primarily related to exertion. While many FA patients are physically restricted, exertional symptoms warranting treatment frequently occur. Drugs, which suppress contractility (negative inotropics) and suppress heart rate (negative chronotropics), have been
the mainstays of therapy. Beta-adrenergic receptor blockers (BB), calcium entry blockers, and Disopyramide have been the drugs of choice although there have been few randomised controlled trials to compare the effects of drugs in HCM. For the treatment of symptomatic patients in the presence of obstruction, BB are negatively inotropic drugs that have been traditionally administered to HCM patients with or without obstruction usually relying on patients’ subjective and historical perception of benefit. If symptoms progress dose may be increased within accepted therapeutic ranges. As these drugs are known to have an effect during high sympathetic tone they are the preferred
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treatment for symptomatic patients with an LVOT gradient present only with exertion. Most clinicians favour the use of beta blockers (BBs) over Verapamil for initial medical treatment of exertional dyspnoea, while Verapamil has been used in patients intolerant to BBs or those with a history of asthma. Verapamil is a negative inotropic agent that has been widely used in both obstructive and non-obstructive forms of HCM reported benefits from many patients including improvement in chest pains. Effects include improving ventricular relaxation and filling, relieving myocardial ischemia and decreasing LV contractility. Verapamil should be used with caution in patients with resting obstruction in the presence of severe symptoms as hemodynamic compromise may occur. Disopyramide is a negative inotrope and class 1A antiarrhythmic agent which has been reported to provide symptomatic benefit in those severely limited because of resting obstruction due to a decrease in the systolic anterior motion of mitral valve, outflow obstruction and mitral regurgitant volume. Disopyramide may be deleterious in non-obstructive HCM by decreasing cardiac output causing its use to be limited to those with outflow obstruction not responding to BB or Ca blockers. Treatment of symptomatic patients without obstruction In the absence of obstruction, symptoms may be related to diastolic dysfunction, which can be relieved by the use of angiotensin converting enzyme inhibitors (ACEI). Drugs, which slow or blunt the heart rate, e.g. BBs, can facilitate left ventricular filling by maintaining an adequate diastolic filling period. Additionally, low-dose diuretics can be useful adjuncts in non-obstructive HCM. Treatment of dilated phase of cardiomopathy Drug treatment strategies in patients with systolic dysfunction differ greatly from the strategy in hypertrophic, non-dilated chambers with preserved systolic function. Treatment of patients with dilated cardiomyopathy should include beta blockade, when stabilised, for survival benefit, ACE inhibitors to reduced afterload, minimum dose loop diuretics to restore and maintain euvolaemia, Digitalis for ionotropic support, if needed, and Aldactone for survival benefit. In all patients with or without obstruction, treatment of atrial fibrillation involves controlling the ventricular rate or cardioverting the rhythm along with prevention of embolic phenomena. Asymptomatic patients The benefit of prophylactic drug therapy to prevent or delay the development of symptoms and improve prognosis has been
debated for years; data to support or refute this do not exist. The efficacy of empiric drug treatment with BB/Ca blockers/ Disopyramide in asymptomatic patients is unresolved. Treatment of drug refractory patients For patients with drug refractory symptoms subsequent therapies depend on the presence or absence of outflow obstruction. Invasive treatment options may be suitable for some patients with FA who have milder forms of disease, a good quality of life and a good prognosis. In the absence of obstruction, treatment is pharmacological as outlined in the dilated phase of the cardiomyopathy. In patients with outflow obstruction surgery in the form of septal myectomy and also less invasive options including dual chamber pacemaker placement and alcohol septal ablation can be considered to reduce the outflow gradient. Although neurodegenerative disease is regarded by some as a contra-indication to transplantation, cardiac transplantation has been successfully carried out on patients with FA who although neurologically impaired had no other contra-indications to transplantation [21, 22]. It has been suggested that heart transplantation should not be contraindicated in neuromuscular diseases provided the estimated survival in that particular patient exceeds average graft life [22]. Use of left ventricular assist device as destination therapy has also been reported [23]. In patients with severe FA with severe neurological impairment, however, invasive treatments require individual justification both clinically and ethically.
Cardioverter defibrillator implantation The mechanism of sudden death in FA patients is not understood; therefore specific methods of preventing sudden deaths in this group have not been determined. For all patients, including those with neuromuscular disorders, guidelines on device implantation [24] and sudden death prevention [25] should be followed. According to these guidelines, patients with neuromuscular disorders should be treated in the same manner as patients without neuromuscular disorders. Patients should be risk stratified for sudden death and medical therapy should be optimised prior to device insertion. The implantation of an ICD for recurrent syncope due to ventricular tachycardia in a patient with FA has been described [13]. Two other case reports regarding ICD placement in neuromuscular disorders have been published, one on a patient with Emery Dreifuss Syndrome, in whom a biventricular ICD was implanted [26], and one on a patient with a Desmin related cardiomyopathy in whom a prophylactic ICD was implanted [27].
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Conclusion Cardiac involvement is common in FA. A cardiac workup, including cardiovascular exam, ECG and ECHO, is essential to determine the presence and extent of cardiac disease at diagnosis and on symptom development. Holter monitoring is indicated in the presence of symptoms. If hypertrophic cardiomyopathy is diagnosed, the possibility of progression to a dilated cardiomyopathy should be kept in mind. While isolated cases of cardiac transplantation, left ventricular assist device insertion and ICD implantation have been described, for the majority of FA patients aggressive medical treatment of cardiomyopathies, arrhythmias and heart failure (especially when instituted early in the course if disease) may help alleviate symptoms, improve quality of life and prevent premature death. A multidisciplinary approach to treatment, involving a wellinformed patient, parents, cardiologist and neurologist, is imperative. Acknowledgments this article.
There was no financial incentive or input into
Conflict of interest
There are no conflicts of interest.
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