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Inherited restrictive cardiomyopathy in a 74-year-old woman: A case of Fabry's disease
Volume 129, Number 1 American Heart Journal
apy in heart failure from dilated cardiomyopathy. Circulation 1989; 79:483-90. 5. Bristow MR. Pathophysiologic and pharmacologic rationales for clinical management of chronic heart failure with beta-blocking agents. Am J Cardiol 1993;71:12-22C. 6. Saini J, Rich MW, Lyss AP. Reversibility of severe left ventricular dysfunction due to doxorubicin cardiotoxicity. Ann Intern Med 1987; 106:814-6.
Inherited restrictive cardiomyopathy in a 74-year-old woman: A case of Fabry's disease Russell E. Hillsley, MD, Eugenio Hernandez, MD, Charles Steenbergen, MD, Thomas M. Bashore, MD, and J. Kevin Harrison, MD Durham, N. C.
Fabry's disease is an X-linked disorder of glycosphingolipid metabolism resulting from deficient activity of the lysosomal hydrolase a-galactosidase A. 1, 2 This defect leads to accumulation of glycosphingolipid in lysosomes of vascular endothelial cells, smooth-muscle cells, cardiac myocytes, and fibroblasts. In hemizygous male patients clinical manifestations begin in adolescence with angiokeratomas and acroparesthesias. By the fourth decade, renal involvement occurs with proteinuria, often progressing to renal failure, along with ocular abnormalities and cardiac manifestations such as hypertension, cardiac hypertrophy and dilatation, congestive heart failure, ischemia and infarction, and valvular diseaseff 6 Death typically occurs in hemizygous males by the fifth decade. Female heterozygores, by contrast, usually have normal life expectancy. Although many affected females are asymptomatic carriers, some have renal or cardiac involvement by the fifth or sixth decade. 7-9 We report on a patient with a restrictive cardiomyopathy, coronary disease, mitral regurgitation, and proteinuria diagnosed at age 74 years by percutaneous and intraoperative myocardial biopsies. A 74-year-old white woman was referred for evaluation of mitral regurgitation and congestive heart failure. Four years earlier she had an acute myocardial infarction treated with right coronary angioplasty. A pacemaker was placed 1 year earlier for symptomatic bradycardia. Over the preceding 9 months the patient had been admitted to the hospital nine times for congestive heart failure. Seven months earlier cardiac catheterization demonstrated moderate mitral regurgitation with normal left ventricular function and insignificant coronary artery disease. After a transesophFrom the Department of Medicine. Division of Cardiology, and Department of Pathology, Duke University Medical Center Reprint requests: Russell E. Hillsley, MD, Division of Cardiology, Box 31046, Duke Umversity Medical Center, Durham, NC 27710. AM HEARTJ 1995;129:199-202. Copyright ~ 1995 by Mosby-Year Book, Inc. 0002-8703/95/$3.00 + 0 4/4/59131
HillsIey et al.
199
ageal echocardiogram revealed biventricular hypertrophy with moderate mitral regurgitation, the patient was referred for mitral valve replacement. On physical examination the blood pressure was 136/70 mm Hg, the heart rate 72 beats/min and regular, and the respiratory rate 16 breaths/min. Dermatologic, ophthalmologic, and neurologic examination results were normal. The lungs were clear. The venous pressure was about 10 cm H20 with a prominent A wave and a prominent Y descent. The carotid upstrokes were normal. The point of maximal impulse was normal, as was S1. The pulmonic component of the second heart sound was increased, and a grade 2 holosystolic blowing murmur was heard at the apex and radiated to the left axilla. An $4 gallop was present. The abdomen was normal, and there was no lower extremity edema. Peripheral pulses were normal. The complete blood count and electrolytes were normal (creatinine 1.1 gm/dl). Lipid profile and thyroid function tests were normal. Serum protein electrophoresis results were unremarkable, and urine protein electrophoresis results were consistent with glomerular proteinuria (1.1 gm/24 hours). A chest radiograph revealed cardiomegaly. An electrocardiogram showed normal sinus rhythm with right bundle branch block, left anterior hemiblock, and left ventricular hypertrophy. An echocardiogram demonstrated marked biventricular hypertrophy (left ventricular posterior wall thickness 16 ram, septal wall thickness 16 mm), biatrial enlargement (left atrial diameter 45 mm in short axis and 55 mm in long axis; right atrial diameter 38 mm in short axis and 40 mm in long axis), mild left ventricular dysfunction (left ventricular end-systolic diameter 27 mm and fractional shortening 0.31), and moderate mitral regurgitation. Cardiac catheterization revealed an ostial 75 % left main stenosis, a 75 % stenosis of the first marginal branch of the circumflex artery, and a 75% stenosis of the first diagonal branch of the left anterior descending coronary artery. Catheterization of the right side of the heart revealed mean right atrial pressure of 12 mm Hg, right ventricular pressure 70/12 mm Hg, pulmonary artery pressure 70/30 mm Hg, mean pulmonary capillary wedge pressure 28 mm Hg, left ventricular end diastolic pressure 23 mm Hg, and cardiac index 1.6 L/min/ m 2. A percutaneous endomyocardial biopsy revealed minimal inflammation, and Congo red stains were negative for amyloid. Immunofluorescence stains were unrevealing. Electron microscopy demonstrated a distinctive population of myocytes containing numerous lysosomes with whorled membranous accumulations of lipid. Although some cardiac myocytes were filled with these lysosomes, some contained few or none of these distinctive lysosomes (Fig. 1). The patient subsequently underwent successful coronary bypass grafting with placement of an internal mammary graft to the left anterior descending and two saphenous vein grafts. An intraoperative left ventricular myocardial biopsy was similar to the percutaneous right ventricular biopsy. The patient had an uneventful postoperative course and was discharged and given sotalol and warfarin for atrial fibrillation and diuretics and nifedipine. An a-galactosidase assay on peripheral leukocytes revealed
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Fig, 1. Electron micrographs from endomyocardial biopsy. A, Portions of several myocytes, one of which has numerous lysosomes filled with lamellar membranous deposits; adjacent myocytes have only a few small lipofucsin granules. (Original magnification x1575). B, Perinuclear location of m a n y characteristic lysosomes. (Original magnification ×2250).
decreased activity (7.6 n m o l / h r / m g of protein; normal 55.2 + 12.7 n m o l / h r / m g of protein) consistent with heterozygous a-galactosidase deficiency, F a b r y ' s disease. The family pedigree is depicted in Fig. 2. Although F a b r y ' s cardiomyopathy is uncommon and there currently exists no direct t r e a t m e n t for the enzyme deficiency, it remains an i m p o r t a n t diagnostic consideration for the p a t i e n t with a restrictive, hypertrophic cardi-
o m y o p a t h y because it is an X-linked disorder t h a t could affect other family members. 1 This is particularly true in view of the availability of screening tests for prenatal diagnosis and the detection of asymptomatic heterozygous females. 2 Percutaneous endomyocardial biopsy appears to be a useful way to diagnose cardiac involvement in F a b r y ' s disease. This finding contrasts with the low yield of endomyocardial biopsy for most dilated cardiomyopathies, lb
Volume 129, Number 1 American Heart Journal
Hillsley et
DEATH AT YOUNaAGE
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PROTEINURIA 65
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Fig. 2. Pedigree of our patient (generation III, arrow). No other members of kindred have been diagnosed with Fabry's disease, although patient's father had proteinuria and died at age 65. Patient's sister died from undiagnosed systemic disease. Patient's children (generation IV) are healthy except for asthma and hypertension.
The lysosomal pathologic characteristics demonstrated in the percutaneous endomyocardial biopsy in this patient were identical to those from the surgical biopsies. To our knowledge, this patient is the oldest patient to have the diagnosis of Fabry's disease made antemortem. There had been no previous diagnosis of Fabry's disease in this kindred despite proteinuria in her father and the death of her sister from multisystem failure. Unlike in hemizygous male patients, in females the presence of one functional and one defective allele makes the partial expression of Fabry's disease possible. Most likely incomplete penetrance is the result of lyonization of the normal X chromosome in some cells but lyonization of the abnormal X chromosome in others, s Consistent with this hypothesis is the pathologic observation in this woman that cardiac myocytes were unevenly involved; some myocytes had few or no abnormal lysosomes, and adjacent myocytes contained numerous lipid-filled lysosomes that occupied up to 50% of cell volume. a-Galactosidase levels are below normal but not zero in heterozygous females, and the clinical manifestations are typically less severe than those of hemizygous males. An atypical milder form of Fabry's disease confined to the myocardium has also been described in a 54-year-old male and may represent a clinically less severe abnormality of the a-galactosidase gene. 6 The differential diagnosis in this patient with proteinuria and restrictive cardiomyopathy was limited by the characteristic myocardial biopsy (Fig. 1), which revealed intracellular lysosomal membranous lipid accumulations and no evidence of amyloid deposition. Fabry's disease may also result in focal myocardial necrosis and fibrosis with hypertrophy and perinuclear vacuolization. 3 The coronary
arteries may show medial hypertrophy with extensive vacuolization of the smooth-muscle cells. Similar vascular changes may be seen in the kidneys. Numerous cytoplasmic bodies that appear birefringent with polarization microscopy are seen. These stain intensely with the lipid stain Sudan black B. The smooth-muscle cells of the endocardium and blood vessels are involved with glycolipid accumulation, as are the atrial and ventricular myocytes and the connective tissue cells of the mitral valve. 3 On electron microscopy, these glycolipid deposits consist of lamellar accumulations within lysosomes.4 There is no direct treatment for Fabry's disease, although enzyme replacement has transiently reduced circulating ceramide trihexosidase concentrations in two patients. 11 However, enzymatic assays 2 and molecular genetic techniques 12 have made prenatal screening and genetic counseling an important part of therapy in these patients. Consequently, although rare, Fabry's cardiomyopathy remains an important diagnostic consideration for patients with unexplained biventricular hypertrophy and heart failure.
REFERENCES
1. Brady RO, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L. Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967;276:1163-7. 2. Desnick R J, Allen KY, Desnick SJ, Raman MK, Bernlohr RW, Krivit W. Fabry's disease: enzymatic diagnosis of hemizygotes and heterozygores. Alpha-galactosidase activities in plasma, serum, urine, and leukocytes. J Lab Clin Med 1973;81:157-71. 3. Ferrans VJ, Hibbs RG, Burda CD. The heart in Fabry's disease. A hlstochemical and electron microscopic study. Am J Cardiol 1969;24:95110. 4. Desnick RJ, Blieden LC, Sharp HL, Hofschire PJ, Moiler JH. Cardiac
2O2
January 1995
T..--
,nutsteyet
al.
valvular anomalies in Fabry disease. Clinical, morphologic, and biochemical studies. Circulation 1976;54:818-25. 5. Sakuraba H, Yanagawa Y, Igarashi T, Suzuki Y, Suzuki T, Watanabe K, Ieki K, Shimoda K, Yamanaka T. Cardiovascular manifestations in Fahry's disease. A high incidence of mitral valve prolapse in hemizygotes and heterozygotes. Clin Ganet 1986;29:276-83. 6. Von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann B, Hubner G, Olsen EGJ, Christomanou H, Kandolf R, Bishop DF, Desnick RJ. An atypical variant of Fabry's disease with manifestations confined to the myocardium. New Engl J Med 1991;324:395-9. 7. Burda CD, Winder PR. Angiokeratoma corporis diffusum universale (Fabry's disease) in female subjects. Am J Med 1967;42:293-301. 8. Broadbent JC, Edwards WD, Gordon H, Hartzler GO, Krawisz JE. Fabry cardiomyopathy in the female confirmed by endomyocardial biopsy. Mayo Clin Proc 1981;56:623-8.
American Heart Journal
9. Rodriguez FH, Hoffman EO, Ordinario AT, Baliga M. Fabry's disease in a heterozygous woman. Arch Pathol Lab Med 1985;109:89-91. 10. Chow LC, Dittrich HC, Shabetai R. Endomyocardial biopsy in patients with unexplained congestive heart failure. Ann Intern Med 1988;109: 535-9. 11. Brady RO, Tallman JF, Johnson WG, Gal AE, Leahy WR, Quirk JM, Dekaban AS. Replacement therapy for inherited enzyme deficiency. Use of purified ceramidetrihexosidase in Fabry's disease. N Engl J Med 1973;289:9-14. 12. Ishii S, Sakuraba H, Shimmoto M, Minamikawa-Tachino R, Suzuki T, Suzuki Y. Fabry disease: detection of 13-bp deletion in alpha-galactosidase A gene and its application to gene diagnosis of heterozygotes. Ann Neurol 1991;29:560-4.
apy in heart failure from dilated cardiomyopathy. Circulation 1989; 79:483-90. 5. Bristow MR. Pathophysiologic and pharmacologic rationales for clinical management of chronic heart failure with beta-blocking agents. Am J Cardiol 1993;71:12-22C. 6. Saini J, Rich MW, Lyss AP. Reversibility of severe left ventricular dysfunction due to doxorubicin cardiotoxicity. Ann Intern Med 1987; 106:814-6.
Inherited restrictive cardiomyopathy in a 74-year-old woman: A case of Fabry's disease Russell E. Hillsley, MD, Eugenio Hernandez, MD, Charles Steenbergen, MD, Thomas M. Bashore, MD, and J. Kevin Harrison, MD Durham, N. C.
Fabry's disease is an X-linked disorder of glycosphingolipid metabolism resulting from deficient activity of the lysosomal hydrolase a-galactosidase A. 1, 2 This defect leads to accumulation of glycosphingolipid in lysosomes of vascular endothelial cells, smooth-muscle cells, cardiac myocytes, and fibroblasts. In hemizygous male patients clinical manifestations begin in adolescence with angiokeratomas and acroparesthesias. By the fourth decade, renal involvement occurs with proteinuria, often progressing to renal failure, along with ocular abnormalities and cardiac manifestations such as hypertension, cardiac hypertrophy and dilatation, congestive heart failure, ischemia and infarction, and valvular diseaseff 6 Death typically occurs in hemizygous males by the fifth decade. Female heterozygores, by contrast, usually have normal life expectancy. Although many affected females are asymptomatic carriers, some have renal or cardiac involvement by the fifth or sixth decade. 7-9 We report on a patient with a restrictive cardiomyopathy, coronary disease, mitral regurgitation, and proteinuria diagnosed at age 74 years by percutaneous and intraoperative myocardial biopsies. A 74-year-old white woman was referred for evaluation of mitral regurgitation and congestive heart failure. Four years earlier she had an acute myocardial infarction treated with right coronary angioplasty. A pacemaker was placed 1 year earlier for symptomatic bradycardia. Over the preceding 9 months the patient had been admitted to the hospital nine times for congestive heart failure. Seven months earlier cardiac catheterization demonstrated moderate mitral regurgitation with normal left ventricular function and insignificant coronary artery disease. After a transesophFrom the Department of Medicine. Division of Cardiology, and Department of Pathology, Duke University Medical Center Reprint requests: Russell E. Hillsley, MD, Division of Cardiology, Box 31046, Duke Umversity Medical Center, Durham, NC 27710. AM HEARTJ 1995;129:199-202. Copyright ~ 1995 by Mosby-Year Book, Inc. 0002-8703/95/$3.00 + 0 4/4/59131
HillsIey et al.
199
ageal echocardiogram revealed biventricular hypertrophy with moderate mitral regurgitation, the patient was referred for mitral valve replacement. On physical examination the blood pressure was 136/70 mm Hg, the heart rate 72 beats/min and regular, and the respiratory rate 16 breaths/min. Dermatologic, ophthalmologic, and neurologic examination results were normal. The lungs were clear. The venous pressure was about 10 cm H20 with a prominent A wave and a prominent Y descent. The carotid upstrokes were normal. The point of maximal impulse was normal, as was S1. The pulmonic component of the second heart sound was increased, and a grade 2 holosystolic blowing murmur was heard at the apex and radiated to the left axilla. An $4 gallop was present. The abdomen was normal, and there was no lower extremity edema. Peripheral pulses were normal. The complete blood count and electrolytes were normal (creatinine 1.1 gm/dl). Lipid profile and thyroid function tests were normal. Serum protein electrophoresis results were unremarkable, and urine protein electrophoresis results were consistent with glomerular proteinuria (1.1 gm/24 hours). A chest radiograph revealed cardiomegaly. An electrocardiogram showed normal sinus rhythm with right bundle branch block, left anterior hemiblock, and left ventricular hypertrophy. An echocardiogram demonstrated marked biventricular hypertrophy (left ventricular posterior wall thickness 16 ram, septal wall thickness 16 mm), biatrial enlargement (left atrial diameter 45 mm in short axis and 55 mm in long axis; right atrial diameter 38 mm in short axis and 40 mm in long axis), mild left ventricular dysfunction (left ventricular end-systolic diameter 27 mm and fractional shortening 0.31), and moderate mitral regurgitation. Cardiac catheterization revealed an ostial 75 % left main stenosis, a 75 % stenosis of the first marginal branch of the circumflex artery, and a 75% stenosis of the first diagonal branch of the left anterior descending coronary artery. Catheterization of the right side of the heart revealed mean right atrial pressure of 12 mm Hg, right ventricular pressure 70/12 mm Hg, pulmonary artery pressure 70/30 mm Hg, mean pulmonary capillary wedge pressure 28 mm Hg, left ventricular end diastolic pressure 23 mm Hg, and cardiac index 1.6 L/min/ m 2. A percutaneous endomyocardial biopsy revealed minimal inflammation, and Congo red stains were negative for amyloid. Immunofluorescence stains were unrevealing. Electron microscopy demonstrated a distinctive population of myocytes containing numerous lysosomes with whorled membranous accumulations of lipid. Although some cardiac myocytes were filled with these lysosomes, some contained few or none of these distinctive lysosomes (Fig. 1). The patient subsequently underwent successful coronary bypass grafting with placement of an internal mammary graft to the left anterior descending and two saphenous vein grafts. An intraoperative left ventricular myocardial biopsy was similar to the percutaneous right ventricular biopsy. The patient had an uneventful postoperative course and was discharged and given sotalol and warfarin for atrial fibrillation and diuretics and nifedipine. An a-galactosidase assay on peripheral leukocytes revealed
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January 1995 American Heart Journal
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Fig, 1. Electron micrographs from endomyocardial biopsy. A, Portions of several myocytes, one of which has numerous lysosomes filled with lamellar membranous deposits; adjacent myocytes have only a few small lipofucsin granules. (Original magnification x1575). B, Perinuclear location of m a n y characteristic lysosomes. (Original magnification ×2250).
decreased activity (7.6 n m o l / h r / m g of protein; normal 55.2 + 12.7 n m o l / h r / m g of protein) consistent with heterozygous a-galactosidase deficiency, F a b r y ' s disease. The family pedigree is depicted in Fig. 2. Although F a b r y ' s cardiomyopathy is uncommon and there currently exists no direct t r e a t m e n t for the enzyme deficiency, it remains an i m p o r t a n t diagnostic consideration for the p a t i e n t with a restrictive, hypertrophic cardi-
o m y o p a t h y because it is an X-linked disorder t h a t could affect other family members. 1 This is particularly true in view of the availability of screening tests for prenatal diagnosis and the detection of asymptomatic heterozygous females. 2 Percutaneous endomyocardial biopsy appears to be a useful way to diagnose cardiac involvement in F a b r y ' s disease. This finding contrasts with the low yield of endomyocardial biopsy for most dilated cardiomyopathies, lb
Volume 129, Number 1 American Heart Journal
Hillsley et
DEATH AT YOUNaAGE
Tr
~
2()1
~-A ~
~
PROTEINURIA 65
71
47 HTN
al.
44 ASTHMA
42
x
2 77
66 65 BRONCHIECTASISMULTISYSTEM FAILURE
4O ASTHMA
Fig. 2. Pedigree of our patient (generation III, arrow). No other members of kindred have been diagnosed with Fabry's disease, although patient's father had proteinuria and died at age 65. Patient's sister died from undiagnosed systemic disease. Patient's children (generation IV) are healthy except for asthma and hypertension.
The lysosomal pathologic characteristics demonstrated in the percutaneous endomyocardial biopsy in this patient were identical to those from the surgical biopsies. To our knowledge, this patient is the oldest patient to have the diagnosis of Fabry's disease made antemortem. There had been no previous diagnosis of Fabry's disease in this kindred despite proteinuria in her father and the death of her sister from multisystem failure. Unlike in hemizygous male patients, in females the presence of one functional and one defective allele makes the partial expression of Fabry's disease possible. Most likely incomplete penetrance is the result of lyonization of the normal X chromosome in some cells but lyonization of the abnormal X chromosome in others, s Consistent with this hypothesis is the pathologic observation in this woman that cardiac myocytes were unevenly involved; some myocytes had few or no abnormal lysosomes, and adjacent myocytes contained numerous lipid-filled lysosomes that occupied up to 50% of cell volume. a-Galactosidase levels are below normal but not zero in heterozygous females, and the clinical manifestations are typically less severe than those of hemizygous males. An atypical milder form of Fabry's disease confined to the myocardium has also been described in a 54-year-old male and may represent a clinically less severe abnormality of the a-galactosidase gene. 6 The differential diagnosis in this patient with proteinuria and restrictive cardiomyopathy was limited by the characteristic myocardial biopsy (Fig. 1), which revealed intracellular lysosomal membranous lipid accumulations and no evidence of amyloid deposition. Fabry's disease may also result in focal myocardial necrosis and fibrosis with hypertrophy and perinuclear vacuolization. 3 The coronary
arteries may show medial hypertrophy with extensive vacuolization of the smooth-muscle cells. Similar vascular changes may be seen in the kidneys. Numerous cytoplasmic bodies that appear birefringent with polarization microscopy are seen. These stain intensely with the lipid stain Sudan black B. The smooth-muscle cells of the endocardium and blood vessels are involved with glycolipid accumulation, as are the atrial and ventricular myocytes and the connective tissue cells of the mitral valve. 3 On electron microscopy, these glycolipid deposits consist of lamellar accumulations within lysosomes.4 There is no direct treatment for Fabry's disease, although enzyme replacement has transiently reduced circulating ceramide trihexosidase concentrations in two patients. 11 However, enzymatic assays 2 and molecular genetic techniques 12 have made prenatal screening and genetic counseling an important part of therapy in these patients. Consequently, although rare, Fabry's cardiomyopathy remains an important diagnostic consideration for patients with unexplained biventricular hypertrophy and heart failure.
REFERENCES
1. Brady RO, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L. Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967;276:1163-7. 2. Desnick R J, Allen KY, Desnick SJ, Raman MK, Bernlohr RW, Krivit W. Fabry's disease: enzymatic diagnosis of hemizygotes and heterozygores. Alpha-galactosidase activities in plasma, serum, urine, and leukocytes. J Lab Clin Med 1973;81:157-71. 3. Ferrans VJ, Hibbs RG, Burda CD. The heart in Fabry's disease. A hlstochemical and electron microscopic study. Am J Cardiol 1969;24:95110. 4. Desnick RJ, Blieden LC, Sharp HL, Hofschire PJ, Moiler JH. Cardiac
2O2
January 1995
T..--
,nutsteyet
al.
valvular anomalies in Fabry disease. Clinical, morphologic, and biochemical studies. Circulation 1976;54:818-25. 5. Sakuraba H, Yanagawa Y, Igarashi T, Suzuki Y, Suzuki T, Watanabe K, Ieki K, Shimoda K, Yamanaka T. Cardiovascular manifestations in Fahry's disease. A high incidence of mitral valve prolapse in hemizygotes and heterozygotes. Clin Ganet 1986;29:276-83. 6. Von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann B, Hubner G, Olsen EGJ, Christomanou H, Kandolf R, Bishop DF, Desnick RJ. An atypical variant of Fabry's disease with manifestations confined to the myocardium. New Engl J Med 1991;324:395-9. 7. Burda CD, Winder PR. Angiokeratoma corporis diffusum universale (Fabry's disease) in female subjects. Am J Med 1967;42:293-301. 8. Broadbent JC, Edwards WD, Gordon H, Hartzler GO, Krawisz JE. Fabry cardiomyopathy in the female confirmed by endomyocardial biopsy. Mayo Clin Proc 1981;56:623-8.
American Heart Journal
9. Rodriguez FH, Hoffman EO, Ordinario AT, Baliga M. Fabry's disease in a heterozygous woman. Arch Pathol Lab Med 1985;109:89-91. 10. Chow LC, Dittrich HC, Shabetai R. Endomyocardial biopsy in patients with unexplained congestive heart failure. Ann Intern Med 1988;109: 535-9. 11. Brady RO, Tallman JF, Johnson WG, Gal AE, Leahy WR, Quirk JM, Dekaban AS. Replacement therapy for inherited enzyme deficiency. Use of purified ceramidetrihexosidase in Fabry's disease. N Engl J Med 1973;289:9-14. 12. Ishii S, Sakuraba H, Shimmoto M, Minamikawa-Tachino R, Suzuki T, Suzuki Y. Fabry disease: detection of 13-bp deletion in alpha-galactosidase A gene and its application to gene diagnosis of heterozygotes. Ann Neurol 1991;29:560-4.