Journal articles: 'Globotriaosylceramide accumulation'

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Li, S. C., S. K. Kundu, R. Degasperi, and Y. T. Li. "Accumulation of globotriaosylceramide in a case of leiomyosarcoma." Biochemical Journal 240, no. 3 (December 15, 1986): 925–27. http://dx.doi.org/10.1042/bj2400925.

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Analysis of the glycosphingolipid composition in one case of uterine leiomyosarcoma metastasized to the liver showed an accumulation of globotriaosylceramide as compared with normal liver and uterus from which the tumour originated. The structure and the amount of glycosphingolipids were established by using specific glycosidases, permethylation analysis and h.p.l.c. The reason for the accumulation of globotriaosylceramide in leiomyosarcoma remains to be answered.

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Taguchi, Atsumi, Hiroki Maruyama, Masaaki Nameta, Tadashi Yamamoto, Junichiro Matsuda, Ashok B. Kulkarni, Hidekatsu Yoshioka, and Satoshi Ishii. "A symptomatic Fabry disease mouse model generated by inducing globotriaosylceramide synthesis." Biochemical Journal 456, no. 3 (November 22, 2013): 373–83. http://dx.doi.org/10.1042/bj20130825.

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A symptomatic mouse model was generated by inducing globotriaosylceramide synthesis. Globotriaosylceramide accumulation is a primary pathogenic factor in the symptomatic phenotype. The new mouse model is useful for studying the pathogenesis of Fabry disease and therapeutic approaches.

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Mutsuga, Mayu, Yoshiji Asaoka, Yuko Togashi, Naoko Imura, Tomoya Miyoshi, and Yohei Miyamoto. "Spontaneous Accumulation of Globotriaosylceramide (Gb3) in Proximal Renal Tubules in an ICR Mouse." Journal of Toxicologic Pathology 26, no. 4 (2013): 429–32. http://dx.doi.org/10.1293/tox.2013-0029.

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Ogawa, Kiyoko, Kumiko Sugamata, Noriaki Funamoto, Toshiaki Abe, Tomohide Sato, Kazuo Nagashima, and Shin-Ichiro Ohkawa. "Restricted accumulation of globotriaosylceramide in the hearts of atypical cases of Fabry's disease." Human Pathology 21, no. 10 (October 1990): 1067–73. http://dx.doi.org/10.1016/0046-8177(90)90258-7.

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Najafian, Behzad, Camilla Tøndel, Einar Svarstad, Marie-Claire Gubler, João-Paulo Oliveira, and Michael Mauer. "Accumulation of Globotriaosylceramide in Podocytes in Fabry Nephropathy Is Associated with Progressive Podocyte Loss." Journal of the American Society of Nephrology 31, no. 4 (March 3, 2020): 865–75. http://dx.doi.org/10.1681/asn.2019050497.

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BackgroundIn males with classic Fabry disease, the processes leading to the frequent outcome of ESKD are poorly understood. Defects in the gene encoding α-galactosidase A lead to accumulation of globotriaosylceramide (GL3) in various cell types. In the glomerular podocytes, accumulation of GL3 progresses with age. Of concern, podocytes are relatively resistant to enzyme replacement therapy and are poorly replicating, with little ability to compensate for cell loss.MethodsIn this study of 55 males (mean age 27 years) with classic Fabry disease genotype and/or phenotype, we performed unbiased quantitative morphometric electron microscopic studies of biopsied kidney samples from patients and seven living transplant donors (to serve as controls). We extracted clinical information from medical records and clinical trial databases.ResultsPodocyte GL3 volume fraction (proportion of podocyte cytoplasm occupied by GL3) increased with age up to about age 27, suggesting that increasing podocyte GL3 volume fraction beyond a threshold may compromise survival of these cells. GL3 accumulation was associated with podocyte injury and loss, as evidenced by increased foot process width (a generally accepted structural marker of podocyte stress and injury) and with decreased podocyte number density per glomerular volume. Worsening podocyte structural parameters (increasing podocyte GL3 volume fraction and foot process width) was also associated with increasing urinary protein excretion—a strong prognosticator of adverse renal outcomes in Fabry disease—as well as with decreasing GFR.ConclusionsGiven the known association between podocyte loss and irreversible FSGS and global glomerulosclerosis, this study points to an important role for podocyte injury and loss in the progression of Fabry nephropathy and indicates a need for therapeutic intervention before critical podocyte loss occurs.

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Najafian, Behzad, Einar Svarstad, Leif Bostad, Marie-Claire Gubler, Camilla Tøndel, Chester Whitley, and Michael Mauer. "Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease." Kidney International 79, no. 6 (March 2011): 663–70. http://dx.doi.org/10.1038/ki.2010.484.

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Tsukimura, Takahiro, Tomoko Shiga, Koki Saito, Yasuhiro Ogawa, Hitoshi Sakuraba, and Tadayasu Togawa. "Does administration of hydroxychloroquine/amiodarone accelerate accumulation of globotriaosylceramide and globotriaosylsphingosine in Fabry mice?" Molecular Genetics and Metabolism Reports 28 (September 2021): 100773. http://dx.doi.org/10.1016/j.ymgmr.2021.100773.

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Kelash, Fnu, Lara Kujtan, and Padmaja V. Mallidi. "Acroparesthesia in a Female: Diagnostic Dilemma." Case Reports in Medicine 2014 (2014): 1–2. http://dx.doi.org/10.1155/2014/172197.

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Fabry disease is an X-linked lysosomal storage disorder caused by deficient activity of a-galactosidase A (also known as ceramide trihexosidase) and resultant accumulation of globotriaosylceramide (Gb3) and related glycophospholipids. The disease affects nearly all major organ systems, with the primary sites damaged by Gb3 including renal glomeruli, myocardium, neurons of the dorsal ganglion and autonomic nervous system, and vascular endothelial and smooth muscle. Progressive deposition in these organ systems leads to renal and heart failure; debilitating pain as a result of nervous system involvement also occurs.

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Shu, Liming, and James A. Shayman. "Caveolin-associated Accumulation of Globotriaosylceramide in the Vascular Endothelium of α-Galactosidase A Null Mice." Journal of Biological Chemistry 282, no. 29 (May 29, 2007): 20960–67. http://dx.doi.org/10.1074/jbc.m702436200.

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Thurberg, Beth L., Helmut Rennke, Robert B. Colvin, Steven Dikman, Ronald E. Gordon, A. Bernard Collins, Robert J. Desnick, and Michael O'Callaghan. "Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy." Kidney International 62, no. 6 (December 2002): 1933–46. http://dx.doi.org/10.1046/j.1523-1755.2002.00675.x.

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Maier, Nadine, Constantin Gatterer, Patrick Haider, Manuel Salzmann, Christoph Kaun, Walter S. Speidl, Gere Sunder-Plassmann, et al. "MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease." Genes 12, no. 8 (July 30, 2021): 1184. http://dx.doi.org/10.3390/genes12081184.

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Background: Fabry disease is a hereditary genetic defect resulting in reduced activity of the enzyme α-galactosidase-A and the accumulation of globotriaosylceramide (Gb3) in body fluids and cells. Gb3 accumulation was especially reported for the vascular endothelium in several organs. Methods: Three Fabry disease patients were screened using a micro-RNA screen. An in vitro approach in human endothelial cells was used to determine miRNA regulation by Gb3. Results: In a micro-RNA screen of three Fabry patients undergoing enzyme replacement therapy, we found that miRNAs let-7a and let-7d were significantly increased after therapy. We demonstrate in vitro in endothelial cells that Gb3 induced activation of NF-κB and activated downstream targets. In addition, NF-κB activity directly reduced let-7a and let-7d miRNA expression as inhibiting NF-kB nuclear entry abolished the Gb3 effects. Conclusion: We suggest that let-7a and let-7d are potential markers for enzyme activity and inflammation in Fabry disease patients.

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Masotti, Martina, Cecilia Delprete, Giovanni Dothel, Vincenzo Donadio, Roberto Rimondini, Juan Manuel Politei, Rocco Liguori, and Marco Caprini. "Altered globotriaosylceramide accumulation and mucosal neuronal fiber density in the colon of the Fabry disease mouse model." Neurogastroenterology & Motility 31, no. 3 (January 4, 2019): e13529. http://dx.doi.org/10.1111/nmo.13529.

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Vardarli, Irfan, Manuel Weber, Christoph Rischpler, Dagmar Führer, Ken Herrmann, and Frank Weidemann. "Fabry Cardiomyopathy: Current Treatment and Future Options." Journal of Clinical Medicine 10, no. 14 (July 7, 2021): 3026. http://dx.doi.org/10.3390/jcm10143026.

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Fabry disease is a multisystem X-linked lysosomal storage disorder caused by a mutation in the alpha-galactosidase A gene. Deficiency or reduced activity of alpha-galactosidase A (GLA) is leading to progressive intracellular accumulation of globotriaosylceramide (GL3) in various organs, including the heart, kidney and nerve system. Cardiac involvement is frequent and is evident as concentric left ventricular hypertrophy. Currently, the standard treatment is enzyme replacement therapy or chaperone therapy. However, early starting of therapy, before myocardial fibrosis has developed, is essential for long-term improvement of myocardial function. For future treatment options, various therapeutic approaches including gene therapy are under development. This review describes the current and potential future therapy options for Fabry cardiomyopathy.

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Niu, Dau-Ming, Fu-Pang Chang, Ming-Jia Hsu, Chia-Lin Hsu, Ting-Rong Hsu, Sheng-kai Chang, and Yung-Hsiu Lu. "Reevaluate current routine histopathologic examinations for Fabry disease- not sensitive enough to identify early globotriaosylceramide accumulation in cardiomyocytes." Molecular Genetics and Metabolism 120, no. 1-2 (January 2017): S103. http://dx.doi.org/10.1016/j.ymgme.2016.11.260.

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Nakamura, Gen, Hiroki Maruyama, Satoshi Ishii, Masaaki Shimotori, Shigemi Kameda, Toru Kono, Jun-ichi Miyazaki, Ashok B. Kulkarni, and Fumitake Gejyo. "Naked Plasmid DNA-Based α-Galactosidase A Gene Transfer Partially Reduces Systemic Accumulation of Globotriaosylceramide in Fabry Mice." Molecular Biotechnology 38, no. 2 (October 13, 2007): 109–19. http://dx.doi.org/10.1007/s12033-007-9008-5.

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Faggiano, A., A. Pisani, F. Milone, M. Gaccione, M. Filippella, A. Santoro, G. Vallone, et al. "Endocrine Dysfunction in Patients with Fabry Disease." Journal of Clinical Endocrinology & Metabolism 91, no. 11 (November 1, 2006): 4319–25. http://dx.doi.org/10.1210/jc.2006-0858.

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Abstract Background: Fabry disease (FD) is a genetic disorder caused by lysosomal α-galactosidase-A deficiency and is characterized by the systemic accumulation of globotriaosylceramide. All endocrine glands are susceptible to globotriaosylceramide accumulation because of their high vascularization and low cellular proliferation rate. Nevertheless, this endocrine system has never been investigated in detail. Objective: We aimed to investigate the function and morphology of the endocrine glands in FD. Patients: The thyroid, gonadal, adrenal, and GH/IGF-I axes were evaluated in 18 FD patients (nine females and nine males, aged 21–64 yr) and 18 sex- and age-matched healthy subjects. Study design: We conducted an observational, analytical, open, prospective study. Interventions: Ten of the 18 patients received enzyme replacement therapy (ERT) with recombinant human α-galactosidase-A (agalsidase β) at a dose of 1 mg/kg body weight every 2 wk. Results: FD patients had higher baseline TSH levels than controls (P < 0.01). Three subjects were diagnosed with an early stage of subclinical primary hypothyroidism associated with negative antithyroid antibodies. A history of menses abnormalities, miscarriage, or assisted delivery was found in 89% of FD women. Asthenozoospermia, oligozoospermia, or both were found in all FD men through seminal fluid analysis. FD patients had significantly higher circulating ACTH and lower cortisol levels than controls (P < 0.05). In patients under ERT, a suboptimal cortisol response to the 250-μg ACTH test was found in 10%, and the ACTH-stimulated cortisol peak was significantly correlated to the health status profile (P < 0.05). Conclusion: A variety of latent endocrine dysfunctions, including life-threatening conditions, occur in patients with FD. Endocrine dysfunctions are also present in patients already receiving ERT and are in part related to their persistent poor quality of life. An endocrine work-up should be recommended in all FD patients. Adequate monitoring and hormonal therapy, when required, have to be performed in cases of subclinical endocrine dysfunction to avoid life-threatening events.

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Akidi, Goutham. "Case Report of Rare Case of Cardiac Variant of Fabry’s Disease in a 2-Year-Old Child." Indian Journal of Cardiovascular Disease in Women WINCARS 04, no. 02 (May 2019): 095–98. http://dx.doi.org/10.1055/s-0039-1697072.

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AbstractFabry’s disease is caused by progressive lysosomal accumulation of neutral glycosphingolipids, primarily globotriaosylceramide. It results from deficiency of the enzyme α-galactosidase A, which is encoded by GLA on the X chromosome. Usually it presents in children as the classic variant, and the cardiac variant is extremely rare. Before labeling as cardiac variant in infants and children we should rule out other causes of the cardiac hypertrophy with left ventricular outflow tract obstruction like metabolic causes, hypertrophic cardiomyopathy in infants, Noonan’s syndrome, and nesidioblastosis.We report a case of cardiac variant of Fabry’s disease in a 2-year-old male child. On evaluation he is found to have cardiac hypertrophy with no other features of Fabry’s disease, with low α galactosidase levels with no other systemic and syndromic features, which is an extremely rare presentation.

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Sorriento, Daniela, and Guido Iaccarino. "The Cardiovascular Phenotype in Fabry Disease: New Findings in the Research Field." International Journal of Molecular Sciences 22, no. 3 (January 29, 2021): 1331. http://dx.doi.org/10.3390/ijms22031331.

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Fabry disease (FD) is a lysosomal storage disorder, depending on defects in alpha-galactosidase A (GAL) activity. At the clinical level, FD shows a high phenotype variability. Among them, cardiovascular dysfunction is often recurrent or, in some cases, is the sole symptom (cardiac variant) representing the leading cause of death in Fabry patients. The existing therapies, besides specific symptomatic treatments, are mainly based on the restoration of GAL activity. Indeed, mutations of the galactosidase alpha gene (GLA) cause a reduction or lack of GAL activity leading to globotriaosylceramide (Gb3) accumulation in several organs. However, several other mechanisms are involved in FD’s development and progression that could become useful targets for therapeutics. This review discusses FD’s cardiovascular phenotype and the last findings on molecular mechanisms that accelerate cardiac cell damage.

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Pineda Galindo, Luis F., and Leslie Moranchel García. "Enfermedad de Fabry y enfermedad renal terminal: importancia de la combinación del trasplante renal y la terapia de reemplazo enzimático." Latin american journal of clinical sciences and medical technology 1, no. 1 (May 6, 2019): 21–27. http://dx.doi.org/10.34141/ljcs8031223.

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Introduction. Fabry disease (FD) is a lysosomal storage disease with an X-linked inheritance caused by an enzyme deficiency leading to tissue accumulation of globotriaosylceramide–GL-3, cellular dysfunction, and tissue inflammation, which will end in progressive damage to multiple organs if untreated. Symptomatology is multi-systemic. In advanced disease, kidney, heart and central nervous system are susceptible to such accumulation and are usually responsible for fatal outcomes. Cases presentation. Two FD cases treated with enzyme replacement therapy (ERT) shortly before receiving a cadaveric kidney transplant are presented. FD therapy is multidisciplinary, requires a symptomatic approach and ERT, targeted to substrate accumulation. ERT is beneficial for organ function and patients’ survival. ERT enables GL-3 clearance from different kidney cell lines, stabilization in glomerular filtration rate decline, and reduction of catastrophic kidney complications. After kidney transplantation, graft survival is similar to or better than transplant for other kidney diseases. Conclusions. A complete treatment must include kidney transplant and ERT. Our cases results confirm the beneficial effect of ERT in patients who underwent renal transplantation for FD-related end-stage renal disease (ESRD). When these patients with minimal disease burden in other organs timely receive a kidney transplant, their potential for a positive long-term outcome is evident.

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Ishii, Satoshi, Atsumi Taguchi, Nozomu Okino, Makoto Ito, and Hiroki Maruyama. "Determination of globotriaosylceramide analogs in the organs of a mouse model of Fabry disease." Journal of Biological Chemistry 295, no. 17 (March 16, 2020): 5577–87. http://dx.doi.org/10.1074/jbc.ra120.012665.

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Fabry disease is a heritable lipid disorder caused by the low activity of α-galactosidase A and characterized by the systemic accumulation of globotriaosylceramide (Gb3). Recent studies have reported a structural heterogeneity of Gb3 in Fabry disease, including Gb3 isoforms with different fatty acids and Gb3 analogs with modifications on the sphingosine moiety. However, Gb3 assays are often performed only on the selected Gb3 isoforms. To precisely determine the total Gb3 concentration, here we established two methods for determining both Gb3 isoforms and analogs. One was the deacylation method, involving Gb3 treatment with sphingolipid ceramide N-deacylase, followed by an assay of the deacylated products, globotriaosylsphingosine (lyso-Gb3) and its analogs, by ultra-performance LC coupled to tandem MS (UPLC-MS/MS). The other method was a direct assay established in the present study for 37 Gb3 isoforms and analogs/isoforms by UPLC-MS/MS. Gb3s from the organs of symptomatic animals of a Fabry disease mouse model were mainly Gb3 isoforms and two Gb3 analogs, such as Gb3(+18) containing the lyso-Gb3(+18) moiety and Gb3(−2) containing the lyso-Gb3(−2) moiety. The total concentrations and Gb3 analog distributions determined by the two methods were comparable. Gb3(+18) levels were high in the kidneys (24% of total Gb3) and the liver (13%), and we observed Gb3(−2) in the heart (10%) and the kidneys (5%). These results indicate organ-specific expression of Gb3 analogs, insights that may lead to a deeper understanding of the pathophysiology of Fabry disease.

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Carnicer-Cáceres, Clara, Jose Antonio Arranz-Amo, Cristina Cea-Arestin, Maria Camprodon-Gomez, David Moreno-Martinez, Sara Lucas-Del-Pozo, Marc Moltó-Abad, et al. "Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up." Journal of Clinical Medicine 10, no. 8 (April 13, 2021): 1664. http://dx.doi.org/10.3390/jcm10081664.

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Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations in the GLA gene, resulting in gradual accumulation of globotriaosylceramide and other derivatives in different tissues. Substrate accumulation promotes different pathogenic mechanisms in which several mediators could be implicated, inducing multiorgan lesions, mainly in the kidney, heart and nervous system, resulting in clinical manifestations of the disease. Enzyme replacement therapy was shown to delay disease progression, mainly if initiated early. However, a diagnosis in the early stages represents a clinical challenge, especially in patients with a non-classic phenotype, which prompts the search for biomarkers that help detect and predict the evolution of the disease. We have reviewed the mediators involved in different pathogenic mechanisms that were studied as potential biomarkers and can be easily incorporated into clinical practice. Some accumulation biomarkers seem to be useful to detect non-classic forms of the disease and could even improve diagnosis of female patients. The combination of such biomarkers with some response biomarkers, may be useful for early detection of organ injury. The incorporation of some biomarkers into clinical practice may increase the capacity of detection compared to that currently obtained with the established diagnostic markers and provide more information on the progression and prognosis of the disease.

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Waldek, S. "Agalsidase beta treatment of patientswith Fabry disease for 54 months reduces globotriaosylceramide accumulation in multiple cell types of the kidney." Clinical Therapeutics 29 (2007): S29—S30. http://dx.doi.org/10.1016/s0149-2918(07)80150-0.

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Kobayashi, Masahisa, Toya Ohashi, Takahiro Fukuda, Tomoyoshi Yanagisawa, Takayuki Inomata, Takashi Nagaoka, Teruo Kitagawa, Yoshikatsu Eto, Hiroyuki Ida, and Eiji Kusano. "No accumulation of globotriaosylceramide in the heart of a patient with the E66Q mutation in the α-galactosidase A gene." Molecular Genetics and Metabolism 107, no. 4 (December 2012): 711–15. http://dx.doi.org/10.1016/j.ymgme.2012.10.018.

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Nagashima, Y., A. Iwata, K. Yoshioka, J. Omachi, J. Shimizu, S. Tsuji, J. Yumoto, and M. Kuwata-Gonokami. "A new method to visualize abnormal lipid accumulation in tissues from Fabry disease patient using Raman spectroscopic marker of globotriaosylceramide." Journal of the Neurological Sciences 381 (October 2017): 700–701. http://dx.doi.org/10.1016/j.jns.2017.08.1973.

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Rothstein, Katherine, Jubby M. Gálvez, Ángela M. Gutiérrez, Laura Rico, Eveling Criollo, and Alejandra De-la-Torre. "Ocular findings in Fabry disease in Colombian patients." Biomédica 39, no. 3 (September 1, 2019): 434–39. http://dx.doi.org/10.7705/biomedica.3841.

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Fabry disease is a rare X-linked disorder caused by an alpha-galactosidase enzyme deficiency, which leads to a progressive lysosomal glycosphingolipids accumulation, mainly globotriaosylceramide, in multiple organism tissues including the eye.This case series describes the first ophthalmological Colombian report of Fabry disease highlighting the importance of ocular signs as markers of the disease, useful in diagnosis and treatment to avoid long-term complications that lead to a morbi-mortality increment.We describe five cases of Fabry disease from Bogotá, Colombia, including a complete clinical history, ophthalmologic, optometric examination, and photographs. We found that all patients had refractive defects and that in all cases corneal verticillata pattern was found. Four patients presented with posterior capsule lens brown-beige deposits and four patients had conjunctival and retinal tortuous vessels. A complete ophthalmologic examination is important for prompt diagnosis, which is key to starting a multidisciplinary treatment and reducing morbi-mortality.

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Tseng, Wei-Lien, Shih-Jie Chou, Huai-Chih Chiang, Mong-Lien Wang, Chian-Shiu Chien, Kuan-Hsuan Chen, Hsin-Bang Leu, et al. "Imbalanced Production of Reactive Oxygen Species and Mitochondrial Antioxidant SOD2 in Fabry Disease-Specific Human Induced Pluripotent Stem Cell-Differentiated Vascular Endothelial Cells." Cell Transplantation 26, no. 3 (March 2017): 513–27. http://dx.doi.org/10.3727/096368916x694265.

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Fabry disease (FD) is an X-linked inherited lysosomal storage disease caused by α-galactosidase A (GLA) deficiency. Progressive intracellular accumulation of globotriaosylceramide (Gb3) is considered to be pathogenically responsible for the phenotype variability of FD that causes cardiovascular dysfunction; however, molecular mechanisms underlying the impairment of FD-associated cardiovascular tissues remain unclear. In this study, we reprogrammed human induced pluripotent stem cells (hiPSCs) from peripheral blood cells of patients with FD (FD-iPSCs); subsequently differentiated them into vascular endothelial-like cells (FD-ECs) expressing CD31, VE-cadherin, and vWF; and investigated their ability to form vascular tube-like structures. FD-ECs recapitulated the FD pathophysiological phenotype exhibiting intracellular Gb3 accumulation under a transmission electron microscope. Moreover, compared with healthy control iPSC-derived endothelial cells (NC-ECs), reactive oxygen species (ROS) production considerably increased in FD-ECs. Microarray analysis was performed to explore the possible mechanism underlying Gb3 accumulation-induced ROS production in FD-ECs. Our results revealed that superoxide dismutase 2 (SOD2), a mitochondrial antioxidant, was significantly downregulated in FD-ECs. Compared with NC-ECs, AMPK activity was significantly enhanced in FD-ECs. Furthermore, to investigate the role of Gb3 in these effects, human umbilical vein endothelial cells (HUVECs) were treated with Gb3. After Gb3 treatment, we observed that SOD2 expression was suppressed and AMPK activity was enhanced in a dose-dependent manner. Collectively, our results indicate that excess accumulation of Gb3 suppressed SOD2 expression, increased ROS production, enhanced AMPK activation, and finally caused vascular endothelial dysfunction. Our findings suggest that dysregulated mitochondrial ROS may be a potential target for treating FD.

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Weissmann, Carina, Adriana A. Albanese, Natalia E. Contreras, María N. Gobetto, Libia C. Salinas Castellanos, and Osvaldo D. Uchitel. "Ion channels and pain in Fabry disease." Molecular Pain 17 (January 2021): 174480692110331. http://dx.doi.org/10.1177/17448069211033172.

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Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A (α-Gal A) activity which results in progressive accumulation of globotriaosylceramide (Gb3) and related metabolites. One prominent feature of Fabry disease is neuropathic pain. Accumulation of Gb3 has been documented in dorsal root ganglia (DRG) as well as other neurons, and has lately been associated with the mechanism of pain though the pathophysiology is still unclear. Small fiber (SF) neuropathy in FD differs from other entities in several aspects related to the perception of pain, alteration of fibers as well as drug therapies used in the practice with patients, with therapies far from satisfying. In order to develop better treatments, more information on the underlying mechanisms of pain is needed. Research in neuropathy has gained momentum from the development of preclinical models where different aspects of pain can be modelled and further analyzed. This review aims at describing the different in vitro and FD animal models that have been used so far, as well as some of the insights gained from their use. We focus especially in recent findings associated with ion channel alterations -that apart from the vascular alterations-, could provide targets for improved therapies in pain.

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Tsuboi, K. "Enzyme Replacement Therapy in Patients with Fabry's Disease." Journal of International Medical Research 35, no. 4 (July 2007): 574–81. http://dx.doi.org/10.1177/147323000703500418.

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Fabry's disease, a disorder affecting the gene for the lysosomal enzyme α-galactosidase A (α-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 α-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 α-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 α-GAL A therapy may be a safe and effective treatment of Fabry's disease.

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Perretta, Fernando, Norberto Antongiovanni, and Sebastián Jaurretche. "Early Renal Involvement in a Girl with Classic Fabry Disease." Case Reports in Nephrology 2017 (2017): 1–4. http://dx.doi.org/10.1155/2017/9543079.

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Fabry disease is an X-linked lysosomal storage disorder resulting from the deficiency or absence of the enzyme alpha galactosidase A; this defect leads to the systemic accumulation of globotriaosylceramide and its metabolites. Organic involvement in men is well known, but in women it is controversial, mainly due to the random X-chromosome inactivation in each of their cells (Lyon hypothesis). This would explain why women (heterozygotes) present a wide variability in the severity of their phenotype. The manifestations are multisystemic and begin in early childhood, reaching a severe compromise in adulthood. Typical acroparesthesia in hands and feet, gastrointestinal symptoms, angiokeratomas, dyshidrosis, hearing loss, arrhythmias, hypertrophic cardiomyopathy, cerebrovascular accidents, and renal failure can be observed. Nephropathy is one of the major complications of Fabry disease. Glomerular and vascular changes are present before progression to overt proteinuria and decreased glomerular filtration rate, even in pediatric patients. A case of incipient renal involvement in a girl with classic Fabry disease is reported.

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Rossi, Federica, and Federico Pieruzzi. "La diagnosi precoce di malattia." Giornale di Clinica Nefrologica e Dialisi 31, no. 1 (March 21, 2019): 58–60. http://dx.doi.org/10.33393/gcnd.2019.502.

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Anderson-Fabry disease is an X-linked, lysosomal, storage disorder characterized by the decreased activity of alpha-Galactosidase A, which results in accumulation of globotriaosylceramide (Gb-3) in cells and tissues throughout the body, leading to a wide spectrum of clinical manifestations. Patients are often misdiagnosed or diagnosed late in their life. This is due to the phenotypic heterogeneity, the poor awareness of this rare disease, and many pitfalls when making a differential diagnosis, in adulthood, as well as in the early stages. Delayed diagnosis has significant clinical implications, because the progression of the disease over time can lead to irreversible end-stage renal disease and life-threatening cardiovascular or cerebrovascular complications. Early diagnosis remains essential in order to start an early treatment and reduce the progression of the disease, thus maximizing the chance to improve patient outcomes. Newborn screening, high-risk patients’ identification, and increasing pediatricians’ and clinicians’ knowledge on this condition, are good strategies to avoid late referrals of Anderson-Fabry patients to reference centers.

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Giugliani, Roberto, Pol Boudes, Dominique P. Germain, Paul Fernhoff, Kathy Nichols, Derralynn Hughes, Atul Mehta, et al. "Evaluation of Globotriaosylceramide (GL-3) Accumulation in 18 Patients with Fabry Disease Nephropathy. Podocytes are More Severely Affected than Peritubular Capillaries." Molecular Genetics and Metabolism 105, no. 2 (February 2012): S31. http://dx.doi.org/10.1016/j.ymgme.2011.11.063.

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Ripeau, D., F. Masllorens, N. Lago, H. Amartino, J. Bortagaray, and H. Repetto. "Globotriaosylceramide (GL-3) Accumulation in the Renal Biopsy of a 1-year-old Patient with Fabry Disease and Ureteropelvic Junction Obstruction." British Journal of Medicine and Medical Research 14, no. 11 (January 10, 2016): 1–6. http://dx.doi.org/10.9734/bjmmr/2016/25294.

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Park, James L., Liming Shu, and James A. Shayman. "Differential involvement of COX1 and COX2 in the vasculopathy associated with the α-galactosidase A-knockout mouse." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 4 (April 2009): H1133—H1140. http://dx.doi.org/10.1152/ajpheart.00929.2008.

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The lysosomal storage disorder Fabry disease is characterized by excessive globotriaosylceramide (Gb3) accumulation in major organs such as the heart and kidney. Defective lysosomal α-galactosidase A (Gla) is responsible for excessive Gb3 accumulation, and one cell sensitive to the effects of Gb3 accumulation is vascular endothelium. Endothelial dysfunction is associated with Fabry disease and excessive cellular Gb3. We previously demonstrated that excessive vascular Gb3 in a mouse model of Fabry disease, the Gla-knockout ( Gla−/0) mouse, results in abnormal vascular function, which includes abnormal endothelium-dependent contractions, a vascular phenomenon known to involve cyclooxygenase (COX). Therefore, we hypothesized that the vasculopathy in the Gla knockout mouse may be due to a vasoactive COX-derived product. To test this hypothesis, vascular reactivity experiments were performed in aortic rings from wild-type ( Gla+/0) and Gla−/0 mice in the presence and absence of specific and nonspecific COX inhibitors. Specific inhibition of COX1 or COX2 in endothelium-intact rings from Gla−/0 mice decreased overall phenylephrine contractility compared with untreated Gla−/0 rings, whereas COX inhibitors had no effect on contractility in endothelium-denuded rings. Nonspecific inhibition of COX with indomethacin (10 μmol/l) or COX1 inhibition with valeryl salicylate (3 mmol/l) improved endothelial function in rings from Gla−/0 mice, but COX2 inhibition with NS-398 (1 μmol/l) further increased endothelial dysfunction in rings from Gla−/0 mice. These results suggest that, in the Gla−/0 mice, COX1 and COX2 activity are increased and localized in the endothelium, producing vasopressor and vasorelaxant products, which contribute to the Fabry-related vasculopathy.

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Trimarchi, Hernán. "SARS-CoV-2 and Fabry nephropathy: potential risks and the pathophysiological perspective." Journal of Nephropathology 9, no. 4 (May 11, 2020): e36-e36. http://dx.doi.org/10.34172/jnp.2020.36.

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Fabry disease is an X-linked disorder due to mutations in alpha-galactosidase A gene. It affects the kidney in virtually all patients with classical and some late onset variants. Podocytes, endothelial cells, vascular smooth muscle, tubular and mesangial cells are involved in different ways. Proteinuria and chronic kidney disease are the result of the progressive accumulation of the enzyme substrates globotriaosylceramide (GB3) and lyso-GB3 in the cytoplasm of these cells (mainly in lysosomes), which leads to cellular and organ dysfunction and eventually renal failure and end-stage kidney disease. Specific enzyme replacement therapy and pharmacological chaperone are at present the main therapeutic approach. After enzyme infusion, the delivered enzyme is differentially uptaken by kidney cells in three different ways: By Mannose-6-phosphate receptor, megalin and sortilin. The delivered enzyme gradually clears cells from the accumulation of the glycosphingolipids and contributes to a cellular healthier status. The recent pandemic caused by SARS-CoV-2 has led to the collapse of health systems around the world and to thousands of deaths. Kidney involvement has been reported to range from proteinuria to acute kidney injury, 30% of which may require renal replacement therapy. In this review the potential causes for which Fabry patients should be at increased risk and the necessity not to discontinue therapy are discussed.

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Niu, Dau-Ming, Ming-Jia Hsu, Fu-Pang Chang, Yung-Hsiu Lu, Sheng-Che Hung, Yu-Chen Wang, An-Hang Yang, and Chia-Lin Hsu. "AB077. Identification of lysosomal and extralysosomal globotriaosylceramide (Gb3) accumulation in endomyocardial biopsies before the occurrence of typical pathological changes of Fabry disease." Annals of Translational Medicine 5, S2 (September 2017): AB077. http://dx.doi.org/10.21037/atm.2017.s077.

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Song, Chien, Yarmishyn, Chou, Yang, Wang, Wang, et al. "Generation of GLA-Knockout Human Embryonic Stem Cell Lines to Model Autophagic Dysfunction and Exosome Secretion in Fabry Disease-Associated Hypertrophic Cardiomyopathy." Cells 8, no. 4 (April 8, 2019): 327. http://dx.doi.org/10.3390/cells8040327.

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Fabry disease (FD) is a rare inherited disorder characterized by a wide range of systemic symptoms; it is particularly associated with cardiovascular and renal problems. Enzyme replacement therapy and pharmacological chaperone migalastat are the only approved and effective treatment strategies for FD patients. It is well documented that alpha-galactosidase A (GLA) enzyme activity deficiency causes globotriaosylceramide (Gb3) accumulation, which plays a crucial role in the etiology of FD. However, the detailed mechanisms remain unclear, and the lack of a reliable and powerful disease model is an obstacle. In this study, we created such a model by using CRISPR/Cas9-mediated editing of GLA gene to knockout its expression in human embryonic stem cells (hESCs). The cardiomyocytes differentiated from these hESCs (GLA-null CMs) were characterized by the accumulation of Gb3 and significant increases of cell surface area, the landmarks of FD-associated cardiomyopathy. Furthermore, we used mass spectrometry to compare the proteomes of GLA-null CMs and parental wild type CMs and found that the Rab GTPases involved in exocytotic vesicle release were significantly downregulated. This caused impairment of autophagic flux and protein turnover, resulting in an increase of reactive oxygen species and apoptosis. To summarize, we established a FD model which can be used as a promising tool to study human hypertrophic cardiomyopathy in a physiologically and pathologically relevant manner and to develop new therapies by targeting Rab GTPases signaling-related exosomal vesicles transportation.

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Miglinas, Marius, Pranas Šerpytis, Urtė Gargalskaitė, Justė Danieliūtė, and Algirdas Utkus. "FABRY NEFROPATIJA." Sveikatos mokslai 23, no. 6 (December 21, 2013): 82–87. http://dx.doi.org/10.5200/sm-hs.2013.137.

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Anderson-Fabry disease (AFD) is a X-linked lysosomal storage disorder caused by mutations of the GLA gene that encodes α-galactosidase A, what causes intracellular accumulation of globotriaosylceramide. The main manifestations of AFD are pain attacks, acroparasthesias, cutaneous angiokeratomas, hypohydrosis, kidney, heart and cerebrovascular disorders. Late life-threatening complications include cardiomyopathy, cerebrovascular disease and renal injury. Fabry nephropathy may not appear with clinical signs and symptoms in childhood, but in the older adulthood occurs with significant proteinuria which leads to terminal kidney disease. Proteinuria, hypertension, high level of serum creatinine and low glomerular filtration rate are the main symptoms of progressive kidney disease. Adequate blood pressure control is recommended as proteinuria appears to be correlated with systemic blood pressure in both sexes. Fabry nephropathy treatment focus on control of hypertension, lipids and proteinuria and the main method of patients with terminal kidney disease treatment is kidney transplantation. When there are lack of the other classical manifestations for patients with renal disease, most of these cases are initially diagnosed as chronic glomerulonephritis. In this clinical case chronic glomerulonephropathy was also stated as preliminary diagnosis. AFD was verified by kidney biopsy and genetic testing.

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Simoncini, C., S. Torri, V. Montano, L. Chico, F. Gruosso, A. Tuttolomondo, A. Pinto, et al. "Oxidative stress biomarkers in Fabry disease: is there a room for them?" Journal of Neurology 267, no. 12 (July 27, 2020): 3741–52. http://dx.doi.org/10.1007/s00415-020-10044-w.

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Abstract Background Fabry disease (FD) is an X-linked lysosomal storage disorder, caused by deficient activity of the alpha-galactosidase A enzyme leading to progressive and multisystemic accumulation of globotriaosylceramide. Recent data point toward oxidative stress signalling which could play an important role in both pathophysiology and disease progression. Methods We have examined oxidative stress biomarkers [Advanced Oxidation Protein Products (AOPP), Ferric Reducing Antioxidant Power (FRAP), thiolic groups] in blood samples from 60 patients and 77 healthy controls. Results AOPP levels were higher in patients than in controls (p < 0.00001) and patients presented decreased levels of antioxidant defences (FRAP and thiols) with respect to controls (p < 0.00001). In a small group of eight treatment-naïve subjects with FD-related mutations, we found altered levels of oxidative stress parameters and incipient signs of organ damage despite normal lyso-Gb3 levels. Conclusions Oxidative stress occurs in FD in both treated and naïve patients, highlighting the need of further research in oxidative stress-targeted therapies. Furthermore, we found that oxidative stress biomarkers may represent early markers of disease in treatment-naïve patients with a potential role in helping interpretation of FD-related mutations and time to treatment decision.

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Kok, Ken, Kimberley C. Zwiers, Rolf G. Boot, Hermen S. Overkleeft, Johannes M. F. G. Aerts, and Marta Artola. "Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions." Biomolecules 11, no. 2 (February 12, 2021): 271. http://dx.doi.org/10.3390/biom11020271.

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Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by the deficiency of α-galactosidase A (α-GalA) and the consequent accumulation of toxic metabolites such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3). Early diagnosis and appropriate timely treatment of FD patients are crucial to prevent tissue damage and organ failure which no treatment can reverse. LSDs might profit from four main therapeutic strategies, but hitherto there is no cure. Among the therapeutic possibilities are intravenous administered enzyme replacement therapy (ERT), oral pharmacological chaperone therapy (PCT) or enzyme stabilizers, substrate reduction therapy (SRT) and the more recent gene/RNA therapy. Unfortunately, FD patients can only benefit from ERT and, since 2016, PCT, both always combined with supportive adjunctive and preventive therapies to clinically manage FD-related chronic renal, cardiac and neurological complications. Gene therapy for FD is currently studied and further strategies such as substrate reduction therapy (SRT) and novel PCTs are under investigation. In this review, we discuss the molecular basis of FD, the pathophysiology and diagnostic procedures, together with the current treatments and potential therapeutic avenues that FD patients could benefit from in the future.

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Parmaksız, Ergün, and Meral Meşe. "Fabry disease: A single-center experience." Ukrainian Journal of Nephrology and Dialysis, no. 2(70) (June 30, 2021): 13–18. http://dx.doi.org/10.31450/ukrjnd.2(70).2021.02.

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Fabry disease (FD) is an inborn X-linked lysosomal storage disorder resulting from α–galactosidase A (α-Gal) activity deficiency in lysosomes. This results in the accumulation of particularly globotriaosylceramide (Gb3) within lysosomes in a wide variety of cells. This study aimed to analyze the clinical presentation, findings and family screenings of index cases, management and outcomes of FD patients in our center. Methods. Data including demographic characteristics, personal history of comorbidities, laboratory findings at the time of diagnosis were recorded. α – Gal activity was measured in all males and females as initial analysis. The cut-off trigger was determined as 1.2 mmol/L per hour. Mutation analysis was performed in males and females with decreased α – Gal activity as a diagnostic assay. In addition, mutation analysis was performed change in females with normal α – Gal providing they have clinical signs or family history for FD. Results. The individuals from nine FD families were presented. Conclusion. Screening for genetic diseases such as FD has crucial conclusions. The detection of FD in an index case leads to appropriate therapy for that patient. Family screening can be started and additional undiagnosed individuals can be detected.

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Jabbarzadeh-Tabrizi, Siamak, Michel Boutin, Taniqua S. Day, Mouna Taroua, Raphael Schiffmann, Christiane Auray-Blais, and Jin-Song Shen. "Assessing the role of glycosphingolipids in the phenotype severity of Fabry disease mouse model." Journal of Lipid Research 61, no. 11 (August 31, 2020): 1410–23. http://dx.doi.org/10.1194/jlr.ra120000909.

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Fabry disease is caused by deficient activity of α-galactosidase A, an enzyme that hydrolyzes the terminal α-galactosyl moieties from glycolipids and glycoproteins, and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb3 isoforms (various fatty acids) and lyso-Gb3 analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb3 and lyso-Gb3 levels in the heart, kidney, and dorsal root ganglion (DRG) were similar in the two strains. However, levels of the C20-fatty acid isoform of Gb3 and particular lyso-Gb3 analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared with Fabry-B6. By contrast, there was no difference in Gb3 and lyso-Gb3 isoforms/analogs in the kidneys and DRG between the two strains. Furthermore, using immunohistochemistry, we found that Gb3 massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb3 accumulation was not observed in nonpeptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of nonpeptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb3 or lyso-Gb3 may play major roles in the pathogenesis of Fabry disease, and that Gb3 and lyso-Gb3 are not responsible for the pathology in all tissues or cell types.

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Kang, Justin J., Liming Shu, James L. Park, James A. Shayman, and Peter F. Bodary. "Endothelial nitric oxide synthase uncoupling and microvascular dysfunction in the mesentery of mice deficient in α-galactosidase A." American Journal of Physiology-Gastrointestinal and Liver Physiology 306, no. 2 (January 15, 2014): G140—G146. http://dx.doi.org/10.1152/ajpgi.00185.2013.

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A defect in the gene for the lysosomal enzyme α-galactosidase A (Gla) results in globotriaosylceramide (Gb3) accumulation in Fabry disease and leads to premature death from cardiac and cerebrovascular events. However, gastrointestinal symptoms are often first observed during childhood in these patients and are not well understood. In this study, we demonstrate an age-dependent microvasculopathy of the mesenteric artery (MA) in a murine model of Fabry disease (Gla-knockout mice) resulting from dysregulation of the vascular homeostatic enzyme endothelial nitric oxide synthase (eNOS). The progressive accumulation of Gb3 in the MA was confirmed by thin-layer chromatographic analysis. A total absence of endothelium-dependent dilation was observed in MAs from mice at 8 mo of age, while suppression of ACh-mediated vasodilation was evident from 2 mo of age. Endothelium-independent dilation with sodium nitroprusside was normal compared with age-matched wild-type mice. The microvascular defect in MAs from Fabry mice was endothelium-dependent and associated with suppression of the active homodimer of eNOS. Phosphorylation of eNOS at the major activation site (Ser1179) was significantly downregulated, while phosphorylation at the major inhibitory site (Thr495) was remarkably enhanced in MAs from aged Fabry mice. These profound alterations in eNOS bioavailability at 8 mo of age were observed in parallel with high levels of 3-nitrotyrosine, suggesting increased reactive oxygen species along with eNOS uncoupling in this vascular bed. Overall, the mesenteric microvessels in the setting of Fabry disease were observed to have an early and profound endothelial dysfunction associated with elevated reactive nitrogen species and decreased nitric oxide bioavailability.

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Boutin, Michel, Pamela Lavoie, Iskren Menkovic, Amanda Toupin, Mona Abaoui, Maha Elidrissi-Elawad, Marie-Françoise Arthus, et al. "Diurnal Variation of Urinary Fabry Disease Biomarkers during Enzyme Replacement Therapy Cycles." International Journal of Molecular Sciences 21, no. 17 (August 25, 2020): 6114. http://dx.doi.org/10.3390/ijms21176114.

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Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the α-galactosidase A enzyme. This enzyme cleaves the last sugar unit of glycosphingolipids, including globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide (Ga2). Enzyme impairment leads to substrate accumulation in different organs, vascular endothelia, and biological fluids. Enzyme replacement therapy (ERT) is a commonly used treatment. Urinary analysis of Gb3 isoforms (different fatty acid moieties), as well as lyso-Gb3 and its analogues, is a reliable way to monitor treatment. These analogues correspond to lyso-Gb3 with chemical modifications on the sphingosine moiety (−C2H4, −C2H4+O, −H2, −H2+O, +O, +H2O2, and +H2O3). The effects of sample collection time on urinary biomarker levels between ERT cycles were not previously documented. The main objective of this project was to analyze the aforementioned biomarkers in urine samples from seven Fabry disease patients (three treated males, three treated females, and one ERT-naïve male) collected twice a day (morning and evening) for 42 days (three ERT cycles). Except for one participant, our results show that the biomarker levels were generally more elevated in the evening. However, there was less variability in samples collected in the morning. No cyclic variations in biomarker levels were observed between ERT infusions.

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Šerpytis, Pranas, Žaneta Petrulionienė, Jolita Badarienė, Urtė Gargalskaitė, Justė Danieliūtė, and Algirdas Utkus. "FABRY KARDIOMIOPATIJA." Sveikatos mokslai 23, no. 6 (December 21, 2013): 76–81. http://dx.doi.org/10.5200/sm-hs.2013.136.

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Anderson-Fabry disease (AFD) is a X-linked lysosomal storage disorder caused by mutations of the GLA gene that encodes α-galactosidase A, what causes intracellular accumulation of globotriaosylceramide and due to this – progressive renal, cardiac and cerebrovascular disease. Whereas men experience the most severe clinical phenotype, clinical presentation in women because of X chromosome inactyvation varies from asymptomatic to severely symptomatic. The most common cardiac manifestations in AFD are left ventricular hypetrophy (LVH), coronary heart disease, conduction system disorders, which causes congestive heart insufficiency, arrhythmias and premature myocardial infarction. Heart disease is the main cause of death in Fabry patients. Electrocardiography, echocardiography, cardiac magnetic resonance, tissue doppler imaging and endomyocardial biopsy are the main Fabry cardiomyopahy diagnostic methods, however the gold standart in AFD diagnosis making is genetic testing. Recent studies show that coronary microvascular dysfunction (CMD) can be the most important factor, that determines LVH and CMD may represent the only sign of cardiac involvement in AFD patients. Interest is now focused on whether Enzyme Replacement Therapy (ERT) can slow or prevent the onset of Fabry cardiomyopathy manifestations with earlier diagnosis and treatment, however recent papers show that ERT may have only minimal effect on symptoms and cardiovascular morphology and function in established AFD.

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Georgiou, Theodoros, Gavriella Mavrikiou, Angelos Alexandrou, Elena Spanou-Aristidou, Isavella Savva, Theodoros Christodoulides, Maria Krasia, et al. "NovelGLADeletion in a Cypriot Female Presenting with Cornea Verticillata." Case Reports in Genetics 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/5208312.

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Fabry disease is an X-linked lysosomal storage disorder resulting from a deficiency of the hydrolytic enzymeα-galactosidase A (α-Gal-A). It is characterized by progressive lysosomal accumulation of globotriaosylceramide (Gb3) and multisystem pathology, affecting the skin, nervous and cerebrovascular systems, kidneys, and heart. Heterozygous females typically exhibit milder symptoms and a later age of onset than males. Rarely, they may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. We report on a 17-year-old female in whom cornea verticillata was found during a routine ophthalmological examination but with no other clinical symptoms. Leucocyteα-galactosidase activity was within the overlap range between Fabry heterozygotes and normal controls. Sanger sequencing of theGLAgene failed to reveal any pathogenic variants. Multiplex Ligation-dependent Probe Amplification (MLPA) analysis revealed a deletion of exon 7. Using a long-range PCR walking approach, we managed to identify the deletion breakpoints. The deletion spans 1182 bp, with its 5′ end located within exon 6 of theGLAgene and its 3′ end located 612 bp downstream of exon 7. This finding represents a novel deletion identified in the first reported Cypriot female carrier of Fabry disease.

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Modrego, Andrea, Marilla Amaranto, Agustina Godino, Rosa Mendoza, José Luis Barra, and José Luis Corchero. "Human α-Galactosidase A Mutants: Priceless Tools to Develop Novel Therapies for Fabry Disease." International Journal of Molecular Sciences 22, no. 12 (June 17, 2021): 6518. http://dx.doi.org/10.3390/ijms22126518.

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Fabry disease (FD) is a lysosomal storage disease caused by mutations in the gene for the α-galactosidase A (GLA) enzyme. The absence of the enzyme or its activity results in the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in different tissues, leading to a wide range of clinical manifestations. More than 1000 natural variants have been described in the GLA gene, most of them affecting proper protein folding and enzymatic activity. Currently, FD is treated by enzyme replacement therapy (ERT) or pharmacological chaperone therapy (PCT). However, as both approaches show specific drawbacks, new strategies (such as new forms of ERT, organ/cell transplant, substrate reduction therapy, or gene therapy) are under extensive study. In this review, we summarize GLA mutants described so far and discuss their putative application for the development of novel drugs for the treatment of FD. Unfavorable mutants with lower activities and stabilities than wild-type enzymes could serve as tools for the development of new pharmacological chaperones. On the other hand, GLA mutants showing improved enzymatic activity have been identified and produced in vitro. Such mutants could overcome several complications associated with current ERT, as lower-dose infusions of these mutants could achieve a therapeutic effect equivalent to that of the wild-type enzyme.

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Tuttolomondo, Antonino, Irene Simonetta, Renata Riolo, Federica Todaro, Tiziana Di Chiara, Salvatore Miceli, and Antonio Pinto. "Pathogenesis and Molecular Mechanisms of Anderson–Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies." International Journal of Molecular Sciences 22, no. 18 (September 18, 2021): 10088. http://dx.doi.org/10.3390/ijms221810088.

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Anderson–Fabry disease (AFD) is a rare disease with an incidenceof approximately 1:117,000 male births. Lysosomal accumulation of globotriaosylceramide (Gb3) is the element characterizing Fabry disease due to a hereditary deficiency α-galactosidase A (GLA) enzyme. The accumulation of Gb3 causes lysosomal dysfunction that compromises cell signaling pathways. Deposition of sphingolipids occurs in the autonomic nervous system, dorsal root ganglia, kidney epithelial cells, vascular system cells, and myocardial cells, resulting in organ failure. This manuscript will review the molecular pathogenetic pathways involved in Anderson–Fabry disease and in its organ damage. Some studies reported that inhibition of mitochondrial function and energy metabolism plays a significant role in AFD cardiomyopathy and in kidney disease of AFD patients. Furthermore, mitochondrial dysfunction has been reported as linked to the dysregulation of the autophagy–lysosomal pathway which inhibits the mechanistic target of rapamycin kinase (mTOR) mediated control of mitochondrial metabolism in AFD cells. Cerebrovascular complications due to AFD are caused by cerebral micro vessel stenosis. These are caused by wall thickening resulting from the intramural accumulation of glycolipids, luminal occlusion or thrombosis. Other pathogenetic mechanisms involved in organ damage linked to Gb3 accumulation are endocytosis and lysosomal degradation of endothelial calcium-activated intermediate-conductance potassium ion channel 3.1 (KCa3.1) via a clathrin-dependent process. This process represents a crucial event in endothelial dysfunction. Several studies have identified the deacylated form of Gb3, globotriaosylsphingosine (Lyso-Gb3), as the main catabolite that increases in plasma and urine in patients with AFD. The mean concentrations of Gb3 in all organs and plasma of Galactosidase A knockout mice were significantly higher than those of wild-type mice. The distributions of Gb3 isoforms vary from organ to organ. Various Gb3 isoforms were observed mainly in the kidneys, and kidney-specific Gb3 isoforms were hydroxylated. Furthermore, the action of Gb3 on the KCa3.1 channel suggests a possible contribution of this interaction to the Fabry disease process, as this channel is expressed in various cells, including endothelial cells, fibroblasts, smooth muscle cells in proliferation, microglia, and lymphocytes. These molecular pathways could be considered a potential therapeutic target to correct the enzyme in addition to the traditional enzyme replacement therapies (ERT) or drug chaperone therapy.

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Braunstein, Hila, Maria Papazian, Gali Maor, Jan Lukas, Arndt Rolfs, and Mia Horowitz. "Misfolding of Lysosomal α-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat." International Journal of Molecular Sciences 21, no. 19 (October 7, 2020): 7397. http://dx.doi.org/10.3390/ijms21197397.

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Fabry disease, an X-linked recessive lysosomal disease, results from mutations in the GLA gene encoding lysosomal α-galactosidase A (α-Gal A). Due to these mutations, there is accumulation of globotriaosylceramide (GL-3) in plasma and in a wide range of cells throughout the body. Like other lysosomal enzymes, α-Gal A is synthesized on endoplasmic reticulum (ER) bound polyribosomes, and upon entry into the ER it undergoes glycosylation and folding. It was previously suggested that α-Gal A variants are recognized as misfolded in the ER and undergo ER-associated degradation (ERAD). In the present study, we used Drosophila melanogaster to model misfolding of α-Gal A mutants. We did so by creating transgenic flies expressing mutant α-Gal A variants and assessing development of ER stress, activation of the ER stress response and their relief with a known α-Gal A chaperone, migalastat. Our results showed that the A156V and the A285D α-Gal A mutants underwent ER retention, which led to activation of unfolded protein response (UPR) and ERAD. UPR could be alleviated by migalastat. When expressed in the fly’s dopaminergic cells, misfolding of α-Gal A and UPR activation led to death of these cells and to a shorter life span, which could be improved, in a mutation-dependent manner, by migalastat.

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Pereira, Ester Miranda, Adalberto Socorro da Silva, Raimundo Nonato da Silva, José Tiburcio Monte Neto, Fernando F. do Nascimento, Jackeline L. M. Sousa, Henrique César Saraiva de Arêa Leão Costa Filho, Herton Luiz Alves Sales Filho, Anatalia Labilloy, and Semiramis Jamil Hadad do Monte. "CD77 levels over enzyme replacement treatment in Fabry Disease Family (V269M)." Brazilian Journal of Nephrology 40, no. 4 (December 2018): 333–38. http://dx.doi.org/10.1590/2175-8239-jbn-3910.

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ABSTRACT Introduction: Fabry disease (FD) is a disorder caused by mutations in the gene encoding for lysosomal enzyme α-galactosidase A (α-GAL). Reduced α-GAL activity leads to progressive accumulation of globotriaosylceramide (Gb3), also known as CD77. The recent report of increased expression of CD77 in blood cells of patients with FD indicated that this molecule can be used as a potential marker for monitoring enzyme replacement therapy (ERT). Objective: The purpose of this study was to evaluate the CD77 levels throughout ERT in FD patients (V269M mutation). Methods: We evaluated the fluctuations in PBMC (peripheral blood mononuclear cell) membrane CD77 expression in FD patients undergoing ERT and correlated these levels with those observed in different cell types. Results: A greater CD77 expression was found in phagocytes of patients compared to controls at baseline. Interestingly, the variability in CD77 levels is larger in patients at baseline (340 - 1619 MIF) and after 12 months of ERT (240 - 530 MIF) compared with the control group (131 - 331 MFI). Furthermore, by analyzing the levels of CD77 in phagocytes from patients throughout ERT, we found a constant decrease in CD77 levels. Conclusion: The increased CD77 levels in the phagocytes of Fabry carriers together with the decrease in CD77 levels throughout ERT suggest that measuring CD77 levels in phagocytes is a promising tool for monitoring the response to ERT in FD.

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Ravarotto, Verdiana, Francesca Simioni, Gianni Carraro, Giovanni Bertoldi, Elisa Pagnin, and Lorenzo Calò. "Oxidative Stress and Cardiovascular-Renal Damage in Fabry Disease: Is There Room for a Pathophysiological Involvement?" Journal of Clinical Medicine 7, no. 11 (November 2, 2018): 409. http://dx.doi.org/10.3390/jcm7110409.

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Fabry disease is an X-linked lysosomal storage disease caused by mutations in the GLA gene that lead to a reduction or an absence of the enzyme α-galactosidase A, resulting in the progressive and multisystemic accumulation of globotriaosylceramide. Clinical manifestation varies from mild to severe, depending on the phenotype. The main clinical manifestations are cutaneous (angiokeratomas), neurological (acroparesthesias), gastrointestinal (nausea, diarrhea abdominal pain), renal (proteinuria and kidney failure), cardiovascular (cardiomyopathy and arrhythmias), and cerebrovascular (stroke). A diagnosis of Fabry disease can be made with an enzymatic assay showing absent or reduced α-galactosidase A in male patients, while in heterozygous female patients, molecular genetic testing is needed. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase is nowadays the most-used disease-specific therapeutic option. Despite ERT, cardiocerebrovascular-renal irreversible organ injury occurs, therefore additional knowledge and a deeper understanding of further pathophysiological mechanisms leading to end organ damage in Fabry disease are needed. Recent data point toward oxidative stress, oxidative stress signaling, and inflammation as some such mechanisms. In this short review, the current knowledge on the involvement of oxidative stress in cardiovascular-renal remodeling is summarized and related to the most recent evidence of oxidative stress activation in Fabry disease, and clearly points toward the involvement of oxidative stress in the pathophysiology of the medium- to long-term cardiovascular-renal damage of Fabry disease.

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Journal articles on the topic 'Globotriaosylceramide accumulation'

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