Gene/Protein Disease Symptom Drug Enzyme Compound
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 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fabry disease is an inherited deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha GalA) due to mutations in the Gal gene at Xq22. The result is intralysosomal accumulation of glycosphingolipids. In males who carry the mutation (1/40,000), severe multisystem disease develops in childhood or adolescence. Attacks of acute pain lasting a few minutes to a few days occur in the hands and feet, joints, muscles, and abdomen, sometimes with a fever. Highly suggestive skin lesions called angiokeratomas develop, as well as cornea verticillata characterized by corneal deposits without visual impairment. Stroke, seizures, heart disorders (conduction disturbances, valve disease, and left heart failure) and kidney disorders (proteinuria and chronic renal failure) develop in the third or fourth decade of life. Women who are heterozygous for the Gal gene can transmit the disease to their sons but are usually free of symptoms, although many have cornea verticillata. However, they may have moderate or severe disease related to uneven chromosome X inactivation. Late-onset variants with predominant neurological, cardiac, or renal manifestations have been described. The diagnosis is difficult when the family history is negative for Fabry disease. Tests on plasma and leukocytes show very low levels of alpha GalA activity in affected men, confirming the diagnosis. The Gal gene mutation should be looked for to detect heterozygous women. Symptomatic treatments include analgesics, antihypertensives, antiplatelet agents or anticoagulants to treat ischemic events, and hemodialysis or kidney transplantation to treat chronic renal failure. The recent introduction of enzyme replacement therapy with recombinant agalsidase alpha or beta has been a major breakthrough in the treatment of Fabry disease. Enzyme replacement therapy relieves the pain and decreases the risk of complications. The safety profile is good. Given the high cost of agalsidase therapy (about 160,000 euro/year/patient) and the low incidence of Fabry disease, patients should be referred to highly specialized centers (see addresses on the France Orphanet web site).
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PMID:Fabry disease: a review. 1547 88

Fabry disease is an X-linked recessive disease resulting from a deficiency of the lysosomal hydrolase alpha-galactosidase A. In male patients with the classic hemizygous form, acroparesthesias, hypohidrosis, corneal opacities, and dysfunction of the heart, brain, and kidney are observed. Recently, it was reported that 0.5-1.2% of male chronic hemodialysis (HD) patients were diagnosed as having Fabry disease based on the measurement of alpha-galactosidase A activity. Fabry disease is thought to be an important cause of end-stage renal disease. There are a few reports of patients with Fabry disease on long-term HD. Here we report two male siblings with classical type Fabry disease on HD. They had acroparesthesias, and hypohidrosis. Their mother had severe heart failure due to a heterozygous form of Fabry disease. Case 1 is a 44-year-old male. He had mid-cerebral apoplexy at 30 years of age. He started maintenance HD in 2000. Remarkable left ventricular hypertophy and conduction disorders of the heart were found. In 2004, he collapsed and ventricular-tachycardia and severe hypoxic brain damage were found. Now his consciousness level has been in the range of 100 to 300 on the Japan Coma Scale. Case 2 is a 40-year-old male. He started maintenance HD in 1993. Malnutrition due to chronic diarrhea and severe ischemic change in the brain were found. In 1998, he had severe joint pain of shoulders and fingers with ectopic calcifications detected by X ray. The ectopic calcifications were extended to the whole body. In 2004, his dementia by ischemic change in the brain has rapidly progressed. In conclusion, cardiovascular complications, cerebrovascular manifestations, painful ectopic carcifications, and chronic diarrheas in our patients were considered to be specific symptoms of Fabry disease. Young HD patients with these symptoms will need to be examined for Fabry disease.
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PMID:[Clinical courses of two male siblings on hemodialysis for Fabry disease ]. 1585 34

Fabry disease is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Progressive accumulation in lysosomes of the undegraded glycosphingolipids leads to a multi-system disease with dermatological, ocular, renal, cardiac, and neurological manifestations. Peripheral nerve involvement, neuropathic pain and chronic acroparesthesiae, are frequent and early-onset signs revealing the disease. They are due to the involvement of small nerve fiber, thus explaining the normality of electroneuromyography. Cochleo-vestibular and autonomic nervous system involvement is frequent. Besides rare aseptic meningitis, central nervous system involvement is essentially represented by cerebrovascular events (stroke, transient ischemic attack). Affecting essentially the posterior circulation, their etiologies have to be clarified: progressive stenosis of small vessels with globotriasocylceramide deposits, arterial remodeling, endothelial dysfunction, pro-thrombotic state, cerebral hypoperfusion consecutive to dysautonaumy, cardiac embolism. MRI shows numerous silent lesions, increasing with age, mainly in small perforant arteries (periventricular white matter, brainstem, cerebellum, basal ganglia). Pulvinar calcifications, due to an increase in cerebral hyperperfusion, could be specific of Fabry disease. Positon tomography analysis shows a reduced cerebral flow velocity and impaired cerebral autoregulation, secondary to the glycosphingolipid storage in vascular endothelial cells. Enzyme replacement therapy has to be carefully monitored.
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PMID:[Neurological aspects of Fabry's disease]. 1671 Jan 23

Fabry Disease (FD) is a rare X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A (alpha-GAL) enzyme activity. Neutral glycosphingolipides (esp. Gb3) accumulate in lysosomes of several tissues, particularly in vascular endothelium and smooth muscle cells. Cerebral manifestations that might be mainly due to progressive cerebrovascular dysfunction, are one major and often life-threatening burden of the disease. We reviewed the present literature concerning brain structural alterations in FD and discuss the possibly relevant underlying pathophysiological aspects of these disturbances. Cerebrovascular events (TIA, stroke) occur in FD at a rather early age. In female FD patients who were considered to be less affected "carriers" for a long time, the prevalence of cerebrovascular events seems to be at last as high as in male patients. In structural imaging white matter lesions (WML) can be found frequently even in young FD patients. In a recent study clinically equally affected men and women with FD showed a comparable severity of WML load. Different pathophysiological aspects of cerebral angiopathy and WML development are discussed against the background of current concepts (e. g. accumulation of Gb3 in vascular endothelium with consecutive cell proliferation and luminal stenosis, acceleration of focal intravasal pressure and disturbances of vascular auto-regulation). Pathological increase of pulvinar signal in T1-weighted MRI has also been described in FD. This finding was assumed to be caused by calcification as a consequence of disturbed local circulation. To enhance our knowledge about the relevant neurobiological processes the authors propose a more sensitive and early detection of brain structural changes in FD. New brain structural MRI methods such as diffusion-tensor imaging could provide a pattern of ultrastructural changes even in young patients without visible WML. This strategy could be as well useful for quantification of possible effects of the enzyme replacement therapy on brain structural alterations in FD. Based on recent data a systematic FD-screening by measuring Gb3 in urine of young patients with cryptogenic stroke should be discussed. Basically in such cases FD should be clinically considered.
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PMID:[Pathophysiological aspects of brain structural disturbances in patients with Fabry disease: literature review]. 1716 27

Fabry's disease is an X-linked lysosomal storage disorder caused by a defect in the gene that encodes the lysosomal enzyme alpha-galactosidase A. Symptoms arise because of accumulation of globotriaosylceramide in multiple organs, resulting in severely reduced quality of life and premature death. Neurological symptoms, such as burning sensations (occasionally accompanied by acroparesthesia) and stroke, are among the first to appear, and occur in both male and female patients. A delay in establishing the diagnosis of Fabry's disease can cause unnecessary problems, especially now that enzyme replacement treatment is available to prevent irreversible organ damage. Females with Fabry's disease who present with pain have often been ignored and misdiagnosed because of the disorder's X-linked inheritance. This Review will stress the importance of recognizing neurological symptoms for the diagnosis of Fabry's disease. The possible pathophysiological background will also be discussed.
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PMID:Neurological manifestations in Fabry's disease. 1727 83

Fabry disease is an X-linked, hereditary, lysosomal storage disease caused by deficiency of the enzyme alpha-galactosidase A, which results in the accumulation of the neutral glycosphingolipid globotriaosylceramide (Gb3) in the walls of small blood vessels, nerves, dorsal root ganglia, renal glomerular and tubular epithelial cells, and cardiomyocytes. It is a complex, multisystem disorder that is characterized clinically by chronic pain and acroparesthesia, gastrointestinal disturbances, characteristic skin lesions (angiokeratomata), progressive renal impairment, cardiomyopathy, and stroke. Enzyme replacement therapy (ERT) with intravenous infusions of recombinant human alpha-galactosidase A consistently decreases Gb3 levels in plasma and clears lysosomal inclusions from vascular endothelial cells. The effects of ERT on other tissues are not as obvious, suggesting that treatment must be initiated early in the course of the disease to be optimally effective or that some complications of the disease are not responsive to enzymes delivered intravenously.
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PMID:Narrative review: Fabry disease. 1737 87

Cardiovascular complications, including stroke and myocardial infarction, result in premature mortality in patients with Fabry disease, an X-linked deficiency of alpha-galactosidase A (alpha-Gal A). The enzymatic defect results in the deposition of globotriaosylceramide (Gb3) in the vascular endothelium. To better understand the underlying pathogenesis of Fabry disease, the caveolar lipid content of primary cultured mouse aortic endothelial cells isolated from alpha-Gal A null mice was measured. Lipid mass analysis revealed that the excessive Gb3 in cultured alpha-Gal A-deficient mouse aortic endothelial cells accumulated in endothelial plasma membrane caveolar fractions. The levels of glucosylceramide and lactosylceramide increased in parallel with Gb3 levels in an age-dependent manner, whereas globotetraosylceramide (Gb4) levels reached maximal levels by 6 months of age and then rapidly decreased at older ages. The levels of cholesterol enriched in caveolar membranes declined in parallel with the progressive deposition of Gb3. Depleting Gb3 with recombinant human alpha-Gal A protein or d-threo-ethylenedioxyphenyl-P4, an inhibitor of glucosylceramide synthase, restored cholesterol in cultured alpha-Gal A-deficient mouse aortic endothelial cell caveolae. By contrast, recombinant human alpha-Gal A was less effective in normalizing the cholesterol content. These results demonstrate the caveolar accumulation of glycosphingolipids in an in vitro model of a lysosomal storage disease and raise the possibility that dynamic changes in the composition of plasma membrane lipid microdomains may mediate the endothelial dysfunction seen in Fabry disease.
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PMID:Caveolin-associated accumulation of globotriaosylceramide in the vascular endothelium of alpha-galactosidase A null mice. 1753 4

Fabry disease, rare X-linked disorder with deficient activity of alpha-galactosidase A, leads to a multiple organ failure caused by a progressive accumulation of the substrat globotriasocylceramide in cells. Peripheral nerve involvement, neuropathic pain and chronic acroparesthesiae, are the most frequently reported signs and often revealing the disease. They are secondary to the small nerve fibres (fibres 5), that explained the normality of electroneuromyography. Cochleovestibular and autonomic nervous system involvement appear later in the illness, aseptic meningitis are rare. Cerebrovascular events (stroke, transient ischaemic attack) are reported in 25% of patients, increasing with age. Affecting essentially the posterior circulation, their etiologies have to be clarified. MRI shows numerous silent lesions, increasing with age, mainly in small perforant arteries and pulvinar calcifications, due to on increase in cerebral perfusion with an impaired cerebral autoregulation, secondary to the glycosphingolipid storage in vascular endothelial cells. Enzyme replacement therapy could improve cerebral regional blood flow disturbances and painful neuropathy
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PMID:[Neurological aspects of Fabry disease]. 1754 71

Fabry disease is an inborn error of glycosphingolipid catabolism resulting from a deficiency of lysosomal enzyme alpha-galactosidase A. The major clinical manifestations of the disease, such as stroke, cardiac dysfunction, and renal impairment, are thought to be caused by vasculopathy due to progressive accumulation of globotriaosylceramide in vascular endothelial cells. The pathogenesis of the vasculopathy has not been elucidated. Since in vitro studies using primary endothelial cells are hampered by the limited lifespan of these cells, the availability of cultured endothelial cells with an extended lifespan is critical for the study of the vasculopathy of Fabry disease. We therefore generated an endothelial cell line from a Fabry hemizygote by introduction of human telomerase reverse transcriptase gene. The cell line has markedly extended lifespan compared to parental primary cells. The cells stably express many key markers of endothelial cells such as von Willebrand factor, CD31, CD34, and endothelial nitric oxide synthase (eNOS) and retain functional characteristics such as uptake of acetylated low-density lipoprotein, responsiveness to angiogenic growth factors, up-regulation of eNOS production upon extracellular stimuli, and formation of tube-like structures on Matrigel basement membrane matrix. The cells show significantly reduced activity of alpha-galactosidase A compared with primary endothelial cells from normal individuals and accumulate globotriaosylceramide in lysosomes. This cell line will provide a useful in vitro model of Fabry disease and will facilitate systematic studies to investigate pathogenic mechanisms and explore new therapeutic approaches for Fabry disease.
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PMID:Establishment and characterization of Fabry disease endothelial cells with an extended lifespan. 1764 84

Fabry disease is a rare, life-threatening, and under-diagnosed disease, with distinctive ocular manifestations identifiable during a routine eye examination. The disease is caused by an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in progressive accumulation of glycosphingolipids throughout the body. Long-term clinical manifestations include renal failure, early stroke, and cardiomyopathy. Recently, enzyme-replacement treatment has become available, heightening the importance of early diagnosis so that treatment can be initiated before irreversible organ damage. Ocular manifestations of Fabry disease include cornea verticillata (whorl-like radial lines emanating from a single vortex, visible on slit-lamp examination), distinctive lenticular opacities, and vascular tortuosity of the conjunctiva and retina. A heightened awareness of Fabry disease among ocular professionals could greatly reduce diagnostic delays and thus reduce the morbidity and mortality of the disease.
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PMID:Ocular features of Fabry disease: diagnosis of a treatable life-threatening disorder. 1857 58


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