[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
Purchase Options:
[Skip to Content Landing]
Figure 1. Pedigree of the Case
Image description not available.
Permission for publication was obtained from the patient.
Figure 2. Retinal and Hepatic Characteristics of Fabry Disease
Image description not available.
A, Retinal image showing tortuous retinal blood vessels. B, Liver biopsy showing lamellar storage material in the cytoplasm of a Kupffer cell. The cell is adjacent to a capillary in which a red blood cell can be seen (original magnification ×17,000).
Figure 3. Renal Characteristics of Fabry Disease
Image description not available.
One-micron section of kidney tissue. Darkly stained storage material can be seen in parietal and visceral renal epithelial cells (thick arrows) and to a lesser extent in interstitial cells and capillary endothelial cells (thin arrow). Storage can also be seen in distal tubular cells (arrowhead) (toluidine blue, original magnification ×100).
Figure 4. Neuroimaging of Fabry Disease
Image description not available.
Magnetic resonance imaging scan of the brain of a patient with Fabry disease using fluid-attenuated inversion-recovery sequence. Typical hyperintense lesions, mostly in the posterior white matter, are thought to be ischemic lesions.
1.
Schiffmann R, Murray GJ, Treco D.  et al.  Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease.  Proc Natl Acad Sci U S A.2000;97:365-370.Google Scholar
2.
Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders.  JAMA.1999;281:249-254.Google Scholar
3.
Fabry J. Ein Beitrag zür kenntnis der Purpura haemorrhargica nodularis (Purpura papulosa haemorrhagic hebrae).  Arch Dermatol Syphilis.1898;43:187-200.Google Scholar
4.
Anderson WA. A case of angiokeratoma.  Br J Dermatol.1898;18:113-117.Google Scholar
5.
Opitz JM, Stiles FC, Wise D. The genetics of angiokeratomas corporis diffusum (Fabry's disease) and its linkage with Xg(a) locus.  Am J Hum Genet.1965;17:325-342.Google Scholar
6.
Sweeley CC, Klionsky B. Fabry's disease: classification as sphingolipidosis and partial characterization of novel glycolipid.  J Biol Chem.1963;238:PC3148-PC3150.Google Scholar
7.
Brady RO, Gal AE, Bradley RM.  et al.  Enzymatic defect in Fabry's disease: ceramidetrihexosidase deficiency.  N Engl J Med.1967;276:1163-1167.Google Scholar
8.
Kint JA. Fabry's disease: alpha-galactosidase deficiency.  Science.1970;167:1268-1269.Google Scholar
9.
Kusiak JW, Quirk JM, Brady RO. Purification and properties of the two major isozymes of α-galactosidase from human placenta.  J Biol Chem.1978;253:184-190.Google Scholar
10.
Desnick RJ, Ioannou YA, Eng CM. α A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 6th ed. New York, NY: McGraw-Hill; 1996:2741-2784.
11.
Yamakawa T, Yokoyama S, Handa N. Chemistry of lipids of mucolipid of human erythrocytes.  J Biochem (Tokyo).1963;53:28-36.Google Scholar
12.
Topaloglu AK, Ashley GA, Tong B.  et al.  Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease.  Mol Med.1999;5:806-811.Google Scholar
13.
Meroni M, Sessa A, Battini G, Tazzari S, Torri Tarelli L. Kidney involvement in Anderson-Fabry disease.  Contrib Nephrol.1997;122:178-184.Google Scholar
14.
Chimenti C, Ricci R, Pieroni M.  et al.  Cardiac variant of Fabry's disease mimicking hypertrophic cardiomyopathy.  Cardiologia.1999;44:469-473.Google Scholar
15.
Nakao S, Takenaka T, Maeda M.  et al.  An atypical variant of Fabry's disease in men with left ventricular hypertrophy.  N Engl J Med.1995;333:288-293.Google Scholar
16.
Crutchfield KE, Patronas NJ, Dambrosia JM.  et al.  Quantitative analysis of cerebral vasculopathy in patients with Fabry disease.  Neurology.1998;50:1746-1749.Google Scholar
17.
Mitsias P, Levine SR. Cerebrovascular complications of Fabry's disease.  Ann Neurol.1996;40:8-17.Google Scholar
18.
DeGraba TJ, Azhar S, Dignat-George F.  et al.  Profile of endothelial and leukocyte activations in Fabry's patients.  Ann Neurol.2000;47:229-233.Google Scholar
19.
Argoff CE, Barton NW, Brady RO, Ziessman HA. Gastrointestinal symptoms and delayed gastric emptying in Fabry's disease: response to metoclopramide.  Nucl Med Commun.1998;19:887-891.Google Scholar
20.
Schachern PA, Shea DA, Paparella MM, Yoon TH. Otologic histopathology of Fabry's disease.  Ann Otol Rhinol Laryngol.1989;98:359-363.Google Scholar
21.
Roberts DH, Gilmore IT. Achalasia in Anderson-Fabry's disease.  J R Soc Med.1984;77:430-431.Google Scholar
22.
Franceschetti AT. Fabry disease: ocular manifestations.  Birth Defects.1976;12:195-208.Google Scholar
23.
Bao LL, Guo LL, Li SN.  et al.  A family with Fabry's disease: ocular manifestations and transmission electron microscopic examination of a skin lesion biopsy.  Chin Med J (Engl).1990;103:134-141.Google Scholar
24.
von Figura K. Molecular recognition and targeting of lysosomal proteins.  Curr Opin Cell Biol.1991;3:642-646.Google Scholar
25.
Brady RO. Sphingolipidoses.  N Engl J Med.1966;275:312-318.Google Scholar
26.
Brady RO, Tallman JF, Johnson WG.  et al.  Replacement therapy for inherited enzyme deficiency: use of purified ceramidetrihexosidase in Fabry's disease.  N Engl J Med.1973;289:9-14.Google Scholar
27.
Barton NW, Brady RO, Dambrosia JM.  et al.  Replacement therapy for inherited enzyme deficiency—macrophage-targeted glucocerebrosidase for Gaucher's disease.  N Engl J Med.1991;324:1464-1470.Google Scholar
28.
Ling GSF, Altarescu G, Frei KP, Moore DF, Schiffmann R. Abnormal cerebrovascular reactivity in Fabry's disease as demonstrated by transcranial Doppler studies [abstract].  Neurology.1999;50(suppl 2):A362-A363.Google Scholar
29.
Moore DF, Altarescu G, Herscovitch P, Schiffmann R. Abnormal cerebral blood flow in Fabry disease as demonstrated by H2O15 [abstract].  J Neuroimaging.2000;10:60.Google Scholar
30.
Schiffmann R, Kopp J, Austin H.  et al.  Efficacy and safety of enzyme replacement therapy in Fabry disease demonstrated by a double-blind placebo-controlled trial [abstract].  Am J Hum Genet.2000;67(suppl 2):38.Google Scholar
31.
Takenaka T, Hendrickson CS, Tworek DM.  et al.  Enzymatic and functional correction along with long-term enzyme secretion from transduced bone marrow hematopoietic stem/progenitor and stromal cells derived from patients with Fabry disease.  Exp Hematol.1999;27:1149-1159.Google Scholar
32.
Takenaka T, Qin G, Brady RO, Medin JA. Circulating alpha-galactosidase A derived from transduced bone marrow cells: relevance for corrective gene transfer for Fabry disease.  Hum Gene Ther.1999;10:1931-1939.Google Scholar
33.
Ziegler RJ, Yew NS, Li C.  et al.  Correction of enzymatic and lysosomal storage defects in Fabry mice by adenovirus-mediated gene transfer.  Hum Gene Ther.1999;10:1667-1682.Google Scholar
34.
Ohshima T, Schiffmann R, Murray GJ.  et al.  Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice.  Proc Natl Acad Sci U S A.1999;96:6423-6427.Google Scholar
35.
Pittenger MF, Mackay AM, Beck SC.  et al.  Multilineage potential of adult human mesenchymal stem cells.  Science.1999;284:143-147.Google Scholar
36.
Abe A, Gregory S, Lee L.  et al.  Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation.  J Clin Invest.2000;105:1563-1571.Google Scholar
37.
Jeyakumar M, Butters TD, Cortina-Borja M.  et al.  Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin.  Proc Natl Acad Sci U S A.1999;96:6388-6393.Google Scholar
38.
Cox T, Lachman R, Hollak C.  et al.  Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis.  Lancet.2000;355:1481-1485.Google Scholar
Grand Rounds
December 6, 2000

Clinical Features of and Recent Advances in Therapy for Fabry Disease

Author Affiliations

Author Affiliations: Developmental Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md.

 

Grand Rounds at the Clinical Center of the National Institutes of Health Section Editors: John I. Gallin, MD, the Clinical Center of the National Institutes of Health, Bethesda, Md; David S. Cooper, MD, Contributing Editor, JAMA.

JAMA. 2000;284(21):2771-2775. doi:10.1001/jama.284.21.2771
Abstract

Fabry disease is an X-linked recessive lysosomal storage disorder caused by a deficiency of α-galactosidase A. Intracellular accumulation of globotriaosylceramide, the glycolipid substrate of this enzyme, leads to severe painful neuropathy with progressive renal, cardiovascular, and cerebrovascular dysfunction and early death. Men are predominantly affected but many female carriers have similar clinical involvement, including increased risk of stroke. Physical stigmata, such as angiokeratomas in skin and mucous membranes and characteristic benign corneal abnormalities, facilitate identification of Fabry disease. The finding of a marked decreased activity of α-galactosidase A in white blood cells or cultured skin fibroblasts confirms the diagnosis. Treatment thus far has been symptomatic only. Etiology-based therapies are being developed that include enzyme replacement therapy, gene therapy, and substrate deprivation. Our recently completed double-blind, placebo-controlled trial of intravenous infusions of α-galactosidase A in patients with Fabry disease demonstrated the safety and efficacy of this treatment.

Case presentation

A 38-year-old man described the onset, at age 7 years, of joint pain and crampy diarrhea associated with meals. Generalized aching and pain in the hands and feet worsened with time. Lately, he has experienced numbness in the hands and feet that varies with the ambient temperature. He has had intermittent bouts of fever with temperature up to 40.6°C, lasting 1 or 2 days, that were partly ascribed to his inability to sweat normally and dissipate body heat. Pain in the hands and feet became extremely intense during the febrile episodes. He obtained considerable relief from the painful acroparesthesias with carbamazepine but discontinued it because of drowsiness. He has taken phenytoin in the past, and more recently, gabapentin. He has had some hearing difficulties, as well as dry eyes and mouth. He has had a generalized lack of sweating throughout his life, although some sweating has recently returned over his forehead and chest. One brother with Fabry disease died at 42 years following a myocardial infarction, and 2 cousins with Fabry disease died from strokes. Two maternal uncles also had the disease; another cousin with the disorder is being treated with hemodialysis (Figure 1).

The patient was well-developed, well-nourished, and in no acute distress. He had extensive reddish-purple angiokeratomas on the eyelids, oral mucosa, arms, fingertips, abdomen (including the umbilical region), flanks, and proximal thighs. Ophthalmologic examination revealed cortical spoking of the lens and tortuous conjunctival and retinal vasculature (Figure 2A). Mild-to-moderate sensorineural hearing loss was present and more marked on the right. Pulmonary function tests revealed mild obstructive disease with normal volumes and diffusion capacity. Echocardiogram and electrocardiogram revealed mild left ventricular hypertrophy, mild aortic and tricuspid regurgitation, intraventricular conduction delay, notched QRS in lead III, and early repolarization in some precordial leads. A magnetic resonance imaging scan of the head was within normal limits. Neurological examination revealed a lessening of cold sensation over the dorsal surface of the hands and forearms; there was no sensation of cold in the lower extremities below the hips. Vibratory, pinprick, light touch, and position sensation modalities were normal. Protein excretion in the urine was 5382 mg/24 h (normal, 30-100 mg/24 h). Creatinine clearance was 1.4 mL/s (normal, 1.5-2.1 mL/s). Serum creatinine and blood urea nitrogen were within reference range. α-Galactosidase A (α-gal A) activity in extracts of the patient's cultured peripheral white blood cells was less than 1% of the mean of 3 normal control specimens assayed simultaneously, confirming the diagnosis of Fabry disease. Sequencing the α-gal A complementary DNA revealed a deletion in exon 1 (1238del26) that caused a shift in the reading frame. No functional α-gal A protein is expected to be produced.

The patient was admitted to the Clinical Center of the National Institutes of Health under Institutional Review Board–approved Protocol 97-N-0066 (α-Galactosidase A Replacement Therapy in Fabry Disease: A Safety and Dose Escalation Clinical Trial of α-Galactosidase A Produced from a Genetically Engineered Human Fibroblast Strain).1 The patient received intravenous α-gal A (0.3 IU per kilogram) over a 14-minute period. The patient tolerated the infusion of α-gal A without incident. No antibody to the enzyme was detected in the serum.

Before infusion of α-gal A, the patient underwent a percutaneous liver biopsy. Histological examination revealed scattered foamy macrophages in the portal areas and within sinusoids. The storage cells were periodic acid–Schiff (PAS) positive. The accumulated material was diastase resistant. Electron microscopy revealed storage inclusions in Kupffer and vascular endothelial cells (Figure 2B). A biopsy of the sural nerve revealed focal areas of myelin loss and interstitial fibrosis confirmed with luxol fast blue, PAS, and trichrome stains. Forty-four hours after infusion, a second percutaneous liver biopsy was performed. The liver specimens were examined histologically, immunocytochemically (for cellular localization of α-gal A), and analytically (for the quantity of globotriaosylceramide [Gb3], the accumulating lipid). Immunocytochemical staining revealed that the infused α-gal A was primarily localized in Kupffer cells and sinusoidal endothelial cells. A significant amount of α-gal A was also found in hepatocytes. The amount of Gb3 in the liver sample obtained before infusion was 25 nmol/mg of protein. After infusion, the value was 16 nmol/mg of protein (36% reduction).

A urine sample was collected 24 hours before infusion, and the amount of Gb3 in the urinary sediment was determined by high-pressure liquid chromatography.1 Postinfusion urine samples were also obtained and analyzed at 24 hours, 7 days, and 28 days. Globotriaosylceramide in the 24-hour preinfusion sample was 1958 nmol/g of creatinine; Gb3 in the 28-day postinfusion sample was 640 nmol/g of creatinine (67% reduction). No reduction of Gb3 was seen in the 24-hour or 7-day postinfusion urine specimens.

Discussion

Fabry disease is the second most prevalent metabolic storage disorder of humans after Gaucher disease. It has an incidence of 1:117,000 live births.2 In 1898, both Fabry3 and Anderson4 published descriptions of patients with extensive angiokeratomas on the body. The condition was called Anderson-Fabry disease, but is now more frequently called Fabry disease. It is an X-linked recessive disorder.5 In 1963, Sweeley and Klionsky6 identified the accumulating lipid as Gb3. In 1967, Brady and coworkers7 identified the metabolic defect in this disorder as a deficiency of the enzyme that catalyzes the hydrolytic cleavage of the terminal molecule of galactose from Gb3. Shortly thereafter, Kint8 showed that the involved enzyme was an α-isozyme. Kusiak et al9 found that human tissues contained 2 α-isozymes. α-Isozyme A is deficient in patients with Fabry disease.10 A major source of accumulating Gb3 is the tetraglycosylsphingolipid called globoside, a principal component of erythrocyte membranes.11 All Fabry patients have mutations in the α-gal A gene. Numerous mutations have been described, with almost every family having its own mutation.12

Clinical Characteristics

In Fabry disease, the progressive lysosomal accumulation of Gb3 occurs in vascular endothelium and smooth muscle cells. It is also found in the renal epithelium (Figure 3), myocardium, dorsal root ganglia, autonomic nervous system, and brain.10 Patients often have a painful small fiber neuropathy unique to this disease that brings them to neurological attention before other serious manifestations appear.10 The clinical manifestations of this neuropathy can occur in patients as young as 5 years, who characteristically present with intermittent bouts of burning, aching pain in the hands and feet, sometimes accompanied by elevated body temperature. Although the pain may be very severe, routine physical examination fails to detect any neurological abnormality.10 Moreover, in patients who have not yet developed renal insufficiency and therefore have not yet developed uremic neuropathy, results of electromyography and nerve conduction velocity studies are normal and may lead one to conclude that the pain has no organic basis. In fact, normal routine neurophysiologic studies indicate that the neuropathy of Fabry disease predominantly involves small nerve fibers.10 Medications such as carbamazepine, phenytoin, gabapentin, and lamotrigine often reduce the neuropathic pain.

Deposits of Gb3 are responsible for the most clinically significant features of the disease: stroke, renal failure, and myocardial infarction.10 Most patients have proteinuria, and progressive renal insufficiency often occurs at the third, fourth, or fifth decade.13 Cardiac hypertrophy is common, as are arrhythmia, valvular insufficiency, cardiac conduction abnormalities, and obstruction of coronary arteries leading to myocardial infarctions.14,15 The disease is also characterized by small-vessel ischemic cerebral infarctions (Figure 4), usually present by the third and fourth decades; both small- and large-vessel strokes are common by the fifth decade.16,17 Dilative arteriopathy of the vertebrobasilar circulation with resultant hemorrhagic strokes has also been described.17 Increase in inflammatory and adhesion molecules likely contributes to the vasculopathy often seen.18

Other clinical manifestations include postprandial intestinal cramps and diarrhea,19 progressive sensorineural hearing loss,20 vertigo, and achalasia.21 Clinical diagnosis of male hemizygotes and of female carriers is helped by the presence of characteristic angiokeratomas and a distinctive, but asymptomatic, corneal dystrophy.22 Ophthalmologic examination often reveals a posterior capsular cataract and excessively tortuous retinal blood vessels.23

Development of Specific Therapy

Many lysosomal hydrolases have mannose-6-phosphate residues that bind to a specific receptor in the Golgi apparatus, and are thus directed to prelysosomal compartments.24 Enzymes that escape this routing system are secreted by the cell via the constitutive secretory pathway and are often recaptured by cell surface mannose-6-phosphate receptors that return the enzyme to the lysosome by the endocytic pathway.24 It is this aspect of lysosomal enzyme trafficking that makes enzyme replacement therapy a feasible therapeutic strategy for patients with lysosomal storage disorders such as Fabry disease. The intravenously infused exogenous lysosomal enzyme will be taken up by various cell types in the body, reach their lysosomal compartments, and there catalyze the hydrolysis of the accumulated substrate. Correction of the metabolic defect is expected to improve the function of individual cells, thereby preventing further deterioration of organ function and even reversing the disease process.

Following the postulation that enzyme supplementation or replacement might be beneficial for patients with sphingolipid storage disorders,25 an early study was carried out in patients with Fabry disease.26 Two men with the disorder received infusions of small quantities of α-gal A isolated from human placental tissue. In each instance, there was a rapid reduction of Gb3 in the blood. The level returned to preinfusion values within 3 days. Six years later, a similar study was performed with α-gal A isolated from human spleen and from plasma.10 Quite similar results were obtained. An important observation in the latter investigation was that the recipients did not develop antibodies to the exogenous enzymes administered several times over a 6-month period.

Further studies of enzyme replacement therapy for Fabry disease were delayed for several years until sufficient quantities of purified α-gal A became available through genetic engineering. The investigation described in this report was carried out with α-gal A produced in cultured human skin fibroblasts.1 It was purified and extensively characterized before infusion. Unlike enzyme replacement therapy for Gaucher disease using β-glucosidase,27 here there was no need to modify the sugar side chains.1 The terminal half-life for elimination of the enzyme in the circulation was about 80 minutes; in the liver, up to 48 hours. Measurable reductions of Gb3 occurred in the liver and in the 28-day postinfusion urinary sediment. The latter finding is especially important for patients with Fabry disease, as it is likely a reflection of storage reduction in kidney tubular cells.

Clinical Trial of α-gal A

Because of these encouraging findings, a pivotal efficacy and safety trial was designed and implemented with this patient and 7 others who participated in the safety and dose-escalation study.1 Since Fabry disease is associated with progressive damage of the brain, heart, kidneys, and peripheral nerves, effective treatment of this disease is expected to halt the deterioration of affected organs and perhaps improve their function. Such treatment is expected, over the years, to dramatically modify the natural history of the disorder by preventing or arresting progressive organ deterioration. Demonstrating the efficacy of this therapy in a short (6-month) clinical trial presented a considerable challenge. Clinically relevant outcome measures, such as those used for Gaucher disease,27 are likely to demonstrate efficacy after a short trial but were not readily available. Therefore, to detect a beneficial therapeutic effect rapidly, we developed outcome measures reflecting both body system function and structure.16,18,28,29

In this double-blind, placebo-controlled study, 26 hemizygous men were randomized to receive 12 infusions of α-gal A (0.2 mg/kg; Transkaryotic Therapies, Inc, Cambridge, Mass) or placebo.30 The infusions were administered every 2 weeks for 20 to 40 minutes, for a total of 6 months. Outcome measures included neuropathic pain measured without analgesics using the Brief Pain Inventory. The effects on kidney function and structure were also determined. Globotriaosylceramide was quantified in plasma, 24-hour urinary sediment, and in renal biopsy tissue. Using intention-to-treat analysis, pain-at-its-worst scores on a 0 (no pain) to 10 (maximal pain) scale decreased from 6.21 to 4.29 with α-gal A and 7.25 to 6.83 with placebo (P = .02). Severity scores, pain-related quality of life scores, and mean number of days with pain medication also decreased significantly in the treated group compared with controls. Four of 14 patients receiving the enzyme were able to discontinue pain medications for the duration of the trial; all patients receiving the placebo still required medication. Mean creatinine clearance increased by 0.07 mL/s with α-gal A, while it decreased by 0.3 mL/s with placebo (P = .02).30 Mean insulin clearance decreased by 0.1 mL/s with α-gal A, and by 0.3 mL/s for placebo (P = .17). In the group receiving α-gal A, there was significant improvement in glomerular histology, while the placebo group experienced a significant deterioration in renal glomerular pathology. Levels of Gb3 in plasma and urinary sediment decreased significantly (P = .02); renal Gb3 decreased by 21% on average. α-Gal A infusions were well tolerated. We concluded that enzyme replacement therapy with α-gal A is safe and likely to improve the prognosis of Fabry disease.30

Development of Other Forms of Therapy

In response to the encouraging results of enzyme replacement therapy for Fabry disease, we and others continue to explore the feasibility of gene therapy for patients with this condition. Recent findings indicate that transduced bone marrow stem/progenitor cells and stromal cells derived from patients with Fabry disease are metabolically corrected and that they produce and secrete α-gal A into the circulation.31,32 These observations are supplemented by the demonstration that adenovirus-mediated gene transfer caused a reduction of accumulated Gb3 in a mouse model of Fabry disease.33 Investigators are encouraged by recent findings concerning bone marrow transplantation in the murine analog of Fabry disease34 to explore other modalities such as ex vivo transfer of the α-gal A gene to mesenchymal stem cells derived from the bone marrow of patients with Fabry disease.35 Finally, another approach to the treatment of the disease is the reduction of synthesis of Gb3. This may be achieved using inhibitors of sphingoglycolipid synthesis.36,37 Trials to test the efficacy of such an approach showed promise in patients with Gaucher disease.38

References
1.
Schiffmann R, Murray GJ, Treco D.  et al.  Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease.  Proc Natl Acad Sci U S A.2000;97:365-370.Google Scholar
2.
Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders.  JAMA.1999;281:249-254.Google Scholar
3.
Fabry J. Ein Beitrag zür kenntnis der Purpura haemorrhargica nodularis (Purpura papulosa haemorrhagic hebrae).  Arch Dermatol Syphilis.1898;43:187-200.Google Scholar
4.
Anderson WA. A case of angiokeratoma.  Br J Dermatol.1898;18:113-117.Google Scholar
5.
Opitz JM, Stiles FC, Wise D. The genetics of angiokeratomas corporis diffusum (Fabry's disease) and its linkage with Xg(a) locus.  Am J Hum Genet.1965;17:325-342.Google Scholar
6.
Sweeley CC, Klionsky B. Fabry's disease: classification as sphingolipidosis and partial characterization of novel glycolipid.  J Biol Chem.1963;238:PC3148-PC3150.Google Scholar
7.
Brady RO, Gal AE, Bradley RM.  et al.  Enzymatic defect in Fabry's disease: ceramidetrihexosidase deficiency.  N Engl J Med.1967;276:1163-1167.Google Scholar
8.
Kint JA. Fabry's disease: alpha-galactosidase deficiency.  Science.1970;167:1268-1269.Google Scholar
9.
Kusiak JW, Quirk JM, Brady RO. Purification and properties of the two major isozymes of α-galactosidase from human placenta.  J Biol Chem.1978;253:184-190.Google Scholar
10.
Desnick RJ, Ioannou YA, Eng CM. α A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 6th ed. New York, NY: McGraw-Hill; 1996:2741-2784.
11.
Yamakawa T, Yokoyama S, Handa N. Chemistry of lipids of mucolipid of human erythrocytes.  J Biochem (Tokyo).1963;53:28-36.Google Scholar
12.
Topaloglu AK, Ashley GA, Tong B.  et al.  Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease.  Mol Med.1999;5:806-811.Google Scholar
13.
Meroni M, Sessa A, Battini G, Tazzari S, Torri Tarelli L. Kidney involvement in Anderson-Fabry disease.  Contrib Nephrol.1997;122:178-184.Google Scholar
14.
Chimenti C, Ricci R, Pieroni M.  et al.  Cardiac variant of Fabry's disease mimicking hypertrophic cardiomyopathy.  Cardiologia.1999;44:469-473.Google Scholar
15.
Nakao S, Takenaka T, Maeda M.  et al.  An atypical variant of Fabry's disease in men with left ventricular hypertrophy.  N Engl J Med.1995;333:288-293.Google Scholar
16.
Crutchfield KE, Patronas NJ, Dambrosia JM.  et al.  Quantitative analysis of cerebral vasculopathy in patients with Fabry disease.  Neurology.1998;50:1746-1749.Google Scholar
17.
Mitsias P, Levine SR. Cerebrovascular complications of Fabry's disease.  Ann Neurol.1996;40:8-17.Google Scholar
18.
DeGraba TJ, Azhar S, Dignat-George F.  et al.  Profile of endothelial and leukocyte activations in Fabry's patients.  Ann Neurol.2000;47:229-233.Google Scholar
19.
Argoff CE, Barton NW, Brady RO, Ziessman HA. Gastrointestinal symptoms and delayed gastric emptying in Fabry's disease: response to metoclopramide.  Nucl Med Commun.1998;19:887-891.Google Scholar
20.
Schachern PA, Shea DA, Paparella MM, Yoon TH. Otologic histopathology of Fabry's disease.  Ann Otol Rhinol Laryngol.1989;98:359-363.Google Scholar
21.
Roberts DH, Gilmore IT. Achalasia in Anderson-Fabry's disease.  J R Soc Med.1984;77:430-431.Google Scholar
22.
Franceschetti AT. Fabry disease: ocular manifestations.  Birth Defects.1976;12:195-208.Google Scholar
23.
Bao LL, Guo LL, Li SN.  et al.  A family with Fabry's disease: ocular manifestations and transmission electron microscopic examination of a skin lesion biopsy.  Chin Med J (Engl).1990;103:134-141.Google Scholar
24.
von Figura K. Molecular recognition and targeting of lysosomal proteins.  Curr Opin Cell Biol.1991;3:642-646.Google Scholar
25.
Brady RO. Sphingolipidoses.  N Engl J Med.1966;275:312-318.Google Scholar
26.
Brady RO, Tallman JF, Johnson WG.  et al.  Replacement therapy for inherited enzyme deficiency: use of purified ceramidetrihexosidase in Fabry's disease.  N Engl J Med.1973;289:9-14.Google Scholar
27.
Barton NW, Brady RO, Dambrosia JM.  et al.  Replacement therapy for inherited enzyme deficiency—macrophage-targeted glucocerebrosidase for Gaucher's disease.  N Engl J Med.1991;324:1464-1470.Google Scholar
28.
Ling GSF, Altarescu G, Frei KP, Moore DF, Schiffmann R. Abnormal cerebrovascular reactivity in Fabry's disease as demonstrated by transcranial Doppler studies [abstract].  Neurology.1999;50(suppl 2):A362-A363.Google Scholar
29.
Moore DF, Altarescu G, Herscovitch P, Schiffmann R. Abnormal cerebral blood flow in Fabry disease as demonstrated by H2O15 [abstract].  J Neuroimaging.2000;10:60.Google Scholar
30.
Schiffmann R, Kopp J, Austin H.  et al.  Efficacy and safety of enzyme replacement therapy in Fabry disease demonstrated by a double-blind placebo-controlled trial [abstract].  Am J Hum Genet.2000;67(suppl 2):38.Google Scholar
31.
Takenaka T, Hendrickson CS, Tworek DM.  et al.  Enzymatic and functional correction along with long-term enzyme secretion from transduced bone marrow hematopoietic stem/progenitor and stromal cells derived from patients with Fabry disease.  Exp Hematol.1999;27:1149-1159.Google Scholar
32.
Takenaka T, Qin G, Brady RO, Medin JA. Circulating alpha-galactosidase A derived from transduced bone marrow cells: relevance for corrective gene transfer for Fabry disease.  Hum Gene Ther.1999;10:1931-1939.Google Scholar
33.
Ziegler RJ, Yew NS, Li C.  et al.  Correction of enzymatic and lysosomal storage defects in Fabry mice by adenovirus-mediated gene transfer.  Hum Gene Ther.1999;10:1667-1682.Google Scholar
34.
Ohshima T, Schiffmann R, Murray GJ.  et al.  Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice.  Proc Natl Acad Sci U S A.1999;96:6423-6427.Google Scholar
35.
Pittenger MF, Mackay AM, Beck SC.  et al.  Multilineage potential of adult human mesenchymal stem cells.  Science.1999;284:143-147.Google Scholar
36.
Abe A, Gregory S, Lee L.  et al.  Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation.  J Clin Invest.2000;105:1563-1571.Google Scholar
37.
Jeyakumar M, Butters TD, Cortina-Borja M.  et al.  Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin.  Proc Natl Acad Sci U S A.1999;96:6388-6393.Google Scholar
38.
Cox T, Lachman R, Hollak C.  et al.  Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis.  Lancet.2000;355:1481-1485.Google Scholar
×