Splenomegaly, hypersplenism and peripheral blood cytopaenias in patients with classical Anderson–Fabry disease

Oliveira, João Paulo; Valbuena, Carmen; Moreira, António Baldaia; Fonseca, Elsa; Soares, Carlos; Leão‐Teles, Elisa; Waldek, Stephen

doi:10.1007/s00428-008-0651-4

Cited by 10 publications

(6 citation statements)

References 44 publications

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“…The ceramide moiety is lipophilic and soluble in non-polar solvents, while the oligosaccharide chains are hydrophilic and may remain within the vacuoles in tissue sections routinely processed for LM. These residual carbohydrates can be non-specifically identified as argyrophilic granules in methenamine silver-stained [18,22] and in PASstained (Valbuena, personal observation) [1] FFPE tissue.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical diagnosis of Fabry nephropathy and localisation of globotriaosylceramide deposits in paraffin-embedded kidney tissue sections

et al. 2011

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Fabry disease (FD) is a rare X-linked lysosomal storage disorder of glycosphingolipids, mostly globotriaosylceramide (Gb3). Proteinuric chronic kidney disease develops frequently, and recognition of Fabry nephropathy on a kidney biopsy may be the first clue to the underlying diagnosis. Since the accumulated glycosphingolipids are largely extracted by the paraffin-embedding procedure, the most characteristic feature of Fabry nephropathy on routine light microscopy (LM) is nonspecific cell vacuolization. To test whether residual Gb3 in kidney tissue might be exploited for the specific diagnosis of Fabry nephropathy, paraffin-embedded kidney biopsies of nine FD patients (one boy, four men, four women) and of a female carrier of a mild genetic mutation, with no evidence of Fabry nephropathy, were immunostained with an anti-Gb3 antibody. The adult biopsies were additionally co-stained with a lysosomal marker (anti-lysosomal-associated membrane protein 2 (anti-LAMP2) antibody). The distribution of Gb3 deposits was scored per cell type and compared to the histological scorings of glycosphingolipid inclusions on semi-thin sections. FD patients had residual Gb3 in all types of glomerular, tubular, interstitial and vascular kidney cells. The highest expression of LAMP2 was seen in tubular cells, but there were no meaningful associations between LAMP2 expression and prevalence of Gb3 deposits on different kidney cell types. The histological scorings of glycosphingolipid inclusions were relatively higher than the corresponding immunohistochemical scorings of Gb3 deposits. In the mildly affected female, Gb3 expression was limited to tubular cells, a pattern similar to controls. Gb3 immunostaining allows the specific diagnosis of Fabry nephropathy even in kidney biopsies routinely processed for LM.

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Section: Discussionmentioning

confidence: 99%

Immunohistochemical diagnosis of Fabry nephropathy and localisation of globotriaosylceramide deposits in paraffin-embedded kidney tissue sections

et al. 2011

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“…Data from the FOS ® and the Fabry Registry ® show that mild peripheral blood cytopenias, particularly anemia [162], are prevalent among patients with FD [163]. …”

Section: Reviewmentioning

confidence: 99%

Fabry disease

Germain

2010

Orphanet J Rare Dis

1,010

1,230

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Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones.

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“…Theoretically, our patient may not have developed full‐blown childhood FD because of his residual enzyme activity. Delayed bone maturation and splenomegaly have been reported in FD (5,6).…”

Section: Discussionmentioning

confidence: 99%

Petechial‐Like Lesions, Eye Abnormalities, and Albuminuria in a Young Boy

Roganović¹

2011

Pediatric Dermatology

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A 10-year-old boy presented with a 1-year history of a solitary brown patch on the right side of his scrotum. In the following months, further asymptomatic lesions similar in appearance developed on his right leg and persisted unchanged. The boy was otherwise healthy, and there was no history of prior skin disease or congenital anomalies. Exogenous triggers, infections, allergies, and intake of drugs were denied.On physical examination, several purpuric to golden-brown, irregularly shaped patches with tiny interspersed red papules were noted on the right side of his scrotum and his right leg in a segmental distribution (Fig. 1). Diascopy revealed a yellowish to brown color of the lesions, which were studded with purpuric spots (Fig. 2). Vesicles were absent. Color-coded ultrasound of the right leg demonstrated a normal venous and arterial vascular system. Laboratory investigations were unremarkable. A biopsy was taken from a lesion on the right leg. Histopathology is shown in Figs 3 and 4.

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Splenomegaly, hypersplenism and peripheral blood cytopaenias in patients with classical Anderson–Fabry disease

Cited by 10 publications

References 44 publications

Immunohistochemical diagnosis of Fabry nephropathy and localisation of globotriaosylceramide deposits in paraffin-embedded kidney tissue sections

Immunohistochemical diagnosis of Fabry nephropathy and localisation of globotriaosylceramide deposits in paraffin-embedded kidney tissue sections

Fabry disease

Petechial‐Like Lesions, Eye Abnormalities, and Albuminuria in a Young Boy

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