Hellenic J Cardiol 2011; 52: 316-326 Review Article Anderson-Fabry Disease: A Cardiomyopathy That Can Be Cured ARIS ANASTASAKIS, ELIAS SEVDALIS, EFSTATHIOS PAPATHEODOROU, CHRISTODOULOS STEFANADIS First Department of Cardiology, University of Athens, Heart Center of the Young and Athletes (E.K.K.A.N), Unit of Inherited Cardiovascular Diseases, Athens, Greece Key words: nderson-Fabry disease (AFD) is a few mm, and are mainly seen in the peri- Anderson- hereditarily transmitted (with X- umbilical region, on the upper thighs and Fabry disease, linked transmission and locus on perinatal area, or on the palmar surface of hypertrophic A cardiomyopathy, chromosome Xq22) lysosomal metabolic the upper limb (Figure 2). Early and signif- enzyme replacement disorder.1 It should be noted that AFD icant deposition of glycosphingolipid in the therapy, Fabry. follows X-linked dominant rather than re- podocytes of renal glomeruli is responsible cessive transmission, as is indicated by the for the albuminuria. fact that the prevalence of cardiac involve- ment in heterozygote females is high and Pathophysiology of Fabry cardiomyopathy might be as high as in males. It is a lyso- somal storage disease, resulting from a de- The classic phenotype of Fabry disease ficiency of the lysosomal hydrolase a-ga- has an estimated incidence of approxi- lactosidase A (a-GalA). The total or par- mately 1 in 50,000 males. But the true in- Manuscript received: tial failure of the activity of this enzyme cidence is likely to be higher than original- July 30, 2009; inhibits the metabolism of glycosphingo- ly thought, owing to the existence of mild- Accepted: lipid (mainly globotriosylceramide, Gb3) er, later-onset variants of the disease as February 3, 2011. to lactosylceramide, resulting in the accu- identified by newborn screening. It seems mulation of significant amounts of Gb3 that the ratio of later-onset to classic phe- Address: within the lysosomes of various tissues, notypes may be as much as 11:1, raising Aris Anastasakis mainly of endothelial cells.2 the incidence of Fabry disease up to 1 in This biochemical disorder and the sub- 3,000 or even 1 in 1,250 male births.4,5 32 Alex. Papanastasiou St. 154 51 Neo Psychiko sequent lysosomal Gb3 accumulation in en- The exact mechanism by which hyper- Athens, Greece dothelial cells lead in turn to regional isch- trophy and fibrosis in the heart are cre- e-mail: anastasakisaris@ emia and infarcts, especially in the kidneys, ated is not fully understood. Lysosomal gmail.com heart muscle and brain.3 The vessels of the Gb3 accumulation in the myocardium is [email protected] microcirculation of the skin are dilated and responsible for only 1-3% of mass in the become hyperplastic, resulting in the for- hypertrophic heart,6-8 indicating that the mation of the characteristic angiokerato- left ventricular hypertrophy is not a direct mas (Figure 1). These skin lesions are accu- result of Gb3 filtration. However it is this mulated in groups of telangiectasias, with a primary Gb3 accumulation that initiates blue or dark red tint that does not change the other pathological processes. with the application of pressure. They mea- Several growth factors, such as the Gb3 sure between the size of a pinhead and a metabolite lyso-Gb3,9-10 or mechanisms of 316 • HJC (Hellenic Journal of Cardiology) Anderson-Fabry Disease Similarly, Gb3 accumulation in the valves and in the atrioventricular node causes valvular heart disease and electrical conduction disturbances. The myocardial fibrosis predisposes to ventricular ar- rhythmias, whereas atrial deposition of Gb3 and the consequent dilatation due to increased ventricular filling pressures lead to an increased incidence of atri- al arrhythmias. Clinical picture Extracardiac events Figure 1. Tissue biopsy of skin showing the dilated blood vessels in the subcutaneous tissue. Reprinted with permission from Elsevier (The Lancet 2001; 357: 138-140). Early symptoms appear on average in males at the age of 9 years and in females at the age of 13. 11 The neurological manifestations include intermit- oxidative stress induced by excess of intracellular tent episodes of severe pain in the extremities (acro- Gb3, resulting in deregulation of cell adhesion mole- paresthesias are especially common in young male cules in vascular endothelial cells, have been implicat- patients aged <15 years),14 poor exercise heat and ed in the development of hypertrophy and fibrosis in cold tolerance, hearing reduction or loss and tinnitus, the myocardium. Mechanisms of oxidative stress may as well as the characteristic Fabry pain crises (severe cause microvascular lesions in coronary vessels, lead- episodes of “burning” pain that are experienced in ing to myocardial necrosis and reduction of cardiac re- the hands and feet or even throughout the body and serve. Similar differences in mitochondrial metabolism can last from several minutes to weeks). that have been observed in the walls of the left ventri- Kidney involvement is a prominent feature and cle of patients with hypertrophic cardiomyopathy, with is the main cause of premature death in classic Fabry a confirmed sarcomeric protein gene mutation, as well disease. Microalbuminuria may be apparent in ado- as in skin fibroblasts of patients with Anderson-Fabry lescence and early adulthood. Progressive kidney dis- disease, led to the hypothesis that the accumulation of ease is marked by the progression of proteinuria, an Gb3 probably destroys the mitochondrial energy me- 12,13 increase in serum creatinine levels, and the reduction tabolism. Further research data will be needed for of the glomerular filtration rate during the third de- us to fully understand the pathophysiological process cade of life. Long-term hemodialysis, and renal trans- of the disease. plantation are often required.15 Central nervous system involvement includes stroke, transient ischemic attack, white matter le- sions of the brain, hemiparesis, vertigo or dizziness episodes, and vascular complications such as diplopia, dysarthria, nystagmus, ataxia, memory loss and hear- ing impairment.16 Ocular manifestations include opacity (cloudi- ness) of the cornea during microscopic slit lamp ex- amination, which does not affect vision, and opacity of the lens. Dermal manifestations of Fabry disease include cutaneous vascular lesions (angiokeratomas) and ab- normal sweating (anhidrosis or, more commonly, hy- pohidrosis). Gastrointestinal manifestations of Fabry Figure 2. Characteristic telangiectasias (angiokeratomas) on the disease are common (epigastric pain, nausea, diar- palmar surface of the upper limbs. Reprinted with permission rhea), and non-specific manifestations in the mental from Elsevier (The Lancet 2001; 357: 138-40). realm (e.g. depression) are also observed. (Hellenic Journal of Cardiology) HJC • 317 A. Anastasakis et al Figure 3. Resting electrocardiogram in a patient with Anderson-Fabry Disease, showing signs of electrical left ventricular hypertrophy, concomitant repolarization abnormalities (strain), and shortening of the PR interval. (Personal archive, E. Sevdalis - E.K.K.A.N). Cardiac events palpitations are present in 26% of both sexes, and 2% of women and 4% of male patients have syncopal epi- The heart is affected in almost all patients with An- sodes. 17 derson-Fabry disease as the disease progresses. Al- The cardiovascular complications of the disease though myocardial infiltration with Gb-3 starts quite include myocardial hypertrophy of the left ventricle early, symptoms from the cardiovascular system ap- (Figures 3 and 4), thickening of the material of the pear much later. In male patients the mean age of on- valves, dilatation of the ascending aorta and conduc- set is 32 years and in females 40 years. The incidence tion disturbances.18,19 In the end stage of Fabry car- of symptoms is the same in both genders. Specifically, diomyopathy, extensive areas of myocardial fibrosis 22% of female and 20% of male patients show dys- are found, as well as severely impaired systolic and di- pnea, 22% of women and 19% of men have angina, astolic left ventricular function.20 A B Figure 4. Two-dimensional echocardiographic imaging of a patient with Anderson-Fabry disease. A: Parasternal long-axis view; B: Para- sternal short axis view. Highly diffuse echogenicity and concentric hypertrophy of the left ventricular myocardium can be distinguished, as well as the thickening of the mitral valvular tissue. (Personal archive, E. Sevdalis - E.K.K.A.N). 318 • HJC (Hellenic Journal of Cardiology) Anderson-Fabry Disease Left ventricular hypertrophy sis, is rarely of particular hemodynamic significance. Abnormalities of the mitral valve are noted more fre- In male patients, it seems that hypertrophy occurs quently. Valvular abnormalities are not associated quite frequently (43% versus 26% in women). Hy- with a significant degree of regurgitation.17,19 pertrophy progressively worsens with age (in women The serious cardiovascular complications cause less than in male patients) and is accompanied by a significant morbidity and contribute to the reduced progressive partial reduction of left ventricular func- life expectancy of male patients, in whom end-stage 21,22 tion. The functional changes occur most frequent- chronic renal failure is the primary cause of death. 20 ly in the lateral wall of the left ventricle. The pres- In female patients it appears that cardiac complica- ence of left ventricular hypertrophy is associated with tions are the leading cause of death. The main cardiac a higher incidence