Ann Thorac Surg 2009;87:625-628. doi:10.1016/j.athoracsur.2008.06.023
© 2009 The Society of Thoracic Surgeons
Case Reports
Fabry Disease With Aortic Regurgitation
Soojeong Choi, MDa,
Haesun Seo, MDa,
Mooyong Park, MDa,
Jinkuk Kim, MDa,
Seungduk Hwang, MDa,*,
Kaewon Kwon, MDb,
Kyun Her, MDc,
Yongsoon Won, MDc
a Department of Internal Medicine, Soonchunhyang University, Bucheon, Korea
b Department of Pathology, Soonchunhyang University, Bucheon, Korea
c Department of Thoracic and Cardiovascular Surgery, College of Medicine, Soonchunhyang University, Bucheon, Korea
Accepted for publication June 11, 2008.
* Address correspondence to Dr Hwang, Division of Nephrology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, 1174 Jung-dong, Wonmi-Gu, Bucheon-Si, 420-767, South Korea (Email: sd7hwang{at}schbc.ac.kr).
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Abstract
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Aortic regurgitation is not so rare in patients with Fabry disease. Enzyme replacement therapy has become the standard medical care for Fabry disease in recent years. A 31-year-old man with Fabry disease, treated with recombinant 
-galactosidase enzyme replacement for 19 months was admitted for evaluation of exertional dyspnea. Cardiac workup revealed left ventricular hypertrophy, increased left ventricular size, and moderate to severe aortic regurgitation. He underwent mechanical valvular replacement and heart biopsy. Histology of his aortic valve showed myxoid degeneration of valve leaflets. His heart muscle revealed extensive hypertrophy with vacuolization and the absence of lamellar bodies. We report a case of Fabry disease with aortic regurgitation in a man who underwent valvular replacement operation during enzyme replacement therapy.
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Introduction
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Fabry disease is an X-linked glycosphingolipid disorder caused by deficient activity of the enzyme -galactosidase A, which results in the systemic accumulation of globotriosylceramide (Gb3) in all tissues of the body, especially the skin, cornea, kidney, and heart [1]. The accumulation of glycosphingolipids in cardiac tissue has been reported to cause increased ventricular wall thickness and impaired function, conduction delay, and the thickening of the valves [2]. A recent study showed that structural changes of the mitral valve, such as thickening and prolapse occur more frequently than aortic valve [3]. Aortic involvement occurs in approximately 25.5% to 47% patients with Fabry disease. Enzyme replacement therapy (ERT) is effective in reversing the microvascular changes in Fabry disease by catabolizing the lipid deposits and improving cardiac function in patients with cardiac involvement [4, 5]. We report the case of Fabry disease with aortic regurgitation and for valvular replacement operation during ERT.
A 31-year-old man with a history of Fabry disease was admitted to evaluation of exertional dyspnea. He was diagnosed as having Fabry disease 2 years earlier by kidney biopsy (Fig 1). His plasma and urine Gb3 levels were increased. His -galactosidase activity in lymphocytes was 0 µmol/min/m. His serum creatinine and proteinuria were 0.9 mg/dL and 1,157 mg/day, respectively. His workup revealed a point mutation (R227X). At that time, transthoracic echocardiography revealed left ventricular (LV) enlargement and eccentric LV hypertrophy with normal LV contractile function (Table 1). The aortic valve was degenerative but coaptation was good without significant aortic regurgitation. He was treated with losartan (50 mg/day) and Fabrazyme (1 mg/kg, every 2 weeks) (Genzyme Corp, Framingham, MA) 19 months before current admission. The electrocardiogram showed normal sinus rhythm and LV hypertrophy. The echocardiogram after admission revealed more thickened, severely degenerative aortic valve with severe aortic regurgitation, resulting in more dilated LV chamber compared with his previous examination (Table 1; Fig 2). The proteinuria was 486 mg/day. He underwent aortic valve replacement (Carbomedics, 23 mm) and a cardiac biopsy. Light microscopy of the heart muscle revealed extensive hypertrophy with vacuolization and cellular expansion (Fig 3A). Transmission electron microcopy showed extensive vacuolization within myocytes and the absence of concentric lamellar bodies, a hallmark of Fabry disease (Fig 3B). Histology of aortic valve showed myxoid degeneration of valve leaflets. Seven day after operation, the echocardiogram showed well-functioning mechanical aortic valve and decreased LV chamber size (Table 1). He was discharged without any complications or symptoms and with optimal medical treatment.
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Fig 1. (A) The kidney biopsy under light microscopy shows glomeruli with enlarged, vacuolated visceral epithelial cells. (Hematoxylin & eosin; x400.) (B) An electron microscopy reveals podocytes filled with myelin bodies of variable size. (Uranyl acetate and lead citrate; x1500).
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Fig 2. Transthoracic echocardiographic image. (A) Two-dimensional echocardiogram shows enlarged left ventricle with thickened aortic and mitral valve. (B) Color Doppler shows severe aortic regurgitant jet flow.
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Fig 3. (A) The heart biopsy under light microscopy shows mild fibrosis, chronic inflammation, and vacuolar changes. (Hematoxylin & eosin; x200, myocardium). (B) Electron microscope image of a treated Fabry myocyte. Normal appearing myofibrils are present at the cell periphery. The middle of the cell is vacuolated (electron microscopy, original magnification; x3,000).
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Comment
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In recent years, ERT has become the standard medical care for Fabry disease. Eng and colleagues [4] reported that microvascular endothelial deposits of Gb3 were reduced in the heart tissue of patients treated with ERT. Because a heart biopsy is invasive, many studies evaluate the improvement of cardiac function while on ERT indirectly, such as by using the echocardiogram and electrocardiogram [2–4]. Weidemann and colleagues [5] observed an improvement in LV hypertrophy and regional myocardial function after 12 months of agalsidase-β (1.0 mg/kg, every 2 weeks) therapy.
Linhart and colleagues [2] found that mitral and aortic valve abnormalities were identified in 17 (57%) and 14 (47%) of 30 patients, respectively. Kampmann and colleagues [3] identified aortic valve thickening, mitral thickening with mild insufficiency, and mitral valve prolapse in 14 (25.5%), 14 (25.5%) and 6 (10.9%) of 50 patients, respectively. Iwase and colleagues [6] reported a 46-year-old man having Fabry disease with aortic regurgitation (grade III/IV) and complete AV block in 1988, when ERT was not yet considered. They did not attempt valvular replacement due to the danger of suture failure. Owen and colleagues [7] reported the first case to demonstrate morphological changes in vivo with ERT, reporting the loss of "myelin figures" in myocytes.
We believe that our patient is the first to undergo valvular replacement, and to present histology of aortic valve during ERT. Histology of aortic valve showed myxoid degeneration of valve leaflets, which is similar to findings in other patients who have received aortic valve surgery. Because we did not see the aortic valve by electron microscopy, we did not find lamellar bodies.
Although his proteinuria was decreased during ERT, his cardiac function was deteriorated. We did not identify the definite cause of cardiac deterioration. Weidemann and colleagues [5] reported that diastolic function and exercise did not improve during ERT. Wilcox and colleagues [8] suggested that treatment before extensive renal damage occurs is critical and that there may be a "point of no return" in which impaired glomeruli will progress irreversibly to failure. Desnick and colleagues [1] recommended therapeutic intervention as early as possible to prevent disease manifestations. Therefore, if these suggestions might occur in the myocardium and connective tissue, despite ERT, the cardiovascular function would not improve as expected.
In conclusion, patients with Fabry disease who had aggravated aortic regurgitation despite ERT should be considered for replacement surgery.
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References
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- Desnick RJ, Brady R, Barranger J, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy Ann Intern Med 2003;138:338-346.[Medline]
- Linhart A, Pale
ek T, Bultas J, et al. New insight in cardiac structural changes in patients with Fabry's disease Am Heart J 2000;139:1101-1108.[Medline] - Kampmann C, Baehner F, Whybra C, et al. Cardiac manifestations of Anderson-Fabry Disease in Heterozygous Females J Am Coll Cardiol 2002;40:1668-1674.[Medline]
- Eng CM, Guffon N, Wilcox WR, et al. Safety and efficiency of recombinant human alfa-galactosidase: a replacement therapy in Fabry's disease N Engl J Med 2001;345:9-16.[Medline]
- Weidemann F, Breunig F, Beer M, et al. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study Circulation 2003;108:1299-1301.[Abstract/Free Full Text]
- Iwase M, Yamauchi K, Aoki T, et al. Echocardiographic findings in a case of Fabry's disease with aortic regurgitation and complete AV block, and in his family members J Cardiol 1988;18:589-598.[Medline]
- Owen CL, Russel S, Halushka MK. Histologic and electron microscopy findings in myocardium of treated Fabry disease Hum Pathol 2006;37:764-768.[Medline]
- Wilcox WR, Banikazemi M, Guffon N, et al. Long-term safety and deficiency of enzyme replacement therapy for Fabry disease Am J Hum Genet 2004;75:65-74.[Medline]
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Abstract
Introduction
