Cardiac Manifestations of Fabry’s Disease: A Story of Mother and Son

Fabry’s disease is an X-linked metabolic disorder that results in a deficiency of lysosomal enzyme α-galactosidase A. It leads to accumulation of glycosphingolipids (predominantly globotriaosylceramide [Gb3]) in the plasma, endothelial, and smooth muscle cells of the renal and cardiovascular systems. Female carriers of this mutation are not affected as severely as males. Typical Fabry’s cardiomyopathy involves only left ventricular hypertrophy. This case report presents the spectrum of cardiac manifestations of Fabry disease within a family, from benign manifestations in a mother to fatal illness in her son. A 65-year-old woman with a history of Fabry’s disease, hypertension, and transient ischemic attacks presented in 2006 with acute onset of chest pain, associated with persistent palpitations, and mild dyspnea. She described similar episodes in the past. Her family history was positive for heart disease, with her paternal grandparents, father, and son having heart failure (HF). Her sister and son were positive for Fabry’s disease. The diagnosis of Fabry’s disease was established based on genetic testing (mutation R227X). On examination, she had an irregular heart rate with a soft systolic murmur and mild, bilateral leg edema. On electrocardiography there was sinus bradycardia with T-wave inversions in leads II, III, aVF, and V3 through V6. Initial cardiac enzymes were negative. During her hospital course, she developed a slight elevation in troponin I 0.24 (cutoff 0.05) with marked ST-T wave depression on multiple leads. Cardiac catheterization demonstrated a 30% plaque involving the left anterior descending artery. A 2-dimensional echocardiogram showed an ejection fraction of 50%, with mild concentric left ventricular hypertrophy (11 mm), mild global hypokinesis, mildly dilated left atrium (41 mm), mild aortic and tricuspid regurgitation, and an estimated right ventricular systolic pressure of 32 mm Hg. The patient’s son was diagnosed with Fabry’s disease at the age 19. He had the same family mutation R227X, and severe deficiency of both α-galactosidase (11% of control) and β-galactosidase (14.5% of control). Prior to this, he had reported burning in his feet secondary to hypohidrosis. As he aged, his paresthesias progressed to his lower extremities and upper extremities, including his hands. He developed renal insufficiency in his 40s, received genzyme treatment, but ultimately was placed on chronic hemodialysis. His first cardiac symptoms occurred in his early 40s when he was found to have pulmonary embolism. A few months later he was admitted for chest pain associated with worsening dyspnea and mild increase in troponin levels. The 2-dimensional echocardiogram at that time was read as mild to moderate concentric left ventricular hypertrophy with a severely reduced left ventricular systolic function, mild mitral regurgitation, moderate aortic insufficiency, and mild tricuspid regurgitation. He subsequently underwent left-sided heart catheterization, which documented mild nonobstructive coronary artery disease. Three months later, he presented again in decompensated HF. Repeat echocardiography showed a dilated left ventricle (end-diastolic dimension 6.7 cm), an ejection fraction of 31%, global hypokinesis, left atrium dilatation (5.6 cm), and severe mitral regurgitation, along with moderate aortic regurgitation and mild tricuspid regurgitation. An automated cardioverter-defibrillator was implanted. Over the next 7 months, he presented to the hospital 4 times with HF exacerbations. His last hospitalization at the age of 47 also concurred with multiple defibrillator firings for ventricular tachycardia. He was treated, stabilized, and evaluated for heart and kidney transplant. He was ultimately rejected by the medical review board because of the systemic nature of the disease. In the process of evaluation, he underwent a repeat coronary angiography, documenting worsening 2-vessel disease. Subsequently he had a coronary artery bypass grafting of 2 vessels, aortic valve replacement, and a defibrillator upgrade to a biventricular pacemaker. He continued to have multiple episodes of sustained ventricular tachycardia, despite several re-programmings of his device. He eventually developed electrical dysrhythmic storm. Comfort measures were added, and he died shortly thereafter. Fabry’s disease, or Anderson-Fabry’s disease, was originally described separately in 1898 by Dr Johann Fabry (a German dermatologist) and Dr William Anderson (a British dermatologist). It is an X-linked recessive disorder (located on Xq 221), resulting in a defective lysosomal enzyme, α-galactosidase A. This inborn error of metabolism leads to the accumulation of glycosphingolipids (predominantly Gb3) in the plasma, endothelium, and smooth muscle cells of the renal, cardiovascular, and cerebrovascular systems. The true incidence of Fabry’s disease is unknown, with current estimates having 1 male afflicted in 40,000 and an estimated general prevalence of 1 in 117,000.2 There is large variability in penetration in women secondary to lyonization. Clinical presentation of Fabry’s disease develops in 3 phases. The first phase occurs in childhood or adolescence, and is marked by myalgia, arthralgia, fever, corneal opacities, and cutaneous angiokeratomas. The second phase is noted for progressive renal involvement, which progresses to end-stage renal disease (third phase), usually occurring in the fourth or fifth decade. Also, during this stage, there is involvement of the cardiovascular and cerebrovascular systems. Death usually results from complications of renal failure and hemodialysis, as well as from cardiovascular and cerebrovascular events. The average lifespan of homozygous patients with Fabry’s disease is 41 years without hemodialysis, but can be extended an additional 10 years with hemodialysis.3 Cardiac involvement in Fabry’s disease is considered to be a significant component of the morbidity and mortality. The pathologic changes that occur within the cardiovascular system are due to the accumulation and storage of Gb3 within the various cells of the heart. These changes include progressive left ventricular hypertrophy, coronary arterial disease (of vasospastic or atherosclerotic origin), valvular disease, and conductional abnormalities, ranging from short PR intervals to atrioventricular block and sudden cardiac death. The more common cardiovascular findings seen are left ventricular hypertrophy and conduction abnormalities. A recent evaluation of the international Fabry Outcome Survey details the cardiac involvement in 714 patients with the confirmed diagnosis of Fabry’s disease.4 The most common cardiac symptoms seen in this cohort included palpitations, arrhythmias, dyspnea on exertion, angina, and syncope. Patients with the presence of left ventricular hypertrophy had a higher frequency of cardiac symptoms. There were also noted to be a low incidence of coronary artery disease, myocardial infarction, and revascularization in this cohort. Sadick and Thomas5 recently published a retrospective study evaluating the clinical and echocardiographic manifestations of cardiac involvement of a cohort of 12 genetically tested Fabry’s disease patients. Most of these patients were asymptomatic from a cardiac standpoint, but all had extracardiac manifestations. A majority of the cohort had left ventricular hypertrophy by voltage criteria or associated ST depression. Echocardiographically, patients with Fabry’s disease had statistically significantly thicker left ventricular walls, larger left atrial volumes, and larger left ventricular masses than healthy controls. Their ejection fractions were similar. Using echo-Doppler and tissue Doppler parameters, the Fabry cohort also had the following statistically significant differences, consistent with greater diastolic dysfunction: lower E′ velocities, longer isovolemic relaxation times, and shorter deceleration times. Progression to systolic heart failure is rare. From the unpublished data of 2255 patients in the Fabry Registry, 1642 (22.1%) patients had recorded left ventricular ejection fractions. Out of them, 35 (2.1%) had ejection fractions ≤40%. (Fabry Registry, unpublished data, 2007). Clinical representation in the female population is extremely varied due to the heterozygous nature and variable genetic expression of the defect. These women can be symptom-free or have lower, attenuated expression of the disease. There also have been reports of some women having significant symptom burden as a result of a random inactivation of the X chromosome 3. In a recent study, cardiac involvement was seen in 56% of heterozygous patients younger than 38 years, and 86% of women older than 38.6 Also, Fabry’s disease has been thought to account for up to 12% of late-onset hypertrophic cardiomyopathy in women.7 Treatment for Fabry’s disease has traditionally been one of supportive care, including medical therapy, hemodialysis, and pacemakers and internal cardiac defibrillators. The importance of early recognition is for close follow-up and prevention of disease progression. Therefore, the current medical management is directed at attempting to improve diastolic HF before or as it develops. Rarely do patients clinically deteriorate to require cardiac transplant. A current literature search only discovers 1 case report of a Canadian woman with severe restrictive cardiomyopathy undergoing heart transplant, without recurrence of cardiac manifestations of her Fabry’s disease up to 1 year after.8 Advancements in the field of enzyme replacement therapy and gene transfer therapy have improved the potential for future treatment options. Due to the rare nature of the disease, large randomized trials have not been able to be performed, leaving smaller observational reports and some nonrandomized trials. Recently, Hughes and colleagues9 reported on the effects of using enzyme replacement therapy for Fabry’s disease, specifically in patients with cardiac involvement. A total of 15 patients were randomized to 6 months of intravenous infusions of agalsidase alfa vs placebo. At the completion of the 6 months, the treatment group demonstrated significant reductions in left ventricular mass and a trend towards statistically significant reduction in myocardial levels of Gb3 (20% reduction vs 10% increase in the placebo group, P=.42). Another recent prospective trial reviewed clinical and echocardiographic data in 29 patients undergoing long-term enzyme replacement therapy.10 After a median duration of 37 months, there was noted improvement in clinical symptoms and no echocardiographic evidence of cardiac disease progression. There was only noted to be a small improvement in diastolic function (a 29% decrease in the E/Ea ratio, P<.002). These results, along with other case reports, seem to suggest benefit with therapy, but further work needs to be performed. Currently there are 2 preparations of enzyme replacement therapy that have been approved for treatment of Fabry’s disease in Europe: agalsidase alfa (Replagal, Shire Human Genetics, Cambridge, MA) and agalsidase beta (Fabrazyme, Cambridge MA).11 Only agalsidase beta is approved for US use. Gene replacement therapy is another mode of ongoing research in treatment for Fabry’s disease. To date, only animal experiments have been performed, showing improvements in α-galactosidase A expression and reduction in Gb3 storage. Unfortunately, the current state for translation to human studies is still far from reality. This case report presents an illustration of the wide range of clinical symptoms and effects of Fabry’s disease on the cardiovascular system. In the mother presented in this case report, there was mild left ventricular hypertrophy, left atrial enlargement, and anginal chest pain. Left ventricular hypertrophy is a common sign of cardiac involvement in Fabry’s disease, while dilated cardiomyopathy is not. Dilated cardiomyopathy developed in our male patient before he acquired coronary artery disease. His ejection fraction was measured at 31% at the time when his coronary angiography displayed only mild, non-obstructive coronary stenosis (<30% obstruction). From the data mentioned above, this is noted to be rare sequelae of his disease. In summary, this case report presents a variety of cardiac manifestations of Fabry’s disease seen within one family. While the heterozygous mother had only mild left ventricular hypertrophy and left atrial dilatation, the son developed terminal cardiac disease with left ventricular hypertrophy, severe systolic dysfunction, and electrical instability, which was the immediate cause of death. The course was complicated by rapid progression of coronary arterial occlusive disease. Poor prognosis associated with HF warrants further study of this group of patients within Fabry’s population. Focusing on patients who develop not only left ventricular hypertrophy but left ventricular failure may help to identify candidates for enzyme replacement treatment, and to start this treatment timely enough to prevent fatal conditions as in the son in this Fabry’s family.

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