Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fabry's disease is glycolipid sphingolipidosis which belongs to the group of lipid storage diseases and has as its underlying cause congenital deficiency of alpha-galactosidase. The pathologic anatomy of visceral lesions is described at the macroscopic, light-optical, and electron-microscopic levels in a 50-year-old male with striking systemic manifestations of Fabry's disease. In addition to lesions typical for glycolipid sphingolipidosis, atherosclerosis involving primarily heart arteries (which is not characteristic for this disease) was found in the patient. This case demonstrates that although cutaneous lesions underlie the traditional designation of Fabry's disease as angiokeratoma corporis diffusum, skin involvement is only one of its external signs.
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PMID:[Visceral manifestations of glycosphingolipidosis (Fabry's disease)]. 311 21

The authors detected on necropsy in a 63-year-old woman with the clinical diagnosis of hypertension, atherosclerosis of the coronary and peripheral arteries, thromboembolism into the cerebral circulation and impaired cardiac conductivity lysosomal storage identified by histochemical and electronoptic analyses along with lipid chromatography as Fabry's disease. The stored lipids were neutral glycosphingolipids of the globo series globotriaosylceramide) and of the gala- series (galabiosylceramide) which accumulated as a result of deficient activity of the degrading enzyme alpha galactosidase A. Marked accumulation of these specific lipids was found in cardiomyocytes, in smooth muscles (of the media in arteries of the heart, kidneys, liver, spleen, lungs) in podocytes and mesangial cells of renal glomeruli, in epithelia of Henle's loop and in the distal tubules. In the vascular endothelium the storage was at the borderline of detectability. Accumulation did not lead to detectable organ disorders with the exception of the heart where it participated, no doubt, significantly in the cardiocyte hypertrophy. Examination of relatives revealed in the proband's son (age 41 years) a combination of renal, cardiac and skin changes typical for Fabry's disease which, however was not clinically diagnosed. The diagnosis was confirmed by proving of alpha-galactosidase A deficiency in the peripheral leucocytes and point mutation L293X in the VIth exon of the appropriate gene. In a granddaughter (age 15 years) biochemical and molecular genetic methods revealed the heterozygous state of Fabry's disease in preclinical stage.
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PMID:[Postmortem diagnosis of Fabry disease in a female heterozygote leading to the detection of undiagnosed manifest disease in the family]. 1074 23

We describe the postmortem findings of a 47-year-old man with Fabry disease, an X-linked glycolipid storage disorder, who was on enzyme replacement therapy with recombinant alpha-galactosidase A for more than 2 years. The patient had widespread atherosclerotic coronary artery disease that culminated in a massive acute myocardial infarction. Atherosclerotic lesions were seen in the right and left coronary systems, aorta, and the basilar artery. Typical Fabry cardiomyopathy and glomerular nephropathy were found. With the exception of vascular endothelial cells, extensive glycolipid storage deposits were seen in all vascular and nonvascular cells and organ systems. We conclude that, at least in this patient, repeated infusions with alpha-galactosidase A over a prolonged period did not appreciably clear storage material in cells other than vascular endothelial cells. These findings also illustrate accelerated atherosclerosis in susceptible patients with Fabry disease.
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PMID:Pathological findings in a patient with Fabry disease who died after 2.5 years of enzyme replacement. 1660 5

Fabry disease, or alpha-galactosidase A (alpha-Gal A) deficiency, is a lysosomal storage disorder in which accumulation of globotriaosylceramide (Gb(3)) is thought to be responsible for the development of renal, cardiac and cerebral complications. The availability of enzyme replacement therapy has led to an increased awareness and the screening of patients suffering from complications that may be associated with Fabry disease. An association between alpha-Gal A deficiency and atherosclerosis has been suggested, although there is controversy. We therefore studied the prevalence of Fabry disease in a Dutch cohort of prematurely atherosclerotic males. Measurement of alpha-Gal A activity was performed in plasma of 440 Dutch male patients with premature atherosclerosis. Patients were included if they were under the age of 50 years and had proven coronary and/or peripheral artery disease. Analysis revealed a mean alpha-Gal A activity of 7.75 +/- 3.48 nmol/h per ml (range 0.55-34.36). In 425 patients (96.5%) alpha-Gal A activity was within the reference range (3.2-14.3 nmol/h per ml, based on historical controls); 13 patients (3%) had values above and 2 patients (0.5%) below the reference range. Additional analysis of alpha-Gal A activity in leukocytes and fresh plasma in these two patients revealed normal values (53 and 47 nmol/h per mg (reference range: 32-60 nmol/h per mg) and 31.1 and 14.2 nmol/h per ml, respectively). Thus Fabry disease was not detected, leading to an overall prevalence of 0% (95 CI 0-0.68). In conclusion, screening for Fabry disease in prematurely atherosclerotic patients seems not to be very useful, although a slightly increased prevalence is not excluded.
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PMID:Failure to detect Fabry patients in a cohort of prematurely atherosclerotic males. 1784 32

Glycosphingolipids (GSLs) have been implicated as potential atherogenic lipids. Studies in apolipoprotein E-null (apoE(-/-)) mice indicate that exacerbated tissue GSL accumulation resulting from alpha-galactosidase deficiency promotes atherosclerosis, whereas the serine palmitoyl transferase inhibitor myriocin (which reduces plasma and tissue levels of several sphingolipids, including sphingomyelin, ceramide, sphingosine-1-phosphate, and GSLs) inhibits atherosclerosis. It is not clear whether GSL synthesis inhibition per se has an impact on atherosclerosis. To address this issue, apoE(-/-) mice maintained on a high-fat diet were treated with a potent glucosylceramide synthesis inhibitor, d-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol (EtDO-P4), 10 mg/kg/day for 94 days, and lesion development was compared in mice that were treated with vehicle only. EtDO-P4 reduced plasma GSL concentration by approximately 50% but did not affect cholesterol or triglyceride levels. Assessment of atherosclerotic lesions at four different sites indicated that EtDO-P4 had no significant impact on lesion area. Thus, despite the previously observed positive correlations between plasma and aortic GSL concentrations and the development of atherosclerosis, and the in vitro evidence implying that GSLs may be pro-atherogenic, our current data indicate that inhibition of GSL synthesis does not inhibit atherosclerosis in vivo.
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PMID:Reduction of plasma glycosphingolipid levels has no impact on atherosclerosis in apolipoprotein E-null mice. 1846 44

Since the foundations laid by Sacco and Mohr in 1989, from the Stroke data bank, cryptogenic infarctions have had a predominant place among the causes of ischemic strokes. In that study, they accounted for approximately 40% of the stroke causes. Cryptogenic infarctions are infarctions without a defined cause, despite a complete work-up; they differ from infarctions of undetermined causes, which may involve overlapping causes or an incomplete investigation. The size of this group will probably shrink as knowledge advances. Patent foramen ovale (PFO), with or without a septal aneurysm, is more frequent in patients with a cryptogenic infarction. Transesophageal echocardiography is the reference examination for screening for these abnormalities. A meta-analysis of several case-control studies showed a significant association between PFO and stroke in subjects younger than 55 years. For now, these septal abnormalities constitute a risk factor but not a cause. Complex aortic atheroma affecting area upstream of the left subclavian artery may be a source of cerebral embolisms in some conditions. The prevalence of this disease increases with age. It is identified most frequently in patients older than 60 years with a cryptogenic infarction. The thickness of the atheromatous plaque determines whether it is a risk factor or a cause. Recent stroke classifications do not consider carotid atheromatous lesions less than 50% to be a source of ischemic stroke. Nonetheless some studies identify moderate stenosis of the carotid artery more frequently in infarctions of unknown causes than in other categories. The increased risk of cerebral infarction when parents and homozygous twins have a history of stroke suggests that there may be genetic causes that have not yet been detected. An unknown genetic cause would thus be included in the infarctions of unknown causes. A recent study tested for Fabry disease in young patients with a cryptogenic infarction: 4.9% of the men and 2.4% of the women had a functional mutation of the alpha-galactosidase gene. These findings must be confirmed. Some studies suggest an association between cryptogenic infarction and hereditary thrombophilias. Nonetheless the risk attributable to these thrombophilic disorders is slight and the discovery may be only a coincidence. The work described above shows the importance of stratification in the identification of stroke causes: age older or younger than 55/60 years, type of interatrial abnormality (PFO and aneurysms of the interatrial septum), type of atheroma of the aortic arch (more or less than 4mm). They also show the difficulty involved in attributing cause to an identified abnormality: is carotid stenosis of less than 50% a marker of atherosclerosis or also a cause of stroke? To continue improving our understanding of the mechanisms of strokes, new investigational techniques are under evaluation. They include magnetic resonance imaging (MRI), computed tomographic angiography (CT), positron emission tomography (PET) of carotid plaque and of the aortic arch, transcranial Doppler, cardiac recording by telemetry, and even new biological assays.
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PMID:[Cryptogenic cerebral infarction: from classification to concept]. 1939 32

Fabry disease is an X-linked lysosomal storage disorder due to deficiency of the enzyme alpha-galactosidase A. The principal clinical manifestations of Fabry disease consist of cardiovascular complications including cerebrovascular, renal and cardiac disease but the pathophysiology of this specific vasculopathy is unclear. With the development of targeted treatment for Fabry disease, i.e. enzyme replacement therapy, it has become apparent that the removal of stored glycosphingolipid from the endothelial cells does not prevent progression of vascular disease in many patients. The aim of this study is to review the current available literature on vascular function tests, imaging and pathology studies and propose a hypothesis on the evolution of arterial complications in Fabry disease. Clearly, although premature atherosclerosis is suggested to occur, most studies describe absence of characteristic plaque formation. Smooth muscle cell hypertrophy, is probably the earliest feature of a complex vasculopathy, as in females and atypical cardiac variants, who have residual enzyme activity, no endothelial storage of significance is found. Subsequently, processes occur as observed in neo intima formation however with formation of more fibrotic structures. In the presence of a hyperdynamic circulation in combination with a less compliant vascular wall, it is hypothesized that upregulation of local renin angiotensine systems may occur. Angiotensin II is known to increase adhesion molecules, cytokines and chemokines and exerts a pro-inflammatory effect on leucocytes, endothelial cells and vascular smooth muscle cells. This enhances release of pro-thrombotic factors and opposes actions mediated through angiotensin 2 (AT2) receptor, including the release of nitric oxide (NO). A combination of reduced vascular compliance and activation of pro-thrombotic factors can lead to vascular complications in Fabry disease.
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PMID:Vasculopathy in patients with Fabry disease: current controversies and research directions. 1990 Aug 28