Many Fabry disease patients experience, from childhood, wheezing, asthma, and dyspnea. As well as otherdisease manifestations, pulmonary involvement appears to be age and gender dependent. In younger patients,functional tests suggest small airways obstruction. Later, overt bronchial obstruction is developing, more so inhemizygous male than in heterozygous female patients.2

Several cases suggest that enzyme-replacement therapy is able to improve the disease at this stage.3 Veryadvanced cases are characterized by combined obstructive and restrictive ventilatory impairment.2 Some authorshave described even diffusion capacity decrease.4 However, this may reflect an overall decrease in ventilatorycapacity rather than impairment of alveolocapillary membrane.

Along with impaired pulmonary function, Fabry disease patients may present with enhanced peribronchialcuffing on chest x-ray and computed tomography findings, compatible with some degree of pulmonary fibrosis.

Cardiopulmonary testing in Fabry disease shows reduced overall exercise capacity associated with a decrease inVO2max and incapacity to reach maximum predicted heart rate. Although the main reason for this finding may bedue to cardiac involvement, the contribution of pulmonary disease cannot be ruled out.5

Assessments of pulmonary involvement should not be omitted since smoking cessation and bronchodilatorytreatment may improve or slow the disease process.

REFERENCES1. Brown LK, Miller A, Bhuptani A, et al. Pulmonary involvement in Fabry disease. Am J Respir Crit Care Med. 1997;155:1004–1010.2. Magage S, Lubanda JC, Susa Z, et al. Natural history of the respiratory involvement in Anderson-Fabry disease. J Inherit Metab Dis.

2007;30:790–799.3. Kariman K, Singletary WV Jr, Sieker HO. Pulmonary involvement in Fabry’s disease. Am J Med. 1978;64:911–912.4. Kim W, Pyeritz RE, Bernhardt BA, et al. Pulmonary manifestations of Fabry disease and positive response to enzyme replacement

therapy. Am J Med Genet A. 2007;143:377–381.5. Koskenvuo JW, Kantola IM, Nuutila P, et al. Cardiopulmonary involvement in Fabry’s disease. Acta Cardiol. 2010;65:185–192.

Blood PressureDr. Alberto Ortiz

Department of Nephrology, IIS-Fundacion Jimenez Diaz, Madrid, Spain

High blood pressure promotes central nervous system, heart, and kidney injury, and the risk for an adversecardiovascular outcome increases continuously from blood pressure values of 115/75 to 185/115 mm Hg. Targetorgans of hypertension are also Fabry disease target organs.

Fabry disease has been historically associated with impaired orthostatic responses and even orthostatic hypo-tension.1 However, a review of older literature and recent data from the Fabry Registry and chart reviews indicatethat many Fabry patients have blood pressure values above those recommended for patients with chronic kidneydisease (CKD) or cardiovascular risk.2–4 CKD is defined as the persistence (for 3 or more months) of decreasedglomerular filtration rate (GFR) (CKD stages 3–5; �60 mL/min/1.73 m2) or evidence of kidney injury with higherGFRs (CKD stage 1–2).5 Such evidence includes either histologic abnormalities or proteinuria or hematuria. GFRmay be estimated from serum creatinine. Thus, many patients with Fabry disease have CKD either because theyhave renal deposits on histology, proteinuria, or decreased GFR. Current recommendations indicate that CKDpatients should have blood pressure values �130 mm Hg for systolic AND �60 mm Hg for diastolic.6 Data fromthe Fabry Registry (446 patients), a Fabry outcomes survey (376 patients), and retrospective chart reviews (447patients) indicate that around 50% of Fabry patients with CKD stage 1–2 and 80% of patients with CKD stages 3–5had blood pressure values above the limits recommended for CKD patients.2–4 The prevalence of uncontrolledhypertension increases with age and stage of CKD. Although there are no interventional trials in Fabry disease, itwould be reasonable to treat blood pressure in Fabry patients as in the general CKD population. In this regard,blood pressure, serum creatinine, and albuminuria or proteinuria should be monitored in Fabry patients. Thetherapy of choice for high blood pressure values would be angiotensin-converting enzyme inhibitors or angiotensinreceptor blockers, since they have antiproteinuric activity and may cooperate with enzyme-replacement therapy topreserve renal function in Fabry patients.7,8

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REFERENCES1. Hilz MJ, Marthol H, Schwab S, et al. Enzyme replacement therapy improves cardiovascular responses to orthostatic challenge in

Fabry patients. J Hypertens. 2010;28:1438–1448.2. Ortiz A, Oliveira JP, Waldek S, et al. Nephropathy in males and females with Fabry disease: cross-sectional description of patients

before treatment with enzyme replacement therapy. Nephrol Dial Transplant. 2008;23:1600–1607.3. Schiffmann R, Warnock DG, Banikazemi M, et al. Fabry disease: progression of nephropathy, and prevalence of cardiac and

cerebrovascular events before enzyme replacement therapy. Nephrol Dial Transplant. 2009;24:2102–2111.4. Kleinert J, Dehout F, Schwarting A, et al. Prevalence of uncontrolled hypertension in patients with Fabry disease. Am J Hypertens.

2006;19:782–787.5. National Kidney Foundation. Kidney Disease Outcomes Quality Initiative (K/DOQI). Am J Kidney Dis. 2002;39(2 Suppl 1):S1–266.6. National Kidney Foundation. Kidney Disease Outcomes Quality Initiative (K/DOQI). Am J Kidney Dis. 2004;43(5 Suppl 1):S1–S290.7. Ortiz A, Oliveira JP, Wanner C, et al. Recommendations and guidelines for the diagnosis and treatment of Fabry nephropathy in

adults. Nat Clin Pract Nephrol. 2008;4:327–360.8. Tahir H, Jackson LL, Warnock DG. Antiproteinuric therapy and Fabry nephropathy: sustained reduction of proteinuria in patients

receiving enzyme replacement therapy with agalsidase-beta. J Am Soc Nephrol. 2007;18:2609–2617.

Peripheral Blood Cytopenias and Spleen PathologyDr. João Paulo Oliveira

Office of Human Genetics, Faculty of Medicine University of Porto, Hospital de São Joao, Porto, Portugal

Fabry disease (�-galactosidase A deficiency) is a lysosomal storage disorder of globotriaosylceramide (Gb-3) andother neutral glycosphingolipids that predominantly affects endothelial and smooth muscle cells of the vascularwall, cardiomyocytes, peripheral nerves, and kidneys.1 Storage of Gb-3 in cells of the reticuloendothelial system(RES) of the bone marrow, lymph nodes, spleen, and liver also occurs in Fabry disease, but in contrast to Gaucherdisease (an RES glycosphingolipidosis with prominent hematologic manifestations), the involvement of the RES isnot clinically recognized in most Fabry patients.

Before the metabolic defect underlying Fabry disease was elucidated, several case reports were published thatdescribed patients with clinically apparent lymph node and spleen enlargement as well as with low plateletcounts.2,3,4,5 Yet although it is recognized that generalized lymph node enlargement may be a presenting sign,1,6

splenomegaly is not regarded as a phenotypic manifestation of Fabry disease.1 Furthermore, anemia has recentlybeen identified as a frequent and early complication of Fabry disease,7 in most instances related to impaired renalfunction, heart failure, and inflammation, but its pathogenesis remains incompletely understood.

A clinical observation—generalized lymphadenopathy, splenomegaly, and peripheral blood cytopenias in thenatural course of the disease in a male carrying an �-galactosidase genetic mutation (GLA p.C94S) causing a severephenotype—led us to test the hypothesis that Fabry disease is associated with a hematologic phenotype morefrequently than is currently recognized.8 In addition, as this patient underwent splenectomy for symptomatichypersplenism, including severe thrombocytopenia, after 15 years on chronic hemodialysis, we had the opportunityto describe in detail the histopathology of the spleen.

The most relevant findings on the surgical specimen were the following: congestion and expansion of the redpulp; signs of extramedullary hematopoiesis; cytoplasmic vacuolation and abundant iron deposits in macrophages;foci of hemophagocytosis; and reactive aspect of the sinusoidal endothelium, with vacuolation and argyrophilicmaterial within the cytoplasm of endothelial cells.

In a review of the clinical records of all of the males with the classic phenotype of Fabry disease who have beendiagnosed and followed up for at least 1 year at our hospital (n � 10; mean age at death or censoring, 26.4 years),we identified another young adult patient presenting with lymphadenopathy, and a child with an enlarged spleenby ultrasonographic criteria. The prevalence of peripheral blood cytopenias in this cohort ranged between 50% foranemia and 20% for leukopenia.

Using the same standard cell count cutoffs in peripheral blood samples, the prevalences of anemia, leukopenia,and thrombocytopenia in adult males enrolled in the Fabry Registry in whom these data were available were,

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