Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
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Fabry disease (FD), the second most common type of lysosomal storage disease (LSD), is one of 41 disorders characterized by accumulation of substances normally degraded within lysosomes. It is an X-linked recessive disorder characterized by a deficiency of lysosomal alpha-galactosidase A (alpha-Gal A). The locus for human alpha-Gal A is located on the Xq22 chromosome. Most FD mutations are confined to a single family. Although FD is an X-linked disorder, up to one third of female carriers develop clinical manifestations of the disease. It typically presents during infancy or adolescence with crisis of neuropathic pain (acroparesthesia), angiokeratomas, and asymptomatic corneal lesions. As Gb3 deposition progresses, clinical manifestations occur in other organs. Patients typically die in the fourth or fifth decade of life due to cardiac, renal or cerebrovascular complications. Usually, there is diffuse deposition of glycosphingolipid in the renal glomeruli, tubules, interstitium, and vasculature. Clinically, the renal disease manifests with hypertension, microscopic hematuria (rare), moderate proteinuria, which can be in the nephrotic range, and lipiduria. End-stage renal disease can be treated with either dialysis or transplantation. Thegene for (x-Gal A was cloned and sequenced, which eventually led to production of enzyme for therapeutic use by either recombinant DNA technology or gene activation.
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PMID:Fabry kidney disease. 1765 9

Fabry's disease, a disorder affecting the gene for the lysosomal enzyme alpha-galactosidase A (alpha-GAL A), can cause accumulation of globotriaosylceramide (GL-3) in the vascular endothelial cells. Symptoms include pain, angiokeratoma, corneal clouding, and damage to the heart and kidneys. Human recombinant alpha-GAL A for use as an enzyme replacement therapy was launched in Japan in April 2004. Eleven ambulatory patients with Fabry's disease were given replacement alpha-GAL A therapy. Three patients died due to factors associated with Fabry's disease. The enzyme replacement therapies in the remaining eight patients continued safely without any notable adverse events. The following were observed: a lowering of the plasma levels of GL-3 in seven cases, an improvement in the daily activities in six cases, and a reduction in corneal clouding in three cases. Although careful observation is necessary, these results suggest that replacement alpha-GAL A therapy may be a safe and effective treatment of Fabry's disease.
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PMID:Enzyme replacement therapy in patients with Fabry's disease. 1769 36

Fabry disease is an X-linked lysosomal disease caused by deficiency of alpha-galactosidase A. Signs and symptoms of Fabry disease occurring during childhood and adolescence were characterized in 352 Fabry Registry patients. At enrollment (median age 12 year), 77% of males and 51% of females reported symptoms. The median age of symptom onset was 6 year in males and 9 year in females. The most frequent symptom, neuropathic pain, was reported by 59% of males (median age 7 year) and 41% of females (median age 9 year). Gastrointestinal symptoms were reported by 18% of children (median age 5 year in males and 9.5 year in females). Males exhibited height and weight values below the US 50th percentile. Females had weight values above the US 50th percentile. A few patients had serious renal and cardiac manifestations, stage 2 or 3 chronic kidney disease (n = 3), arrhythmia (n = 9), and left ventricular hypertrophy (n = 3). Thus, many pediatric Fabry patients report early symptoms, particularly pain, gastrointestinal symptoms, and impaired quality of life. Some children experience major complications during the pediatric years.
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PMID:Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. 1859 79

Fabry disease (OMIM 301500) is a rare X-linked recessive disorder caused by mutations in the alpha-galactosidase gene (GLA). Loss of alpha-galactosidase (alpha-Gal) activity leads to the abnormal accumulation of glycosphingolipids in lysosomes predominantly of vascular endothelial cells. Clinically the disorder presents with angiokeratomas, clouding of the cornea, and renal, cardiac, and cerebrovascular complications. In addition, there is an increased incidence of neuropathic pain in Fabry patients. In this study, we investigated the implications of loss of alpha-galactosidase A activity on sensorimotor function and peripheral nervous system. Similar to the described in Fabry disease patients, the sensorimotor assessment of Fabry mice revealed diminished locomotor activity and warm hypoalgesia as assessed in the hot-plate. Moreover Fabry mice displayed alterations both in balance and co-ordination. By histological analysis, the cyto-architecture of Fabry mice sciatic nerves showed an increase in mean cross-sectional area accompanied by a decrease in the density of non-myelinated fibers as well as a trend for a decreased number of small myelinated fibers, a well established feature of Fabry disease. A relative preservation of large myelinated fibers and nerve conduction velocity measurements was observed. Our findings demonstrate for the first time that Fabry knockout mice have Gb3 accumulation in the peripheral nervous system, alterations in sensorimotor function, hypoalgesia and no impairment of motor nerve conduction.
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PMID:Neurophysiological, behavioral and morphological abnormalities in the Fabry knockout mice. 1884 93

Fabry's disease is an X-linked lysosomal storage disorder caused by abnormalities in the GLA gene, which leads to a deficiency in alpha-galactosidase A. The consequent abnormal accumulation of glycosphingolipids results in several clinical signs and symptoms and substantial morbidity and mortality. This review covers all basic aspects of the disease such as epidemiology, pathophysiology, clinical presentation by systems, diagnosis, management, prevention, and repercussions on quality of life. With the development of enzyme replacement therapy in the past few years, early initiation of treatment is key for improvement in major affected organs with decreased cardiac mass and stabilisation of kidney function, and improvement in neuropathic pain, sweating, gastrointestinal symptoms, hearing loss, and pulmonary symptoms. However, treatment of individual symptoms in addition to enzyme replacement therapy seems to be needed for many patients, especially those who have had some degree of organ dysfunction. Additional data are needed to document long-term treatment outcomes.
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PMID:Fabry's disease. 1894 Apr 66

Fabry disease is a lysosomal storage disorder that is caused by mutations in the gene encoding a-galactosidase A on Xq22.1. Typically hemizygous male patients exhibit classic phenotypes such as angiokeratoma, acroparesthesias, episodic pain "crises," hypohidrosis, and whorl-shaped corneal opacities from childhood. However, during adulthood, they gradually develop kidney failure, heart disease, and strokes resulting in early death between 40 to 50 years of age. However, recent studies have indicated a high prevalence of disabling clinical symptoms in heterozygous females patients. Patients having the cardiac variant of Fabry's disease exhibit only left ventricular hypertrophy, while patients having the renal variant exhibit only kidney failure. Individuals affected by these variants show higher residual enzyme activity of alpha-galactosidase A than individuals affected by the classic form of Fabry's disease due to missense mutations of the GLA gene. The cerebrovascular involvement in Fabry disease is not rare in both adult hemizygotes and heterozygotes. Infarctions caused by the occulsion of small vessels involving mostly the vertebrobasilar region in approximately two-thirds of the cases, and that is associated with the deposition glycoshingolipids including GL-3 in the walls of these vessels. In Caucasian patients, elongated, ectatic, and tortuous vertebral and basilar arteries are frequently observed on MRAs. Life-threatening megadolichobasilar anomaly with thrombosis has been identified in a large Hungarian family in which the family members share L16P mutation. On performing MRI, an increased signal intensity was observed in the pulvinar in T1-weighted images; this is the characteristic so-called "pulvinar sign". Enzyme replacement therapy has been approved in Japan since 2004 and 2007 for agalsidase beta and agalsidase alpha, respectively. This treatment modestly improves the small-fiber neuropathy, hypohidrosis, hypertrophic cardiomyopathy, and stabilizes the renal function in the long term for up to 54 months. However, it has not helped in decreasing the incidence of strokes.
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PMID:[Fabry disease in light of recent review]. 1906 57

Fabry disease is a rare, X-linked inborn error of glycosphingolipid catabolism caused by a deficiency in the activity of the lysosomal enzyme, alpha-galactosidase A. In affected patients, the enzyme substrate, globotriaosylceramide (Gb3), accumulates in cells of various tissues and organs. Lysosomal accumulation of Gb3 begins in utero, and signs and symptoms of Fabry disease emerge in childhood and adolescence. The earliest presenting symptoms are typically neuropathic pain and gastrointestinal problems, which can have a substantial impact on health-related quality of life. Life-threatening major organ involvement is rare in young patients, but signs of kidney dysfunction (e.g., proteinuria), left ventricular hypertrophy, and stroke have been reported in children. There are two enzyme preparations for therapy: agalsidase alfa and beta. In two clinical trials of enzyme replacement therapy (ERT) with agalsidase alfa, including 37 children, boys demonstrated reductions in plasma Gb3 levels, and both boys and girls reported reductions in neuropathic pain and in the use of neuropathic pain medications. Heart rate variability, which is reduced in boys with Fabry disease, was statistically significantly improved with 6 months of agalsidase alfa treatment. In a single clinical study of agalsidase beta in children (n =16), skin Gb3 deposits and plasma Gb3 levels were reduced in boys. Differences exist in the administration and the safety profile of these two enzyme formulations. Follow-up of these cohorts and additional studies will be necessary to fully evaluate long-term efficacy of ERT in children with Fabry disease.
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PMID:Fabry disease in children and the effects of enzyme replacement treatment. 1924 21

Fabry disease is a X-linked lysosomal storage disorder. Two preparations of the enzyme alpha-galactosidase A are available in Europe since 2001: agalsidase alpha and agalsidase beta. Clinical evidence of efficacy are mandatory considering the absence of a robust biomarker. A literature review was performed to assess the clinical efficacy of these two enzyme replacement therapies. Only open or randomised controlled trials were considered. No unflawed direct comparison exists between the two drugs. Significant clinical benefits have been demonstrated with enzyme replacement therapy (ERT), mainly at an early phase of the disease, with positive effects on heart, kidneys, pain, and quality of life. Further prospective studies are required to confirm the long term clinical benefits of ERT. More specific studies are also needed in women or with ERT earlier in the course of Fabry disease to assess prevention of organ damage.
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PMID:[Clinical efficacy of enzyme replacement therapy in Fabry disease. A critical review]. 1952 34

Fabry disease is an X-linked inherited lysosomal disorder with dysfunction of the lysosomal enzyme alpha-galactosidase A causing accumulation of glycolipids in multiple organs including the nervous system. Pain and somatosensory disturbances are prominent manifestations of this disease. Until recently disease manifestations in female carriers of Fabry disease have been questioned. To explore the frequency of symptoms and the functional and structural involvement of the nervous system in female patients we examined the presence of pain, manifestations of peripheral neuropathy and nerve density in skin biopsies in 19 female patients with Fabry disease and 19 sex- and age-matched controls. Diaries, quantitative sensory testing, neurophysiologic tests and skin biopsies were performed. Daily pain was present in 63% of patients, with a median VAS score of 4.0. Tactile detection threshold and pressure pain threshold were lower and cold detection thresholds increased in patients. Sensory nerve action potential amplitude and maximal sensory conduction velocity were not different, whereas there was a highly significant reduction in intraepidermal nerve fiber density. We found no correlation between pain VAS score, quantitative sensory testing and intraepidermal nerve fiber density. Our study demonstrates that careful evaluation of symptoms in female Fabry patients is important as small fiber disease manifestations are present, which in some cases is only detected by skin biopsy.
Pain 2009 Sep
PMID:Functional and structural nerve fiber findings in heterozygote patients with Fabry disease. 1966 44

Fabry disease is an X-linked lysosomal disorder that results from a deficiency of the lysosomal enzyme alpha-galactosidase A leading to accumulation of glycolipids, mainly globotriaosylceramide in the cells from different tissues. Classical Fabry disease affects various organs. Clinical manifestations start at early age and include angiokeratoma, acroparesthesia, hypohydrosis, heat/exercise intolerance, gastrointestinal pain, diarrhea, and fever. The main complications of Fabry disease are more prominent after the age of 30 when kidney, heart, and/or cerebrovascular disorders appear. Most of the heterozygous females are symptomatic. Enzyme replacement therapy (ERT) is the only specific treatment for Fabry disease. The beneficial effect of ERT on different organs/systems has been extensively evaluated. Quality of life of patients receiving ERT is improved. Enzyme replacement stabilizes or slows the decline in renal function and reduces left ventricular hypertrophy. Fabry disease may be underdiagnosed because of nonspecific and multiorgan symptoms. Different screening strategies have been carried out in different at-risk populations in order to detect undiagnosed Fabry patients. An increasing knowledge about Fabry disease within the medical community increases the chances of patients to receive a timely diagnosis and, consequently, to access the appropriate therapy.
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PMID:Fabry disease: treatment and diagnosis. 1985 78


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