This is a rare metobolic storage disorder. It is caused by a deficiency of an enzyme located on the X-chromosome. This enzyme is known as ceramidetrihexosidase, also called alpha-galactosidase A, and is needed to Its function is to cleave a molecule of galactose from a lipid that arises primarily from old red blood cells. In this disease, there are mutations in the gene that codes for the enzyme resulting in a deficiency. The result is an accumulation of these lipids that are normally degraded.
Since the disease is an X-linked disorder, a mother carrying one dose of the defective gene can pass it on to her children, in a sex-linked fashion. Male children have a 50% chance of having the condition and female children have a 50% chance of being a carrier.
Male children bear most of manifestations of the disease. They may have burning sensations in their hands and feet, secondary to involvement of the vessels and peripheral nerves. A characteristic skin tumor is an angiokeratoma, characterized by raised, reddish-purple blemishes. More serious complications of the disease included impaired arterial circulation with early heart attacks and strokes. The kidneys are progressively damaged leading to kidney failure. Gastrointestinal difficulties with frequent bowel movements after eating may also occur.
Female carriers may show cloudiness of the cornea and lesser degrees of the disease that it is usually manifest in male children.
Epidemiology Pathogenesis Laboratory/Radiologic/
Other Diagnostic Testing
Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS
Alpha-galactosidase A deficiency
Angiokeratoma corporis diffusum,
INCIDENCE/PREVALENCE Rare AGE From birth SEX X-linked recessive
Males have greater chance of full manifestations of the disease
Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes.
Whybra C, Kampmann C, Willers I, Davies J, Winchester B, Kriegsmann J, Bruhl K, Gal A, Bunge S, Beck M.
Children's Hospital, University of Mainz, University Hospital Hamburg-Eppendorf, Germany.
J Inherit Metab Dis 2001 Dec;24(7):715-24 Abstract quote
Anderson-Fabry disease is a rare, X-chromosomal lipid storage disorder caused by a deficiency of lysosomal alpha-galactosidase A. Clinical manifestations of Anderson-Fabry disease include excruciating pain in the extremities (acroparaesthesia), skin vessel ectasia (angiokeratoma), corneal and lenticular opacity, cardiovascular disease, stroke and renal failure, only renal failure being a frequent cause of death.
Heterozygote female carriers have often been reported as being asymptomatic or having an attenuated form of the disease. To evaluate the spectrum of clinical signs in heterozygotes, a comprehensive clinical examination was performed on 20 carriers of Anderson-Fabry disease. This revealed that, in addition to the skin manifestation, various other clinical manifestations of the disease are present, including acroparaesthesia, kidney dysfunction, cerebrovascular disease, and gastrointestinal and heart problems.
It therefore appears that Anderson-Fabry disease affects both hemizygotes and heterozyotes and therefore should be considered to be an X-linked dominant disease.
PATHOGENESIS CHARACTERIZATION ALPHA-GALACTOSIDASE A MUTATIONS
Fabry disease: twenty novel alpha-galactosidase A mutations and genotype-phenotype correlations in classical and variant phenotypes.
Germain DP, Shabbeer J, Cotigny S, Desnick RJ.
Department of Genetics, Hopital Europeen Georges Pompidou, Paris, France.
Mol Med 2002 Jun;8(6):306-12 Abstract quote
BACKGROUND: Fabry disease (OMIM 301500) is an X-linked inborn error of glycosphingolipid metabolism resulting from mutations in the alpha-galactosidase A (alpha-Gal A) gene. The disease is phenotypically heterogeneous with classic and variant phenotypes. To assess the molecular heterogeneity, define genotype/phenotype correlations, and for precise carrier identification, the nature of the molecular lesions in the alpha-Gal A gene was determined in 40 unrelated families with Fabry disease.
MATERIALS AND METHODS: Genomic DNA was isolated from affected males or obligate carrier females and the entire alpha-Gal A coding region and flanking sequences were amplified by PCR and analyzed by automated sequencing. Haplotype analyses were performed with polymorphisms within and flanking the alpha-Gal A gene.
RESULTS: Twenty new mutations were identified (G43R, R49G, M72I, G138E, W236X, L243F, W245X, S247C, D266E, W287C, S297C, N355K, E358G, P409S, g1237del15, g10274insG, g10679insG, g10702delA, g11018insA, g11185-delT), each in a single family. In the remaining 20 Fabry families, 18 previously reported mutations were detected (R49P, D92N, C94Y, R112C [two families], F113S, W162X, G183D, R220X, R227X, R227Q, Q250X, R301X, R301Q, G328R, R342Q, E358K, P409A, g10208delAA [two families]). Haplotype analyses indicated that the families with the R112C or g10208delAA mutations were not related. The proband with the D266E lesion had a severe classic phenotype, having developed renal failure at 15 years. In contrast, the patient with the S247C mutation had a variant phenotype, lacking the classic manifestations and having mild renal involvement at 64 years.
CONCLUSIONS: These results further define the heterogeneity of alpha-Gal A mutations causing Fabry disease, permit precise heterozygote detection and prenatal diagnosis in these families, and provide additional genotype/phenotype correlations in this lysosomal storage disease.
Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis.
Eitzman DT, Bodary PF, Shen Y, Khairallah CG, Wild SR, Abe A, Shaffer-Hartman J, Shayman JA.
Divisions of Cardiology and Nephrology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
J Am Soc Nephrol 2003 Feb;14(2):298-302 Abstract quote
ABSTRACT. Fabry disease is an X-linked lysosomal storage disorder due to deficiency of alpha-galactosidase A (GLA) activity that results in the widespread accumulation of neutral glycosphingolipids. Renal failure, neuropathy, premature myocardial infarction, and stroke occur in patients with this condition primarily due to deposition of glycosphingolipids in vascular endothelial cells.
The clinical consequences of Fabry disease suggest that vascular thrombosis may play a prominent role in the pathogenesis of this disease; however, the vasculopathy associated with Fabry disease has not been extensively studied.
To determine if mice genetically deficient in Gla are susceptible to vascular thrombosis, a photochemical carotid injury model was used to induce occlusive thrombosis. In this model, Gla-/0 mice displayed a progressive age-dependent shortening of the time to occlusive thrombosis after vascular injury that correlated with progressive accumulation of globotriasylceramide (Gb3) in the arterial wall. Bone marrow transplantation from Gla-/0 to Gla+/0 mice and from Gla+/0 to Gla-/0 mice did not change the thrombotic phenotype of the host.
These studies reveal a potent vascular prothrombotic phenotype in Gla-deficient mice and suggest that antithrombotic therapies as well as therapies designed to reduce the vascular accumulation of Gb3 may have beneficial effects on thrombotic complications in patients with Fabry disease.
CHARACTERIZATION RADIOLOGIC LABORATORY MARKERS ENZYME LEVELS
Rapid quantitation of globotriaosylceramide in human plasma and urine: a potential application for monitoring enzyme replacement therapy in Anderson-Fabry disease.
Boscaro F, Pieraccini G, la Marca G, Bartolucci G, Luceri C, Luceri F, Moneti G.
Centro Interdipartimentale di Spettrometria di Massa, Universita di Firenze, Viale G. Pieraccini 6, 50139 Firenze, Italy.
Rapid Commun Mass Spectrom 2002;16(16):1507-14 Abstract quote
A method for measuring globotriaosylceramide (Gb3, or GL3) levels in plasma and urine of humans affected by Anderson-Fabry disease has been developed. The analyses are performed using flow injection analysis-electrospray ionization-tandem mass spectrometry (FIA-ESI-MS/MS).
The method is rapid, sensitive and hence suitable for high-throughput analyses, requiring only a simple 50-fold dilution for the preparation of plasma and urine samples. The detection of the analytes of interest was achieved using a triple quadrupole instrument operating in the multiple reaction monitoring mode. The linearity of the calibration standard responses, the intra- and inter-assay precision, the accuracy and the detection limit of the method were evaluated.
The proposed method allows a rapid and accurate assessment of globotriaosylceramide in biological samples. Data obtained from healthy volunteers and Anderson-Fabry affected subjects suggest a potential role for this technique in monitoring the effectiveness of Anderson-Fabry disease therapy.
The results obtained in two actual cases treated with enzyme replacement therapy are reported and discussed.
Myelin bodies in urine sediment in hemizygotes with Anderson-Fabry disease.
Wenk RE, Bhagavan BS, Francis E.
Ultrastruct Pathol 1983 Sep-Oct;5(2-3):123-7 Abstract quote
Urine sediment of a hemizygous patient with Anderson-Fabry disease contained characteristic myelin bodies on ultrastructural examination.
Such examination offers an alternative, noninvasive, relatively simple means of establishing early diagnosis.
CHARACTERIZATION FABRY DISEASE
Pediatr Dermatol. 2005 Jul-Aug;22(4):334-7. Abstract quote
Fabry disease is a rare X-linked recessive lysosomal storage disease. Patients typically have angiokeratomas distributed between the umbilicus and knees, painful crises of the hands and feet, and renal, ophthalmologic, and cardiac abnormalities.
An 11-year-old boy presented with a 6-year history of widespread petechial-like lesions and painful crises of the hands and feet. On physical examination, he had numerous erythematous, nonblanching pinpoint macules and rare papules with an overlying crust. These lesions were widely distributed on his trunk, palms, and soles, while sparing the area between the umbilicus and knees.
Histologic evaluation of one of these lesions found several dilated, blood-filled vessels in the upper dermis beneath a thinned epidermis. The patient also had markedly decreased alpha galactosidase A levels. Although the distribution of the angiokeratomas was atypical, the clinical and histologic findings were consistent with a diagnosis of Fabry disease.
Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy.
Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, Grabowski G, Packman S, Wilcox WR.
Department of Human Genetics, Box 1498, Mount Sinai School of Medicine, Fifth Avenue at 100th Street, New York, NY 10029.
Ann Intern Med 2003 Feb 18;138(4):338-46 Abstract quote
Fabry disease (alpha-galactosidase A deficiency) is an X-linked recessive lysosomal storage disorder. Although the disease presents in childhood and culminates in cardiac, cerebrovascular, and end-stage renal disease, diagnosis is often delayed or missed.
This paper reviews the key signs and symptoms of Fabry disease and provides expert recommendations for diagnosis, follow-up, medical management, and the use of enzyme replacement therapy. Recommendations are based on reviews of the literature on Fabry disease, results of recent clinical trials, and expertise of the authors, all of whom have extensive clinical experience with Fabry disease and lysosomal storage disorders and represent subspecialties involved in treatment. All males and female carriers affected with Fabry disease should be followed closely, regardless of symptoms or treatment status.
Clinical trials have shown that recombinant human alpha-galactosidase A replacement therapy-the only disease-specific therapy currently available for Fabry disease-is safe and can reverse substrate storage in the lysosome, the pathophysiologic basis of the disease.
Enzyme replacement therapy in all males with Fabry disease (including those with end-stage renal disease) and female carriers with substantial disease manifestations should be initiated as early as possible. Additional experience is needed before more specific recommendations can be made on optimal dosing regimens for reversal; maintenance; and prevention of disease manifestations in affected males, symptomatic carrier females, children, and patients with compromised renal function.
Cardiac involvement in Fabry disease.
Linhart A, Magage S, Palecek T, Bultas J.
1st School of Medicine, Charles University, Prague, Czech Republic.
Acta Paediatr Suppl 2002;91(439):15-20 Abstract quote
Fabry disease is a rare X-linked defect of the lysosomal enzyme alpha-galactosidase A. The disease is characterized by progressive intracellular accumulation of neutral glycosphingolipids. The storage occurs within various tissues and cells, including cardiocytes, the cardiac conduction system, and valvular fibrocytes.
Cardiac involvement may be the sole manifestation of the disease, particularly in individuals with residual enzyme activity. In general, hemizygous men are more seriously affected than heterozygous women. The main cardiac manifestations include myocardial hypertrophy, which, in some patients, mimics hypertrophic cardiomyopathy. Conduction system involvement leads to PR shortening or, in later stages, to AV blocks. Arrhythmias presenting with variable severity also appear to be common. Valvular involvement is frequently noted but generally mild and clinically non-significant. Newly available enzyme replacement therapy has produced promising results in preventing further functional deterioration of affected organs and possibly also in reversing impaired function.
CONCLUSIONS: With the advent of effective enzyme replacement therapy, early diagnosis of Fabry disease may be crucial for patient prognosis.
Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy.
Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, Elliott PM.
Department of Cardiological Sciences, St Georges Hospital Medical School, London, UK.
Circulation 2002 Mar 26;105(12):1407-11 Abstract quote
BACKGROUND: Although studies have suggested that "late-onset" hypertrophic cardiomyopathy (HCM) may be caused by sarcomeric protein gene mutations, the cause of HCM in the majority of patients is unknown. This study determined the prevalence of a potentially treatable cause of hypertrophy, Anderson-Fabry disease, in a HCM referral population.
METHODS AND RESULTS: Plasma alpha-galactosidase A (alpha-Gal) was measured in 79 men with HCM who were diagnosed at > or =40 years of age (52.9+/-7.7 years; range, 40-71 years) and in 74 men who were diagnosed at <40 years (25.9+/-9.2 years; range, 8-39 years). Five patients (6.3%) with late-onset disease and 1 patient (1.4%) diagnosed at <40 years had low alpha-Gal activity. Of these 6 patients, 3 had angina, 4 were in New York Heart Association class 2, 5 had palpitations, and 2 had a history of syncope. Hypertrophy was concentric in 5 patients and asymmetric in 1 patient. One patient had left ventricular outflow tract obstruction. All patients with low alpha-Gal activity had alpha-Gal gene mutations.
CONCLUSION: Anderson-Fabry disease should be considered in all cases of unexplained hypertrophy. Its recognition is important given the advent of specific replacement enzyme therapy.
Patients affected with Fabry disease have an increased incidence of progressive hearing loss and sudden deafness: an investigation of twenty-two hemizygous male patients.
Germain DP, Avan P, Chassaing A, Bonfils P.
Department of Genetics, Hopital Europeen Georges Pompidou, 75015 Paris, France.
BMC Med Genet 2002 Oct 11;3(1):10 Abstract quote
BACKGROUND: Fabry disease (FD, OMIM 301500) is an X-linked inborn error of glycosphingolipid metabolism due to the deficient activity of alpha-galactosidase A, a lysosomal enzyme. While the progressive systemic deposition of uncleaved glycosphingolipids throughout the body is known to have protean clinical manifestations, few data are available regarding the cochlear involvement.
METHODS: We non-invasively investigated cochlear functions in 22 consecutive hemizygous males (age 19-64 years, mean 39) affected with classic FD. Conventional audiometry, tympanometry, ABR audiometry, otoacoustic emissions were performed in all patients, together with medical history record and physical examination as part of an exhaustive baseline evaluation prior to enzyme replacement therapy.
RESULTS: A total of 12 patients (54.5%) with classic FD were found to have abnormal audition. Five patients had progressive hearing loss and seven patients (32%) experienced sudden deafness. In addition, a hearing loss on high-tone frequencies was found in 7 out of the 10 remaining patients without clinical impairment, despite their young age at time of examination. The incidence of hearing loss appeared significantly increased in FD patients with kidney failure (P < 0.01) or cerebrovascular lesions (P < 0.01), whereas there was no correlation with left ventricular hypertrophy. In addition, tinnitus aurium was also found in six patients (27%).
CONCLUSION: This is the first evidence of a high incidence of both progressive hearing loss and sudden deafness in a cohort of male patients affected with classic Fabry disease. The exact pathophysiologic mechanism(s) of the cochlear involvement deserves further studies.
Evaluation of peripheral and autonomic nerve function in Fabry disease.
Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.
Acta Paediatr Suppl 2002;91(439):38-42 Abstract quote
The neurological manifestations of Fabry disease include severe episodes of lancinating pain and burning paraesthesias in the extremities, often triggered by changes in temperature.
The preferential involvement of small nerve fibres and the accumulation of storage product in the central autonomic nervous system and autonomic ganglia means that standard neurophysiological procedures cannot adequately evaluate the peripheral and autonomic nervous systems of affected patients.
This paper describes the various methods that have been developed to assess impairment of temperature perception, vibratory perception, sudomotor and sweat gland function, and limb and superficial skin blood flow and vasoreactivity. These methods, including thermal provocation tests, quantitative sudomotor axon reflex testing and venous occlussion plethsmography, have been used effectively in patients with Fabry disease to measure the extent of neurological dysfunction.
CONCLUSIONS: Effective methods for measuring neurological involvement in patients with Fabry disease have been developed. These methods will be valuable in assessing the response of patients to enzyme replacement therapy.
Arterial remodelling in Fabry disease.
Boutouyrie P, Laurent S, Laloux B, Lidove O, Grunfeld JP, Germain DP.
Department of Pharmacology, INSERM EMI 107, Hopital Europeen Georges Pompidou, Paris, France.
Acta Paediatr Suppl 2002;91(439):62-6 Abstract quote
AIM: The enzymatic defect in Fabry disease results in the slow systemic deposition of uncleaved glycosphingolipids in the lysosomes of vascular endothelium and smooth muscle cells, leading to ischaemic strokes, cardiomyopathy and renal failure. Whereas it is known that Fabry disease affects small blood vessels, little is known about its effects on peripheral large arteries. We therefore set out to compare parameters of arterial wall structure and function in a cohort of patients with Fabry disease and an age-matched control group.
METHODS: Large artery phenotype was non-invasively investigated in 21 hemizygous patients with Fabry disease and 24 age-matched male controls. Common carotid and radial artery diameter, intima-media thickness (IMT) and distensibility were determined with high-definition echotracking systems and aplanation tonometry.
RESULTS: Patients with Fabry disease had a significant twofold increase in radial artery IMT and distensibility, independent of body surface area, age and mean blood pressure. In both groups, older age at the time of examination was significantly associated with larger radial artery IMT. The relationship between age and radial IMT was 2.3-fold higher in patients with Fabry disease than in controls (p < 0.01). Carotid IMT was mildly but significantly increased in patients with Fabry disease (+18%), whereas distensibility was unchanged.
CONCLUSION: This study presents evidence of a major increase in arterial wall thickness and distensibility, measurable at the site of a medium-sized artery, in a cohort of patients with classic Fabry disease.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL CORNEA
Histopathologic findings of cornea verticillata in a woman heterozygous for Fabry's disease.
Hirano K, Murata K, Miyagawa A, Terasaki H, Saigusa J, Nagasaka T, Kobayashi M.
Department of Ophthalmology, Nagoya University School of Medicine, Japan.
Cornea 2001 Mar;20(2):233-6 Abstract quote
PURPOSE: To report the histopathologic findings of the cornea verticillata observed in a woman who was heterozygous for Fabry's disease.
METHOD: A 67-year-old woman was found to have a whorl-like corneal opacity on her visit to the Department of Ophthalmology. Aichi Saiseikai Hospital. Her visit was because of a sudden loss of vision in her right eye owing to a central retinal artery occlusion in association with an ophthalmic artery occlusion. The patient died suddenly of an acute heart failure; with family consent, an autopsy was performed and the right eye was removed for histopathologic examination by light and electron microscopy.
RESULTS: Low levels of alpha-galactosidase in the leukocytes together with the corneal finding led to the diagnosis of heterozygous Fabry's disease. Light microscopy revealed a 0.3- to 0.5-microm thick layer between the epithelial and Bowman's layers. Oil red O positive deposits were accumulated in the subepithelial layer, and the density varied in different regions. Electron microscopy showed that subepithelial layer differed in thickness, and the basal lamina reduplicated regionally. We were not able to determine the structure that correlated with the "ridge" in the central part of the cornea.
CONCLUSION: The oil red O positive deposits and their variation in density in the subepithelial area of the cornea may have caused the characteristic whorl-like corneal opacity in this woman who was heterozygous for Fabry's disease.
Hum Pathol. 2006 Jun;37(6):764-8. Abstract quote
The well-described histologic and electron microscopic findings in Fabry disease cardiomyopathy are hypertrophic vacuolated cells with electron dense concentric lamellar bodies.
We present altered findings in an endomyocardial biopsy from a patient with treated Fabry disease. A 51-year-old male with Fabry disease, treated with recombinant alpha-galactosidase enzyme replacement therapy for over 18 months, underwent an endomyocardial biopsy for heart failure. The histologic changes showed widespread hypertrophy and vacuolization with rare eosinophilic bodies. Electron microscopy failed to reveal the characteristic globotriaosylceramide concentric lamellar bodies (myelin figures) in the sarcoplasm. Instead, extensive aggregates and single tubular crystalline structures, giant secondary lysosomes as well as abnormal branched chain glycogen were present.
This is the first histologic description of long-standing treated Fabry disease in cardiac myocytes.
Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy.
Thurberg BL, Rennke H, Colvin RB, Dikman S, Gordon RE, Collins AB, Desnick RJ, O'Callaghan M.
Department of Pathology, Genzyme Corporation, Cambridge, Massachusetts, USA.
Kidney Int 2002 Dec;62(6):1933-46 Abstract quote
BACKGROUND: Fabry disease, a lysosomal storage disease caused by deficient lysosomal alpha-galactosidase A activity, is characterized by globotriaosylceramide (GL-3) accumulation in multiple cell types, particularly the vasculature, leading to end organ failure. Accumulation in the kidney is responsible for progressive decline in renal function in male patients with the classical phenotype, resulting in renal failure in their third to fifth decades of life. With the advent of recombinant protein synthesis technology, enzyme replacement therapy has become a viable alternative to dialysis or renal transplantation, previously the only available treatment options for end-stage renal disease.
METHODS: The pre- and post-treatment renal biopsies were analyzed from fifty-eight Fabry patients enrolled in a Phase 3 double-blind, randomized, placebo-controlled trial followed by a six-month open label extension study of the recombinant human enzyme, alpha-galactosidase A (r-halphaGalA), administered IV at 1 mg/kg biweekly. The purpose of this investigation was to detail the pathologic changes in glycosphingolipid distribution and the pattern of post-treatment clearance in the kidney.
RESULTS: Baseline evaluations revealed GL-3 accumulations in nearly all renal cell types including vascular endothelial cells, vascular smooth muscle cells, mesangial cells and interstitial cells, with particularly dense accumulations in podocytes and distal tubular epithelial cells. After 11 months of r-halphaGalA treatment there was complete clearance of glycolipid from the endothelium of all vasculature as well as from the mesangial cells of the glomerulus and interstitial cells of the cortex. Moderate clearance was noted from the smooth muscle cells of arterioles and small arteries. Podocytes and distal tubular epithelium also demonstrated evidence for decreased GL-3, although this clearance was more limited than that observed in other cell types. No evidence of immune complex disease was found by immunofluorescence despite circulating anti-r-halphaGalA IgG antibodies.
CONCLUSIONS: These findings indicate a striking reversal of renal glycosphingolipid accumulation in the vasculature and in other renal cell types, and suggest that long-term treatment with r-halphaGalA may halt the progression of pathology and prevent renal failure in patients with Fabry disease.
Renal pathological changes in Fabry disease.
Sessa A, Meroni M, Battini G, Maglio A, Brambilla PL, Bertella M, Nebuloni M, Pallotti F, Giordano F, Bertagnolio B, Tosoni A.
Nefrologia e Dialisi, Ospedale di Vimercate, Italia
J Inherit Metab Dis 2001;24 Suppl 2:66-70; discussion 65 Abstract quote
Fabry disease is a rare X-linked disorder, characterized by deficient activity of the lysosomal enzyme alpha-galactosidase A. This leads to systemic accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in all body tissues and organs, including the kidney. Renal manifestations are less evident in female heterozygotes than in male hemizygotes, according to the Lyon hypothesis. Accumulation of Gb3 occurs mainly in the epithelial cells of Henle's loop and distal tubule, inducing early impairment in renal concentrating ability; involvement of the proximal tubule induces Fanconi syndrome. All types of glomerular cells are involved, especially podocytes, and glomerular proteinuria may occur at a young age. The evolution of renal Fabry disease is characterized by progressive deterioration of renal function to end-stage renal failure (ESRF).
Ultrastructural study of kidney biopsies reveals typical bodies in the cytoplasm of all types of renal cells, characterized by concentric lamellation of clear and dark layers with a periodicity of 35-50 A.
Management of progressive renal disease requires dietetic and therapeutic strategies, usually indicated in developing chronic renal failure, with dialysis and renal transplantation required for patients with ESRF. The recent development of enzyme replacement therapy, however, should make it possible to prevent or reverse the progressive renal dysfunction associated with Fabry disease.
Histopathologic and ultrastructural studies of angiokeratoma corporis diffusum in Kanzaki disease.
Yokota M, Koji M, Yotsumoto S.
Department of Dermatology, Nagoya City University Medical School, Japan.
J Dermatol 1995 Jan;22(1):10-8 Abstract quote
A novel metabolic disease, angiokeratoma corporis diffusum (Kanzaki), was the subject of an extensive histopathologic and ultrastructural study. Findings included dilated lymph and blood vessels in the upper dermis with an orthokeratortic, thickened, horny layer in well developed angiokeratoma.
In the early papules, a few sporadic dyskeratotic keratinocytes were present in the epidermis with or without a thickened horny layer. Vesicular clear vacuolation was clearly observed in the cytoplasm of the secretory portion of the eccrine sweat glands, but none was observed in the vascular endothelial cells with hematoxylin-eosin staining. Using electron microscopy, lysosomal vacuolation was observed in many cell types, including eccrine sweat gland cells, vascular endothelial cells, dermal fibroblasts, dermal neural cells, lymphocytes of peripheral blood in the skin, and glomerular endothelial cells, but none was noted in the epithelial cells of the kidney.
Widely dilated vacuoles were found to contain only a small amount of fuzzy filamentous material in the vascular endothelial cells, filamentous or electron-dense granular substances in fibroblasts, and electron-dense, lamellated or homogeneous structures in eccrine sweat gland cells and in neural cells.
Ultracytochemical examination revealed glycoconjugates in dilated lysosomes. Characteristics of Kanzaki Disease were shown to differ from those of Fabry disease or any other lysosomal storage disease.
CHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE ELECTRON MICROSCOPY Intracytoplasmic osmiophilic bodies with a characteristic "zebra" or "onion-skin" appearance due to concentric lamellation of alternating clear and dark layers
Fabry disease with few clinical signs and symptoms.
Asahi K, Katoh T, Watanabe K, Watanabe T.
Department of Internal Medicine III, Fukushima Medical University School of Medicine, Fukushima.
Intern Med 2002 Nov;41(11):983-5 Abstract quote
We describe a 25-year-old man with Fabry disease who remained undiagnosed until progressive renal involvement had begun, because of few clinical signs or symptoms except intermittent acroparesthesia. He had non-nephrotic proteinuria and normal renal function.
Renal biopsy revealed focal and segmental glomerular sclerosis with vacuolated podocytes.
Electron microscopy demonstrated characteristic lamellated bodies. Alpha-galactosidase A (alpha-galA) activity was markedly decreased. Early diagnosis of Fabry disease is becoming important because of the prospect of recombinant alpha-galA replacement therapy.
Careful history taking, physical examinations, and renal histology with electron microscopy are essential for the diagnosis in the course of the disease.
The ultrastructural study in a case of Fabry disease.
Palungwachira P, Yaguchi H.
Srinakharinwirot University Skin Center, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand.
J Med Assoc Thai 2002 Jul;85(7):842-9 Abstract quote
An investigation of the ultrastructural study was conducted on specimens from a typical patient with Fabry disease.
Numerous characteristic cytoplasmic inclusions were observed in the vascular endothelial cell, pericyte, smooth muscle cell, nerve and eccrine sweat glands, the lamellar pattern of which were considerably variable in various types of gland cells. Large vacuolar inclusions predominated in clear cells of the secretory coil; lesser vacuoles were also seen in the coiled duct, and the basal cells of the straight duct toward the coiled duct displayed mulberry-like figures.
There were some clear cells showing cell damage and necrosis in the secretory coil. Lamellated bodies were noted in the axons and schwann cells around the eccrine sweat glands. The small blood vessels around the eccrine glands were narrowed by swollen endothelial cells with heavy inclusions.
These intracytoplasmic deposits may be responsible for the decreased sweating ability in Fabry disease. The factors related to hypohidrosis are also discussed.
Renal ultrastructural findings in Anderson-Fabry disease.
Sessa A, Toson A, Nebuloni M, Pallotti F, Giordano F, Battini G, Maglio A, Meroni M, Calconi G, Bertolone G, Gatti P.
Division of Nephrology and Dialysis, Vimercate Hospital, Italy.
J Nephrol 2002 Mar-Apr;15(2):109-12 Abstract quote
Anderson-Fabry disease (AFd) is caused by an X-linked inborn error in the glycosphingoLipid metabolic pathway due to an enzymatic defect in a lysosomal hydrolase: alpha-galactosidase A. The defect results in the progressive accumulation of neutral glycosphingolipids in most body fluids and several tissues. The clinical manifestations of AFd are related to organ damage and, obviously, are more severe in hemizygous males than in heterozygous females. In the third decade of life, the course of the disease involves severe deterioration of kidney function progressing to end-stage renal failure. All kind of cells of renal structures are filled with glycosphingolipid deposits.
Electron microscopic studies document typical intracytoplasmic osmiophilic bodies with a characteristic "zebra" or "onion-skin" appearance due to concentric lamellation of alternating clear and dark layers.
Clinical interest in Fabry patients is related to recent advances in treatment with an intravenous specific enzyme to modify the biochemical error of the glycosphingolipid catabolic pathway.
Immunoelectron microscopic analysis of lysosomal deposits in alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum.
Kanda A, Tsuyama S, Murata F, Kodama K, Hirabayashi Y, Kanzaki T.
Department of Dermatology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
J Dermatol Sci 2002 May;29(1):42-8 Abstract quote
Alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency with angiokeratoma corporis diffusum (AKCD) is one of the lysosomal storage diseases. GalNAc(alpha))1-O-Ser/Thr (Tn) is theoretically deposited in lysosomes, but substances with attached galactose and neuraminic (sialic) acid (T and sialosyl Tn, respectively) are excreted in patients' urine.
In this study, in two Japanese cases we analyzed the material accumulated in lysosomes using immunoelectron microscopy with mouse antibodies to Tn, sialosyl Tn and T (Thomsen-Friedenreich) antigens in order to find out what substance(s) is really deposited in lysosomes.
We found that only GalNAc(alpha)1-O-Ser/Thr (Tn) was actually accumulated in vacuolated lysosomes of vascular endothelial cells, eccrine sweat gland cells, fibroblasts and pericytes. Galactosylation and sialylation of Tn appears to occur in cells other than those in the skin. The results suggest that this disease is caused by a single enzyme deficiency.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES CHLOROQUINE-INDUCED CHANGES
- Chloroquine-induced lipidosis mimicking Fabry disease.
Albay D, Adler SG, Philipose J, Calescibetta CC, Romansky SG, Cohen AH.
 1Harbor-UCLA Medical Center, Torrance, CA, USA  2UCLA School of Medicine, USA.
Mod Pathol. 2005;18:733-738 Abstract quote
Intracellular accumulation of phospholipids may be a consequence of inherited or acquired metabolic disorders. In Fabry disease, deficiency of alpha-galactosidase A results in storage of globotriasylceramide in numerous cells including endothelium, striated muscle (skeletal, cardiac), smooth muscle, and renal epithelium among others; the ultrastructural appearance of the inclusions is of whorled layers of alternating dense and pale material ('zebra bodies' or myeline figures). Chloroquine therapy may result in storage of biochemically and ultrastructurally similar inclusions in many of the same cells as Fabry disease and often results in similar clinical manifestations.
We report a 56-year-old woman with rheumatoid arthritis treated with chloroquine, who developed muscle weakness and renal insufficiency; information regarding therapy was not emphasized at the time of renal biopsy, leading to initial erroneous interpretation of Fabry disease. Following muscle biopsy, genetic and enzyme evaluation, and additional studies on the kidney biopsy, a diagnosis of chloroquine toxicity was established. One year following cessation of chloroquine, renal and muscle dysfunction greatly improved.
In chloroquine toxicity, inclusions in glomeruli are not only in visceral epithelial, endothelial and mesangial cells but are in infiltrating monocytes/macrophages, which are most commonly present in the mesangium. Curvilinear bodies, the ultrastructural features of chloroquine toxicity in striated muscle, are not present in renal cells.
This report documents differences in appearance, cells affected and morphological differential diagnostic features to distinguish these two entities.
Chloroquine-induced phospholipidosis of the kidney mimicking fabry's disease: Case report and review of the literature.
Muller-Hocker J, Schmid H, Weiss M, Dendorfer U, Braun GS.
Pathologische Institut and medizinische Klinik-Poliklinik, Ludwig-Maximilians-Universitat, Munich, Germany.
Hum Pathol 2003 Mar;34(3):285-9 Abstract quote
A 46-year-old female patient with Sjogren's syndrome, hypertension, and stable chronic renal insufficiency (creatinine [CR], 1.9 to 2.1 mg/dL) had a progressive worsening of renal function (CR, 5.0 mg/dL) after 11 months of chloroquine therapy (155 mg/day; cumulative dose of approximately 51 g).
Light microscopy revealed nonspecific angionephrosclerosis. Electron microscopy showed accumulations of lamellated myelinoid material and occasionally also of curvilinear bodies, especially in the glomerular podocytes and to a lesser extent in vascular myothelial and endothelial cells. In the tubular system, mainly protein droplets were stored. Activity of alpha-galactosidase A was normal in isolated leukocytes (56 nmol/mg; range, 33.2 to 109 nmol/mg), ruling out Fabry's disease. Clinical, morphological, and biochemical findings were consistent with chloroquine-associated deterioration of renal function that improved considerably after discontinuation of chloroquine treatment.
Adverse effects of chloroquine may aggravate preexisting renal disease. Electron microscopy is a worthwhile tool for establishing the correct diagnosis.
J Cutan Pathol. 2005 Aug;32(7):506-11. Abstract quote
Fucosidosis is a rare lysosomal storage disease due to alpha-L-fucosidase deficiency. It presents clinically with neurological, skeletal, and cutaneous findings, including mainly angiokeratoma corporis diffusum.
Electronmicroscopic examination reveals characteristic electron-lucent cytoplasmic vacuolization present in several cell types of the skin and other tissues.
We present here a new patient suffering from fucosidosis with angiokeratoma, whose normal and diseased skin was studied by lightmicroscopy and electronmicroscopy. The salient clinicopathological features of this disease are briefly reviewed.
J Dermatol. 2004 Nov;31(11):931-5. Abstract quote
Beta-mannosidosis is a lysosomal disorder which is caused by a deficiency of beta-mannosidase. This disorder was first described in goats. Twelve human cases have already been reported.
We present the first case in Japan in whom the diagnosis was reached from angiokeratoma corporis diffusum. Futhermore, mental retardation, hearing loss, and renal failure were also detected. Pseudoxanthoma elasticum was also present, but whether it is a complication of beta-mannosidosis or not remains unknown. The activity level of beta-mannosidase in the patient's plasma was only 2% of the normal range, while that in the patient's mother was 40%.
We suggest that beta-mannosidosis should be one of the differential diagnoses when lysosomal enzyme disorders are suspected in cases of angiokeratoma corporis diffusum.
PROGNOSIS CHARACTERIZATION MALES
Natural history of Fabry disease in males: preliminary observations.
Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1260, USA
J Inherit Metab Dis 2001;24 Suppl 2:15-7; discussion 11-2 Abstract quote
A large cohort of patients with Fabry disease is being studied to determine the natural history of the disease and how this relates to the specific mutation involved and the amount of residual alpha-galactosidase A activity.
To date, we have investigated the progression of cerebral lesions and stroke, as identified by magnetic resonance imaging, and renal disease. Results have shown that cerebral lesions do not appear until 23 years of age, but are present in all patients by 55 years of age. The peak onset of proteinuria occurred in the fourth decade, and the peak onset of chronic renal insufficiency and end-stage renal disease occurred in the fifth decade of life. Renal outcome was related to the type of mutation and residual enzyme activity.
Data from these studies in untreated patients will be important when assessing the long-term efficacy of enzyme replacement therapy.
Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males.
MacDermot KD, Holmes A, Miners AH.
Department of Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
J Med Genet 2001 Nov;38(11):750-60 Abstract quote
OBJECTIVES: To determine the natural history of Anderson-Fabry disease (AFD) as a baseline for efficacy assessment of potentially therapeutic drugs. DESIGN: The first large cross sectional study of a patient cohort from the AFD clinical and genetic register (UK), maintained for the last 15 years.
MEASURES: Prevalence, mortality, frequency of AFD manifestations, and impact of disease on patient lives, assessed from the AFD register and the disease specific questionnaire.
RESULTS: The median cumulative survival was 50 years (n=51), which represents an approximately 20 year reduction of life span. Neuropathic pain was present in 77% (n=93) with mean pain score of 5 (scale 0-10) despite treatment with anticonvulsants and opiates. Pain stopped in only 11%. Cerebrovascular complications developed in 24.2% and renal failure in 30%. The onset and progression of serious AFD manifestations was highly variable. The relationship of gastrointestinal manifestations on weight, using body mass index (BMI), was significant (p=0.01). High frequency sensorineural deafness was confirmed in 78% of audiograms. Neuropathic pain and angiokeratoma were absent in five adult males (approximately 5%). Median age at diagnosis of AFD was 21.9 years (n=64).
IMPACT OF DISEASE: Attendance at school, sports, and social activity were significantly affected by AFD. Only 56.6% (n=46) of patients were employed. Psychosexual effects of genital angiokeratoma, genital pain, and impotence were not previously recognised.
CONCLUSION: The majority of males experience multiple disease manifestations and the duration of neuropathic pain was lifelong. The AFD register proved useful for the determination of baseline disease parameters in this cohort.
TREATMENT CHARACTERIZATION GENERAL ENZYME REPLACEMENT
Recombinant enzyme therapy for Fabry disease: absence of editing of human alpha-galactosidase A mRNA.
Blom D, Speijer D, Linthorst GE, Donker-Koopman WG, Strijland A, Aerts JM.
Department of Biochemistry, University of Amsterdam, Amsterdam, The Netherlands.
Am J Hum Genet 2003 Jan;72(1):23-31 Abstract quote
For more than a decade, protein-replacement therapy has been employed successfully for the treatment of Gaucher disease. Recently, a comparable therapy has become available for the related lipid-storage disorder Fabry disease.
Two differently produced recombinant alpha-galactosidase A (alpha-gal A) preparations are used independently for this purpose. Agalsidase alpha is obtained from human fibroblasts that have been modified by gene activation; agalsidase beta is obtained from Chinese hamster ovary cells that are transduced with human alpha-gal A cDNA. It has previously been claimed that alpha-gal A mRNA undergoes editing, which may result in coproduction of an edited protein (Phe 396 Tyr) that might have a relevant physiological function. We therefore analyzed the occurrence of alpha-gal A editing, as well as the precise nature, in this respect, of the therapeutic enzymes. No indications were obtained for the existence of editing at the protein or RNA level.
Both recombinant enzymes used in therapy are unedited and are capable of functionally correcting cultured fibroblasts from Fabry patients in their excessive globotriaosylceramide accumulation. Although RNA editing is apparently not relevant in the case of alpha-gal A, a thorough analysis of the potential occurrence of editing of transcripts is nevertheless advisable in connection with newly developed protein-replacement therapies.
Fabry disease: recent advances in enzyme replacement therapy.
Department of Genetics, Hopital Europeen Georges Pompidou, 20, rue Leblanc, 75015 Paris, France.
Expert Opin Investig Drugs 2002 Oct;11(10):1467-76 Abstract quote
Fabry disease is an X-linked inherited disorder of metabolism due to mutations in the gene encoding alpha-galactosidase A, a lysosomal enzyme. The enzymatic defect leads to the systemic accumulation of incompletely metabolised glycosphingolipids, primarily globotriaosylceramide, in plasma and lysosomes within various tissues.
Inability to prevent the progression of glycosphingolipid deposition causes significant morbidity, associated with significant impact on quality of life and diminished lifespan from early onset strokes, heart attack and progressive renal failure. The disease manifests primarily in hemizygous males; however, there is increasing recognition that heterozygous (carrier) females may also develop disease-related complications. Indeed, most heterozygotes present with cardiac, renal or neurological symptoms, although with later-onset and to a lesser extent than is observed in hemizygotes.
Until recently, medical management was symptomatic, consisting of partial pain relief with analgesic drugs (carbamazepin, gabapentin), kidney and vascular protection with angiotensin-converting enzyme inhibitors, statins and folic acid, whereas renal transplantation or dialysis is available for patients experiencing end stage renal failure. The ability to produce high doses of alpha-galactosidase A has opened the way to preclinical studies, and enzyme replacement therapy has recently been validated as a therapeutic agent in clinical trials.
Long-term safety and efficacy of replacement therapy are currently being investigated. Increasing knowledge of the natural history of Fabry disease and greater experience with enzyme therapy should enable optimal patient care. The complexity and relative rarity of Fabry disease necessitates a multi-disciplinary team approach that may be facilitated by a disease registry.
Enzyme replacement reverses abnormal cerebrovascular responses in Fabry disease.
Moore DF, Altarescu G, Herscovitch P, Schiffmann R.
Developmental and Metabolic Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
BMC Neurol 2002 Jun 18;2(1):4 Abstract quote
BACKGROUND: Fabry disease is a lysosomal X-linked enzyme deficiency of alpha-galactosidase A associated with an increased mortality and morbidity due to renal failure, cardiac disease and early onset stroke.
METHODS: We examined the functional blood flow response of the brain after visual stimulation (reversing checkerboard pattern), and cerebral vasoreactivity following acetazolamide (15 mg/kg) with [15O]H2O and positron emission tomography (PET) in Fabry disease. Twenty-six hemizygous patients (age range 19-47 years) were enrolled in a randomized double-blind placebo-controlled 6-month trial of enzyme replacement therapy administered by intravenous infusion every two weeks. Regional cerebral blood flow (rCBF) was measured with PET at the beginning and end of the trial.
RESULTS: Fabry patients had a significantly greater increase in rCBF following visual stimulation and acetazolamide challenge compared to controls. Visual reactivity was normal. The time for recovery of the cerebral vasculature following acetazolamide was prolonged in Fabry patients compared to controls. The abnormal rCBF response induced by visual stimulation and acetazolamide decreased significantly following enzyme replacement therapy, as did the prolonged recovery of the cerebral vasculature.
CONCLUSIONS: Enzyme replacement therapy reverses the exaggerated cerebrovascular response in Fabry disease.
Enzyme replacement therapy in Fabry disease: a randomized controlled trial.
Schiffmann R, Kopp JB, Austin HA 3rd, Sabnis S, Moore DF, Weibel T, Balow JE, Brady RO.
Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, Bldg 10, Room 3D03, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-1260, USA.
JAMA 2001 Jun 6;285(21):2743-9 Abstract quote
CONTEXT: Fabry disease is a metabolic disorder without a specific treatment, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). Most patients experience debilitating neuropathic pain and premature mortality because of renal failure, cardiovascular disease, or cerebrovascular disease. OBJECTIVE: To evaluate the safety and efficacy of intravenous alpha-gal A for Fabry disease.
DESIGN AND SETTING: Double-blind placebo-controlled trial conducted from December 1998 to August 1999 at the Clinical Research Center of the National Institutes of Health.
PATIENTS: Twenty-six hemizygous male patients, aged 18 years or older, with Fabry disease that was confirmed by alpha-gal A assay.
INTERVENTION: A dosage of 0.2 mg/kg of alpha-gal A, administered intravenously every other week (12 doses total).
MAIN OUTCOME MEASURE: Effect of therapy on neuropathic pain while without neuropathic pain medications measured by question 3 of the Brief Pain Inventory (BPI).
RESULTS: Mean (SE) BPI neuropathic pain severity score declined from 6.2 (0.46) to 4.3 (0.73) in patients treated with alpha-gal A vs no significant change in the placebo group (P =.02). Pain-related quality of life declined from 3.2 (0.55) to 2.1 (0.56) for patients receiving alpha-gal A vs 4.8 (0.59) to 4.2 (0.74) for placebo (P =.05). In the kidney, glomeruli with mesangial widening decreased by a mean of 12.5% for patients receiving alpha-gal vs a 16.5% increase for placebo (P =.01). Mean inulin clearance decreased by 6.2 mL/min for patients receiving alpha-gal A vs 19.5 mL/min for placebo (P =.19). Mean creatinine clearance increased by 2.1 mL/min (0.4 mL/s) for patients receiving alpha-gal A vs a decrease of 16.1 mL/min (0.3 mL/s) for placebo (P =.02). In patients treated with alpha-gal A, there was an approximately 50% reduction in plasma glycosphingolipid levels, a significant improvement in cardiac conduction, and a significant increase in body weight.
CONCLUSION: Intravenous infusions of alpha-gal A are safe and have widespread therapeutic efficacy in Fabry disease.
Renal transplantation in patients with Fabry disease.
Sessa A, Meroni M, Battini G, Maglio A, Nebuloni M, Tosoni A, Panichi V, Bertagnolio B.
UO Nefrologia e Dialisi, Vimercate, Italia.
Nephron 2002 Jun;91(2):348-51 Abstract quote
Anderson-Fabry disease (AFd) is a rare X-linked disorder characterized by deficiency of alpha-galactosidase A that leads to systemic accumulation of neutral glycosphingolipids, predominantly globotriaosylceramide (Gb3), in body fluids and visceral tissues, including the kidney. End-stage renal failure is a common manifestation in hemizygous males that often occurs by the third to fourth decade of life. Usually transplanted patients exhibit improvement in clinical symptoms of the disease, probably related to the production of alpha-galactosidase A from the grafted kidney, but mainly related to the increase in Gb3 clearance by the functioning kidney, and increased survival of red cells due to the correction of the uremic status with an evident decrease in the production of Gb3 depending from hemolysis. Several Fabry patients with successful kidney graft survived for 10-15 years and died for cardiovascular complications related to the metabolic disease. The loss of grafted kidney is due to rejection, thrombosis or sepsis. An important issue considering renal transplantation in AFd is the recurrence of the disease in the kidney graft; however, no evidence regarding this possibility has occurred up to now.
We report herein the ultrastructural study of the urinary sediment of a 35-year-old male Fabry patient with a severe clinical form of the disease with progression to ESRF at age 29, and submitted to renal transplantation at 33 years. Ultrastructural findings of the urinary sediment documented several cells, probably tubular epithelial cells, with typical accumulation of myelinic bodies resulting from intracellular storage of neutral glycosphingolipids.
This morphological evidence arises the problem of the possible recurrence of AFd in the kidney graft in patients with severe phenotype of the metabolic disease.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation
Commonly Used Terms
This is a glossary of terms often found in a pathology report.
Learn how a pathologist makes a diagnosis using a microscope
Surgical Pathology Report
Examine an actual biopsy report to understand what each section means
Understand the tools the pathologist utilizes to aid in the diagnosis
How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate
Recent teaching cases and lectures presented in conferences
Last Updated June 22, 2006
Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.
Copyright © The Doctor's Doctor