AUTHOR AND EDITOR INFORMATION

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• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
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• Follow-up
• Miscellaneous
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Background

In 1898, Johann Fabry and William Anderson independently described the first patients with angiokeratoma corporis diffusum. The enzyme deficiency that leads to the disease was identified in the 1960s.

Fabry disease is a progressive, destructive, life-threatening, X-linked disorder of glycosphingolipid metabolism caused by a deficiency in alpha-galactosidase A (alpha-Gal A), which is encoded by a gene on the long arm of the X chromosome (Xq22.1). Through DNA analysis, more than 300 alpha-Gal A mutations been identified in the gene that codifies alpha-Gal A (band Xq21.33-q.22.1). Most mutations occur only in a single pedigree (private mutation). Fabry disease is also commonly known as angiokeratoma corporis diffusum. Fabry disease is characterized by cutaneous angiokeratomas; hypohidrosis; acral pain and paresthesias; corneal opacities; renal failure; and disturbances in the cardiovascular, gastrointestinal, and central nervous systems.

Pathophysiology

Human alpha-Gal A is a lysosomal enzyme that catalyzes the hydrolysis of alpha-galactosidic linkages of glycoconjugates. The enzymatic defect, transmitted by an X-linked recessive gene, leads to the accumulation of neutral glycosphingolipids with terminal alpha-galactosyl moieties in most visceral tissues and body fluids. The most prominent of these glycosphingolipids is a globotriaosylceramide (GL-3), a degradation product of a constituent of membrane globoside. A second neutral glycosphingolipid, galabiosylceramide, occurs in affected males in abnormally high concentrations. Increased concentrations of GL-3 occur in all tissues except erythrocytes.

Most anatomic and physiologic abnormalities observed in persons with Fabry disease are related to the cumulative deposition of glycosphingolipid, particularly in the lysosomes of the cardiovascular-renal system. Lipid deposits are also prominent in the epithelial cells of cutaneous angiokeratomas, in the cornea, in the glomeruli and tubules of the kidney, in the muscle fibers of the heart, and in the ganglion cells of the dorsal roots and perineural cells of the autonomic nervous system.

Glycosphingolipid deposition in vascular smooth muscle of the media of larger vessels causes the vessels to lose resiliency and a weakening of the walls. Redistribution of tension in the vessel wall eventually causes dilation and results in tortuosity.

Frequency

International

The rate is approximately 1 case in 40,000-60,000 males. Recent population estimates have ranged from 1 case in 80,000 live births to 1 case in 117,000 live births.

Mortality/Morbidity

The mean patient age at death is 41 years, but patients may survive into their 60s.

Race

The disease is found among persons of all ethnicities.

Sex

The X-linked disorders affect males, while the female carriers are generally asymptomatic, owing in part to the random inactivation of the X chromosome. Carrier females for the classic phenotype are asymptomatic or have only mild disease manifestations, usually with a late onset and mild form of the disease.

• Some males may express residual alpha-Gal A activity, so they may be asymptomatic, or, they may have late-onset mild manifestations that are often limited to the heart. Males with blood group B or AB have a more severe course because of the accumulation of blood group B substance, which is normally degraded by alpha-Gal A. Patients with A or O blood groups accumulate globotriaosylceramide and galabiosylceramide.
• At times, the disease occurs in limited form in heterozygous females. Heterozygous females may have an attenuated form of the disease, usually with corneal opacities. Rarely, female carriers may develop disease manifestations as severe as those of affected males because of random X-chromosome inactivation.

Age

Clinical onset is variable. The disease usually appears in children, but it may occur in persons aged 20-30 years.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
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• Follow-up
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History

Fabry disease can be classified into 2 clinical phenotypes: the classic form and the cardiac variant. The classic form is mainly characterized, in affected hemizygous males, by angiokeratomas, acroparesthesias, hypohidrosis, pains, fever crises, and involvement of the kidneys, brain, and heart. Neurological and/or psychological manifestations with personality disturbances can also occur. The cardiac variant is characterized by symptoms restricted to cardiac abnormalities, including conduction defects and/or late-onset cardiomyopathy with left ventricular hypertrophy.

• Hemizygous males with classic manifestations
• • The disease usually begins during childhood (age 4-8 y) or adolescence.
  • Early manifestations include intermittent paresthesias and acroparesthesias (ie, chronic, burning, tingling pain, initially in the palms and soles). It can occur daily or, particularly, with a low-grade fever. Patients have episodic Fabry crises of agonizing, incapacitating pain that last for minutes to days. These events can disappear or worsen with adulthood, and they are often precipitated by emotional stress, fatigue, illness, physical exertion, or rapid climatic changes in temperature and humidity.
  • As the patients age to their 30s and 40s, these crises usually decrease in frequency and severity.
  • The paresthesias may occur daily during the late afternoon.
  • Attacks of abdominal or flank pain may simulate appendicitis or renal colic. Episodic diarrhea, nausea, and vomiting are the most common gastrointestinal symptoms.
  • Patients may have anginal chest pain related to the cardiovascular manifestations.

• Heterozygous females
• • Of heterozygous females, 70-90% have eye findings. Typical findings are cornea verticillata and tortuousities of the conjunctival and retinal vessels, as well as cataracts (lenticular opacities) that do not impair vision.
  • The clinical manifestations in carrier females for Fabry disease range from females being asymptomatic throughout a normal lifespan to females being as severely affected as males. Patients may have intermittent pain in their legs.
  • Patients may have chronic abdominal pain and diarrhea.
  • Carriers may develop mild-to-moderate enlargement of the left side of the heart (left ventricular hypertrophy), mild mitral valve prolapse, and renal failure.
  • Skin lesions (angiokeratomas) are usually isolated or sparse. Other skin findings can include pain in the extremities (acroparesthesia) and a decreased ability to sweat (hypohidrosis).

Physical

The signs and symptoms of Fabry disease vary. The clinical diagnosis in hemizygous males is most readily made on the basis of the history and the observation of the characteristic skin lesions and corneal dystrophy.

The disorder is often misdiagnosed as rheumatic fever or erythromelalgia. Angiokeratomas may also occur in a number of other hereditary deficiency states, such as fucosidosis, sialidosis, beta-mannosidase deficiency, galactosialidosis, aspartylglycosaminuria, adult-onset GM gangliosidosis, and alpha-N-acetylgalactosaminidase deficiency (Kanzaki disease). In occasional patients with disseminated angiokeratomas, no underlying disease can be discerned after a full evaluation.

Physical findings in patients with Fabry disease may include the following:

• Hemizygous males with classic phenotype
• • The clinical features predominantly result from the progressive deposition of glycosphingolipid GL-3 Gal-Gal-Glc-Cer in the vascular endothelium. The patients have very low or nondetectable alpha-Gal A activity.
  
  
  • Angiokeratomas usually appear in childhood. The lesions are punctate, flat, or slightly raised; they are dark red to blue-black; and they do not blanch with pressure. The larger nodules may have slight hyperkeratosis. The lesions increase in number and size as patients age. The cluster of lesions is most dense between the umbilicus and the knees, but the lesions may occur anywhere (hips, back, thighs, buttocks, penis, scrotum), including the oral mucosa and conjunctiva.
  
  
  • Sweating is usually decreased or absent, and the patient's hair may be sparse. An impaired ability to perspire leads to dry skin, which results in heat, cold, and exercise intolerance. Anhidrosis, or more commonly hypohidrosis, is found in approximately 50% of patients. Causes of such symptoms include lipid accumulation in the eccrine cells of the sweat glands and dysfunction of the autonomic nervous system.
  
  
  • Ocular involvement is most prominent in the cornea, lens, conjunctiva, and retina. Corneal opacities and lenticular angiokeratomas are present in affected men and asymptomatic heterozygous patients. Typically, the whorl-like opacities are inferior and cream colored. The conjunctival and retinal vessels may have mild-to-marked tortuosity, with aneurysmal dilatations of the thin-walled venules and angulation and segmental sausagelike dilatation of the veins. Neither corneal dystrophy nor the vascular lesions in the conjunctiva and retina impair the patient's vision. The 2 specific types of lenticular changes are (1) a granular anterior capsular or subcapsular deposit, which occurs in approximately one third of affected males but rarely in carrier females, and (2) lenticular opacity, which occurs in both affected males and carrier females. Acute visual loss may occur as a result of unilateral total central artery occlusion.
  
  
  • Cardiovascular manifestations occur in adulthood and may include anginal chest pain, myocardial ischemia and infarction, congestive heart failure, left ventricular hypertrophy usually with normal systolic function but mild-to-moderate impairment of diastolic function, mitral valve prolapse, mitral insufficiency, cardiac enlargement or arrhythmias, and atrioventricular block or short PR interval.
  
  
  • Cerebrovascular manifestations result from the multifocal involvement of small blood vessels and may include thromboses, hemianesthesia, basilar artery ischemia and aneurysm, seizures, hemiplegia, hemianesthesia, aphasia, labyrinthine disorders, and frank cerebral hemorrhage. Personality changes and psychotic behavior may occur as the patient ages.
  
  
  • Progressive glycosphingolipid deposition in the kidney results in proteinuria and other signs of renal impairment, with gradual deterioration of renal function and development of azotemia in middle age.
  
  
  • Because of the widespread visceral distribution of the glycosphingolipid deposits, symptoms of this disorder arise in many other organs and systems. Other manifestations include chronic bronchitis, wheezing respiration, or dyspnea with alveolar capillary block. Lymphedema of the lower extremities may be present in adults without hypoproteinemia or varices. Lymphedema reflects the progressive glycosphingolipid deposition in the lymphatic vessels and lymph nodes. Priapism has been associated with Fabry disease.
  
  
  • Gastrointestinal symptoms include episodic diarrhea, flank pain, weight loss, nausea, and vomiting.
  
  
  • Anemia is probably due to decreased red blood cell survival. Patients may have decreased iron concentrations, normal red blood cell fragility, and elevated reticulocyte counts.
  
  
  • Many hemizygous males appear to have retarded growth or delayed onset of puberty and sparse, fine facial and body hair.
  
  
  • Death is due to renal failure or vascular disease of the heart or brain.


• Atypical hemizygous males with the cardiac variant
• • Patients are asymptomatic during most of their lives and present in the sixth to eighth decade of life with cardiac or cardiopulmonary disease, including cardiomegaly, left ventricular wall and interventricular septum with mitral insufficiency, and/or cardiomyopathy.
  
  
  • Males have residual alpha-Gal A activity.
  
  
  • Mild proteinuria may be present.


• Carrier female
• • In some heterozygous patients, severe renal or cardiac involvement develops with advanced age. Other manifestations may include vascular lesions in the conjunctiva and retina or corneal opacities.
  
  
  • Angiokeratomas are less prominent (approximately 30%) in affected female patients than in affected male patients. These lesions may occur in a characteristic distribution on the lips, breasts, back, posterolateral thighs or trunk. The lesions have been detected in heterozygous patients during childhood.
  
  
  • Urologic findings and signs of renal impairment may be present. Renal findings include hyposthenuria and proteinuria, along with other signs of renal impairment (see Lab Studies).

Causes

Fabry disease results from deficient activity of the enzyme alpha-Gal A and progressive lysosomal deposition of GL-3 in cells throughout the body. The classic form, occurring in males with less than 1% alpha-Gal A activity, usually has its onset in childhood or adolescence, with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of vascular cutaneous lesions (angiokeratomas), hypohidrosis, characteristic corneal and lenticular opacities, and proteinuria. Cardiac involvement is frequent, and, in individuals with some residual enzyme activity, it may be the sole manifestation of the disease. The dominant cardiac manifestation includes left ventricular hypertrophy, which may mimic hypertrophic cardiomyopathy.

Gradual deterioration of renal function to end-stage renal disease usually occurs in the third to fifth decade. In middle age, most males successfully treated for end-stage renal disease develop cardiovascular and/or cerebrovascular disease, a major cause of morbidity and mortality.

• Heterozygous carrier females may be relatively asymptomatic throughout a normal life span, manifesting some symptoms of the disease with increasing age. Rarely, they may express disease that is as severe as that observed in males with the classic phenotype.
• Males with greater than 1% alpha-Gal A activity have a cardiac or renal variant phenotype.
• Cardiac variants usually manifest in the sixth to eighth decade with left ventricular hypertrophy, mitral insufficiency and/or cardiomyopathy, and proteinuria.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Adult-onset GM gangliosidosis
Alpha-N-acetylgalactosaminidase deficiency
Aspartylglycosaminuria
Beta-mannosidase deficiency
Erythromelalgia
Fucosidosis
Galactosialidosis
Kanzaki disease
Rheumatic fever
Sialidosis

WORKUP

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Lab Studies

• The diagnosis is biochemically confirmed by the demonstration of markedly deficient alpha-Gal A activity in the plasma or serum, leukocytes, or cultured lymphoblasts or skin fibroblasts. Heterozygous females may have intermediate levels of alpha-Gal A in their plasma or cells. The test is a fluorometric assay.


• Urinary findings include the following:
• • Increased GL-3 levels are found in the urinary sediment, plasma, and cultured fibroblasts.
  
  
  • Maltese crosses can be observed inside and outside the cells in the urinary sediment by using polarized light microscopy.
  
  
  • Protein, red blood cells, casts, and desquamated cells from the kidneys and urinary tract appear in the urine. In heterozygous patients, signs of renal impairment may also include hyposthenuria and the presence leukocytes and granular and hyaline casts in urinary sediment.


• Significant increases of vitronectin receptor in urinary excretion (integrin alpha V beta 3) and expression of vitronectin receptor in kidney tissues suggest pathophysiological involvement of integrins in the progression of renal injury.


• As reported by Pieroni et al in 2004, the development of effective enzyme replacement/enhancement therapy allows significant modification of clinical disease progression and encourages the need for early diagnosis of Fabry cardiomyopathy.


• The erythrocyte sedimentation rate is elevated. Iron concentrations are decreased in serum. The reticulocyte count is elevated.

Imaging Studies

• Cardiovascular system
• • Dysrhythmias such as ST segment changes, T-wave inversion, intermittent supraventricular tachycardias, and a short PR interval may be caused by infiltration of the conduction system.
  • Echocardiographic studies demonstrate an increased frequency of mitral valve prolapse and an increased thickness of the interventricular septum and the left ventricular posterior wall.
  • Tissue Doppler imaging may provide early detection of cardiac involvement in persons with Fabry disease and represents the most accurate and sensitive noninvasive tool for the diagnosis of myocardial dysfunction and for the assessment of cardiac improvement during enzyme replacement therapy.

• Ocular system: Characteristic corneal dystrophy can be observed during slit-lamp examination or with a confocal-laser scanning microscope.
• Neurological system: MRI, transcranial Doppler techniques, and water positron tomography emission may be more sensitive than a neurological examination for detection central nervous system involvement and progression in persons with Fabry disease.

Other Tests

• Tests for prenatal diagnosis may be useful (see Special Concerns).

Histologic Findings

Angiokeratomas of Fabry disease are typical angiokeratomas that demonstrates true vascular ectasia of the papillary dermis with overlying epidermal hyperplasia. Thus, hyperkeratosis, acanthosis, and elongated rete ridges overlie numerous thin-walled, dilated, and predominantly papillary dermal capillaries. Endothelial cells may have cytoplasmic vacuoles as lipid accumulates. Similar vacuoles may also be evident in fibroblasts and pericytes.

Lipid-containing macrophages may be evident in bone marrow aspirates. Patients with Fabry disease have only a small amount of glycolipid present in the skin; therefore, the use of special stains on unfixed or formalin-fixed frozen sections is required. Sudan black staining is useful in revealing these lipid deposits in the endothelial cells and pericytes (see Media Files 2-3), and it may be more helpful than scarlet red staining. The lipid deposits may also be evident in the fibroblasts and in arrector pilorum muscles. Periodic acid-Schiff staining with diastase shows the carbohydrate component well.

Because the lipid is doubly refractile, polariscopic examination may also be performed. These deposits may be seen within the endothelial cells and pericytes of normal-appearing skin in patients with Fabry disease. Under electron microscopy, lipid inclusions have a concentric lamellar structure with alternating light- and dark-staining bands (ie, zebra bodies). In the peripheral nerves, densely stained inclusions are present in the cytoplasm of perineurial fibroblasts and in the endothelial cells of the endoneurial blood vessels. Unmyelinated neurons but not myelinated neurons are lost. Some neurons contain ceramide trihexoside. An accumulation of glycosphingolipid may be evident in endothelial and epithelial cells of the glomerulus, in the Bowman space, and in the epithelium of the loop Henle and distal tubules. Other histologic changes in the kidneys are the sequelae or are nonspecific. Peripheral nerves may be swollen, and unmyelinated axons may be disrupted.

TREATMENT

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Medical Care

• Chronic acroparesthesias may be relieved with corticosteroids or with phenytoin, diphenylhydantoin, carbamazepine, or gabapentin.
• Alpha-Gal A purified from human placenta has been administered to several hemizygotes.
• Enzyme replacement with purified splenic and plasmic forms of alpha-galactosidase is an excellent option (agalsidase beta and agalsidase alfa).
• Cardiac, pulmonary, and cerebrovascular manifestations are nonspecific.
• Gastrointestinal manifestations may improve with the oral prokinetic drug, metoclopramide.

Surgical Care

• Renal insufficiency can be treated with long-term hemodialysis.
• Other options are renal transplantation or fetal liver transplantation.
• The implantation of the pacemaker may be useful.

MEDICATION

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Phenytoin, gabapentin, and carbamazepine decrease the frequency and severity of the chronic acroparesthesias and the periodic pain crises.

Drug Category: Anticonvulsants

These agents have central and peripheral anticholinergic effects and sedative effects, and they block the active reuptake of norepinephrine and serotonin. The multifactorial mechanism of analgesia could include improved sleep, an altered perception of pain, and an increased pain threshold.

Drug Category: Enzyme replacement therapy agents

FOLLOW-UP

Section 8 of 11  

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Further Outpatient Care

• Patients with this disorder need regular evaluations.

Prognosis

• The disorder is progressive, and death is usually the result of hypertension and renal failure.
• The mean patient age at death is 41 years, but patients may survive into their 60s.

Patient Education

• Extensive patient education is essential.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• The signs and symptoms of Fabry disease vary, but making the correct diagnosis is important because advancing disease results in increased morbidity and, ultimately, early mortality.

Special Concerns

• Prenatal testing is available and can be performed on fetal cells obtained from either chorionic villus sampling at approximately 10-12 weeks' pregnancy or amniocentesis usually performed at approximately 15-18 weeks' gestation. In males, Fabry disease can be prenatally diagnosed on the basis of the following:
• • Deficient alpha-Gal A activity in the first trimester
  • Specific mutation in the chorionic villi in the first trimester
  • Cultured amniocytes in the second trimester

• Positive results include deficient alpha-Gal A activity, an XY karyotype in cultured amniotic cells, and an accumulation of trihexosylceramide in the amniotic fluid.

MULTIMEDIA

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Media file 1:  Large number of 1- to 2-mm angiokeratomas in a patient with Fabry disease.
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Media type:  Photo

Media file 2:  Cutaneous histologic section shows lipid granules in the endothelial cells (Sudan black stain, original magnification X12). See Image 3.
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Media type:  Image

Media file 3:  Higher-power photomicrograph of the section in Image 2 better demonstrates the lipid granules in the endothelial cells (Sudan black stain, original magnification X315).
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Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
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• Baehner F, Kampmann C, Whybra C, Miebach E, Wiethoff CM, Beck M. Enzyme replacement therapy in heterozygous females with Fabry disease: results of a phase IIIB study. J Inherit Metab Dis. 2003;26(7):617-27. [Medline].
• Brady RO, Schiffmann R. Clinical features of and recent advances in therapy for Fabry disease. JAMA. Dec 6 2000;284(21):2771-5. [Medline].
• Brown LK, Miller A, Bhuptani A, Sloane MF, Zimmerman MI, Schilero G, et al. Pulmonary involvement in Fabry disease. Am J Respir Crit Care Med. Mar 1997;155(3):1004-10. [Medline].
• Davies JP, Winchester BG, Malcolm S. Mutation analysis in patients with the typical form of Anderson-Fabry disease. Hum Mol Genet. Jul 1993;2(7):1051-3. [Medline].
• Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. Feb 18 2003;138(4):338-46. [Medline].
• Eckart RE, Kinney KG, Belnap CM, Le TD. Ventricular fibrillation refractory to automatic internal cardiac defibrillator in Fabry's disease. Review of cardiovascular manifestations. Cardiology. 2000;94(3):208-12. [Medline].
• Grewal RP. Stroke in Fabry's disease. J Neurol. Jan 1994;241(3):153-6. [Medline].
• Hasholt L, Sørensen SA, Wandall A, Andersen EB, Arlien-Søborg P. A Fabry's disease heterozygote with a new mutation: biochemical, ultrastructural, and clinical investigations. J Med Genet. May 1990;27(5):303-6. [Medline].
• Jardim L, Vedolin L, Schwartz IV, Burin MG, Cecchin C, Kalakun L, et al. CNS involvement in Fabry disease: clinical and imaging studies before and after 12 months of enzyme replacement therapy. J Inherit Metab Dis. 2004;27(2):229-40. [Medline].
• Kodama K, Kobayashi H, Abe R, Ohkawara A, Yoshii N, Yotsumoto S, et al. A new case of alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum, with Ménière's syndrome and without mental retardation. Br J Dermatol. Feb 2001;144(2):363-8. [Medline].
• Kosch M, Koch HG, Oliveira JP, Soares C, Bianco F, Breuning F, et al. Enzyme replacement therapy administered during hemodialysis in patients with Fabry disease. Kidney Int. Sep 2004;66(3):1279-82. [Medline].
• Lidove O, Klein I, Lelièvre JD, Lavallée P, Serfaty JM, Dupuis E. Imaging features of Fabry disease. AJR Am J Roentgenol. Apr 2006;186(4):1184-91. [Medline].
• MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet. Nov 2001;38(11):769-75. [Medline].
• Mastropasqua L, Nubile M, Lanzini M, Carpineto P, Toto L, Ciancaglini M. Corneal and conjunctival manifestations in Fabry disease: in vivo confocal microscopy study. Am J Ophthalmol. Apr 2006;141(4):709-18. [Medline].
• Pieroni M, Chimenti C, Russo A, Russo MA, Maseri A, Frustaci A. Tissue Doppler imaging in Fabry disease. Curr Opin Cardiol. Sep 2004;19(5):452-7. [Medline].
• Ries M, Bettis KE, Choyke P, Kopp JB, Austin HA 3rd, Brady RO, et al. Parapelvic kidney cysts: a distinguishing feature with high prevalence in Fabry disease. Kidney Int. Sep 2004;66(3):978-82. [Medline].
• Rodriguez FH Jr, Hoffmann EO, Ordinario AT Jr, Baliga M. Fabry's disease in a heterozygous woman. Arch Pathol Lab Med. Jan 1985;109(1):89-91. [Medline].
• Scriver CR, Beaudet AL, Sly WS. The Metabolic and Molecular Bases of Inherited Diseases. New York: McGraw-Hill; 1995.
• Seino Y, Takahashi H, Fukumoto H, Utsumi K, Hirai Y. Cardiovascular manifestations of Fabry disease and the novel therapeutic strategies. J Nippon Med Sch. Oct 2005;72(5):254-61. [Medline].
• Utsumi K, Itoh K, Kase R, Shimmoto M, Yamamoto N, Katagiri Y, et al. Urinary excretion of the vitronectin receptor (integrin alpha V beta 3) in patients with Fabry disease. Clin Chim Acta. Jan 1999;279(1-2):55-68. [Medline].
• Wilcox WR, Banikazemi M, Guffon N, Waldek S, Lee P, Linthorst GE, et al. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet. Jul 2004;75(1):65-74. [Medline].

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