Sample records for fabry disease fd

  1. Energy utilization of induced pluripotent stem cell-derived cardiomyocyte in Fabry disease.

    PubMed

    Chou, Shih-Jie; Yu, Wen-Chung; Chang, Yuh-Lih; Chen, Wen-Yeh; Chang, Wei-Chao; Chien, Yueh; Yen, Jiin-Cherng; Liu, Yung-Yang; Chen, Shih-Jen; Wang, Chien-Ying; Chen, Yu-Han; Niu, Dau-Ming; Lin, Shing-Jong; Chen, Jaw-Wen; Chiou, Shih-Hwa; Leu, Hsin-Bang

    2017-04-01

    Fabry disease (FD) is a lysosomal storage disease in which glycosphingolipids (GB3) accumulate in organs of the human body, leading to idiopathic hypertrophic cardiomyopathy and target organ damage. Its pathophysiology is still poorly understood. We aimed to generate patient-specific induced pluripotent stem cells (iPSC) from FD patients presenting cardiomyopathy to determine whether the model could recapitulate key features of the disease phenotype and to investigate the energy metabolism in Fabry disease. Peripheral blood mononuclear cells from a 30-year-old Chinese man with a diagnosis of Fabry disease, GLA gene (IVS4+919G>A) mutation were reprogrammed into iPSCs and differentiated into iPSC-CMs and energy metabolism was analyzed in iPSC-CMs. The FD-iPSC-CMs recapitulated numerous aspects of the FD phenotype including reduced GLA activity, cellular hypertrophy, GB3 accumulation and impaired contractility. Decreased energy metabolism with energy utilization shift to glycolysis was observed, but the decreased energy metabolism was not modified by enzyme rescue replacement (ERT) in FD-iPSCs-CMs. This model provided a promising in vitro model for the investigation of the underlying disease mechanism and development of novel therapeutic strategies for FD. This potential remedy for enhancing the energetic network and utility efficiency warrants further study to identify novel therapies for the disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Fabry disease: Review and experience during newborn screening.

    PubMed

    Hsu, Ting-Rong; Niu, Dau-Ming

    2018-05-01

    Fabry disease (FD) is an X-linked lysosomal storage disease and is the result of mutation in the α-Galactosidase A gene; such mutations cause a deficiency in α-Galactosidase A enzyme and an accumulation of glycosphingolipid in tissue. Affected males with classic FD have little or no enzyme activity and have an early onset of symptoms and signs, including acroparesthesias, hypohidrosis, angiokeratomas, gastrointestinal dysfunction and/or a characteristic corneal dystrophy during childhood/adolescence. Males with late-onset FD who have residual enzyme activity develop progressive multi-systemic involvement that leads to renal failure and hypertrophic cardiomyopathy, as well as cerebrovascular disease; these events mostly occur during the fourth to seventh decades of life. Heterozygous females can develop vital organ damage that in turn causes severe morbidity and mortality; these symptoms may be as severe as those in affected males. For the treatable disease, this review aims to raise awareness of early recognition and further management of FD based on newborn screening. As newborn screening for FD has been implemented worldwide, it allows the early detection of individuals with Fabry mutations. Based on screening studies, the prevalence of the later-onset type FD is much higher than that of classical type FD. Newborn screening studies have also revealed that patients with FD may develop insidious but ongoing irreversible organ damage. The timing of enzyme replacement therapy, which is able to stabilize the progression of disease, is important in order to prevent irreversible organ damage. Therapies that may become available in the future include pharmacological chaperones and substrate reduction therapy, both of which are still under investigation as ways of improving the health of individuals with FD. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Identification of mutations in Colombian patients affected with Fabry disease.

    PubMed

    Uribe, Alfredo; Mateus, Heidi Eliana; Prieto, Juan Carlos; Palacios, Maria Fernanda; Ospina, Sandra Yaneth; Pasqualim, Gabriela; da Silveira Matte, Ursula; Giugliani, Roberto

    2015-12-15

    Fabry Disease (FD) is an X-linked inborn error of glycosphingolipid catabolism, caused by a deficiency of the lisosomal α-galactosidase A (AGAL). The disorder leads to a vascular disease secondary to the involvement of kidney, heart and the central nervous system. The mutation analysis is a valuable tool for diagnosis and genetic counseling. Although more than 600 mutations have been identified, most mutations are private. Our objective was to describe the analysis of nine Colombian patients with Fabry disease by automated sequencing of the seven exons of the GLA gene. Two novel mutations were identified in two patients affected with the classical subtype of FD, in addition to other 6 mutations previously reported. The present study confirms the heterogeneity of mutations in Fabry disease and the importance of molecular analysis for genetic counseling, female heterozygotes detection as well as therapeutic decisions. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. [Role of cardiac magnetic resonance in cardiac involvement of Fabry disease].

    PubMed

    Serra, Viviana M; Barba, Miguel Angel; Torrá, Roser; Pérez De Isla, Leopoldo; López, Mónica; Calli, Andrea; Feltes, Gisela; Torras, Joan; Valverde, Victor; Zamorano, José L

    2010-09-04

    Fabry disease is a hereditary disorder. Clinical manifestations are multisystemic. The majority of the patients remain undiagnosed until late in life, when alterations could be irreversible. Early detection of cardiac symptoms is of major interest in Fabry's disease (FD) in order to gain access to enzyme replacement therapy. Echo-Doppler tissular imaging (TDI) has been used as a cardiologic early marker in FD. This study is intended to determine whether the cardiac magnetic resonance is as useful tool as TDI for the early detection of cardiac affectation in FD. Echocardiography, tissue Doppler and Cardio magnetic resonance was performed in 20 patients with confirmed Fabry Disease. Left ventricular hypertrophy was defined as septum and left ventricular posterior wall thickness ≥12 mm. An abnormal TDI velocity was defined as (Sa), (Ea) and/or (Aa) velocities <8 cm/s at either the septal or lateral corner. Late phase gadolinium-enhanced images sequences were obtained using magnetic resonance. Twenty patients included in the study were divided into three groups: 1. Those without left ventricular hypertrophy nor tissue Doppler impairment 2. Those without left ventricular hypertrophy and tissue Doppler impairment 3. Those with left ventricular hypertrophy and Tissue Doppler impairment. Late gadolinium enhancement was found in only one patient, who has already altered DTI and LVH. Tissue Doppler imaging (TDI) is the only diagnostic tool able to provide early detection of cardiac affectation in patients with FD. Magnetic resonance provides information of the disease severity in patients with LVH, but can not be used as an early marker of cardiac disease in patients with FD. However MRI could be of great value for diagnostic stratification. Copyright © 2009 Elsevier España, S.L. All rights reserved.

  5. Value of the CHA2DS2-VASc score and Fabry-specific score for predicting new-onset or recurrent stroke/TIA in Fabry disease patients without atrial fibrillation.

    PubMed

    Liu, Dan; Hu, Kai; Schmidt, Marie; Müntze, Jonas; Maniuc, Octavian; Gensler, Daniel; Oder, Daniel; Salinger, Tim; Weidemann, Frank; Ertl, Georg; Frantz, Stefan; Wanner, Christoph; Nordbeck, Peter

    2018-05-24

    To evaluate potential risk factors for stroke or transient ischemic attacks (TIA) and to test the feasibility and efficacy of a Fabry-specific stroke risk score in Fabry disease (FD) patients without atrial fibrillation (AF). FD patients often experience cerebrovascular events (stroke/TIA) at young age. 159 genetically confirmed FD patients without AF (aged 40 ± 14 years, 42.1% male) were included, and risk factors for stroke/TIA events were determined. All patients were followed up over a median period of 60 (quartiles 35-90) months. The pre-defined primary outcomes included new-onset or recurrent stroke/TIA and all-cause death. Prior stroke/TIA (HR 19.97, P < .001), angiokeratoma (HR 4.06, P = .010), elevated creatinine (HR 3.74, P = .011), significant left ventricular hypertrophy (HR 4.07, P = .017), and reduced global systolic strain (GLS, HR 5.19, P = .002) remained as independent risk predictors of new-onset or recurrent stroke/TIA in FD patients without AF. A Fabry-specific score was established based on above defined risk factors, proving somehow superior to the CHA 2 DS 2 -VASc score in predicting new-onset or recurrent stroke/TIA in this cohort (AUC 0.87 vs. 0.75, P = .199). Prior stroke/TIA, angiokeratoma, renal dysfunction, left ventricular hypertrophy, and global systolic dysfunction are independent risk factors for new-onset or recurrent stroke/TIA in FD patients without AF. It is feasible to predict new or recurrent cerebral events with the Fabry-specific score based on the above defined risk factors. Future studies are warranted to test if FD patients with high risk for new-onset or recurrent stroke/TIA, as defined by the Fabry-specific score (≥ 2 points), might benefit from antithrombotic therapy. Clinical trial registration HEAL-FABRY (evaluation of HEArt invoLvement in patients with FABRY disease, NCT03362164).

  6. Fabry disease: A fundamental genetic modifier of cardiac function.

    PubMed

    Tadevosyan, A

    Fabry disease (FD) is an inherited X-linked metabolic storage disorder triggered by abnormalities in the GLA gene at Xq22, which leads to a deficiency in α-galactosidase A and massive accumulation of intralysosomal glycosphingolipids. Cardiac complications are very common in FD and are the main cause of late morbidity, as well as early mortality in both hemizygous men and heterozygous women. There is a need for a multidisciplinary approach to evaluation and management of FD patients as there is a wide range of presentation of FD, which varies with mutation and other organ involvement/dysfunction. An overview of common cardiac involvement and clinical characteristics in FD including: left ventricular hypertrophy (LVH), conduction abnormalities and arrhythmias, coronary artery disease and valvular infiltrative myopathy are provided in this review. Current therapeutic approaches such as enzyme replacement therapy as well as the emergence of novel therapeutic options such as gene therapy to optimize disease outcomes in FD patients will be highlighted in this paper. Crown Copyright © 2016. Published by Elsevier Masson SAS. All rights reserved.

  7. Long-Term Outcomes of Kidney Transplantation in Fabry Disease.

    PubMed

    Ersözlü, Sara; Desnick, Robert J; Huynh-Do, Uyen; Canaan-Kühl, Sima; Barbey, Frédéric; Genitsch, Vera; Müller, Thomas; Cheetham, Marcus; Flammer, Andreas; Schaub, Stefan; Nowak, Albina

    2018-04-24

    Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene that obliterate or markedly reduce α-galactosidase A activity. This results in the systemic accumulation of its glycosphingolipid substrates in body fluids and organs, including the kidney. Fabry nephropathy can lead to end-stage renal disease requiring kidney transplantation. Little is known about its long-term outcomes and the overall patient survival after kidney transplantation. Here, we report 17 Fabry patients (15 males, 2 females) who received kidney transplants and their long-term treatment and follow-up at 4 specialized Fabry centers. The posttransplant follow-up ranged to 25 years, with a median of 11.5 [range 0.8-25.5] years. Graft survival was similar and death-censored graft survival was superior to matched controls. Fabry patients died with functioning kidneys, mostly from cardiac causes. In 2 males 14 and 23 years posttransplant, the grafts had a few typical FD lamellar inclusions, presumably originating from invading host macrophages and vascular endothelial cells. We conclude that kidney transplantation has an excellent long-term outcome in Fabry disease.

  8. Social-adaptive and psychological functioning of patients affected by Fabry disease.

    PubMed

    Laney, Dawn Alyssia; Gruskin, Daniel J; Fernhoff, Paul M; Cubells, Joseph F; Ousley, Opal Y; Hipp, Heather; Mehta, Ami J

    2010-12-01

    Fabry disease (FD) is an X-linked lysosomal storage disorder caused by the deficiency of alpha-galactosidase A. In addition to the debilitating physical symptoms of FD, there are also under-recognized and poorly characterized psychiatric features. As a first step toward characterizing psychiatric features of FD, we administered the Achenbach adult self report questionnaire to 30 FD patients and the Achenbach adult behavior checklist questionnaire to 28 partners/parents/friends of FD patients. Data from at least one of the questionnaires were available on 33 subjects. Analysis focused on social-adaptive functioning in various aspects of daily life and on criteria related to the Diagnostic and statistical manual of mental disorders IV (DSM-IV). Adaptive functioning scale values, which primarily measure social and relationship functioning and occupational success, showed that eight FD patients (six female and two male) had mean adaptive functioning deficits as compared to population norms. Greater rates of depression (P < 0.01), anxiety (P = 0.05), depression and anxiety (P = 0.03), antisocial personality (P < 0.001), attention-deficit/hyperactivity (AD/H; P < 0.01), hyperactivity-impulsivity (P < 0.01), and aggressive behavior (P = 0.03) were associated with poorer adaptive functioning. Decreased social-adaptive functioning in this study was not statistically significantly associated to disease severity, pain, or level of vitality. This study shows for the first time that FD patients, particularly women, are affected by decreased social-adaptive functioning. Comprehensive treatment plans for FD should consider assessments and interventions to evaluate and improve social, occupational, and psychological functioning. Attention to the behavioral aspects of FD could lead to improved treatment outcome and improved quality of life. Individuals affected by Fabry disease exhibited social-adaptive functioning deficits that were significantly correlated with anxiety

  9. Update on role of agalsidase alfa in management of Fabry disease

    PubMed Central

    Ramaswami, Uma

    2011-01-01

    Fabry disease (FD) is an X-linked lysosomal storage disorder that affects both men and women. The manifestations of this heterogeneous disease are multisystemic and progressive. Prior to the development of enzyme replacement therapy, the management and treatment for Fabry disease was largely nonspecific and supportive. Because enzyme replacement therapy became commercially available in 2001, a variety of clinical benefits in Fabry patients have been consistently reported, including improved renal pathology and cardiac function, and reduced severity of neuropathic pain and improved pain-related quality of life. This update focuses on published data on the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa, and gives a brief overview on some of the outstanding management issues in the treatment of this complex disease. PMID:21552486

  10. Diagnosis and Treatment of the Cardiovascular Consequences of Fabry Disease.

    PubMed

    Baig, S; Vijapurapu, R; Alharbi, F; Nordin, S; Kozor, R; Moon, J; Bembi, B; Geberhiwot, T; Steeds, R P

    2018-06-06

    Fabry Disease (FD) has been a diagnostic challenge since it was first recognised in 1898, with patients traditionally suffering from considerable delay before a diagnosis is made. Cardiac involvement is the current leading cause of death in FD. A combination of improved enzyme assays, availability of genetic profiling, together with more organised clinical services for rare diseases, has led to a rapid growth in the prevalence of FD. The earlier and more frequent diagnosis of asymptomatic individuals before development of the phenotype has focussed attention on early detection of organ involvement and closer monitoring of disease progression. The high cost of enzyme replacement therapy at a time of constraint within many health economies moreover, has challenged clinicians to target treatment effectively. This article provides an outline of FD for the general physician and summarises the aetiology and pathology of FD, the cardiovascular (CV) consequences thereof, modalities used in diagnosis, and then discusses current indications for treatment, including pharmacotherapy and device implantation.

  11. Fabry Disease

    MedlinePlus

    ... Page You are here Home » Disorders » All Disorders Fabry Disease Information Page Fabry Disease Information Page What research is being done? The ... treat and prevent lipid storage diseases such as Fabry disease. Researchers hope to identify biomarkers--signs that may ...

  12. Exocrine pancreatic insufficiency is not a cause of abdominal complaints in patients with Fabry disease.

    PubMed

    Vujasinovic, Miroslav; Tepes, Bojan; Vujkovac, Bojan; Cokan Vujkovac, Andreja; Tretjak, Martin; Korat, Vesna

    2015-12-01

    Fabry disease (FD), also called Anderson-Fabry disease, is the second most prevalent lysosomal storage disorder after Gaucher disease. Gastrointestinal (GI) symptoms are very common among male and female individuals, although the age of onset is later among female patients. To our best knowledge, exocrine pancreatic insufficiency (EPI) has not yet been studied in patients with FD as a possible cause of abdominal complaints. The aim of our study was to determine whether exocrine pancreatic function is impaired in patients with FD. We analysed medical records of patients with FD treated in Fabry Center in Slovenj Gradec General Hospital (Slovenian referral centre for FD) by the evaluation of the following features: gender, age, first symptoms before confirmation of FD diagnosis, time interval between first symptoms and diagnosis, therapy and current abdominal complaints. Diagnosis of FD was established by genetic analysis and confirmation of mutation in the α-galactosidase A gene. Faecal elastase-1 (FE-1) measurements were performed using enzyme-linked immunosorbent assay and the commercial kit ScheBo Biotech, Giessen, Germany. There were 28 adult patients (Slovene, Caucasians) with known FD included in the study: 12 male and 16 female; mean age, 45.6 ± 14.3 (range, 19-75) years. Seventeen patients (63%) were on enzyme replacement therapy (ERT). In seven (25.9%) patients, abdominal complaints (diarrhoea, bloating and feeling of satiety) were present before introduction of ERT. In three out of these seven patients, abdominal complaints resolved after ERT, and in four patients, they were still occasionally present. FE-1 was normal in all patients (547.9 ± 104.5 µg/g). Our results show that exocrine pancreatic function is normal in all patients with FD and is most likely not a cause of abdominal complaints in this group of patients. Nevertheless, EPI still could not be completely excluded as an aetiology factor for GI problems in patients with FD because all our

  13. Enzyme replacement therapy for Fabry disease: some answers but more questions.

    PubMed

    Alfadhel, Majid; Sirrs, Sandra

    2011-01-01

    Fabry disease (FD) is a multisystem, X-linked disorder of glycosphingolipid metabolism caused by enzyme deficiency of α-galactosidase A. Affected patients have symptoms including acroparesthesias, angiokeratomas, and hypohidrosis. More serious manifestations include debilitating pain and gastrointestinal symptoms, proteinuria and gradual deterioration of renal function leading to end-stage renal disease, hypertrophic cardiomyopathy, and stroke. Heterozygous females may have symptoms as severe as males with the classic phenotype. Before 2001, treatment of patients with FD was supportive. The successful development of enzyme replacement therapy (ERT) has been a great advancement in the treatment of patients with FD and can stabilize renal function and cardiac size, as well as improve pain and quality of life of patients with FD. In this review, we have provided a critical appraisal of the literature on the effects of ERT for FD. This analysis shows that data available on the treatment of FD are often derived from studies which are not controlled, rely on surrogate markers, and are of insufficient power to detect differences on hard clinical endpoints. Further studies of higher quality are needed to answer the questions that remain concerning the efficacy of ERT for FD.

  14. A pilot study of circulating microRNAs as potential biomarkers of Fabry disease.

    PubMed

    Cammarata, Giuseppe; Scalia, Simone; Colomba, Paolo; Zizzo, Carmela; Pisani, Antonio; Riccio, Eleonora; Montalbano, Michaela; Alessandro, Riccardo; Giordano, Antonello; Duro, Giovanni

    2018-06-08

    Patients suffering from Fabry disease (FD), a lysosomal storage disorder, show a broad range of symptoms and the diagnosis followed by the therapeutic decision remains a great challenge. The biomarkers available today have not proven to be useful for predicting the evolution of the disease and for assessing response to therapy in many patients. Here, we used high-throughput microRNA profiling methodology to identify a specific circulating microRNA profile in FD patients. We discovered a pattern of 10 microRNAs able to identify FD patients when compared to healthy controls. Notably, two of these: the miR199a-5p and the miR-126-3p are able to discriminate FDs from the control subjects with left ventricular hypertrophy, a frequent but non-specific FD symptom. These same microRNAs are also sensitive to enzyme replacement therapy showing variation in the subjects under treatment. Furthermore, two other microRNAs of the profile, the miR-423-5p and the miR-451a, seem useful to highlight cardiac involvement in FD patients. A literature and database search revealed that miR-199a-5p, miR-126-3p, miR-423-5p and miR-451a are known to be linked to pathological states that occur during the FD development. In particular, miR-199a-5p, and miR-126-3p are involved in endothelial dysfunction and miR-423-5p and miR-451a in myocardial remodeling. In conclusion, in this study we identified a common plasma microRNA profile in FD patients, useful not only for the correct classification of Fabry patients regardless of sex and age, but also to evaluate the response to therapy. Furthermore, our observations suggest that some microRNAs of this profile demonstrate prognostic qualities.

  15. Adaptive pathway development for Fabry disease: a clinical approach.

    PubMed

    Schuller, Yvonne; Arends, Maarten; Körver, Simon; Langeveld, Mirjam; Hollak, Carla E M

    2018-06-01

    Fabry disease (FD) is a rare X-chromosome-linked lysosomal storage disorder. Although initial expectations of enzyme replacement therapy (ERT) were high, it is now clear that real-world effectiveness is disappointing and evidence gathering has been inadequate. In retrospect, development of ERT for FD had several shortcomings. Little convincing evidence on the effectiveness existed at time of authorization. Also, post-marketing evaluation failed to generate sufficient and relevant data for adequate evaluation on effectiveness. Adaptive pathways might have benefitted ERT development by: (i) involving healthcare professionals, patients, health technology assessment bodies and payers in the development process; (ii) iterative development, starting with initial authorization in classical males; (iii) a clear real-world data collection plan; (iv) an independent disease registry; and (v) prescription control. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. Continuous cardiac troponin I release in Fabry disease.

    PubMed

    Feustel, Andreas; Hahn, Andreas; Schneider, Christian; Sieweke, Nicole; Franzen, Wolfgang; Gündüz, Dursun; Rolfs, Arndt; Tanislav, Christian

    2014-01-01

    Fabry disease (FD) is a rare lysosomal storage disorder also affecting the heart. The aims of this study were to determine the frequency of cardiac troponin I (cTNI) elevation, a sensitive parameter reflecting myocardial damage, in a smaller cohort of FD-patients, and to analyze whether persistent cTNI can be a suitable biomarker to assess cardiac dysfunction in FD. cTNI values were determined at least twice per year in 14 FD-patients (6 males and 8 females) regularly followed-up in our centre. The data were related to other parameters of heart function including cardiac magnetic resonance imaging (cMRI). Three patients (21%) without specific vascular risk factors other than FD had persistent cTNI-elevations (range 0.05-0.71 ng/ml, normal: <0.01). cMRI disclosed late gadolinium enhancement (LGE) in all three individuals with cTNI values ≥0.01, while none of the 11 patients with cTNI <0.01 showed a pathological enhancement (p<0.01). Two subjects with increased cTNI-values underwent coronary angiography, excluding relevant stenoses. A myocardial biopsy performed in one during this procedure demonstrated substantial accumulation of globotriaosylceramide (Gb3) in cardiomyocytes. Continuous cTNI elevation seems to occur in a substantial proportion of patients with FD. The high accordance with LGE, reflecting cardiac dysfunction, suggests that cTNI-elevation can be a useful laboratory parameter for assessing myocardial damage in FD.

  17. Continuous Cardiac Troponin I Release in Fabry Disease

    PubMed Central

    Schneider, Christian; Sieweke, Nicole; Franzen, Wolfgang; Gündüz, Dursun; Rolfs, Arndt

    2014-01-01

    Background Fabry disease (FD) is a rare lysosomal storage disorder also affecting the heart. The aims of this study were to determine the frequency of cardiac troponin I (cTNI) elevation, a sensitive parameter reflecting myocardial damage, in a smaller cohort of FD-patients, and to analyze whether persistent cTNI can be a suitable biomarker to assess cardiac dysfunction in FD. Methods cTNI values were determined at least twice per year in 14 FD-patients (6 males and 8 females) regularly followed-up in our centre. The data were related to other parameters of heart function including cardiac magnetic resonance imaging (cMRI). Results Three patients (21%) without specific vascular risk factors other than FD had persistent cTNI-elevations (range 0.05–0.71 ng/ml, normal: <0.01). cMRI disclosed late gadolinium enhancement (LGE) in all three individuals with cTNI values ≥0.01, while none of the 11 patients with cTNI <0.01 showed a pathological enhancement (p<0.01). Two subjects with increased cTNI-values underwent coronary angiography, excluding relevant stenoses. A myocardial biopsy performed in one during this procedure demonstrated substantial accumulation of globotriaosylceramide (Gb3) in cardiomyocytes. Conclusion Continuous cTNI elevation seems to occur in a substantial proportion of patients with FD. The high accordance with LGE, reflecting cardiac dysfunction, suggests that cTNI-elevation can be a useful laboratory parameter for assessing myocardial damage in FD. PMID:24626231

  18. Genetics Home Reference: Fabry disease

    MedlinePlus

    ... Sheet (PDF) Disease InfoSearch: Fabry Disease Emory University School of Medicine (PDF) International Center for Fabry Disease, Mount Sinai School of Medicine MalaCards: fabry disease Merck Manual Consumer ...

  19. CD77 levels over enzyme replacement treatment in Fabry Disease Family (V269M).

    PubMed

    Pereira, Ester Miranda; Silva, Adalberto Socorro da; Silva, Raimundo Nonato da; Monte Neto, José Tiburcio; Nascimento, Fernando F do; Sousa, Jackeline L M; Costa Filho, Henrique César Saraiva de Arêa Leão; Sales Filho, Herton Luiz Alves; Labilloy, Anatalia; Monte, Semiramis Jamil Hadad do

    2018-06-04

    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). The purpose of this study was to evaluate the CD77 levels throughout ERT in FD patients (V269M mutation). 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. 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. 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.

  20. Evaluation of oxidative stress markers and cardiovascular risk factors in Fabry Disease patients

    PubMed Central

    Müller, Karen B.; Galdieri, Luciano C.; Pereira, Vanessa G.; Martins, Ana M.; D’Almeida, Vânia

    2012-01-01

    Fabry Disease, an X-linked inborn error of metabolism, is characterized by progressive renal insufficiency, with cardio and cerebrovascular involvement. Homocysteine (Hcy) is considered a risk factor for vascular diseases, but the mechanisms by which it produces cardiovascular damage are still poorly understood. Regarding the vascular involvement in FD patients, the analysis of factors related to thromboembolic events could be useful to improving our understanding of the disease. The aim of this study was to evaluate plasma Hcy and other parameters involved in the methionine cycle, as well as oxidative stress markers. The sample consisted of a group of 10 male FD patients and a control group of 8 healthy individuals, paired by age. Venous blood was collected for Hcy determination, molecular analysis, identification of thiobarbituric acid reactive substances, total glutathione and antioxidant enzymes activity, as well as vitamins quantification. Comparative analysis of FD patients versus the control group indicated hyperhomocysteinemia in 8 of the 10 FD patients, as well as a significant increase in overall glutathione levels and catalase activity. It is inferred that FD patients, apart from activation of the antioxidant system, present increased levels of plasma Hcy, although this is probably unrelated to common alterations in the methionine cycle. PMID:22888289

  1. Cardiac Phenotype of Prehypertrophic Fabry Disease.

    PubMed

    Nordin, Sabrina; Kozor, Rebecca; Baig, Shanat; Abdel-Gadir, Amna; Medina-Menacho, Katia; Rosmini, Stefania; Captur, Gabriella; Tchan, Michel; Geberhiwot, Tarekegn; Murphy, Elaine; Lachmann, Robin; Ramaswami, Uma; Edwards, Nicola C; Hughes, Derralynn; Steeds, Richard P; Moon, James C

    2018-06-01

    Fabry disease (FD) is a rare and treatable X-linked lysosomal storage disorder. Cardiac involvement determines outcomes; therefore, detecting early changes is important. Native T1 by cardiovascular magnetic resonance is low, reflecting sphingolipid storage. Early phenotype development is familiar in hypertrophic cardiomyopathy but unexplored in FD. We explored the prehypertrophic cardiac phenotype of FD and the role of storage. A prospective, international multicenter observational study of 100 left ventricular hypertrophy-negative FD patients (mean age: 39±15 years; 19% male) and 35 age- and sex-matched healthy volunteers (mean age: 40±14 years; 25% male) who underwent cardiovascular magnetic resonance, including native T1 and late gadolinium enhancement, and 12-lead ECG. In FD, 41% had a low native T1 using a single septal region of interest, but this increased to 59% using a second slice because early native T1 lowering was patchy. ECG abnormalities were present in 41% and twice as common with low native T1 (53% versus 24%; P =0.005). When native T1 was low, left ventricular maximum wall thickness, indexed mass, and ejection fraction were higher (maximum wall thickness 9±1.5 versus 8±1.4 mm, P <0.005; indexed left ventricular mass 63±10 versus 58±9 g/m 2 , P <0.05; and left ventricular ejection fraction 73±8% versus 69±7%, P <0.01). Late gadolinium enhancement was more likely when native T1 was low (27% versus 6%; P =0.01). FD had higher maximal apical fractal dimensions compared with healthy volunteers (1.27±0.06 versus 1.24±0.04; P <0.005) and longer anterior mitral valve leaflets (23±2 mm versus 21±3 mm; P <0.005). There is a detectable prehypertrophic phenotype in FD consisting of storage (low native T1), structural, functional, and ECG changes. © 2018 The Authors.

  2. PrEFiNe Plan: Strategic plan for Fabry diseases in Nephrology.

    PubMed

    Del Pino, M D; Ortiz, A; Torra, R; Hernandez, D

    2016-01-01

    Renal failure is one of the main causes of death in patients with Fabry disease (FD). Due to the low prevalence of FD, delayed diagnosis and misdiagnosis, often the correct diagnosis is made when organ damage is already present. Early recognition of the disease would allow the prevention of severe complications and the premature death of patients with FD. We present here the PrEFiNE project, which includes a wide spectrum of activities with the aim of improve knowledge and diagnosis of FD. The project is sponsored by Shire Iberia (http://shireiberica.com/) From January 2016 to the end of 2017 several activities will be carried out, starting with a survey to evaluate current FD knowledge among nephrologists; in addition some studies to assess prevalence of this disease will be performed. One study will include patients receiving dialysis, another study will cover kidney transplant patients, and a pilot study in chronic kidney disease in stage 3-5 predialysis. Also planned is a pharmacoeconomic study to focus on burden of FD. At the same time medical education activities will be conducted both on line and on site. Plan for dissemination will include medical publications and diffusion to media. PrEFiNE Project will finish with the publication of a compilation book on FD in Nephrology including all planned activities and proposing recommendations based on results and detected unmet needs. PrEfiNE Plan will be coordinated by severa scientific committees, one at national level and 10 other regionals comittees, tha will be responsible to ensure the maximum scientific quality of proposed activities. An advisory board will supervise the project. PrEfiNE project will evaluate an action plan focused on improving FD knowledge to make necessary recommendations for an early recognition of the disease. In addition will generate a plan to improve previously undetected needs. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights

  3. [Fabry's disease and hypoparathyroidism].

    PubMed

    Misery, Laurent; Gregoire, Madeleine; Prieur, Fabienne; Froissart, Régis; Guffon, Nathalie; Maitre, Séverine; Fond, Laurent; Denis, Laurence; Perrot, Jean-Luc; Cambazard, Frédéric

    2002-06-01

    Fabry's disease is due to alpha-galactosidase deficiency. This rare lysosomal storage disease is transmitted by recessive X-linked heredity. Sphingolipids (galactosyl-glucosyl-ceramide) accumulate in many organs. A 19-year-old man with known hypoparathyroidism presented with telangiectasia and angiokeratomas on the buttocks, the hips, the hands and around the navel. For many years, he suffered from paroxysmal pain in the hands and feet. From childhood, he had complained of diffuse abdominal pain, associated with diarrhea. Ophthalmological slit lamp fundus examination showed corneal telangiectasia and cornea verticella. There was no kidney or heart involvement. The diagnosis of Fabry's disease was confirmed by very low levels of alpha-galactosidase. We did not find any other association of hypoparathyroidism and Fabry's disease in the literature. Hypoparathyroidism is not a manifestation of Fabry's disease. Idiopathic hypoparathyroidism is very rare and a genetic origin is known. This disease can be recessive X-linked. A co-transmission of idiopathic hypoparathyroidism and Fabry's disease is probable in our patient.

  4. Fabry disease

    PubMed Central

    2010-01-01

    Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs

  5. Brain magnetic resonance imaging findings fail to suspect Fabry disease in young patients with an acute cerebrovascular event.

    PubMed

    Fazekas, Franz; Enzinger, Christian; Schmidt, Reinhold; Grittner, Ulrike; Giese, Anne-Katrin; Hennerici, Michael G; Huber, Roman; Jungehulsing, Gerhard J; Kaps, Manfred; Kessler, Christof; Martus, Peter; Putaala, Jukka; Ropele, Stefan; Tanislav, Christian; Tatlisumak, Turgut; Thijs, Vincent; von Sarnowski, Bettina; Norrving, Bo; Rolfs, Arndt

    2015-06-01

    Fabry disease (FD) may cause stroke and is reportedly associated with typical brain findings on magnetic resonance imaging (MRI). In a large group of young patients with an acute cerebrovascular event, we wanted to test whether brain MRI findings can serve to suggest the presence of FD. The Stroke in Young Fabry Patients (SIFAP 1) study prospectively collected clinical, laboratory, and radiological data of 5023 patients (18-55 years) with an acute cerebrovascular event. Their MRI was interpreted centrally and blinded to all other information. Biochemical findings and genetic testing served to diagnose FD in 45 (0.9%) patients. We compared the imaging findings between FD and non-FD patients in patients with at least a T2-weighted MRI of good quality. A total of 3203 (63.8%) patients had the required MRI data set. Among those were 34 patients with a diagnosis of FD (1.1%), which was definite in 21 and probable in 13 cases. The median age of patients with FD was slightly lower (45 versus 46 years) and women prevailed (70.6% versus 40.7%; P<0.001). Presence or extent of white matter hyperintensities, infarct localization, vertebrobasilar artery dilatation, T1-signal hyperintensity of the pulvinar thalami, or any other MRI finding did not distinguish patients with FD from non-FD cerebrovascular event patients. Pulvinar hyperintensity was not present in a single patient with FD but seen in 6 non-FD patients. Brain MRI findings cannot serve to suspect FD in young patients presenting with an acute cerebrovascular event. This deserves consideration in the search for possible causes of young patients with stroke. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583. © 2015 American Heart Association, Inc.

  6. Prevalence of Fabry Disease in Familial Mediterranean Fever Patients from Central Anatolia of Turkey.

    PubMed

    Huzmeli, Can; Candan, Ferhan; Alaygut, Demet; Bagci, Gokhan; Akkaya, Lale; Bagci, Binnur; Sozmen, Eser Yıldırım; Kurtulgan, Hande Kucuk; Kayatas, Mansur

    2016-08-01

    Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal alpha-galactosidase A (AGALA) activity. FD and familial Mediterranean fever (FMF) have typical clinical similarities, and both diseases may progress to end-stage renal diseases. In this study, we aimed to determine the prevalence of FD in patients with FMF from Central Anatolia of Turkey. The study group consisted of 177 FMF patients, followed up by the Adult and Pediatric Nephrology Clinic of Cumhuriyet University Hospital. Screening for AGALA activity was performed by the dry blood spot method. Mutation analysis for GLA gene was carried out for patients having an AGALA enzyme activity value lower than the normal reference value. Low AGALA activity was detected in 23 (13 %) patients. Heterozygous GLA gene mutation c.[937G>T] p.[D313Y] was detected in one female patient (0.56 %). The patient was a 53-year-old female with proteinuria and who had undergone left nephrectomy; her glomerular filtration rate (GFR) by scintigraphy was found to be 70 ml/min. She had M694V mutation and no clinical manifestation of FD. In our study, the prevalence rate of FD was found as 0.56 % in FMF patients. The similarities between the symptoms of FMF and FD might lead to a diagnostic dilemma in physicians at countries where FMF is observed frequently. Although the prevalence of FD is rare, physicians should keep in mind that FD has an ambiguous symptomology pattern of FMF.

  7. Comparison of left atrial size and function in hypertrophic cardiomyopathy and in Fabry disease with left ventricular hypertrophy.

    PubMed

    Saccheri, María Cristina; Cianciulli, Tomás Francisco; Challapa Licidio, Wilde; Lax, Jorge A; Beck, Martín A; Morita, Luis A; Gagliardi, Juan A

    2018-05-01

    Fabry disease (FD) and hypertrophic cardiomyopathy (HCM) are two diseases with a different pathophysiology, both cause left ventricular hypertrophy (LVH) and myocardial fibrosis. Although remodeling and systolic dysfunction of the left atrium (LA) are associated with atrial fibrillation and stroke in HCM, changes in the size and function of the LA have not been well studied in FD with LVH. The following groups were studied prospectively, and their respective findings compared: 19 patients with non-obstructive HCM (Group I), 20 patients with a diagnosis of Fabry cardiomyopathy (Group II), and 20 normal subjects matched for sex and age (Group III). Left ventricular mass index was measured using Devereux' formula, left atrial volume with Simpson's biplane method and left atrial mechanical function, including strain and strain rate, was measured using the speckle tracking technique. Strain and strain rate of the reservoir were measured during the three phases: reservoir (SR S), passive conduit (SR E) and atrial contraction (SR A). Patients with HCM had a larger left atrial volume than patients with FD (48.16 ± 14.3 mL/m 2 vs 38.9 ± 14.9 mL/m 2 respectively, P < .001), but in both disorders there was a severe decrease in left atrial function: reservoir strain in the apical four-chamber view: 17.47% in HCM vs 22.5% in FD, P = .24), strain rate in the apical chamber view: SR A: -0.80/seconds in HCM vs -1.04/seconds in FD (P = .88), SR S: 0.69/seconds in HCM vs 0.93 in FD (P = .12), SR E: -0.80 seconds in HCM vs -0.97/seconds in FD (P = .18). In this echocardiographic study we used speckle tracking to assess left atrial mechanical function and showed that FD is associated to an atrial cardiomyopathy, affecting the three phasic functions of the LA. Although in patients with HCM left atrial volume is larger than in patients with FD, both disorders exhibit severe decrease in left atrial function. These findings should be considered, given the potentially

  8. Cardiopulmonary involvement in Fabry's disease.

    PubMed

    Koskenvuo, Juha W; Kantola, Ilkka M; Nuutila, Pirjo; Knuuti, Juhani; Parkkola, Riitta; Mononen, Ilkka; Hurme, Saija; Kalliokoski, Riikka; Viikari, Jorma S; Wendelin-Saarenhovi, Maria; Kiviniemi, Tuomas O; Hartiala, Jaakko J

    2010-04-01

    Fabry's disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A enzyme activity. Decreased enzyme activity leads to accumulation of glycosphingolipid in different tissues, including endothelial and smooth-muscle cells and cardiomyocytes. There is controversial data on cardiopulmonary involvement in Fabry's disease, because many reports are based on small and selected populations with Fabry's disease. Furthermore, the aetiology of cardiopulmonary symptoms in Fabry's disease is poorly understood. We studied cardiopulmonary involvement in seventeen patients with Fabry's disease (20-65 years, 6 men) using ECG, bicycle stress, cardiac magnetic resonance imaging, spirometry, diffusing capacity and pulmonary high-resolution computed tomography (HRCT) tests. Cardiopulmonary symptoms were compared to observed parameters in cardiopulmonary tests. Left ventricular hypertrophy (LVH) and reduced exercise capacity are the most apparent cardiac changes in both genders with Fabry's disease. ECG parameters were normal when excluding changes related to LVH. Spirometry showed mild reduction in vital capacity and forced expiratory volume in one second (FEV I), and mean values in diffusing capacity tests were within normal limits. Generally, only slight morphological pulmonary changes were detected using pulmonary HRCT, and they were not associated with changes in pulmonary function. The self-reported amount of pulmonary symptoms associated only with lower ejection fraction (P < 0.001) and longer QRS-duration (P = 0.04) of all measured cardiopulmonary parameters, whereas cardiac symptoms have no statistically significant association with any of these parameters. LVH and reduced exercise capacity are the most apparent cardiopulmonary changes in Fabry's disease but they have only a minor association to cardiopulmonary symptoms.Therefore, routine cardiopulmonary evaluation in Fabry's disease using echocardiography is maybe enough when integrated to

  9. Prevalence of Fabry Disease in Young Patients with Stroke in Argentina.

    PubMed

    Reisin, Ricardo C; Mazziotti, Julieta; Cejas, Luciana León; Zinnerman, Alberto; Bonardo, Pablo; Pardal, Manuel Fernández; Martínez, Alejandra; Riccio, Patricia; Ameriso, Sebastián; Bendersky, Eduardo; Nofal, Pedro; Cairola, Patricia; Jure, Lorena; Sotelo, Andrea; Rozenfeld, Paula; Ceci, Romina; Casas-Parera, Ignacio; Sánchez-Luceros, Analía

    2018-03-01

    Fabry disease (FD) is an underdiagnosed cause of stroke in young adults, but the frequency of this association is largely unknown. We estimated the prevalence of FD in a nationwide cohort of young adults who had stroke and transient ischemic attack (TIA) in Argentina. This was a prospective, multicenter study of stroke and FD in young adults (18-55 years) conducted in Argentina between 2011 and 2015. Patients were enrolled if they had had a TIA or an ischemic or hemorrhagic stroke within the previous 180 days. FD was diagnosed by measuring α-galactosidase A activity (males) and through genetic studies (females). We enrolled 311 patients (54% men, mean age: 41 years). Ischemic events occurred in 89% of patients (80% infarcts, 9% TIA) and hemorrhagic strokes in 11%. One female (.3% of the total group, 1% of the cryptogenic ischemic strokes) had the pathogenic mutation c.888G>A/p.Met296Ile /Exon 6 on the GAL gene. Her only other manifestation of FD was angiokeratoma. Eighteen females had nonpathogenic intronic variations: c.-10C>T, c.-12G>A, or both. Two patients had the nonpathogenic mutation D313Y, while a third had the likely benign mutation S126G. FD was identified in 1 patient (.3%) in this first Latin American study. The patient presented with a late-onset oligo-symptomatic form of the disease. A large number of nonpathogenic mutations were present in our cohort, and it is essential that they not be mistaken for pathogenic mutations to avoid unnecessary enzyme replacement treatment. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  10. Identification of lysosomal and extralysosomal globotriaosylceramide (Gb3) accumulations before the occurrence of typical pathological changes in the endomyocardial biopsies of Fabry disease patients.

    PubMed

    Hsu, Ming-Jia; Chang, Fu-Pang; Lu, Yung-Hsiu; Hung, Sheng-Che; Wang, Yu-Chen; Yang, An-Hang; Lee, Han-Jui; Sung, Shih-Hsien; Wang, Yen-Feng; Yu, Wen-Chung; Hsu, Ting-Rong; Huang, Po-Hsun; Chang, Sheng-Kai; Dzhagalov, Ivan; Hsu, Chia-Lin; Niu, Dau-Ming

    2018-06-06

    Evaluation standards and treatment initiation timing have been debated for a long time, particularly for late-onset Fabry disease (FD), because of its slow progression. However, early initiation of enzyme replacement therapy (ERT) for FD could be effective in stabilizing the disease progression and potentially preventing irreversible organ damage. We aimed to examine globotriaosylceramide (Gb3) deposits in patients' endomyocardial biopsies to understand the early pathogenesis of FD cardiomyopathy. Immunofluorescent (IF) staining of Gb3 and lysosomal-associated membrane protein 1 (LAMP-1) was performed on endomyocardial biopsies of patients suspected of Fabry cardiomyopathy who had negative or only slight Gb3 accumulation determined by toluidine blue staining and electron microscopic examination. The IF staining results revealed that all patients examined had abundant Gb3 accumulation in their cardiomyocytes, including the ones who are negative for inclusion bodies. Furthermore, we found that early Gb3 deposits were mostly confined within lysosomes, while they appeared extralysosomally at a later stage. A significant amount of lysosomal Gb3 deposits could be detected by IF staining in cardiac tissue before the formation of inclusion bodies, suggesting the cardiomyocytes might have been experiencing cellular stress and damage early on, before the appearance of typical pathological changes of FD during the disease progression.

  11. [The switch of enzyme therapy in Fabry disease].

    PubMed

    Riccio, Eleonora; Pisani, Antonio

    2014-01-01

    Fabry disease (FD) is a multiorgan X-linked lysosomal storage disorder resulted from the deficiency of the lysosomal enzyme alpha galactosidase A. It particularly affects the heart, kidneys and cerebrovascular system. The treatment options for FD patients include long-term enzyme replacement therapy (ERT). Two recombinant enzyme formulations for the ERT of FD are available on European market: agalsidase alfa and agalsidase beta. Numerous evidences in the literature have confirmed the safety and efficacy of ERT. However, to date, there have been limited comparisons between the two agents, and no firm conclusion can be drawn regarding their specific efficacy and safety. In June 2009, a viral contamination in the manufacturing process of Fabrazyme led to a global shortage of agalsidase beta. Recommendations to shift patients to the recommended dose of Replagal were published by the European Medicines Agency (EMA) for all patients receiving Fabrazyme. This offered the unique opportunity to compare, although indirectly, the two drugs evaluating any clinical modification or adverse events that occurred after the switch. Moreover, with the increased availability of agalsidase beta in the last 3 months of 2012, some of the patients who previously switched to agalsidase alfa, were switched-back and returned to full-dose agalsidase beta. This article reviews the published evidence for the clinical efficacy of the two available enzyme preparations and compare it with the experience of our center.

  12. Effect of reduced agalsidase Beta dosage in fabry patients: the Australian experience.

    PubMed

    Ghali, Joanna; Nicholls, Kathy; Denaro, Charles; Sillence, David; Chapman, Ian; Goldblatt, Jack; Thomas, Mark; Fletcher, Janice

    2012-01-01

    In Australia, enzyme replacement therapy (ERT) for Fabry Disease (FD), both Agalsidase alfa (Replagal, Shire HGT) and beta (Fabrazyme, Genzyme), is funded and monitored through a specific government program. Agalsidase beta supply has been rationed by Genzyme since 2009 due to manufacturing issues. Consequently, the Australian Fabry Disease Advisory Committee has treated patients on Agalsidase beta at 50% of their usual dose from mid-2009, with a further reduction to 30% for some patients from late 2009. To determine the clinical effect of Agalsidase beta dose reduction in the Australian FD patient cohort. A questionnaire assessing FD symptoms was administered to 40 patients on long-term ERT. Clinical data from The Fabry Registry for patients receiving Agalsidase alfa or beta, for at least 2 years prior to the time of enforced Agalsidase beta dose reduction, were reviewed. Disease burden and quality of life (QOL) were graded using the Disease Severity Scoring System, Mainz Severity Score Index, Brief Pain Inventory and Short Form 36 Health Survey at 2 years before dose reduction, at the time of dose reduction and at the most recent clinical review following dose reduction. Disease severity and QOL scores did not change between the ERT groups. Males on Agalsidase beta reported lower energy levels after dose reduction, while no change was reported by females on either product or by males on a stable dose of Agalsidase alfa. This study suggests that energy levels in male patients worsen after dose reduction of Agalsidase beta.

  13. Uneventful pregnancy outcome after enzyme replacement therapy with agalsidase beta in a heterozygous female with Fabry disease: A case report.

    PubMed

    Germain, Dominique P; Bruneval, Patrick; Tran, Thi-Chien; Balouet, Pierre; Richalet, Bernard; Benistan, Karelle

    2010-01-01

    No reproductive studies have been performed with enzyme replacement therapy (ERT) for Fabry disease (FD, OMIM 301500), a lysosomal storage disorder. Therefore, use during pregnancy is theoretically contraindicated. We report the first case of agalsidase beta treatment throughout pregnancy. High-range proteinuria remained stable and the patient gave birth to a healthy boy after an uncomplicated pregnancy. The decision to administer ERT during pregnancy should be made on an individual basis, considering the FD status and possible risks. Copyright 2009 Elsevier Masson SAS. All rights reserved.

  14. The Frequency of Fabry Disease among Young Cryptogenic Stroke Patients in the City of Sakarya.

    PubMed

    Gündoğdu, Aslı Aksoy; Kotan, Dilcan; Alemdar, Murat

    2017-06-01

    Fabry disease (FD) is known as a rare cause of stroke. Recent studies suggested that FD is an underdiagnosed entity among young stroke patients. We aimed to investigate the frequency of FD in young cryptogenic stroke patients who lived in the City of Sakarya and to define the clinical features that help in recognizing patients with FD. Acute ischemic stroke patients aged 18-55 years who were admitted to our hospital between October 2013 and September 2016 were evaluated for inclusion. Patients with other recognized causes of stroke were excluded. The screening was performed for alpha-galactosidase A (α-Gal A) activity on dried blood spot, and DNA was sequenced for GLA mutation in patients with low plasma α-Gal A activity. Among the 484 acute ischemic stroke patients, 54 (24 male, 44.4%) young cryptogenic stroke patients were enrolled. The α-Gal A activity was detected as low in 3 patients. c.[680G > A] p.[R227Q] missense mutation was identified in 2 male patients. The frequency of FD was calculated as 3.7%. Our research is the first FD screening study in Turkish stroke patients. Our results underlined the importance of considering FD during the etiologic evaluation of young cryptogenic stroke patients as it is a rare but potentially treatable entity. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  15. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document.

    PubMed

    Biegstraaten, Marieke; Arngrímsson, Reynir; Barbey, Frederic; Boks, Lut; Cecchi, Franco; Deegan, Patrick B; Feldt-Rasmussen, Ulla; Geberhiwot, Tarekegn; Germain, Dominique P; Hendriksz, Chris; Hughes, Derralynn A; Kantola, Ilkka; Karabul, Nesrin; Lavery, Christine; Linthorst, Gabor E; Mehta, Atul; van de Mheen, Erica; Oliveira, João P; Parini, Rossella; Ramaswami, Uma; Rudnicki, Michael; Serra, Andreas; Sommer, Claudia; Sunder-Plassmann, Gere; Svarstad, Einar; Sweeb, Annelies; Terryn, Wim; Tylki-Szymanska, Anna; Tøndel, Camilla; Vujkovac, Bojan; Weidemann, Frank; Wijburg, Frits A; Woolfson, Peter; Hollak, Carla E M

    2015-03-27

    Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD. A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement. For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m(2)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly

  16. Proposed Stages of Myocardial Phenotype Development in Fabry Disease.

    PubMed

    Nordin, Sabrina; Kozor, Rebecca; Medina-Menacho, Katia; Abdel-Gadir, Amna; Baig, Shanat; Sado, Daniel M; Lobascio, Ilaria; Murphy, Elaine; Lachmann, Robin H; Mehta, Atul; Edwards, Nicola C; Ramaswami, Uma; Steeds, Richard P; Hughes, Derralynn; Moon, James C

    2018-05-11

    The authors sought to explore the Fabry myocardium in relation to storage, age, sex, structure, function, electrocardiogram changes, blood biomarkers, and inflammation/fibrosis. Fabry disease (FD) is a rare, x-linked lysosomal storage disorder. Mortality is mainly cardiovascular with men exhibiting cardiac symptoms earlier than women. By cardiovascular magnetic resonance, native T1 is low in FD because of sphingolipid accumulation. A prospective, observational study of 182 FD (167 adults, 15 children; mean age 42 ± 17 years, 37% male) who underwent cardiovascular magnetic resonance including native T1, late gadolinium enhancement (LGE), and extracellular volume fraction, 12-lead electrocardiogram, and blood biomarkers (troponin and N-terminal pro-brain natriuretic peptide). In children, T1 was never below the normal range, but was lower with age (9 ms/year, r = -0.78 children; r = -0.41 whole cohort; both p < 0.001). Over the whole cohort, the T1 reduction with age was greater and more marked in men (men: -1.9 ms/year, r = -0.51, p < 0.001; women: -1.4 ms/year, r = -0.47 women, p < 0.001). Left ventricular hypertrophy (LVH), LGE, and electrocardiogram abnormalities occur earlier in men. Once LVH occurs, T1 demonstrates major sex dimorphism: with increasing LVH in women, T1 and LVH become uncorrelated (r = -0.239, p = 0.196) but in men, the correlation reverses and T1 increases (toward normal) with LVH (r = 0.631, p < 0.001), a U-shaped relationship of T1 to indexed left ventricular mass in men. These data suggest that myocyte storage starts in childhood and accumulates faster in men before triggering 2 processes: a sex-independent scar/inflammation regional response (LGE) and, in men, apparent myocyte hypertrophy diluting the T1 lowering of sphingolipid. Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  17. Clinical significance of plasma globotriaosylsphingosine levels in Chinese patients with Fabry disease.

    PubMed

    Ouyang, Yan; Chen, Bing; Pan, Xiaoxia; Wang, Zhaohui; Ren, Hong; Xu, Yaowen; Ni, Liyan; Yu, Xialian; Yang, Li; Chen, Nan

    2018-04-01

    Although plasma globotriaosylsphingosine (lyso-Gb3) is a promising biomarker of Fabry disease (FD), few studies have assessed the impact of lyso-Gb3 in patients with FD. A total of 38 patients diagnosed with FD at Ruijin Hospital between January 2012 and December 2014 were recruited in the current study. An additional 120 unrelated healthy individuals were selected as healthy controls. A simplified liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was performed to determine lyso-Gb3 levels in plasma. Protein precipitation and glycolipid extraction were conducted using acetone/methanol. Clinical performance, including diagnostic value and disease surveillance, were compared between plasma lyso-Gb3 levels and α-galactosidase A (α-gal A) enzyme activity. The overall coefficient of variation values between inter- and intra-days varied between 2.8 and 18.9% and linearity correlation coefficients were ≥0.99 for all assays. Therefore, the effectiveness of the LC-MS/MS method was validated. Furthermore, a cut-off value of 0.81 ng/ml plasma lyso-Gb3 was able to separate patients with FD from healthy individuals. The sensitivity of this cut-off was 94.7% and the specificity was 100%. Compared with α-gal A enzyme activity, the diagnostic rate of patients assessed using plasma lyso-Gb3 levels was similar; however, there was a tighter correlation between plasma lyso-Gb3 levels and the mainz severity score index score in male patients (r=0.711 vs. r=-0.687). The sensitivity of plasma lyso-Gb3 in diagnosing female patients with FD was higher than α-gal A enzyme activity (82.4 vs. 23.5%). To the best of our knowledge, the present study is the first to report the effectiveness of plasma lyso-Gb3 levels in diagnosing Chinese patients with FD. Using α-gal A activity as a reference, the results of current study indicated that plasma lyso-Gb3 levels are more useful at diagnosing female patients with FD. Furthermore, plasma lyso-Gb3 levels are more suitable at

  18. Neuropathic pain in a Fabry disease rat model

    PubMed Central

    Miller, James J.; Aoki, Kazuhiro; Murphy, Carly A.; O’Hara, Crystal L.; Tiemeyer, Michael; Stucky, Cheryl L.; Dahms, Nancy M.

    2018-01-01

    Fabry disease, the most common lysosomal storage disease, affects multiple organs and results in a shortened life span. This disease is caused by a deficiency of the lysosomal enzyme α-galactosidase A, which leads to glycosphingolipid accumulation in many cell types. Neuropathic pain is an early and severely debilitating symptom in patients with Fabry disease, but the cellular and molecular mechanisms that cause the pain are unknown. We generated a rat model of Fabry disease, the first nonmouse model to our knowledge. Fabry rats had substantial serum and tissue accumulation of α-galactosyl glycosphingolipids and had pronounced mechanical pain behavior. Additionally, Fabry rat dorsal root ganglia displayed global N-glycan alterations, sensory neurons were laden with inclusions, and sensory neuron somata exhibited prominent sensitization to mechanical force. We found that the cation channel transient receptor potential ankyrin 1 (TRPA1) is sensitized in Fabry rat sensory neurons and that TRPA1 antagonism reversed the behavioral mechanical sensitization. This study points toward TRPA1 as a potentially novel target to treat the pain experienced by patients with Fabry disease. PMID:29563343

  19. De novo Diagnosis of Fabry Disease among Italian Adults with Acute Ischemic Stroke or Transient Ischemic Attack.

    PubMed

    Romani, Ilaria; Borsini, Walter; Nencini, Patrizia; Morrone, Amelia; Ferri, Lorenzo; Frusconi, Sabrina; Donadio, Vincenzo Angelo; Liguori, Rocco; Donati, Maria Alice; Falconi, Serena; Pracucci, Giovanni; Inzitari, Domenico

    2015-11-01

    Cerebrovascular complications are often the first cause of hospitalization in patients with Fabry disease (FD). Screenings for FD among stroke patients have yielded discrepant results, likely as a result of heterogeneous or incomplete assessment. We designed a study to identify FD among adults 60 years of age or younger who were consecutively admitted for acute ischemic stroke or transient ischemic attack (TIA) to a stroke neurology service in Italy. Patients with first-ever or recurrent events were included, irrespective of gender, risk factors, or stroke type. We screened male patients using α-galactosidase A enzyme assay, and female patients using DNA sequencing. FD was eventually established after a broad multidisciplinary discussion. We screened 108 patients (61% males, median age: 48 years); 84% of these patients had stroke. De novo FD diagnosis was established in 3 patients (2.8%; 95% confidence interval, .57-8.18): a 59-year-old man with recurrent lacunar-like strokes and multiple risk factors; a 42-year-old woman with recurrent cryptogenic minor strokes; and a 32-year-old woman with recurrent strokes previously attributed to Behçet's disease. Screened patients were systematically asked for typical FD symptoms; each of the de novo patients reported one or more of the following: episodes of hand/foot pain during fever, angiokeratoma, and family history of heart disease. In all of the patients events were recurrent, and lacunar-like infarcts characterized their brain imaging. Prevalence of FD among nonselected adults 60 years of age or younger with acute ischemic stroke or TIA is not negligible. A systematic search for FD in a stroke setting, using a comprehensive clinical, biochemical, and genetic screening protocol, may be worthwhile. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  20. Nailfold capillaroscopy: Specific features in Fabry disease.

    PubMed

    Wasik, Jan S; Simon, Roger W; Meier, Thomas; Steinmann, Beat; Amann-Vesti, Beatrice R

    2009-01-01

    Fabry disease is a rare X-linked disorder caused by deficiency of alpha-galactosidase A. The metabolic defect results in the progressive accumulation of globotriaosylceramide within vascular cells leading to renal, cardiac and cerebrovascular manifestations. The aim of this study was to evaluate nailfold capillaroscopy as a non-invasive diagnostic tool in Fabry disease and to characterize morphological and functional changes of the capillaries in vivo. Twenty-five consecutive patients with Fabry disease (17 males) without enzyme-replacement therapy had been studied by fluorescence nailfold capillaroscopy. Macrocirculation of digital arteries was tested by digital pulse volume recording and patients had been asked about the presence of Raynaud phenomenon. Significant more bushy capillaries and clusters were present in Fabry patients (72%) compared to healthy controls (10%). No avascular fields had been seen, and in only one patient atypical architecture and in another one a giant capillary was present. Enhanced natrium-fluorescein diffusion into the pericapillary area has been observed in three male patients. Six patients (one female) reported Raynaud phenomenon of all fingers. In Fabry disease morphological and functional microangiopathy of nailfold capillaries is present. Furthermore, these new findings might explain, at least in part, the unusual high frequency of Raynaud phenomenon in Fabry patients, which has not been described so far. Our data suggest that capillaroscopy might be used as an additional non-invasive diagnostic tool for Fabry disease.

  1. Spotlight on agalsidase beta in Fabry disease.

    PubMed

    Keating, Gillian M; Simpson, Dene

    2007-01-01

    Agalsidase beta (Fabrazyme) is a recombinant human alpha-galactosidase A enzyme approved for intravenous use in the treatment of Fabry disease. Fabry disease is a progressive, multisystemic, potentially life-threatening disorder caused by a deficiency of alpha-galactosidase A. This deficiency results in accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3), in the lysosomes of various tissues. This accumulation is the underlying driver of disease progression. Agalsidase beta provides an exogenous source of alpha-galactosidase A. Intravenous agalsidase beta is effective and well tolerated in patients with Fabry disease. In a phase III trial, agalsidase beta was shown to clear GL-3 from various target cells and, in a subsequent extension of this trial, prevent GL-3 reaccumulation. In a post-approval trial, agalsidase beta was shown to provide significant clinical benefit by reducing the risk of a major clinical event. Thus, agalsidase beta represents an important advance in the treatment of Fabry disease, and agalsidase beta therapy should be strongly considered in patients with Fabry disease who are suitable candidates.

  2. Globotriaosylsphingosine (Lyso-Gb3) as a biomarker for cardiac variant (N215S) Fabry disease.

    PubMed

    Alharbi, Fahad J; Baig, Shanat; Auray-Blais, Christiane; Boutin, Michel; Ward, Douglas G; Wheeldon, Nigel; Steed, Rick; Dawson, Charlotte; Hughes, Derralynn; Geberhiwot, Tarekegn

    2018-03-01

    Fabry disease (FD) is a multi-systemic X-linked lysosomal disorder caused by the deficient activity of α-galactosidase-A enzyme, which leads to accumulation of glycosphingolipids in various body tissues. The N215S mutation is a known variant of FD, with a late onset cardiac phenotype. Consensus guidelines acknowledged the use of globotriaosylsphingosine (Lyso-Gb 3 ) as a diagnostic marker for classical FD but its utility for cardiac variant FD is not clear. We aim to characterize the clinical features and evaluate the diagnostic accuracy of plasma and urinary Lyso-Gb 3 levels in N215S cardiac variant FD patients. Thirty-four FD patients with the late-onset N215S cardiac variant mutation were enrolled along with 62 classical FD patients and 109 healthy controls. Plasma and urinary Lyso-Gb 3 and its analogues were analyzed by LC-MS/MS. Both FD males and females with N215S mutation showed Lyso-Gb 3 levels of (mean ± SEM) 9.7 ± 1.0 and 5.4 ± 0.8 nM, respectively. These levels were significantly higher than healthy control and lower than classical FD patients (p < 0.0001). Plasma Lyso-Gb 3 levels equal to or higher than 2.7 nM yielded a diagnostic sensitivity and specificity of 100% (AUC = 1, p < 0.0001). Cardiac involvement was frequent with 16/34 (47%) developing left ventricular hypertrophy. Three patients who underwent renal biopsy had the characteristic sphingolipid deposition in the podocytes while 6/19 (32%) had evidence of white matter changes or infarct on brain MRI. Taken together, cardiac variant N215S mutation is rather an attenuated form of classical FD. Plasma Lyso-Gb 3 is a diagnostic hallmark to differentiate N215S variant phenotype from subjects with no FD.

  3. Cognitive and Psychological Functioning in Fabry Disease

    PubMed Central

    Sigmundsdottir, Linda; Tchan, Michel C.; Knopman, Alex A.; Menzies, Graham C.; Batchelor, Jennifer; Sillence, David O.

    2014-01-01

    Fabry disease is an X-linked lysosomal storage disorder which can result in renal, cardiac, and cerebrovascular disease. Patients are at increased risk of stroke and neuroimaging studies note cerebrovascular pathology. This study provides a cognitive profile of a cohort of individuals with Fabry disease and investigates the impact of pain, age, renal, cardiac, and cerebrovascular functioning on cognition and psychological functioning. Seventeen Fabry patients (12 males) with ages ranging 25 to 60 years (M = 46.6+11.8), and 15 age-matched healthy controls (M = 46.2+12.7) were administered a comprehensive neuropsychological battery. Fabry males demonstrated slower speed of information processing, reduced performance on measures of executive functions (verbal generation, reasoning, problem solving, perseveration), were more likely to show clinically significant reductions, and were more likely to report symptoms of anxiety and depression. Conversely, Fabry females performed at a similar level to controls. Correlational analyses indicated a link between cognitive and clinical measures of disease severity. PMID:25319043

  4. Enzyme replacement therapy in Fabry disease: influence on cardiac manifestations.

    PubMed

    Caballero, L; Climent, V; Hernández-Romero, D; Quintanilla, M A; de la Morena, G; Marín, F

    2010-01-01

    Fabry disease (FD) is an X-linked glycosphingolipid storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. This leads to a progressive accumulation of globotriaosylceramide (Gb3) in the lysosomes of different cells and tissues, causing principally ventricular hypertrophy, renal failure and cerebrovascular accidents, reducing lifespan both in hemizygous males and heterozygous females. Residual enzyme activity might lead to slow progression of the disease and result in the so-called cardiac or renal variants with delayed presentation. Two different forms of alpha-galactosidase A enzyme replacement therapies (ERT) are available for the treatment of FD, one genetically engineered in human cell line (agalsidase alfa, Replagal, Shire) and the other produced in a Chinese hamster ovary cell line (agalsidase beta, Fabrazyme, Genzyme). Although both proteins are structurally and functionally very similar, with the same amino acid sequence as the native human enzyme, they differ in the pattern of glycosilation of the protein depending on the originating cell line. Studies with both preparations have described a reduction in plasma, urinary sediment and tissue levels of Gb3, a decrease in the frequency of pain crisis and a reduction in left ventricular mass and improvement or stabilization of renal function. Studies have generally shown the greatest benefit when treatment is started at an early stage of the disease before extensive fibrosis or other irreversible tissue damage takes place. However, more data are needed to document long-term treatment outcomes. The aim of the present review is to provide an update overview of the two different forms of ERT for FD, their clinical effects in cardiac manifestations and their possible differences in terms of efficacy, side effects and safety profiles.

  5. Non-specific gastrointestinal features: Could it be Fabry disease?

    PubMed

    Hilz, Max J; Arbustini, Eloisa; Dagna, Lorenzo; Gasbarrini, Antonio; Goizet, Cyril; Lacombe, Didier; Liguori, Rocco; Manna, Raffaele; Politei, Juan; Spada, Marco; Burlina, Alessandro

    2018-05-01

    Non-specific gastrointestinal symptoms, including pain, diarrhoea, nausea, and vomiting, can be the first symptoms of Fabry disease. They may suggest more common disorders, e.g. irritable bowel syndrome or inflammatory bowel disease. The confounding clinical presentation and rarity of Fabry disease often cause long diagnostic delays and multiple misdiagnoses. Therefore, specialists involved in the clinical evaluation of non-specific upper and lower gastrointestinal symptoms should recognize Fabry disease as a possible cause of the symptoms, and should consider Fabry disease as a possible differential diagnosis. When symptoms or family history suggest Fabry disease, in men, low alpha-galactosidase A enzyme levels, and in women, specific Fabry mutations confirm the diagnosis. In addition to symptomatic treatments, disease-specific enzyme replacement therapy with recombinant human alpha-galactosidase A enzyme or chaperone therapy (migalastat) in patients with amenable mutations can improve the disease, including gastrointestinal symptoms, and should be initiated as early as possible after Fabry disease has been confirmed; starting enzyme replacement therapy at as young an age as possible after diagnosis improves long-term clinical outcomes. Improved diagnostic tools, such as a modified gastrointestinal symptom rating scale, may facilitate diagnosing Fabry disease in patients with gastrointestinal symptoms of unknown cause and thus assure timely initiation of disease-specific treatment. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. Awareness of Fabry disease in cardiology: A gap to be filled.

    PubMed

    Brito, Dulce; Cardim, Nuno; Lopes, Luís Rocha; Belo, Adriana; Mimoso, Jorge; Gonçalves, Lino; Madeira, Hugo

    2018-06-01

    In adults, unexplained left ventricular hypertrophy is usually due to sarcomeric hypertrophic cardiomyopathy (HCM). Fabry disease (FD) is rare but may mimic sarcomeric HCM, and has an adverse prognosis in the absence of specific treatment. We aimed to assess cardiologists' awareness of FD based on data from the Portuguese Registry of Hypertrophic Cardiomyopathy. A total of 811 index patients, aged 55 ± 16 years, 486 (59.9%) male, were included. Three groups were characterized: A - 128 patients, 74 (57.8%) male, with pathogenic or likely pathogenic mutation(s) in sarcomeric genes; B - 234 patients, 146 (62.4%) male, with negative genetic testing; and C - 449 patients, 266 (59.2%) male, no genetic testing performed. The groups were compared in terms of whether FD was excluded in the registry. Potential red flags for FD were also analyzed and compared between groups. Patients in group A were younger and more frequently had familial HCM (A - 53.9% vs. B - 20.1% vs. C - 18.3%; p <0.001). FD was recorded as excluded in 217 (26.8%), similar in all groups; GLA gene testing was performed in only 50/217 patients (A - 48.6%, B - 25.7%, p = 0.019; C - 13.4%, p = 0.036 for B vs. C), mostly in women (p <0.001) in groups B and C. Alpha-galactosidase A (α-Gal A) activity was assessed in 39/217 (18%) patients, with no difference between groups, but more often in men (p = 0.005). Among patients with potential red flags for FD, only 46.7% underwent specific tests (GLA gene testing and/or α-Gal A activity). When GLA genotyping was performed no mutations were identified. There is a need to improve cardiologists' alertness for the identification of FD among the Portuguese HCM population. Copyright © 2018 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

  7. eNOS gene Glu298Asp and 4b/a polymorphisms are associated with renal function parameters in Mexican patients with Fabry disease.

    PubMed

    Marin-Medina, A; Brambila-Tapia, A J L; Picos-Cárdenas, V J; Gallegos-Arreola, M P; Figuera, L E

    2016-10-24

    Fabry disease (FD) is an inherited X-linked lysosomal disease that causes renal failure in a high percentage of affected individuals. The eNOS gene encodes for endothelial nitric oxide synthase, which plays an important role in glomerular hemodynamics. This gene has two main polymorphisms (Glu298Asp and 4b/a) that have been studied in the context of many different diseases, including those involving cardiovascular and renal alterations. Considering the lack of information regarding eNOS variants and FD, we investigated whether there were associations between eNOS genetic variants and renal function parameters in Mexican patients with FD and renal impairment. In total, 15 FD patients with renal alterations were included in the present study, and associations between eNOS polymorphisms and renal function parameters (urea, creatinine, and GFR) were evaluated. The Asp298 and 4a alleles of the eNOS gene were found to be significantly associated with increased levels of urea and creatinine, and a decreased glomerular filtration rate in FD patients, and this association behaved in a co-dominant fashion. Our results coincide with previous reports showing an association between these polymorphisms and kidney disease, and along with other studies regarding their role in the nitric oxide pathway, suggest that these variants affect the severity of nephropathy in patients with FD.

  8. Echocardiographic Assessment of Patients with Fabry Disease.

    PubMed

    Yeung, Darwin F; Sirrs, Sandra; Tsang, Michael Y C; Gin, Kenneth; Luong, Christina; Jue, John; Nair, Parvathy; Lee, Pui K; Tsang, Teresa S M

    2018-06-01

    Fabry disease is an X-linked lysosomal storage disorder that results from a deficiency of α-galactosidase A. Increased left ventricular wall thickness has been the most commonly described cardiovascular manifestation of the disease. However, a variety of other structural and functional abnormalities have also been reported. Echocardiography is an effective noninvasive method of assessing the cardiac involvement of Fabry disease. A more precise and comprehensive characterization of Fabry cardiomyopathy using conventional and novel echocardiographic techniques may lead to earlier diagnosis, more accurate prognostication, and timely treatment. The aim of this review is to provide a comprehensive overview of the structural and functional abnormalities on echocardiography that have thus far been described in patients with Fabry disease and to highlight potential areas that would benefit from further research. Copyright © 2018 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

  9. Ventricular arrhythmia and sudden cardiac death in Fabry disease: a systematic review of risk factors in clinical practice.

    PubMed

    Baig, Shanat; Edward, Nicky C; Kotecha, Dipak; Liu, Boyang; Nordin, Sabrina; Kozor, Rebecca; Moon, James C; Geberhiwot, Tarekegn; Steeds, Richard P

    2017-10-17

    Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of α-galactosidase A enzyme. Cardiovascular (CV) disease is a common cause of mortality in FD, in particular as a result of heart failure and arrhythmia, with a significant proportion of events categorized as sudden. There are no clear models for risk prediction in FD. This systematic review aims to identify the risk factors for ventricular arrhythmia (VA) and sudden cardiac deaths (SCD) in FD. A systematic search was performed following PRISMA guidelines of EMBASE, Medline, PubMed, Web of Science, and Cochrane from inception to August 2016, focusing on identification of risk factors for the development of VA or SCD. Thirteen studies were included in the review (n = 4185 patients) from 1189 articles, with follow-up of 1.2-10 years. Weighted average age was 37.6 years, and 50% were male. Death from any cause was reported in 8.3%. Of these, 75% was due to CV problems, with the majority being SCD events (62% of reported deaths). Ventricular tachycardia was reported in 7 studies, with an average prevalence of 15.3%. Risk factors associated with SCD events were age, male gender, left ventricular hypertrophy, late gadolinium enhancement on CV magnetic resonance imaging, and non-sustained ventricular tachycardia. Although a multi-system disease, FD is a predominantly cardiac disease from a mortality perspective, with death mainly from SCD events. Limited evidence highlights the importance of clinical and imaging risk factors that could contribute to improved decision-making in the management of FD. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: journals.permissions@oup.com.

  10. Enzyme replacement therapy stabilized white matter lesion progression in Fabry disease.

    PubMed

    Fellgiebel, Andreas; Gartenschläger, Martin; Wildberger, Kerstin; Scheurich, Armin; Desnick, Robert J; Sims, Katherine

    2014-01-01

    The central nervous system manifestations in Fabry disease (FD) include progressive white matter lesions (WMLs) and stroke. Due to progressive microvascular involvement, men and women with FD over 35 years of age develop WMLs. Moreover, the prevalence of stroke has been estimated to be 12 times higher in FD compared with the general population. Enzyme replacement therapy (ERT) is available and has shown beneficial effects on renal, cardiac, and peripheral nerve function in FD, but the ERT effect on the progression of WMLs, or the reduction in cerebrovascular events, remains unknown. The WML burden and the effect of agalsidase beta 1 mg/kg biweekly on WML progression were assessed longitudinally in a Phase 4 agalsidase-beta placebo-controlled analysis of untreated and treated FD patients with mild-to-moderate renal involvement (serum creatinine measurements of ≥1.2 mg/dl and <3.0 mg/dl). The primary end point was the difference in the number of patients with increased WML burden between the agalsidase beta and placebo groups at the end of treatment. The diameters of the WMLs were determined manually using axial flow-attenuated-inversion-recovery-weighted magnetic resonance imaging (MRI) scans taken at baseline and follow-up. MRI scans from 41 FD patients (mean age 43.9, age range 20-68, 3 females; n=25 on ERT, n=16 on placebo) were analyzed. WML burden was present in 63% of patients at baseline, increased over a mean of 27 months (range 12-33 months) follow-up, and correlated with left ventricular hypertrophy (LVPW). Patients with previous or recent strokes (n=11, 39-68 years) showed an increase in the number of WMLs (p=0.005). A greater proportion of younger patients (≤50 years) on ERT (n=18) had stable WML burden compared with younger patients in the placebo group (n=13): 44% (8 of 18) versus 31% (4 of 13), p=0.014. The number needed to treat was 8. This FD patient cohort, with mild-to-moderate renal involvement, had a significant WML burden and high inter

  11. Fabry disease in children: a federal screening programme in Russia.

    PubMed

    Namazova-Baranova, Leyla Seymurovna; Baranov, Alexander Alexandrovich; Pushkov, Aleksander Alekseevich; Savostyanov, Kirill Victorovich

    2017-10-01

    Our objective was to examine the prevalence of Fabry disease in Russian children with chronic pain in the distal limbs. This non-interventional, multi-centre study included children 2-18 years of age with chronic recurrent unilateral or bilateral pain, burning, or acroparesthesia in the hands or feet. The presence of Fabry disease was defined by abnormal alpha-galactosidase A activity in males or alpha-galactosidase gene (GLA) mutation in females. Among 214 patients (110 males), 84.1% had bilateral limb pain and 31.8% had unilateral limb pain recorded at some time point; 61 (28.5%) patients had a positive family history possibly associated with Fabry disease. Alpha-galactosidase A activity was within the normal range in all 109 of the male patients tested. One female patient had a GLA mutation (C937G > T) and alpha-galactosidase A activity within the normal range. We did not find definitive evidence of Fabry disease in these children with a history of chronic recurrent unilateral or bilateral limb pain or acroparesthesia. The presence of chronic limb pain does not appear to be highly predictive of a diagnosis of Fabry disease in Russian children and adolescents, suggesting that key early signs and symptoms of Fabry disease are not specific to the disease. What is Known: • Signs and symptoms of Fabry disease are seen in children < 10 years of age; pain in the distal limbs is a common early symptom. What is New: • Fabry disease was not diagnosed in this population of Russian children with a history of chronic limb pain. • The presence of acroparesthesia or chronic limb pain does not appear to be highly predictive of a diagnosis of Fabry disease in Russian children and adolescents, suggesting that these early symptoms of Fabry disease are not specific to the disease.

  12. Later Onset Fabry Disease, Cardiac Damage Progress in Silence: Experience With a Highly Prevalent Mutation.

    PubMed

    Hsu, Ting-Rong; Hung, Sheng-Che; Chang, Fu-Pang; Yu, Wen-Chung; Sung, Shih-Hsien; Hsu, Chia-Lin; Dzhagalov, Ivan; Yang, Chia-Feng; Chu, Tzu-Hung; Lee, Han-Jui; Lu, Yung-Hsiu; Chang, Sheng-Kai; Liao, Hsuan-Chieh; Lin, Hsiang-Yu; Liao, Tsan-Chieh; Lee, Pi-Chang; Li, Hsing-Yuan; Yang, An-Hang; Ho, Hui-Chen; Chiang, Chuan-Chi; Lin, Ching-Yuang; Desnick, Robert J; Niu, Dau-Ming

    2016-12-13

    Recently, several studies revealed a much higher prevalence of later onset Fabry disease (FD) than previously expected. It suggested that later onset FD might present as an important hidden health issue in certain ethnic or demographic populations in the world. However, the natural history of its phenotype has not been systemically investigated, especially the cardiac involvement. The study analyzed a large-scale newborn screening program for FD to understand the natural course of later onset FD. To date, 916,383 newborns have been screened for FD in Taiwan, including more than 1,200 individuals with the common, later onset IVS4+919G>A (IVS4) mutation. Echocardiography was performed in 620 adults with the IVS4 mutation to analyze the prevalence of left ventricular hypertrophy (LVH), and gadolinium-enhanced cardiac magnetic resonance imaging was performed in 129 patients with FD, including 100 IVS4 adults. LVH was observed in 67% of men and 32% of women older than 40 years. Imaging evidenced significant late gadolinium enhancement in 38.1% of IVS4 men and 16.7% of IVS4 women with the IVS4 mutation but without LVH. Seventeen patients underwent endomyocardial biopsies, which revealed significant globotriaosylceramide substrate accumulation in their cardiomyocytes. Significant cardiomyocyte substrate accumulation in IVS4 patients led to severe and irreversible cardiac fibrosis before development of LVH or other significant cardiac manifestations. Thus, it might be too late to start enzyme replacement therapy after the occurrence of LVH or other significant cardiac manifestations in patients with later onset FD. This study also indicated the importance of newborn screening for early detection of the insidious, ongoing, irreversible cardiac damage in patients with later onset FD. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  13. Increased resting cerebral blood flow in adult Fabry disease: MRI arterial spin labeling study.

    PubMed

    Phyu, Po; Merwick, Aine; Davagnanam, Indran; Bolsover, Fay; Jichi, Fatima; Wheeler-Kingshott, Claudia; Golay, Xavier; Hughes, Deralynn; Cipolotti, Lisa; Murphy, Elaine; Lachmann, Robin H; Werring, David John

    2018-04-17

    To assess resting cerebral blood flow (CBF) in the whole-brain and cerebral white matter (WM) and gray matter (GM) of adults with Fabry disease (FD), using arterial spin labeling (ASL) MRI, and to investigate CBF correlations with WM hyperintensity (WMH) volume and the circulating biomarker lyso-Gb3. This cross-sectional, case-control study included 25 patients with genetically confirmed FD and 18 age-matched healthy controls. We quantified resting CBF using Quantitative Signal Targeting With Alternating Radiofrequency Labeling of Arterial Regions (QUASAR) ASL MRI. We measured WMH volume using semiautomated software. We measured CBF in regions of interest in whole-brain, WM, and deep GM, and assessed correlations with WMH volume and plasma lyso-Gb3. The mean age (% male) for FD and healthy controls was 42.2 years (44%) and 37.1 years (50%). Mean whole-brain CBF was 27.56 mL/100 mL/min (95% confidence interval [CI] 23.78-31.34) for FD vs 22.39 mL/100 mL/min (95% CI 20.08-24.70) for healthy controls, p = 0.03. In WM, CBF was higher in FD (22.42 mL/100 mL/min [95% CI 17.72-27.12] vs 16.25 mL/100 mL/min [95% CI 14.03-18.48], p = 0.05). In deep GM, CBF was similar between groups (40.41 mL/100 mL/min [95% CI 36.85-43.97] for FD vs 37.46 mL/100 mL/min [95% CI 32.57-42.35], p = 0.38). In patients with FD with WMH (n = 20), whole-brain CBF correlated with WMH volume ( r = 0.59, p = 0.006), not with plasma lyso-Gb3. In FD, resting CBF is increased in WM but not deep GM. In FD, CBF correlates with WMH, suggesting that cerebral perfusion changes might contribute to, or result from, WM injury. © 2018 American Academy of Neurology.

  14. Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes.

    PubMed

    Adalsteinsdottir, Berglind; Palsson, Runolfur; Desnick, Robert J; Gardarsdottir, Marianna; Teekakirikul, Polakit; Maron, Martin; Appelbaum, Evan; Neisius, Ulf; Maron, Barry J; Burke, Michael A; Chen, Brenden; Pagant, Silvere; Madsen, Christoffer V; Danielsen, Ragnar; Arngrimsson, Reynir; Feldt-Rasmussen, Ulla; Seidman, Jonathan G; Seidman, Christine E; Gunnarsson, Gunnar Th

    2017-08-01

    The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA (α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities. © 2017 American Heart Association, Inc.

  15. Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study

    PubMed Central

    Wanner, Christoph; Hughes, Derralynn; Mehta, Atul; Oder, Daniel; Watkinson, Oliver T.; Elliott, Perry M.; Linthorst, Gabor E.; Wijburg, Frits A.; Biegstraaten, Marieke; Hollak, Carla E.

    2017-01-01

    Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean age 43 years old; 41% men; 57% with the classical phenotype) from three international centers of excellence. We classified patients by phenotype on the basis of characteristic symptoms and enzyme activity. Men and women with classical Fabry disease had higher event rate than did those with nonclassical disease (hazard ratio for men, 5.63, 95% confidence interval, 3.17 to 10.00; P<0.001; hazard ratio for women, 2.88, 95% confidence interval, 1.54 to 5.40; P<0.001). Furthermore, men with classical Fabry disease had lower eGFR, higher left ventricular mass, and higher plasma globotriaosylsphingosine concentrations than men with nonclassical Fabry disease or women with either phenotype (P<0.001). In conclusion, before treatment with enzyme replacement therapy, men with classical Fabry disease had a history of more events than men with nonclassical disease or women with either phenotype; women with classical Fabry disease were more likely to develop complications than women with nonclassical disease. These data may support the development of new guidelines for the monitoring and treatment of Fabry disease and studies on the effects of intervention in subgroups of patients. PMID:27979989

  16. Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease

    PubMed Central

    Karl, Franziska; Sommer, Claudia; Üçeyler, Nurcan

    2017-01-01

    Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A (α-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with α-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (≥ 18 months) mice were tested in the naïve state and after i.pl. injection of complete Freund`s adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety-like behavior in naïve young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and naïve young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors. PMID:28662189

  17. Efficacy and safety of enzyme-replacement-therapy with agalsidase alfa in 36 treatment-naïve Fabry disease patients.

    PubMed

    Tsuboi, Kazuya; Yamamoto, Hiroshi

    2017-06-07

    Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from the α-galactosidase A gene mutations. Enzyme-replacement-therapy (ERT) products for FD currently used include agalsidase alfa and agalsidase beta. There are many reports on efficacy and safety of ERT. However, most of the previous studies are done as a retrospective medical records analysis. The Japan Fabry Research - 002 (JFR-002) was a prospective observational clinical study of 36 ERT-naïve FD patients (14 men and 22 women) at baseline (BL) and after initiation of ERT with agalsidase alfa 0.2 mg/kg every two weeks, a median period 62.5 months. The parameters measured included globotriaosylceramide (Gb3), globotriaosylsphingosine (Lyso-Gb3), left ventricular mass index (LVMI), brain natriuretic peptide (BNP), high-sensitivity troponin I (hs-Trop I), estimated glomerular filtration rate (eGFR), and anti-agalsidase alfa IgG antibody formation. All parameters remained steady during ERT treatment period. BNP levels in 14 patients whose BL levels were within the normal range (<19.5 pg/mL) remained within the same range, while 22 patients whose BL levels were abnormally high (≥19.5 pg/mL) gradually showed decreased levels after start of ERT. Gb3 and Lyso-Gb3 levels remarkably decreased after the initiation of ERT and remained low. The JFR-002 suggests that agalsidase alfa is effective in maintaining organ function in FD patients, and that the incidence of infusion reactions related to the treatment with agalsidase alfa is low, indicating the good tolerability to this ERT. The JFR-002 was retrospectively registered at Japan Medical Association Center for Clinical Trials (Registration number: JMA-IIA00291 ) on May 19th, 2017.

  18. Globotriaosylceramide induces lysosomal degradation of endothelial KCa3.1 in fabry disease.

    PubMed

    Choi, Shinkyu; Kim, Ji Aee; Na, Hye-Young; Cho, Sung-Eun; Park, Seonghee; Jung, Sung-Chul; Suh, Suk Hyo

    2014-01-01

    Globotriaosylceramide (Gb3) induces KCa3.1 downregulation in Fabry disease (FD). We investigated whether Gb3 induces KCa3.1 endocytosis and degradation. KCa3.1, especially plasma membrane-localized KCa3.1, was downregulated in both Gb3-treated mouse aortic endothelial cells (MAECs) and human umbilical vein endothelial cells. Gb3-induced KCa3.1 downregulation was prevented by lysosomal inhibitors but not by a proteosomal inhibitor. Endoplasmic reticulum stress-inducing agents did not induce KCa3.1 downregulation. Gb3 upregulated the protein levels of early endosome antigen 1 and lysosomal-associated membrane protein 2 in MAECs. Compared with MAECs from age-matched wild-type mice, those from aged α-galactosidase A (Gla)-knockout mice, an animal model of FD, showed downregulated KCa3.1 expression and upregulated early endosome antigen 1 and lysosomal-associated membrane protein 2 expression. In contrast, no significant difference was found in early endosome antigen 1 and lysosomal-associated membrane protein 2 expression between young Gla-knockout and wild-type MAECs. In aged Gla-knockout MAECs, clathrin was translocated close to the cell border and clathrin knockdown recovered KCa3.1 expression. Rab5, an effector of early endosome antigen 1, was upregulated, and Rab5 knockdown restored KCa3.1 expression, the current, and endothelium-dependent relaxation. -Gb3 accelerates the endocytosis and lysosomal degradation of endothelial KCa3.1 via a clathrin-dependent process, leading to endothelial dysfunction in FD.

  19. Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke

    PubMed Central

    Kilarski, Laura L.; Rutten-Jacobs, Loes C. A.; Bevan, Steve; Baker, Rob; Hassan, Ahamad; Hughes, Derralynn A.; Markus, Hugh S.

    2015-01-01

    Background and Purpose Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene, is the most common monogenic disorder causing lacunar stroke and cerebral small vessel disease (SVD). Fabry disease (FD) due to mutations in the GLA gene has been suggested as an underdiagnosed cause of stroke, and one feature is SVD. Previous studies reported varying prevalence of CADASIL and FD in stroke, likely due to varying subtypes studied; no studies have looked at a large cohort of younger onset SVD. We determined the prevalence in a well-defined, MRI-verified cohort of apparently sporadic patients with lacunar infarct. Methods Caucasian patients with lacunar infarction, aged ≤70 years (mean age 56.7 (SD8.6)), were recruited from 72 specialist stroke centres throughout the UK as part of the Young Lacunar Stroke DNA Resource. Patients with a previously confirmed monogenic cause of stroke were excluded. All MRI’s and clinical histories were reviewed centrally. Screening was performed for NOTCH3 and GLA mutations. Results Of 994 subjects five had pathogenic NOTCH3 mutations (R169C, R207C, R587C, C1222G and C323S) all resulting in loss or gain of a cysteine in the NOTCH3 protein. All five patients had confluent leukoaraiosis (Fazekas grade ≥2). CADASIL prevalence overall was 0.5% (95% CI 0.2%-1.1%) and among cases with confluent leukoaraiosis 1.5% (95% CI 0.6%-3.3%). No classic pathogenic FD mutations were found; one patient had a missense mutation (R118C), associated with late-onset FD. Conclusion CADASIL cases are rare and only detected in SVD patients with confluent leukoaraiosis. No definite FD cases were detected. PMID:26305465

  20. Disease Progression Modeling to Evaluate the Effects of Enzyme Replacement Therapy on Kidney Function in Adult Patients with the Classic Phenotype of Fabry Disease.

    PubMed

    Nowak, Albina; Koch, Gilbert; Huynh-Do, Uyen; Siegenthaler, Martin; Marti, Hans-Peter; Pfister, Marc

    2017-01-01

    Fabry disease (FD) is a rare inherited lysosomal storage disease with common and serious kidney complications. Enzyme replacement therapies (ERT) with agalsidase-α and -β were investigated to characterize their therapeutic effect on kidney function in FD patients with Classic phenotype. The prospective FD cohort consisted of 98 genetically confirmed patients (females, n = 61, males, n = 37). The median [interquartile range] follow-up time (time difference from first to last visit) was 9 [6, 12] years. The median age of ERT start was 36 [21 - 54] years for females and 39 [28 - 49] years for males. A disease progression model was developed to (i) characterize the time course of estimated glomerular filtration rate (eGFR) and (ii) evaluate therapeutic effects of ERT on kidney function. Change in eGFR over time was best described by the linear model. Females had stable kidney function with and without ERT (eGFR slopes of -0.07 ml/min/1.73m^2 per year and 0.52 ml/min/1.73m^2 per year, respectively). Males with ERT showed an eGFR decrease of -3.07 ml/min/1.73m^2 per year. Mathematical disease progression modeling indicates that there is no clear therapeutic effect of ERT on kidney function in adult patients with Classic Phenotype of FD. Interpretation of these findings should take into account that the study is not randomized and lacks a placebo controlled group. Further investigations are warranted to clarify whether earlier ERT initiation before 18 years of age, higher ERT dose or more intensive therapies can preserve kidney function. © 2017 The Author(s)Published by S. Karger AG, Basel.

  1. Treatment with agalsidase beta during pregnancy in Fabry disease.

    PubMed

    Politei, Juan M

    2010-04-01

    Fabry disease is an X-linked lysosomal storage disease caused by a deficiency of alpha-galactosidase A, which leads to excessive accumulation of glycosphingolipids in most tissues in the body, with life-threatening clinical consequences in the kidney, heart, and cerebrovascular system. Enzyme replacement therapy using exogenously produced alpha-galactosidase has been available for treatment of this multisystem progressive disease since 2001. Two different preparations of enzyme replacement therapy for Fabry disease are available outside of the USA: agalsidase alfa and agalsidase beta. Despite being X-linked, Fabry disease affects many female patients, and this report presents a successful pregnancy of a female patient receiving agalsidase beta.

  2. Pain management strategies for neuropathic pain in Fabry disease--a systematic review.

    PubMed

    Schuller, Y; Linthorst, G E; Hollak, C E M; Van Schaik, I N; Biegstraaten, M

    2016-02-24

    Neuropathic pain is one of the key features of (classical) Fabry disease (FD). No randomized clinical trials comparing effectiveness of different pain management strategies have been performed. This review aims to give an overview of existing pain management strategies. PubMed and Embase were searched up to September 2014 for relevant articles on treatment of neuropathic pain in FD. Seven-hundred-thirty-one articles were identified of which 26 were included in the analysis. Studies reported on 55 individuals in total, with group-sizes ranging from 1 to 8. Carbamazepine appeared most beneficial: complete pain relief in 5/25, partial relief in 17/25, and no benefit in 3/25 patients. Phenytoin resulted in complete relief in 1/27, partial relief in 12/27 and no benefit in 6/27 patients. In 8 patients a significant reduction in the frequency of pain attacks was described. Gabapentin caused partial relief in 6/7 and no relief in 1/7 patients. Little evidence was reported for SSNRI's or treatment combinations. Adverse-effects were reported in all treatment strategies. Only for carbamazepine, phenytoin and gabapentin there is evidence of effectiveness in neuropathic pain due to FD, but comparison of effectiveness between these drugs is lacking. In routine clinical practice adverse-effects may discourage use of carbamazepine and phenytoin in favor of second-generation antiepileptic drugs, but this is currently not supported by clinical evidence. This review suffers greatly from incomplete outcome reports and a predominance of case reports, which emphasizes the need for robust clinical trials and observational cohort studies.

  3. Serum Bilirubin Levels and Promoter Variations in HMOX1 and UGT1A1 Genes in Patients with Fabry Disease.

    PubMed

    Jirásková, Alena; Bortolussi, Giulia; Dostálová, Gabriela; Eremiášová, Lenka; Golaň, Lubor; Danzig, Vilém; Linhart, Aleš; Vítek, Libor

    2017-01-01

    The aim of our study was to assess the possible relationships among heme oxygenase (HMOX), bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variations, serum bilirubin levels, and Fabry disease (FD). The study included 56 patients with FD (M : F ratio = 0.65) and 185 healthy individuals. Complete standard laboratory and clinical work-up was performed on all subjects, together with the determination of total peroxyl radical-scavenging capacity. The (GT)n and (TA)n dinucleotide variations in the HMOX1 and UGT1A1 gene promoters, respectively, were determined by DNA fragment analysis. Compared to controls, patients with FD had substantially lower serum bilirubin levels (12.0 versus 8.85  μ mol/L, p = 0.003) and also total antioxidant capacity ( p < 0.05), which showed a close positive relationship with serum bilirubin levels ( p = 0.067) and the use of enzyme replacement therapy ( p = 0.036). There was no association between HMOX1 gene promoter polymorphism and manifestation of FD. However, the presence of the TA 7 allele UGT1A1 gene promoter, responsible for higher systemic bilirubin levels, was associated with a twofold lower risk of manifestation of FD (OR = 0.51, 95% CI = 0.27-0.97, p = 0.038). Markedly lower serum bilirubin levels in FD patients seem to be due to bilirubin consumption during increased oxidative stress, although UGT1A1 promoter gene polymorphism may modify the manifestation of FD as well.

  4. E-Learning for Rare Diseases: An Example Using Fabry Disease.

    PubMed

    Cimmaruta, Chiara; Liguori, Ludovica; Monticelli, Maria; Andreotti, Giuseppina; Citro, Valentina

    2017-09-24

    Rare diseases represent a challenge for physicians because patients are rarely seen, and they can manifest with symptoms similar to those of common diseases. In this work, genetic confirmation of diagnosis is derived from DNA sequencing. We present a tutorial for the molecular analysis of a rare disease using Fabry disease as an example. An exonic sequence derived from a hypothetical male patient was matched against human reference data using a genome browser. The missense mutation was identified by running BlastX, and information on the affected protein was retrieved from the database UniProt. The pathogenic nature of the mutation was assessed with PolyPhen-2. Disease-specific databases were used to assess whether the missense mutation led to a severe phenotype, and whether pharmacological therapy was an option. An inexpensive bioinformatics approach is presented to get the reader acquainted with the diagnosis of Fabry disease. The reader is introduced to the field of pharmacological chaperones, a therapeutic approach that can be applied only to certain Fabry genotypes. The principle underlying the analysis of exome sequencing can be explained in simple terms using web applications and databases which facilitate diagnosis and therapeutic choices.

  5. Coexistence of Fabry disease and IgA nephropathy: a report of two cases.

    PubMed

    Yin, G; Wu, Y; Zeng, C-H; Chen, H-P; Liu, Z-H

    2014-12-01

    Coexistence of Fabry disease and IgA nephropathy is rare. Moreover, the coexisting Fabry disease may be unrecognized due to unapparent clinical manifestations. We described two cases with coexisting Fabry disease and IgA nephropathy. The clinicopathological features of these two patients were studied. A 54-year-old male presented with proteinuria, hematuria, and hypertension, and a 33-year-old male presented with proteinuria without clinical signs or family history of Fabry disease. Both of them were diagnosed with IgA nephropathy at admission, whereas Fabry disease was not suspected. Subsequent immunofluorescent study confirmed the diagnosis of IgA nephropathy by showing positive staining for IgA and complement C3 in the mesangium. Meanwhile, light microscopy showed remarkable vacuolation of podocytes with mild mesangial expansion, which was characteristic of Fabry nephropathy. Further examination of toluidine blue-stained semi-thin sections and electron microscopy demonstrated blue bodies and myelin figures in the cytoplasm of podocytes, respectively. The diagnosis of coexisting Fabry disease was finally established based on deficient α-galactosidase A activity in both patients. This case study is an important reminder of the role of kidney biopsy as an indicator of Fabry disease and its rare coexistence with IgA nephropathy.

  6. Specific storage of glycoconjugates with terminal α-galactosyl moieties in the exocrine pancreas of Fabry disease patients with blood group B.

    PubMed

    Rybová, Jitka; Kuchar, Ladislav; Hulková, Helena; Asfaw, Befekadu; Dobrovolný, Robert; Sikora, Jakub; Havlícek, Vladimír; Škultéty, Ludovít; Ledvinová, Jana

    2018-06-01

    Blood group B glycosphingolipids (B-GSLs) are substrates of the lysosomal alpha-galactosidase A (AGAL). Similar to its major substrate-globotriaosylceramide (Gb3Cer)-B-GSLs are not degraded and accumulate in the cells of patients affected by an inherited defect of AGAL activity (Fabry disease-FD).The pancreas is a secretory organ known to have high biosynthesis of blood group GSLs. Herein, we provide a comprehensive overview of the biochemical and structural abnormalities in pancreatic tissue from two male FD patients with blood group B. In both patients, we found major accumulation of a variety of complex B-GSLs carrying predominantly hexa- and hepta-saccharide structures. The subcellular pathology was dominated by deposits containing B-glycoconjugates and autofluorescent ceroid. The contribution of Gb3Cer to the storage was minor. This abnormal storage pattern was specific for the pancreatic acinar epithelial cells. Other pancreatic cell types including those of islets of Langerhans were affected much less or not at all.Altogether, we provide evidence for a key role of B-antigens in the biochemical and morphological pathology of the exocrine pancreas in FD patients with blood group B. We believe that our findings will trigger further studies aimed at assessing the potential pancreatic dysfunction in this disease.

  7. Fibrosis: a key feature of Fabry disease with potential therapeutic implications

    PubMed Central

    2013-01-01

    Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease. PMID:23915644

  8. Fabry disease in children: agalsidase-beta enzyme replacement therapy.

    PubMed

    Borgwardt, L; Feldt-Rasmussen, U; Rasmussen, A K; Ballegaard, M; Meldgaard Lund, A

    2013-05-01

    Fabry disease is a rare, multiorgan disease. The most serious complications involve the kidney, brain and heart. This study aims to assess the effect of enzyme replacement therapy (ERT) using agalsidase-beta in children with Fabry disease. We carried out a nationwide, descriptive and observational retrospective cohort study of 10 children (9-16 years at baseline), who underwent regular systematic investigations for 1-8 years after initiation of ERT with agalsidase-beta (Fabryzyme®, Genzyme). Ophthalmological, echocardiographic abnormalities and hypohidrosis were found at baseline and during the follow-up period. Serious kidney, heart or brain involvement had not developed at the last follow-up examination. For the majority of the patients improvements were found concerning headache, acroparaesthesias and gastrointestinal pain during the follow-up period. The level of energy and physical activity also increased. Treatment with agalsidase-beta was associated with a reduction of neuropathic and abdominal pain and headache. Although all aspects of the Fabry pain phenotype cannot be treated with ERT, the observed effects were clinically significant in the lives of the majority of Fabry children and together with the absence of serious Fabry manifestations at last follow-up, we argue that early initiation of ERT may be considered. © 2012 John Wiley & Sons A/S.

  9. Delayed-enhanced cardiac MRI for differentiation of Fabry's disease from symmetric hypertrophic cardiomyopathy.

    PubMed

    De Cobelli, Francesco; Esposito, Antonio; Belloni, Elena; Pieroni, Maurizio; Perseghin, Gianluca; Chimenti, Cristina; Frustaci, Andrea; Del Maschio, Alessandro

    2009-03-01

    Fabry's disease may be difficult to differentiate from symmetric hypertrophic cardiomyopathy. Our aim was to compare the myocardial location and distribution patterns of delayed enhancement between patients with Fabry's disease who are affected by symmetric myocardial hypertrophy and patients with symmetric hypertrophic cardiomyopathy in order to identify a specific sign to best differentiate the two diseases. Patients with Fabry's disease-related hypertrophy showed left ventricular (LV) delayed enhancement with a typical and consistently found pattern characterized by the involvement of the inferolateral basal or mid basal segments and a mesocardial distribution that spared the subendocardium. This pattern seems to be specific to Fabry's disease; in fact, patients with symmetric hypertrophic cardiomyopathy had variable locations and distributions of delayed enhancement. These observations may contribute to identifying Fabry's disease as a specific cause of symmetric hypertrophy.

  10. Variations in plasma and urinary lipids in response to enzyme replacement therapy for Fabry disease patients by nanoflow UPLC-ESI-MS/MS.

    PubMed

    Byeon, Seul Kee; Kim, Jin Yong; Lee, Jin-Sung; Moon, Myeong Hee

    2016-03-01

    A deficiency of α-galactosidase A causes Fabry disease (FD) by disrupting lipid metabolism, especially trihexosylceramide (THC). Enzyme replacement therapy (ERT) is clinically offered to FD patients in an attempt to lower the accumulated lipids. Studies on specific types of lipids that are directly or indirectly altered by FD are very scarce, even though they are crucial in understanding the biological process linked to the pathogenesis of FD. We performed a comprehensive lipid profiling of plasma and urinary lipids from FD patients with nanoflow liquid chromatography electrospray-ionization tandem mass spectrometry (nLC-ESI-MS/MS) and identified 129 plasma and 111 urinary lipids. Among these, lipids that exhibited alternations (>twofold) in patients were selected as targets for selected reaction monitoring (SRM)-based high-speed quantitation using nanoflow ultra-performance LC-ESI-MS/MS (nUPLC-ESI-MS/MS) and 31 plasma and 26 urinary lipids showed significant elevation among FD patients. Higher percentages of sphingolipids (SLs; 48% for plasma and 42% for urine) were highly elevated in patients; whereas, a smaller percentage of phospholipids (PLs; 15% for plasma and 13% for urine) were significantly affected. Even though α-galactosidase A is reported to affect THC only, the results show that other classes of lipids (especially SLs) are changed as well, indicating that FD not only alters metabolism of THC but various classes of lipids too. Most lipids showing significant increases in relative amounts before ERT decreased after ERT, but overall, ERT influenced plasma lipids more than urinary lipids.

  11. Increased Arterial Diameters in the Posterior Cerebral Circulation in Men with Fabry Disease

    PubMed Central

    Üçeyler, Nurcan; Homola, György A.; Guerrero González, Hans; Kramer, Daniela; Wanner, Christoph; Weidemann, Frank; Solymosi, László; Sommer, Claudia

    2014-01-01

    A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males – females; normal – impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13%) and 5/57 (9%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87%, specificity: 86%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity. PMID:24475221

  12. Hemizygous Fabry disease associated with membranous nephropathy: A rare case report
.

    PubMed

    Zhou, Wenyan; Ni, Zhaohui; Zhang, Minfang

    2018-05-24

    Fabry disease may coexist with various glomerular diseases, including IgA nephropathy, focal segmental glomerulosclerosis, etc. In this study, we report a rare case of Fabry disease associated with membranous nephropathy (MN). A 30-year-old man with nephrotic proteinuria, normal renal function, and no other extrarenal manifestations underwent a renal biopsy in February 2017. Light microscopy and immunofluorescence indicated MN (stage 1). Under an electron microscope, there were subepithelial electron-dense deposits and abundant zebra bodies in podocytes. Both the findings of low-activity α-galactosidase A (α-Gal A, GLA) and base deletion in exon 7 of the GLA gene (GLA-E07.1286_*7 del, a newly reported mutation) confirmed that this patient was simultaneously afflicted with Fabry disease. This case report is an important reminder of the role of kidney biopsy, especially electron microscopy, as an indicator of Fabry disease and its rare coexistence with MN.
.

  13. Musculoskeletal manifestations of Fabry disease: A retrospective study.

    PubMed

    Lidove, Olivier; Zeller, Valérie; Chicheportiche, Valérie; Meyssonnier, Vanina; Sené, Thomas; Godot, Sophie; Ziza, Jean-Marc

    2016-07-01

    Fabry disease is a rare X-linked metabolic disorder characterized by a deficiency in the enzyme alpha-galactosidase A. Both males and females can be affected. The main presenting symptom is pain in the extremities, whereas at a more advanced stage, the manifestations include hypertrophic cardiomyopathy, cardiac dysrhythmia, proteinuria, chronic kidney dysfunction, stroke, and hearing loss. When not diagnosed and treated, Fabry disease causes early death. No studies specifically designed to describe the musculoskeletal manifestations of Fabry disease are available. We conducted a single-center retrospective study of patients receiving follow-up at a Fabry disease referral center. We described the musculoskeletal manifestations and analyzed the differential diagnoses. Our study included 40 patients belonging to 20 families, including 25 females with a mean age of 44.2 years (range, 20-76 years) and 15 males with a mean age of 40.1 years (range, 16-61 years). Mean age at the diagnosis of Fabry disease was 37.2 years (range, 7-71 years) in the females and 26.9 years (range, 9-51 years) in the males. Specific enzyme replacement therapy was given to 10 (40%) females and 12 (80%) males. Musculoskeletal manifestations were as follows: past or present pain in the extremities (13 females and 10 males), combined in some patients with vasomotor disorders in the extremities and telangiectasia; exercise intolerance (12 females and 12 males); osteoporotic fractures (2 brothers aged 45 and 44 years, respectively); osteoporosis (3 females, aged 57, 63, and 75 years, respectively), which contributed to death in the oldest patient; osteopenia (2 females aged 38 and 47 years, respectively; and 1 male aged 43 years); Charcot foot and lymphedema with serious infectious complications (4 males older than 40 years), with avascular osteonecrosis of the lower limbs in 2 cases; toe amputations (3 cases); bilateral lower-limb amputation (1 case); abnormally slender lower limbs (5 females and

  14. Inner ear involvement in Fabry disease: Clinical and audiometric evaluation of a large cohort of patients followed in a reference centre.

    PubMed

    Rodrigues, Jorge; Azevedo, Olga; Sousa, Nuno; Cunha, Damião; Mexedo, Alexandre; Fonseca, Rui

    2018-06-01

    Fabry disease (FD) is a lysosomal storage disorder (LSD) that involves the cochleovestibular system. Tinnitus and progressive sensorineural hearing loss are frequent complains. A stabilization of hearing function has been reported with enzyme replacement therapy (ERT). This study aims to characterize the inner ear involvement, identify factors associated to hearing loss and evaluate the effect of ERT on the hearing function of FD patients. We reviewed the clinical records of patients with confirmed diagnosis of FD followed in a Reference Centre on LSD in the North of Portugal. We included a total of 122 patients with a mean age of 47.1 ± 17.6 years and 48.3% males. Hearing loss was reported by 26.2% of the patients and 23.0% mentioned tinnitus. Pure tone audiometry revealed sensorineural hearing loss in 36.9% of the cases. FD patients presented worse age-adjusted hearing thresholds in all analysed frequencies compared to the normal population (p = .001). Patients with hearing loss presented a significantly higher value of microalbuminuria (p = .001) and a higher frequency of acroparesthesias (p = .032). Patients presented a comparable hearing level one year after starting ERT (p = .384). In FD, hearing loss is common and age-matched hearing thresholds by frequency are worse than in the general population. Hearing loss was associated to the presence of acroparesthesias and higher values of microalbuminuria. Hearing loss stabilized in patients under ERT. A careful cochleo-vestibular evaluation should be part of the clinical assessment of FD. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  15. Enzyme replacement therapy of Fabry disease.

    PubMed

    Clarke, Joe T R; Iwanochko, R Mark

    2005-08-01

    Fabry disease is an X-linked lysosomal storage disease caused by deficiency of the enzyme alpha-galactosidase A and results in pain, progressive renal impairment, cardiomyopathy, and cerebrovascular disease. The results of two major randomized, double-blind, placebo-controlled clinical trials and open-label extensions have shown that replacement of the deficient enzyme with either of two preparations of recombinant human alpha-galactosidase A, agalsidase-alfa, and agalsidase-beta is safe. Biweekly i.v. infusions of 0.2 mg/kg of agalsidase-alfa were associated with a significant decrease in pain and stabilization of renal function. Biweekly infusions of 1 mg/kg of agalsidase-beta were associated with virtually complete clearing of accumulated glycolipid substrate from renal and cutaneous capillary endothelial cells. Several smaller, open-label studies, along with observations made in the course of monitoring large numbers of patients on enzyme replacement therapy, indicated that treatment stabilizes renal function and produces significant improvements in myocardial mass and function. Treatment of Fabry disease by enzyme replacement has a significant impact on at least some serious complications of the disease.

  16. Galactosidase Alpha p.A143T Variant Fabry Disease May Result in a Phenotype With Multifocal Microvascular Cerebral Involvement at a Young Age.

    PubMed

    Hauth, Lothar; Kerstens, Jeroen; Yperzeele, Laetitia; Eyskens, François; Parizel, Paul M; Willekens, Barbara

    2018-01-01

    A 16-year-old male presented with episodic headaches and a brain magnetic resonance imaging (MRI) that showed multifocal punctate to patchy white matter lesions. The diagnosis of Fabry disease (FD) was suggested upon the finding of significantly reduced plasma alpha-galactosidase A activity (0.62 µmol/L or 13% of normal; normal range ≥ 1.65 μmol/L) and genetic investigation confirmed the presence of a hemizygous missense variant in the galactosidase alpha (GLA) gene (p.A143T). Baseline assessment of other systemic involvement showed only a discrete proteinuria. FD is a rare lysosomal storage disorder. Genetic screening studies have revealed over 600 variants in the GLA gene. The p.A143T variant is a genetic variant of unknown significance, with its associated phenotype ranging from classical FD to healthy unaffected patients. Some authors, however, deem this variant non-pathogenic. We describe the case of a 16-year-old male with multifocal white matter lesions on brain MRI, who was diagnosed with FD and carried this genetic variant. The causative p.A143T mutation can be associated with a more severe subclinical phenotype than has been reported to date. Furthermore, a diagnosis of FD should be considered when finding asymptomatic cerebral white matter lesions in a young patient.

  17. Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study

    PubMed Central

    Biegstraaten, Marieke; Wanner, Christoph; Sirrs, Sandra; Mehta, Atul; Elliott, Perry M; Oder, Daniel; Watkinson, Oliver T; Bichet, Daniel G; Khan, Aneal; Iwanochko, Mark; Vaz, Frédéric M; van Kuilenburg, André B P; West, Michael L; Hughes, Derralynn A; Hollak, Carla E M

    2018-01-01

    Background Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. Methods In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex. Results 387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (β: −18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar. Conclusions Treatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta. PMID:29437868

  18. Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study.

    PubMed

    Arends, Maarten; Biegstraaten, Marieke; Wanner, Christoph; Sirrs, Sandra; Mehta, Atul; Elliott, Perry M; Oder, Daniel; Watkinson, Oliver T; Bichet, Daniel G; Khan, Aneal; Iwanochko, Mark; Vaz, Frédéric M; van Kuilenburg, André B P; West, Michael L; Hughes, Derralynn A; Hollak, Carla E M

    2018-05-01

    Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex. 387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (β: -18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar. Treatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. Screening Fabry's disease in chronic kidney disease patients not on dialysis: a multicenter study.

    PubMed

    Yeniçerioğlu, Yavuz; Akdam, Hakan; Dursun, Belda; Alp, Alper; Sağlam Eyiler, Funda; Akın, Davut; Gün, Yelda; Hüddam, Bülent; Batmazoğlu, Mehmet; Gibyeli Genek, Dilek; Pirinççi, Serhat; Ersoy, İsmail Rıfkı; Üzüm, Atilla; Soypaçacı, Zeki; Tanrısev, Mehmet; Çolak, Hülya; Demiral Sezer, Sibel; Bozkurt, Gökay; Akyıldız, Utku Oğan; Akyüz Ünsal, Ayşe İpek; Ünübol, Mustafa; Uslu, Meltem; Eryılmaz, Ufuk; Günel, Ceren; Meteoğlu, İbrahim; Yavaşoğlu, İrfan; Ünsal, Alparslan; Akar, Harun; Okyay, Pınar

    2017-11-01

    Fabry's disease is an X-linked inherited, rare, progressive, lysosomal storage disorder, affecting multiple organs due to the deficient activity of α-galactosidase A (α-Gal A) enzyme. The prevalence has been reported to be 0.15-1% in hemodialysis patients; however, the information on the prevalence in chronic kidney disease not on dialysis is lacking. This study aimed to determine the prevalence of Fabry's disease in chronic kidney disease. The patients older than 18 years, enclosing KDIGO 2012 chronic kidney disease definitions, not on dialysis, were enrolled. Dried blood spots on Guthrie papers were used to analyze α-Gal A enzyme and genetic analysis was performed in individuals with enzyme activity ≤1.2 μmol/L/h. A total of 1453 chronic kidney disease patients not on dialysis from seven clinics in Turkey were screened. The mean age of the study population was 59.3 ± 15.9 years. 45.6% of patients were female. The creatinine clearance of 77.3% of patients was below 60 mL/min/1.73 m 2 , 8.4% had proteinuria, and 2.5% had isolated microscopic hematuria. The mean value of patients' α-Gal A enzyme was detected as 2.93 ± 1.92 μmol/L/h. 152 patients had low levels of α-Gal A enzyme activity (≤1.2 μmol/L/h). In mutation analysis, A143T and D313Y variants were disclosed in three male patients. The prevalence of Fabry's disease in chronic kidney disease not on dialysis was found to be 0.2% (0.4% in male, 0.0% in female). Fabry's disease should be considered in the differential diagnosis of chronic kidney disease with unknown etiology even in the absence of symptoms and signs suggestive of Fabry's disease.

  20. Quantitative comparison of 2D and 3D late gadolinium enhancement MR imaging in patients with Fabry disease and hypertrophic cardiomyopathy.

    PubMed

    Morsbach, F; Gordic, S; Gruner, C; Niemann, M; Goetti, R; Gotschy, A; Kozerke, S; Alkadhi, H; Manka, R

    2016-08-15

    This study aims to determine whether the quantification of myocardial fibrosis in patients with Fabry disease (FD) and hypertrophic cardiomyopathy (HCM) using a late gadolinium enhancement (LGE) singlebreath-hold three-dimensional (3D) inversion recovery magnetic resonance (MR) imaging sequence is comparable with a clinically established two-dimensional (2D) multi-breath-hold sequence. In this retrospective, IRB-approved study, 40 consecutive patients (18 male; mean age 50±17years) with Fabry disease (n=18) and HCM (n=22) underwent MR imaging at 1.5T. Spatial resolution was the same for 3D and 2D images (field-of-view, 350×350mm(2); in-plane-resolution, 1.2×1.2mm(2); section-thickness, 8mm). Datasets were analyzed for subjective image quality; myocardial and fibrotic mass, and total fibrotic tissue percentage were quantified. There was no significant difference in subjective image quality between 3D and 2D acquisitions (P=0.1 and P=0.3) for either disease. In patients with Fabry disease there were no significant differences between 3D and 2D acquisitions for myocardial mass (P=0.55), fibrous tissue mass (P=0.89), and total fibrous percentage (P=0.67), with good agreement between acquisitions according to Bland-Altman analyses. In patients with HCM there were also no significant differences between acquisitions for myocardial mass (P=0.48), fibrous tissue mass (P=0.56), and total fibrous percentage (P=0.67), with good agreement according to Bland-Altman analyses. Acquisition time was significantly shorter for 3D (25±5s) as compared to the 2D sequence (349±62s, P<0.001). In patients with Fabry disease and HCM, 3D LGE imaging provides equivalent diagnostic information in regard to quantification of myocardial fibrosis as compared with a standard 2D sequence, but at superior acquisition speed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Agalsidase Beta: a review of its use in the management of Fabry disease.

    PubMed

    Keating, Gillian M; Simpson, Dene

    2007-01-01

    Agalsidase beta (Fabrazyme) is a recombinant human alpha-galactosidase A enzyme approved for intravenous use in the treatment of Fabry disease. Fabry disease is a progressive, multisystemic, potentially life threatening disorder caused by a deficiency of alpha-galactosidase A. This deficiency results in accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3), in the lysosomes of various tissues. This accumulation is the underlying driver of disease progression. Agalsidase beta provides an exogenous source of alpha-galactosidase A.Intravenous agalsidase beta is effective and well tolerated in patients with Fabry disease. In a phase III trial, agalsidase beta was shown to clear GL-3 from various target cells and, in a subsequent extension of this trial, prevent GL-3 reaccumulation. In a post-approval trial, agalsidase beta was shown to provide significant clinical benefit by reducing the risk of a major clinical event. Thus, agalsidase beta represents an important advance in the treatment of Fabry disease, and agalsidase beta therapy should be strongly considered in patients with Fabry disease who are suitable candidates.

  2. Anderson-Fabry disease in heart failure.

    PubMed

    Akhtar, M M; Elliott, P M

    2018-06-16

    Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene that result in deficiency of the enzyme alpha-galactosidase A. The worldwide incidence of Fabry's disease is reported to be in the range of 1 in 40,000-117,000, although this value may be a significant underestimate given under recognition of symptoms and delayed or missed diagnosis. Deficiency in alpha-galactosidase A causes an accumulation of neutral glycosphingolipids such as globotriaosylceramide (Gb3) in lysosomes within various tissues including the vascular endothelium, kidneys, heart, eyes, skin and nervous system. Gb3 accumulation induces pathology via the release of pro-inflammatory cytokines, growth-promoting factors and by oxidative stress, resulting in myocardial extracellular matrix remodelling, left ventricular hypertrophy (LVH), vascular dysfunction and interstitial fibrosis. Cardiac involvement manifesting as ventricular hypertrophy, systolic and diastolic dysfunction, valvular abnormalities and conduction tissue disease is common in AFD and is associated with considerable cardiovascular morbidity and mortality from heart failure, sudden cardiac death and stroke-related death.

  3. Genital angiokeratoma in a woman with Fabry disease: the dermatologist's role.

    PubMed

    Jesus, Patricia Moraes Resende de; Martins, Ana Maria; Chiacchio, Nilton Di; Aranda, Carolina Sanchez

    2018-06-01

    Fabry disease is a rare lysosomal storage disorder, inherited in an X-linked manner. It is characterized by the deficiency of the enzyme alpha-galactosidase, leading to a buildup of glycosphingolipids in the cells. Angiokeratoma is one of the cutaneous manifestations of this condition, and it helps making the diagnosis. The typical site involves the genital area in men and lumbosacral, buttocks and trunk region in both sexes. We report a case of genital angiokeratoma in a woman with Fabry disease. The diagnosis is through molecular analysis and, when made early, starting treatment reduces the morbidity and mortality of the disease. Thus, the dermatologist has an important role in the identification of angiokeratoma as a cutaneous marker, and the knowledge of its different presentations is essential for the early diagnosis and management of Fabry disease.

  4. Nicotiana benthamiana α-galactosidase A1.1 can functionally complement human α-galactosidase A deficiency associated with Fabry disease.

    PubMed

    Kytidou, Kassiani; Beekwilder, Jules; Artola, Marta; van Meel, Eline; Wilbers, Ruud H P; Moolenaar, Geri F; Goosen, Nora; Ferraz, Maria J; Katzy, Rebecca; Voskamp, Patrick; Florea, Bogdan I; Hokke, Cornelis H; Overkleeft, Herman S; Schots, Arjen; Bosch, Dirk; Pannu, Navraj; Aerts, Johannes M F G

    2018-04-19

    α-Galactosidases (EC 3.2.1.22) are retaining glycosidases that cleave terminal α-linked galactose residues from glycoconjugate substrates. α-Galactosidases take part in the turnover of cell wall-associated galactomannans in plants and in the lysosomal degradation of glycosphingolipids in animals. Deficiency of human α-galactosidase A (α-Gal A) causes Fabry disease (FD), a heritable, X-linked lysosomal storage disorder, characterized by accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3). Current management of FD involves enzyme-replacement therapy (ERT). An activity-based probe (ABP) covalently labeling the catalytic nucleophile of α-Gal A has been previously designed to study α-galactosidases for use in FD therapy. Here, we report that this ABP labels proteins in Nicotiana benthamiana leaf extracts, enabling the identification and biochemical characterization of an N. benthamiana α-galactosidase we name here A1.1 (gene accession GJZM-1660). The transiently overexpressed and purified enzyme was a monomer lacking N-glycans and was active toward 4-methylumbelliferyl-α-D-galactopyranoside substrate (Km = 0.17 mM) over a broad pH range. A1.1 structural analysis by X-ray crystallography revealed marked similarities with human α-Gal A, even including A1.1's ability to hydrolyze Gb3 and lysoGb3, which are not endogenous in plants. Of note, A1.1 uptake into FD fibroblasts reduced the elevated lysoGb3 levels in these cells, consistent with A1.1 delivery to lysosomes as revealed by confocal microscopy. The ease of production and the features of A1.1, such as stability over a broad pH range, combined with its capacity to degrade glycosphingolipid substrates, warrant further examination of its value as a potential therapeutic agent for ERT-based FD management. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

  5. The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies

    PubMed Central

    Ferreira, Susana; Ortiz, Alberto; Germain, Dominique P.; Viana-Baptista, Miguel; Gomes, António Caldeira; Camprecios, Marta; Fenollar-Cortés, Maria; Gallegos-Villalobos, Ángel; Garcia, Diego; García-Robles, José Antonio; Egido, Jesús; Gutiérrez-Rivas, Eduardo; Herrero, José Antonio; Mas, Sebastián; Oancea, Raluca; Péres, Paloma; Salazar-Martín, Luis Manuel; Solera-Garcia, Jesús; Alves, Helena; Garman, Scott C.; Oliveira, João Paulo

    2015-01-01

    Summary Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis caused by pathogenic mutations affecting the GLA gene. The early-onset, multi-systemic FD classical phenotype is associated with absent or severe enzyme deficiency, as measured by in vitro assays, but patients with higher levels of residual α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue – GLA p.(Arg118Cys) –, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-Gal activity in vitro, it has been classified as a pathogenic mutation, mainly on the basis of theoretical arguments about the chemistry of the cysteine residue. However its pathogenicity has never been convincingly demonstrated by pathology criteria. We reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the Cys118 allele, including 3 homozygous females. Cases were identified either on the differential diagnosis of possible FD manifestations and on case-finding studies (n=11; 4 males), or on unbiased cascade screening of probands’ close relatives (n=11; 3 males). Overall, those data strongly suggest that the GLA p.(Arg118Cys) variant does not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease, since the allelic frequency in stroke patients was 0.0087 (p=0.0185 vs the general population). The Cys118 allelic frequency in healthy Portuguese adults (n=696) has been estimated as 0.001, therefore not qualifying for “rare” condition. PMID:25468652

  6. The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies.

    PubMed

    Ferreira, Susana; Ortiz, Alberto; Germain, Dominique P; Viana-Baptista, Miguel; Caldeira-Gomes, António; Camprecios, Marta; Fenollar-Cortés, Maria; Gallegos-Villalobos, Ángel; Garcia, Diego; García-Robles, José Antonio; Egido, Jesús; Gutiérrez-Rivas, Eduardo; Herrero, José Antonio; Mas, Sebastián; Oancea, Raluca; Péres, Paloma; Salazar-Martín, Luis Manuel; Solera-Garcia, Jesús; Alves, Helena; Garman, Scott C; Oliveira, João Paulo

    2015-02-01

    Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis caused by pathogenic mutations affecting the GLA gene. The early-onset, multi-systemic FD classical phenotype is associated with absent or severe enzyme deficiency, as measured by in vitro assays, but patients with higher levels of residual α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue - GLA p.(Arg118Cys) -, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-Gal activity in vitro, it has been classified as a pathogenic mutation, mainly on the basis of theoretical arguments about the chemistry of the cysteine residue. However its pathogenicity has never been convincingly demonstrated by pathology criteria. We reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the Cys118 allele, including 3 homozygous females. Cases were identified either on the differential diagnosis of possible FD manifestations and on case-finding studies (n=11; 4 males), or on unbiased cascade screening of probands' close relatives (n=11; 3 males). Overall, those data strongly suggest that the GLA p.(Arg118Cys) variant does not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease. The Cys118 allelic frequency in healthy Portuguese adults (n=696) has been estimated as 0.001, therefore not qualifying for "rare" condition. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. A survey of the pain experienced by males and females with Fabry disease

    PubMed Central

    Gibas, Andrea L; Klatt, Regan; Johnson, Jack; Clarke, Joe TR; Katz, Joel

    2006-01-01

    BACKGROUND The clinical onset of Fabry disease, a rare, X-linked, multisystemic disorder, is marked by neuropathic pain. Males suffer extensively from this disease. Females, as genetic ‘carriers’, have traditionally been viewed as either asymptomatic or mildly afflicted with this disease. OBJECTIVES To describe Fabry-related pain and compare experiences between the sexes. Patients’ perceptions of physician pain assessments were also examined. METHODS A disease-specific questionnaire was accessible on-line (www.fabry.org) and mailed to 552 members of a Fabry disease support group. RESULTS The response rate was 14.3% for the support group-based mail questionnaire. Females (58.0%) were significantly older (mean ± SD 45.9±13.5 years) than males (mean ± SD 40.0±12.1; t [86]=−2.11, P<0.05). Females were diagnosed with Fabry disease later (31.1±14.0 years) than males (24.2±11.9 years; t [86]=−2.43, P<0.05). Females (mean score for pain disability rating 3.0±1.4) suffered more extensive disability from migraine pain (mean score 2.2±1.3; F [1, 74]=45.0, P<0.005), and, unlike males, did not exhibit a decline in pain intensity with disease duration. Satisfaction with physician pain assessments was moderate. CONCLUSIONS Contrary to the traditional view of females as carriers, females with Fabry disease experienced intense disease-related pain; pain produced comparable distress and impairment in both sexes. The diagnostic delay and absence of a decline in pain symptoms over time in females suggest additional disease burden. Females may be triply disadvantaged in the health care system due to disease rarity, devalued carrier status and sex. PMID:16960635

  8. Fabry disease, enzyme replacement therapy and the significance of antibody responses.

    PubMed

    Deegan, Patrick B

    2012-03-01

    Fabry disease is an X-linked disorder caused by a deficiency of α-galactosidase A. This leads to a progressive accumulation of globotriaosylceramide in tissues throughout the body. Cardiac, renal and neurological manifestations are common and life expectancy is significantly reduced relative to the general population. Management of Fabry disease involves the administration of intravenous enzyme replacement therapy (ERT). Two forms - agalsidase alfa and agalsidase beta - have been licensed in certain jurisdictions and are generally well tolerated; however, some patients develop antibodies to the infused enzyme, which may impair the efficacy and safety of treatment. Agalsidase alfa and agalsidase beta are produced in different systems; this leads to certain differences in post-translational modification that may affect immunogenicity. Immunoglobulin (Ig) G antibodies have frequently been reported in patients with Fabry disease receiving ERT; IgG responses are reported in a greater proportion of patients receiving agalsidase beta than in patients receiving agalsidase alfa. IgE antibodies are less common than IgG antibodies, and have not been observed in patients receiving agalsidase alfa. However, these data are difficult to interpret due to methodological differences in the assessment of seropositivity, and in the doses of enzyme used. The clinical impact of the development of IgG antibodies to ERT in patients with Fabry disease remains unclear, due to lack of data and to the marked heterogeneity of patients both in terms of disease manifestations and response to therapy. Further studies that examine the development of antibodies in patients with Fabry disease and the potential impact of such antibodies on the outcome of ERT are necessary.

  9. Early Renal Involvement in a Girl with Classic Fabry Disease.

    PubMed

    Perretta, Fernando; Antongiovanni, Norberto; Jaurretche, Sebastián

    2017-01-01

    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.

  10. Atypical patterns of cardiac involvement in Fabry disease.

    PubMed

    Coughlan, J J; Elkholy, K; O'Brien, J; Kiernan, T

    2016-03-17

    A 58-year-old woman was referred to our cardiology service with chest pain, exertional dyspnoea and palpitations on a background of known Fabry disease diagnosed with genetic testing in 1994. ECG showed sinus rhythm, shortened PR interval, widespread t wave inversion, q waves in the lateral leads and left ventricular hypertrophy (LVH). Coronary angiogram showed only mild atheroma. Transthoracic echocardiogram showed anterolateral LVH and reduced left ventricular cavity size in keeping with Fabry cardiomyopathy. Cardiac MRI demonstrated asymmetric hypertrophy with evidence of diffuse myocardial fibrosis in the maximally hypertrophied segments from base to apex with late gadolinium enhancement in the anterior and anteroseptal walls. This was quite an atypical appearance for Fabry cardiomyopathy. This case highlights the heterogeneity of patterns of cardiac involvement that may be associated with this rare X-linked lysosomal disorder. 2016 BMJ Publishing Group Ltd.

  11. Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case–control study

    PubMed Central

    2013-01-01

    Background Fabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy. We set out to investigate small fiber conduction in Fabry patients using pain-related evoked potentials (PREP). Methods In this case–control study we prospectively studied 76 consecutive Fabry patients for electrical small fiber conduction in correlation with small fiber function and morphology. Data were compared with healthy controls using non-parametric statistical tests. All patients underwent neurological examination and were investigated with pain and depression questionnaires. Small fiber function (quantitative sensory testing, QST), morphology (skin punch biopsy), and electrical conduction (PREP) were assessed and correlated. Patients were stratified for gender and disease severity as reflected by renal function. Results All Fabry patients (31 men, 45 women) had small fiber neuropathy. Men with Fabry disease showed impaired cold (p < 0.01) and warm perception (p < 0.05), while women did not differ from controls. Intraepidermal nerve fiber density (IENFD) was reduced at the lower leg (p < 0.001) and the back (p < 0.05) mainly of men with impaired renal function. When investigating A-delta fiber conduction with PREP, men but not women with Fabry disease had lower amplitudes upon stimulation at face (p < 0.01), hands (p < 0.05), and feet (p < 0.01) compared to controls. PREP amplitudes further decreased with advance in disease severity. PREP amplitudes and warm (p < 0.05) and cold detection thresholds (p < 0.01) at the feet correlated positively in male patients. Conclusion Small fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity. PREP are well-suited to measure A-delta fiber conduction. PMID:23705943

  12. Safety and efficacy of enzyme replacement therapy in the nephropathy of Fabry disease

    PubMed Central

    Fervenza, Fernando C; Torra, Roser; Warnock, David G

    2008-01-01

    Kidney involvement with progressive loss of kidney function (Fabry nephropathy) is an important complication of Fabry disease, an X-linked lysosomal storage disorder arising from deficiency of α-galactosidase activity. Clinical trials have shown that enzyme replacement therapy (ERT) with recombinant human α-galactosidase clears globotriaosylceramide from kidney cells, and can stabilize kidney function in patients with mild to moderate Fabry nephropathy. Recent trials show that patients with more advanced Fabry nephropathy and overt proteinuria do not respond as well to ERT alone, but can benefit from anti-proteinuric therapy given in conjunction with ERT. This review focuses on the use of enzyme replacement therapy with agalsidase-alfa and agalsidase-beta in adults with Fabry nephropathy. The current results are reviewed and evaluated. The issues of dosing of enzyme replacement therapy, the use of adjunctive agents to control urinary protein excretion, and the individual factors that affect disease severity are reviewed. PMID:19707461

  13. Enhancing the diagnosis of fabry disease in cardiology with a targeted information: a before–after control–impact study

    PubMed Central

    Savary, Anne-Louise; Morello, Remy; Brasse-Lagnel, Carole; Milliez, Paul; Bekri, Soumeya; Labombarda, Fabien

    2017-01-01

    Background Cardiac complications in Fabry disease are frequent and dominated by a high frequency of left ventricular hypertrophy; therefore, cardiologists may have an essential role in screening for this disease. Providing cardiologists with targeted information on Fabry disease would be valuable and could reduce both diagnostic and therapeutic delays. The aim of this study was to evaluate the efficiency of such strategy for Fabry screening. Methods We conducted a before–after control–impact study by comparing observations made before and after targeted information on Fabry disease among cardiologists. The information on Fabry disease consisted of (1) an educational booklet, (2) oral information and (3) screening kits. The programme was evaluated at the end of a 12-month study period. Results Forty-two cardiologists participated to this study. None of them had conducted screening test and new diagnostic for Fabry disease in the 3 years prior the information. After the information, screening with dried blood spots was performed in 55 patients (ranged 18–77 years, men: 39) with cardiac monitoring for supposed sarcomeric hypertrophic cardiomyopathy (n=41) or unexplained left ventricular hypertrophy (n=14) from January 2015 to January 2016. Two new cases of Fabry disease were diagnosed (3.4%) in two men (ages 58 and 51 years). The information was deemed relevant in both content and structure and was deemed useful for everyday practice. Conclusion Cardiologists valued the targeted information on Fabry disease. This information had a direct clinical impact by allowing the diagnosis of two new families with Fabry disease. PMID:28409012

  14. Contribution of inflammatory pathways to Fabry disease pathogenesis.

    PubMed

    Rozenfeld, Paula; Feriozzi, Sandro

    2017-11-01

    Lysosomal storage diseases are usually considered to be pathologies in which the passive deposition of unwanted materials leads to functional changes in lysosomes. Lysosomal deposition of unmetabolized glycolipid substrates stimulates the activation of pathogenic cascades, including immunological processes, and particularly the activation of inflammation. In lysosomal storage diseases, the inflammatory response is continuously being activated because the stimulus cannot be eliminated. Consequently, inflammation becomes a chronic process. Lysosomes play a role in many steps of the immune response. Leukocyte perturbation and over-expression of immune molecules have been reported in Fabry disease. Innate immunity is activated by signals originating from dendritic cells via interactions between toll-like receptors and globotriaosylceramide (Gb3) and/or globotriaosylsphingosine (lyso-Gb3). Evidence indicates that these glycolipids can activate toll-like receptors, thus triggering inflammation and fibrosis cascades. In the kidney, Gb3 deposition is associated with the increased release of transforming growth factor beta and with epithelial-to-mesenchymal cell transition, leading to the over-expression of pro-fibrotic molecules and to renal fibrosis. Interstitial fibrosis is also a typical feature of heart involvement in Fabry disease. Endomyocardial biopsies show infiltration of lymphocytes and macrophages, suggesting a role for inflammation in causing tissue damage. Inflammation is present in all tissues and may be associated with other potentially pathologic processes such as apoptosis, impaired autophagy, and increases in pro-oxidative molecules, which could all contribute synergistically to tissue damage. In Fabry disease, the activation of chronic inflammation over time leads to organ damage. Therefore, enzyme replacement therapy must be started early, before this process becomes irreversible. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights

  15. Enzyme replacement therapy with agalsidase beta improves cardiac involvement in Fabry's disease.

    PubMed

    Spinelli, L; Pisani, A; Sabbatini, M; Petretta, M; Andreucci, M V; Procaccini, D; Lo Surdo, N; Federico, S; Cianciaruso, B

    2004-08-01

    Fabry's disease is an X-linked lysosomal storage disease caused by a deficiency of alpha-galactosidase that results in an accumulation of neutral glycosphingolipids throughout the body, including the cardiovascular system. Fabry cardiomyopathy, characterized by progressive severe concentric left ventricular (LV) hypertrophy, is very frequent and is the most important cause of death in affected patients. Enzyme replacement therapy (ERT) allows a specific treatment for this disease, however, there are very few data on the effectiveness of therapy on cardiac involvement. Nine patients with Fabry cardiac disease were studied on basal condition and after 6 and 12 months of treatment with algasidase beta (Fabrazyme). A complete clinical, electrocardiographic and echocardiographic evaluation was performed in all patients. Interpretable Doppler recordings of transmitral flow and pulmonary flow velocity curves were also acquired. At baseline, the patients with Fabry's disease had increased LV septum and posterior wall thickness, normal LV fractional shortening, LV ejection fraction, normal Doppler parameters of mitral inflow but a duration of pulmonary vein flow velocity wave exceeding that of the mitral wave at atrial systole. ERT did not affect heart rate and arterial pressure. LV internal diameters did not change, there was a slight but not significant decrease in the LV posterior wall thickening and a progressive decrease in the interventricular septum thickening (p < 0.025) and in LV mass (p < 0.001) The difference in duration between pulmonary vein flow velocity wave and mitral wave at atrial systole significantly decreased (p < 0.001). These results suggest that ERT in patients with Fabry cardiomyopathy is able to reduce the LV mass and ameliorate the LV stiffness. Copyright 2004 Blackwell Munksgaard

  16. Impact of cardio-renal syndrome on adverse outcomes in patients with Fabry disease in a long-term follow-up.

    PubMed

    Siegenthaler, M; Huynh-Do, U; Krayenbuehl, P; Pollock, E; Widmer, U; Debaix, H; Olinger, E; Frank, M; Namdar, M; Ruschitzka, F; Nowak, A

    2017-12-15

    Fabry disease (FD) is a rare X-linked lysosomal storage disease with a deficiency of α-galactosidase A leading to progressive sphingolipid accumulation in different organs, among them heart and kidney. We evaluated the impact of cardio-renal syndrome (CRS) on the incidence of major cardiovascular complications and death in a prospective FD cohort. A total of 104 genetically proven FD patients were annually followed at the University Hospitals Zurich and Bern. The main outcome was a composite of incident renal replacement therapy (RRT), hospitalisation due to decompensated Heart Failure, new onset atrial fibrillation, pacemaker/ICD implantation, stroke/TIA and death. Estimated glomerular filtration rate (eGFR) and left ventricular myocardial mass index (LVMMI) where explored as the primary exposure variables. During the median follow-up of 103 [59-155] months, events occurred in 27 patients. In a Cox regression analysis, both higher LVMMI and lower eGFR were independently associated with a greater risk of developing adverse events after adjustment for multiple confounders (HR 1.67 [1.04-2.73] P=0.03 per SD increase in LVMMI, HR 0.45 [0.25-0.83], P=0.01 per SD decrease in eGFR). In patients with CRS, the risk to develop events was significantly increased if adjusted for demographics and RRT (HR 4.46 [1.07-18.62], P=0.04), approaching significance if additionally adjusted for hypertension (HR 4.05 [0.95-17.29], P=0.06). In Kaplan-Meier-Analysis, the poorest event-free survival was observed among patients with CRS. CRS was associated with a high risk to develop cardiovascular complications and death, emphasizing the importance of its prevention and early recognition. A focus on cardio-reno-protective therapies is crucial. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy.

    PubMed

    van Breemen, Mariëlle J; Rombach, Saskia M; Dekker, Nick; Poorthuis, Ben J; Linthorst, Gabor E; Zwinderman, Aeilko H; Breunig, Frank; Wanner, Christoph; Aerts, Johannes M; Hollak, Carla E

    2011-01-01

    Fabry disease is treated by two-weekly infusions with α-galactosidase A, which is deficient in this X-linked globotriaosylceramide (Gb3) storage disorder. Elevated plasma globotriaosylsphingosine (lysoGb3) is a hallmark of classical Fabry disease. We investigated effects of enzyme replacement therapy (ERT) on plasma levels of lysoGb3 and Gb3 in patients with classical Fabry disease treated with agalsidase alfa at 0.2mg/kg, agalsidase beta at 0.2mg/kg or at 1.0mg/kg bodyweight. Each treatment regimen led to prominent reductions of plasma lysoGb3 in Fabry males within 3 months (P=0.0313), followed by relative stability later on. Many males developed antibodies against α-galactosidase A, particularly those treated with agalsidase beta. Patients with antibodies tended towards smaller correction in plasma lysoGb3 concentration, whereas treatment with high dose agalsidase beta allowed a reduction comparable to patients without antibodies. Pre-treatment plasma lysoGb3 concentrations of Fabry females were relatively low. In all females and with each treatment regimen, ERT gave reduction or stabilisation of plasma lysoGb3. Our investigation revealed that ERT of Fabry patients reduces plasma lysoGb3, regardless of the recombinant enzyme used. This finding shows that ERT can correct a characteristic biochemical abnormality in Fabry patients. Copyright © 2010 Elsevier B.V. All rights reserved.

  18. Cardiac involvement in genotype-positive Fabry disease patients assessed by cardiovascular MR.

    PubMed

    Kozor, Rebecca; Grieve, Stuart M; Tchan, Michel C; Callaghan, Fraser; Hamilton-Craig, Christian; Denaro, Charles; Moon, James C; Figtree, Gemma A

    2016-02-15

    Cardiac magnetic resonance (CMR) has the potential to provide early detection of cardiac involvement in Fabry disease. We aimed to gain further insight into this by assessing a cohort of Fabry patients using CMR. Fifty genotype-positive Fabry subjects (age 45±2 years; 50% male) referred for CMR and 39 matched controls (age 40±2 years; 59% male) were recruited. Patients had a mean Mainz severity score index of 15±2 (range 0-46), reflecting an overall mild degree of disease severity. Compared with controls, Fabry subjects had a 34% greater left ventricular mass (LVM) index (82±5 vs 61±2 g/m(2), p=0.001) and had a significantly greater papillary muscle contribution to total LVM (13±1 vs 6±0.5%, p<0.001), even in the absence of left ventricular hypertrophy (LVH). Late gadolinium enhancement (LGE) was present in 15 Fabry subjects (9/21 males and 6/23 females). The most common site for LGE was the basal inferolateral wall (93%, 14/15). There was a positive association between LVM index and LGE. Despite this, there were two males and three females with no LVH that displayed LGE. Of Fabry subjects who were not on enzyme replacement therapy at enrolment (n=28), six were reclassified as having cardiac involvement (four LVH-negative/LGE-positive, one LVH-positive/LGE-positive and one LVH-positive/LGE-negative). CMR was able to detect cardiac involvement in 48% of this Fabry cohort, despite the overall mild disease phenotype of the cohort. Of those not on ERT, 21% were reclassified as having cardiac involvement allowing improved risk stratification and targeting of therapy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  19. Changes in Ionic Conductance Signature of Nociceptive Neurons Underlying Fabry Disease Phenotype

    PubMed Central

    Namer, Barbara; Ørstavik, Kirstin; Schmidt, Roland; Mair, Norbert; Kleggetveit, Inge Petter; Zeidler, Maximillian; Martha, Theresa; Jorum, Ellen; Schmelz, Martin; Kalpachidou, Theodora; Kress, Michaela; Langeslag, Michiel

    2017-01-01

    The first symptom arising in many Fabry patients is neuropathic pain due to changes in small myelinated and unmyelinated fibers in the periphery, which is subsequently followed by a loss of sensory perception. Here we studied changes in the peripheral nervous system of Fabry patients and a Fabry mouse model induced by deletion of α-galactosidase A (Gla−/0). The skin innervation of Gla−/0 mice resembles that of the human Fabry patients. In Fabry diseased humans and Gla−/0 mice, we observed similar sensory abnormalities, which were also observed in nerve fiber recordings in both patients and mice. Electrophysiological recordings of cultured Gla−/0 nociceptors revealed that the conductance of voltage-gated Na+ and Ca2+ currents was decreased in Gla−/0 nociceptors, whereas the activation of voltage-gated K+ currents was at more depolarized potentials. Conclusively, we have observed that reduced sensory perception due to small-fiber degeneration coincides with altered electrophysiological properties of sensory neurons. PMID:28769867

  20. How well does urinary lyso-Gb3 function as a biomarker in Fabry disease?

    PubMed

    Auray-Blais, Christiane; Ntwari, Aimé; Clarke, Joe T R; Warnock, David G; Oliveira, João Paulo; Young, Sarah P; Millington, David S; Bichet, Daniel G; Sirrs, Sandra; West, Michael L; Casey, Robin; Hwu, Wuh-Liang; Keutzer, Joan M; Zhang, X Kate; Gagnon, René

    2010-12-14

    Fabry disease is characterized by accumulation of glycosphingolipids, such as globotriaosylceramide (Gb(3)), in many tissues and body fluids. A novel plasma biomarker, globotriaosylsphingosine (lyso-Gb(3)), is increased in patients with the disease. Until now, lyso-Gb(3) was not detectable in urine, possibly because of the presence of interfering compounds. We undertook to: 1) characterize lyso-Gb(3) in urine; 2) develop a method to quantitate urinary lyso-Gb(3) by mass spectrometry; 3) evaluate urinary lyso-Gb(3) as a potential biomarker for Fabry disease; and 4) determine whether lyso-Gb(3) is an inhibitor of α-galactosidase A activity. We analyzed urinary lyso-Gb(3) from 83 Fabry patients and 77 healthy age-matched controls. The intraday and interday bias and precision of the method were <15%. Increases in lyso-Gb(3)/creatinine correlated with the concentrations of Gb(3) (r(2)=0.43), type of mutations (p=0.0006), gender (p<0.0001) and enzyme replacement therapy status (p=0.0012). Urine from healthy controls contained no detectable lyso-Gb(3). Lyso-Gb(3) did not inhibit GLA activity in dried blood spots. Increased urinary excretion of lyso-Gb(3) of Fabry patients correlated well with a number of indicators of disease severity. Lyso-Gb(3) is a reliable independent biomarker for clinically important characteristics of Fabry disease. Copyright © 2010 Elsevier B.V. All rights reserved.

  1. Fabry nephropathy: a review - how can we optimize the management of Fabry nephropathy?

    PubMed

    Waldek, Stephen; Feriozzi, Sandro

    2014-05-06

    Fabry disease is a rare, X-linked, lysosomal storage disease caused by mutations in the gene encoding the enzyme alpha-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, epithelial cells and the tubular cells of the distal tubule and loop of Henle contribute to the renal symptoms of Fabry disease, which manifest as proteinuria and reduced glomerular filtration rate leading to chronic kidney disease and progression to end-stage renal disease. Early diagnosis and timely initiation of treatment of Fabry renal disease is an important facet of disease management. Initiating treatment with enzyme replacement therapy (ERT; agalsidase alfa, Replagal®, Shire; agalsidase beta, Fabrazyme®, Genzyme) as part of a comprehensive strategy to prevent complications of the disease, may be beneficial in stabilizing renal function or slowing its decline. Early initiation of ERT may also be more effective than initiating therapy in patients with more advanced disease. Several strategies are required to complement the use of ERT and treat the myriad of associated symptoms and organ involvements. In particular, patients with renal Fabry disease are at risk of cardiovascular events, such as high blood pressure, cardiac arrhythmias and stroke. This review discusses the management of renal involvement in Fabry disease, including diagnosis, treatments, and follow-up, and explores recent advances in the use of biomarkers to assist with diagnosis, monitoring disease progression and response to treatment.

  2. Improvement of Fabry Disease-Related Gastrointestinal Symptoms in a Significant Proportion of Female Patients Treated with Agalsidase Beta: Data from the Fabry Registry.

    PubMed

    Wilcox, William R; Feldt-Rasmussen, Ulla; Martins, Ana Maria; Ortiz, Alberto; Lemay, Roberta M; Jovanovic, Ana; Germain, Dominique P; Varas, Carmen; Nicholls, Katherine; Weidemann, Frank; Hopkin, Robert J

    2018-01-01

    Fabry disease, an X-linked inherited lysosomal storage disorder, is caused by mutations in the gene encoding α-galactosidase, GLA. In patients with Fabry disease, glycosphingolipids accumulate in various cell types, triggering a range of cellular and tissue responses that result in a wide spectrum of organ involvement. Although variable, gastrointestinal symptoms are among the most common and significant early clinical manifestations; they tend to persist into adulthood if left untreated. To further understand the effects of sustained enzyme replacement therapy (ERT) with agalsidase beta on gastrointestinal symptoms in heterozygotes, a data analysis of female patients enrolled in the Fabry Registry was conducted. To be included, females of any age must have received agalsidase beta (average dose 1.0 mg/kg every 2 weeks) for at least 2.5 years. Measured outcomes were self-reported gastrointestinal symptoms (abdominal pain, diarrhea). Outcomes at baseline and last follow-up, and their change from baseline to last follow-up, were assessed. Relevant data were available for 168 female patients. Mean age at the start of ERT was 43 years and mean treatment duration 5.7 years. Baseline pre-treatment abdominal pain was reported by 45% of females and diarrhea by 39%. At last follow-up, 31% reported abdominal pain (p < 0.01) and 27% diarrhea (p < 0.01). The results of this Fabry Registry analysis suggest that while on sustained treatment with agalsidase beta (1.0 mg/kg every 2 weeks), both abdominal pain and diarrhea improved in many female patients with Fabry disease.

  3. Left Ventricular Geometry and Blood Pressure as Predictors of Adverse Progression of Fabry Cardiomyopathy.

    PubMed

    Krämer, Johannes; Bijnens, Bart; Störk, Stefan; Ritter, Christian O; Liu, Dan; Ertl, Georg; Wanner, Christoph; Weidemann, Frank

    2015-01-01

    In spite of several research studies help to describe the heart in Fabry disease (FD), the cardiomyopathy is not entirely understood. In addition, the impact of blood pressure and alterations in geometry have not been systematically evaluated. In 74 FD patients (mean age 36±12 years; 45 females) the extent of myocardial fibrosis and its progression were quantified using cardiac magnetic-resonance-imaging with late enhancement technique (LE). Results were compared to standard echocardiography complemented by 2D-speckle-tracking, 3D-sphericity-index (SI) and standardized blood pressure measurement. At baseline, no patient received enzyme replacement therapy (ERT). After 51±24 months, a follow-up examination was performed. Systolic blood pressure (SBP) was higher in patients with vs. without LE: 123±17 mmHg vs. 115±13 mmHg; P = 0.04. A positive correlation was found between SI and the amount of LE-positive myocardium (r = 0.51; P<0.001) indicating an association of higher SI in more advanced stages of the cardiomyopathy. SI at baseline was positively associated with the increase of LE-positive myocardium during follow-up. The highest SBP (125±19 mmHg) and also the highest SI (0.32±0.05) was found in the subgroup with a rapidly increasing LE (ie, ≥0.2% per year; n = 16; P = 0.04). Multivariate logistic regression analysis including SI, SBP, EF, left ventricular volumes, wall thickness and NT-proBNP adjusted for age and sex showed SI as the most powerful parameter to detect rapid progression of LE (AUC = 0.785; P<0.05). LV geometry as assessed by the sphericity index is altered in relation to the stage of the Fabry cardiomyopathy. Although patients with FD are not hypertensive, the SBP has a clear impact on the progression of the cardiomyopathy.

  4. Left Ventricular Geometry and Blood Pressure as Predictors of Adverse Progression of Fabry Cardiomyopathy

    PubMed Central

    Krämer, Johannes; Bijnens, Bart; Störk, Stefan; Ritter, Christian O.; Liu, Dan; Ertl, Georg; Wanner, Christoph; Weidemann, Frank

    2015-01-01

    Background In spite of several research studies help to describe the heart in Fabry disease (FD), the cardiomyopathy is not entirely understood. In addition, the impact of blood pressure and alterations in geometry have not been systematically evaluated. Methods In 74 FD patients (mean age 36±12 years; 45 females) the extent of myocardial fibrosis and its progression were quantified using cardiac magnetic-resonance-imaging with late enhancement technique (LE). Results were compared to standard echocardiography complemented by 2D-speckle-tracking, 3D-sphericity-index (SI) and standardized blood pressure measurement. At baseline, no patient received enzyme replacement therapy (ERT). After 51±24 months, a follow-up examination was performed. Results Systolic blood pressure (SBP) was higher in patients with vs. without LE: 123±17 mmHg vs. 115±13 mmHg; P = 0.04. A positive correlation was found between SI and the amount of LE-positive myocardium (r = 0.51; P<0.001) indicating an association of higher SI in more advanced stages of the cardiomyopathy. SI at baseline was positively associated with the increase of LE-positive myocardium during follow-up. The highest SBP (125±19 mmHg) and also the highest SI (0.32±0.05) was found in the subgroup with a rapidly increasing LE (ie, ≥0.2% per year; n = 16; P = 0.04). Multivariate logistic regression analysis including SI, SBP, EF, left ventricular volumes, wall thickness and NT-proBNP adjusted for age and sex showed SI as the most powerful parameter to detect rapid progression of LE (AUC = 0.785; P<0.05). Conclusions LV geometry as assessed by the sphericity index is altered in relation to the stage of the Fabry cardiomyopathy. Although patients with FD are not hypertensive, the SBP has a clear impact on the progression of the cardiomyopathy. PMID:26600044

  5. Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications

    PubMed Central

    Weidemann, F; Niemann, M; Störk, S; Breunig, F; Beer, M; Sommer, C; Herrmann, S; Ertl, G; Wanner, C

    2013-01-01

    Objective The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards ‘hard’ clinical end-points in comparison with the natural course of the disease. Methods A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain. Results During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min−1 per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry. Conclusion Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease. PMID:23586858

  6. Patients with Fabry disease after enzyme replacement therapy dose reduction versus treatment switch.

    PubMed

    Weidemann, Frank; Krämer, Johannes; Duning, Thomas; Lenders, Malte; Canaan-Kühl, Sima; Krebs, Alice; Guerrero González, Hans; Sommer, Claudia; Üçeyler, Nurcan; Niemann, Markus; Störk, Stefan; Schelleckes, Michael; Reiermann, Stefanie; Stypmann, Jörg; Brand, Stefan-Martin; Wanner, Christoph; Brand, Eva

    2014-04-01

    Because of the shortage of agalsidase-beta in 2009, many patients with Fabry disease were treated with lower doses or were switched to agalsidase-alfa. This observational study assessed end-organ damage and clinical symptoms during dose reduction or switch to agalsidase-alfa. A total of 105 adult patients with Fabry disease who had received agalsidase-beta (1.0 mg/kg body weight) for ≥1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=38), receive a reduced dose of 0.3-0.5 mg/kg (dose-reduction group, n=29), or switch to 0.2 mg/kg agalsidase-alfa (switch group) and were followed prospectively for 1 year. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD); changes in cardiac, renal, and neurologic function; and Fabry-related symptoms (neuropathic pain, hypohidrosis, diarrhea, and disease severity scores). Organ function and Fabry-related symptoms remained stable in the regular-dose group. In contrast, estimated GFR decreased by about 3 ml/min per 1.73 m(2) (P=0.01) in the dose-reduction group, and the median albumin-to-creatinine ratio increased from 114 (0-606) mg/g to 216 (0-2062) mg/g (P=0.03) in the switch group. Furthermore, mean Mainz Severity Score Index scores and frequencies of pain attacks, chronic pain, gastrointestinal pain, and diarrhea increased significantly in the dose-reduction and switch groups. In conclusion, patients receiving regular agalsidase-beta dose had a stable disease course, but dose reduction led to worsening of renal function and symptoms. Switching to agalsidase-alfa is safe, but microalbuminuria may progress and Fabry-related symptoms may deteriorate.

  7. Fabry nephropathy: a review – how can we optimize the management of Fabry nephropathy?

    PubMed Central

    2014-01-01

    Fabry disease is a rare, X-linked, lysosomal storage disease caused by mutations in the gene encoding the enzyme alpha-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, epithelial cells and the tubular cells of the distal tubule and loop of Henle contribute to the renal symptoms of Fabry disease, which manifest as proteinuria and reduced glomerular filtration rate leading to chronic kidney disease and progression to end-stage renal disease. Early diagnosis and timely initiation of treatment of Fabry renal disease is an important facet of disease management. Initiating treatment with enzyme replacement therapy (ERT; agalsidase alfa, Replagal®, Shire; agalsidase beta, Fabrazyme®, Genzyme) as part of a comprehensive strategy to prevent complications of the disease, may be beneficial in stabilizing renal function or slowing its decline. Early initiation of ERT may also be more effective than initiating therapy in patients with more advanced disease. Several strategies are required to complement the use of ERT and treat the myriad of associated symptoms and organ involvements. In particular, patients with renal Fabry disease are at risk of cardiovascular events, such as high blood pressure, cardiac arrhythmias and stroke. This review discusses the management of renal involvement in Fabry disease, including diagnosis, treatments, and follow-up, and explores recent advances in the use of biomarkers to assist with diagnosis, monitoring disease progression and response to treatment. PMID:24886109

  8. Treatment in Fabry disease.

    PubMed

    López Rodríguez, M

    2018-04-13

    Fabry disease is an X-linked inborn disease caused by deficit of alpha-galactosidaseA. This results in accumulation of glycosphingolipids in all cells and tissues. All males should receive enzyme replacement treatment in case of very low or undetectable levels of alpha-galactosidaseA. Female carriers and males with marginally levels of alpha-galactosidaseA should be treated in case of renal, neurologic o cardiac manifestations. There are two intravenous formulations of human recombinant enzyme, agalsidase alpha and agalsidase beta, showing similar efficacy and safety. Patients with amenable mutations of alpha-galactosidase can be treated with oral migalastat hydrochloride. Migalastat hydrochloride is a pharmacological chaperone that facilitates trafficking of alpha-galactosidaseA to lysosomes increasing enzyme activity. Patients treated with migalastat hydrochloride had significant improvements in left ventricular mass and gastrointestinal symptoms. Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

  9. Teenager male with burning pain in extremities--suspect Fabry disease, 2 case reports.

    PubMed

    Patil, Rajesh B; Joglekar, V K

    2014-01-01

    We present 2 cases of teenager males presented with burning pain in extremities and turned out to be cases of Fabry disease.The purpose of presenting this case is to highlight the fact that suspicion of Fabry disease in patients presenting with these symptoms will lead to early diagnosis and treatment of this condition before occurrences of complications. A 14-year-old male presented with severe burning pain in both hands and feet since last 4 yrs which persisted despite consumption of painkillers and becoming more disabling and without having any family history for such condition. On general examination patient had small reddish coloured lesions around the umbilicus, appearing like angiokeratomas. Skin biopsy confirmed the lesion. On enzyme assay his alpha galactosidase activity found to be '0' nmol/hr/mg of protein, confirming his diagnosis. Patient's creatinine and 2 D ECHO were normal and urine had 1+ proteinuria. Patient started on carbamazepine tablets for pain and referred to higher centre for genetic diagnosis and enzyme replacement therapy. CASE REPORT 2: An 18-year-old male referred to our hospital by general practitioner for fatigue and pedal oedema with deranged renal function tests. On history taking patient gave history of severe burning pain in both hands and feet since age of 9 yrs. Patient's general examination revealed hypertension with pallor, pedal oedema along with angiokeratomas in bathing suit distribution. Patient's ultrasonography of kidney revealed bilaterally normal sized kidneys with altered echotexture and urine examination showed fine granular foamy cells with sub nephrotic range proteinuria. 2 D ECHO revealed concentric left ventricular hypertrophy. Skin biopsy report supported the diagnosis of Fabry disease. Patient advised to undergo renal biopsy to confirm Fabry nephropathy but patient denied any further diagnostic workup for nephropathy or Fabry disease. Patient started on conservative treatment and carbamazepine in renal dose

  10. High-Sensitivity Troponin: A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease.

    PubMed

    Seydelmann, Nora; Liu, Dan; Krämer, Johannes; Drechsler, Christiane; Hu, Kai; Nordbeck, Peter; Schneider, Andreas; Störk, Stefan; Bijnens, Bart; Ertl, Georg; Wanner, Christoph; Weidemann, Frank

    2016-05-31

    High-sensitivity troponin (hs-TNT), a biomarker of myocardial damage, might be useful for assessing fibrosis in Fabry cardiomyopathy. We performed a prospective analysis of hs-TNT as a biomarker for myocardial changes in Fabry patients and a retrospective longitudinal follow-up study to assess longitudinal hs-TNT changes relative to fibrosis and cardiomyopathy progression. For the prospective analysis, hs-TNT from 75 consecutive patients with genetically confirmed Fabry disease was analyzed relative to typical Fabry-associated echocardiographic findings and total myocardial fibrosis as measured by late gadolinium enhancement (LE) on magnetic resonance imaging. Longitudinal data (3.9±2.0 years), including hs-TNT, LE, and echocardiographic findings from 58 Fabry patients, were retrospectively collected. Hs-TNT level positively correlated with LE (linear correlation coefficient, 0.72; odds ratio, 32.81 [95% CI, 3.56-302.59]; P=0.002); patients with elevated baseline hs-TNT (>14 ng/L) showed significantly increased LE (median: baseline, 1.9 [1.1-3.3] %; follow-up, 3.2 [2.3-4.9] %; P<0.001) and slightly elevated hs-TNT (baseline, 44.7 [30.1-65.3] ng/L; follow-up, 49.1 [27.6-69.5] ng/L; P=0.116) during follow-up. Left ventricular wall thickness and EF of patients with elevated hs-TNT were decreased during follow-up, indicating potential cardiomyopathy progression. hs-TNT is an accurate, easily accessible clinical blood biomarker for detecting replacement fibrosis in patients with Fabry disease and a qualified predictor of cardiomyopathy progression. Thus, hs-TNT could be helpful for staging and follow-up of Fabry patients. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  11. Patients with Fabry Disease after Enzyme Replacement Therapy Dose Reduction Versus Treatment Switch

    PubMed Central

    Krämer, Johannes; Duning, Thomas; Lenders, Malte; Canaan-Kühl, Sima; Krebs, Alice; González, Hans Guerrero; Sommer, Claudia; Üçeyler, Nurcan; Niemann, Markus; Störk, Stefan; Schelleckes, Michael; Reiermann, Stefanie; Stypmann, Jörg; Brand, Stefan-Martin; Wanner, Christoph; Brand, Eva

    2014-01-01

    Because of the shortage of agalsidase-beta in 2009, many patients with Fabry disease were treated with lower doses or were switched to agalsidase-alfa. This observational study assessed end-organ damage and clinical symptoms during dose reduction or switch to agalsidase-alfa. A total of 105 adult patients with Fabry disease who had received agalsidase-beta (1.0 mg/kg body weight) for ≥1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=38), receive a reduced dose of 0.3–0.5 mg/kg (dose-reduction group, n=29), or switch to 0.2 mg/kg agalsidase-alfa (switch group) and were followed prospectively for 1 year. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD); changes in cardiac, renal, and neurologic function; and Fabry-related symptoms (neuropathic pain, hypohidrosis, diarrhea, and disease severity scores). Organ function and Fabry-related symptoms remained stable in the regular-dose group. In contrast, estimated GFR decreased by about 3 ml/min per 1.73 m2 (P=0.01) in the dose-reduction group, and the median albumin-to-creatinine ratio increased from 114 (0–606) mg/g to 216 (0–2062) mg/g (P=0.03) in the switch group. Furthermore, mean Mainz Severity Score Index scores and frequencies of pain attacks, chronic pain, gastrointestinal pain, and diarrhea increased significantly in the dose-reduction and switch groups. In conclusion, patients receiving regular agalsidase-beta dose had a stable disease course, but dose reduction led to worsening of renal function and symptoms. Switching to agalsidase-alfa is safe, but microalbuminuria may progress and Fabry-related symptoms may deteriorate. PMID:24556354

  12. Risk factors for severe clinical events in male and female patients with Fabry disease treated with agalsidase beta enzyme replacement therapy: Data from the Fabry Registry.

    PubMed

    Hopkin, Robert J; Cabrera, Gustavo; Charrow, Joel; Lemay, Roberta; Martins, Ana Maria; Mauer, Michael; Ortiz, Alberto; Patel, Manesh R; Sims, Katherine; Waldek, Stephen; Warnock, David G; Wilcox, William R

    2016-09-01

    Fabry disease, an X-linked lysosomal storage disorder, causes intracellular accumulation of glycosphingolipids leading to progressive renal, cardiovascular, and cerebrovascular disease, and premature death. This longitudinal Fabry Registry study analyzed data from patients with Fabry disease to determine the incidence and type of severe clinical events following initiation of enzyme replacement therapy (ERT) with agalsidase beta, as well as risk factors associated with occurrence of these events. Severe events assessed included chronic dialysis, renal transplantation, cardiac events, stroke, and death. The analyses included 969 male and 442 female Fabry patients. The mean age at first agalsidase beta infusion was 35 and 44, and median treatment follow-up 4.3years and 3.2years, respectively. Among males, cardiac events were the most common on-ERT events, followed by renal, stroke, and non-cardiac death. Among females, cardiac events were also most common followed by stroke and renal events. Patients with on-ERT events had significantly more advanced cardiac and renal disease at baseline as compared with patients without on-ERT events. Severe events were also associated with older age at ERT initiation (males and females), a history of pre-ERT events (females; approaching statistical significance in males), and a higher urinary protein/creatinine ratio (females). Approximately 65% of patients with pre-ERT events did not experience subsequent on-ERT events. Of patients without pre-ERT events, most (84% of males, 92% of females) remained event-free. Patients with on-ERT severe events had more advanced Fabry organ involvement at baseline than those without such events and patients who initiated ERT at a younger age had less residual risk of on-ERT events. The observed patterns of residual risk may aid clinicians in multidisciplinary monitoring of male and female patients with Fabry disease receiving ERT, and in determining the need for administration of adjunctive

  13. Migalastat improves diarrhea in patients with Fabry disease: clinical-biomarker correlations from the phase 3 FACETS trial.

    PubMed

    Schiffmann, Raphael; Bichet, Daniel G; Jovanovic, Ana; Hughes, Derralynn A; Giugliani, Roberto; Feldt-Rasmussen, Ulla; Shankar, Suma P; Barisoni, Laura; Colvin, Robert B; Jennette, J Charles; Holdbrook, Fred; Mulberg, Andrew; Castelli, Jeffrey P; Skuban, Nina; Barth, Jay A; Nicholls, Kathleen

    2018-04-27

    Fabry disease is frequently characterized by gastrointestinal symptoms, including diarrhea. Migalastat is an orally-administered small molecule approved to treat the symptoms of Fabry disease in patients with amenable mutations. We evaluated minimal clinically important differences (MCID) in diarrhea based on the corresponding domain of the patient-reported Gastrointestinal Symptom Rating Scale (GSRS) in patients with Fabry disease and amenable mutations (N = 50) treated with migalastat 150 mg every other day or placebo during the phase 3 FACETS trial (NCT00925301). After 6 months, significantly more patients receiving migalastat versus placebo experienced improvement in diarrhea based on a MCID of 0.33 (43% vs 11%; p = .02), including the subset with baseline diarrhea (71% vs 20%; p = .02). A decline in kidney peritubular capillary globotriaosylceramide inclusions correlated with diarrhea improvement; patients with a reduction > 0.1 were 5.6 times more likely to have an improvement in diarrhea than those without (p = .031). Migalastat was associated with a clinically meaningful improvement in diarrhea in patients with Fabry disease and amenable mutations. Reductions in kidney globotriaosylceramide may be a useful surrogate endpoint to predict clinical benefit with migalastat in patients with Fabry disease. NCT00925301 ; June 19, 2009.

  14. Identification of a Novel GLA Gene Mutation, p.Ile239Met, in Fabry Disease With a Predominant Cardiac Phenotype.

    PubMed

    Csányi, Beáta; Hategan, Lidia; Nagy, Viktória; Obál, Izabella; Varga, Edina T; Borbás, János; Tringer, Annamária; Eichler, Sabrina; Forster, Tamás; Rolfs, Arndt; Sepp, Róbert

    2017-05-31

    Fabry disease (FD) is an X-linked inherited lysosomal storage disorder caused by mutations in the GLA gene, encoding for the enzyme α-galactosidase A. Although hundreds of mutations in the GLA gene have been described, many of them are variants of unknown significance. Here we report a novel GLA mutation, p.Ile239Met, identified in a large Hungarian three-generation family with FD. A 69 year-old female index patient with a clinical history of renal failure, hypertrophic cardiomyopathy, and 2nd degree AV block was screened for mutation in the GLA gene. Genetic screening identified a previously unreported heterozygous mutation in exon 5 of the GLA gene (c.717A>G; p.Ile239Met). Family screening indicated that altogether 6 family members carried the mutation (5 females, 1 male, average age: 55 ± 16 years). Three family members, including the index patient, manifested the cardiac phenotype of hypertrophic cardiomyopathy, while two other family members were diagnosed with left ventricular hypertrophy. Taking affection status as the presence of hypertrophic cardiomyopathy, left ventricular hypertrophy or elevated lyso-Gb3 levels, all affected family members carried the mutation. Linkage analysis of the family gave a two-point LOD score of 2.01 between the affection status and the p.Ile239Met GLA mutation. Lyso-Gb3 levels were elevated in all carrier family members (range: 2.4-13.8 ng/mL; upper limit of normal +2STD: ≤ 1.8 ng/mL). The GLA enzyme level was markedly reduced in the affected male family member (< 0.2 µmol/L/hour; upper limit of normal ± 2STD: ≥ 2.6 µmol/L/hour). We conclude that the p. Ile239Met GLA mutation is a pathogenic mutation for FD associated with predominant cardiac phenotype.

  15. Safe and Successful Treatment With Agalsidase Beta During Pregnancy in Fabry Disease.

    PubMed

    Senocak Tasci, Elif; Bicik, Zerrin

    2015-09-01

    Fabry disease, an X-linked lysosomal storage disorder, is caused by α-galactosidase A deficiency and leads to accumulation of glycospinhgolipids in most tissues, with life-theratening consequences in the kidney, heart, and cerebrovascular system. Enzyme replacement therapy is available as 2 different preparations: agalsidase alfa and agalsidase beta. Enzyme replacement therapy is started as soon as the diagnosis is confirmed, but there is no data available in the literature about its safety during preganacy. Herein, we described 2 patients with Fabry disease who received agalsidase beta during their pregnancy. This report is important as the data about enzyme replacement therapy during pregnancy is restricted with case reports.

  16. Myocardial lipid content in Fabry disease: a combined 1H-MR spectroscopy and MR imaging study at 3 Tesla.

    PubMed

    Petritsch, B; Köstler, H; Weng, A M; Horn, M; Gassenmaier, T; Kunz, A S; Weidemann, F; Wanner, C; Bley, T A; Beer, M

    2016-10-28

    Fabry disease is characterized by a progressive deposition of sphingolipids in different organ systems, whereby cardiac involvement leads to death. We hypothesize that lysosomal storage of sphingolipids in the heart as occurring in Fabry disease does not reflect in higher cardiac lipid concentrations detectable by 1 H magnetic resonance spectroscopy (MRS) at 3 Tesla. Myocardial lipid content was quantified in vivo by 1 H-MRS in 30 patients (12 male, 18 female; 18 patients treated with enzyme replacement therapy) with genetically proven Fabry disease and in 30 healthy controls. The study protocol combined 1 H-MRS with cardiac cine imaging and LGE MRI in a single examination. Myocardial lipid content was not significantly elevated in Fabry disease (p = 0.225). Left ventricular (LV) mass was significantly higher in patients suffering from Fabry disease compared to controls (p = 0.019). Comparison of patients without signs of myocardial fibrosis in MRI (LGE negative; n = 12) to patients with signs of fibrosis (LGE positive; n = 18) revealed similar myocardial lipid content in both groups (p > 0.05), while the latter showed a trend towards elevated LV mass (p = 0.076). This study demonstrates the potential of lipid metabolic investigation embedded in a comprehensive examination of cardiac morphology and function in Fabry disease. There was no evidence that lysosomal storage of sphingolipids influences cardiac lipid content as measured by 1 H-MRS. Finally, the authors share the opinion that a comprehensive cardiac examination including three subsections (LGE; 1 H-MRS; T 1 mapping), could hold the highest potential for the final assessment of early and late myocardial changes in Fabry disease.

  17. Agalsidase alfa: a review of its use in the management of Fabry disease.

    PubMed

    Keating, Gillian M

    2012-10-01

    The enzyme replacement therapy agalsidase alfa (Replagal®) has an amino acid sequence identical to that of native α-galactosidase A; intravenous agalsidase alfa 0.2 mg/kg every other week is indicated for the long-term treatment of patients with confirmed Fabry disease. This article reviews the efficacy and tolerability of agalsidase alfa in patients with Fabry disease, as well as summarizing its pharmacologic properties. Agalsidase alfa had beneficial effects in adult men with Fabry disease, according to the results of two randomized, double-blind, placebo-controlled, 6-month trials (n = 15 and 26). For example, left ventricular mass index was reduced to a significantly greater extent with agalsidase alfa than with placebo. Although the change in myocardial globotriaosylceramide content (primary endpoint in one study) did not significantly differ between agalsidase alfa and placebo recipients, the change in the Brief Pain Inventory (BPI) 'pain at its worst' score (reflecting neuropathic pain while without pain medications; primary endpoint in the second study) was improved to a significantly greater extent with agalsidase alfa than with placebo. In addition, the change in creatinine clearance, but not inulin clearance, significantly favored agalsidase alfa versus placebo recipients. Abnormalities in functional cerebral blood flow and cerebrovascular responses were also reversed with agalsidase alfa therapy. In extensions of these placebo-controlled trials, the reduction in left ventricular mass and improvements in BPI pain scores were maintained after longer-term agalsidase alfa therapy. The significant decline in estimated glomerular filtration rate (eGFR) seen after 48 months' agalsidase alfa treatment was mainly driven by a marked decline in eGFR seen in four patients with stage 3 chronic kidney disease at baseline (although the progression of decline appeared slower than that seen in historic controls); renal function appeared stable in patients with

  18. Screening for Fabry disease in left ventricular hypertrophy: documentation of a novel mutation.

    PubMed

    Baptista, Ana; Magalhães, Pedro; Leão, Sílvia; Carvalho, Sofia; Mateus, Pedro; Moreira, Ilídio

    2015-08-01

    Fabry disease is a lysosomal storage disease caused by enzyme α-galactosidase A deficiency as a result of mutations in the GLA gene. Cardiac involvement is characterized by progressive left ventricular hypertrophy. To estimate the prevalence of Fabry disease in a population with left ventricular hypertrophy. The patients were assessed for the presence of left ventricular hypertrophy defined as a left ventricular mass index ≥ 96 g/m2 for women or ≥ 116 g/m2 for men. Severe aortic stenosis and arterial hypertension with mild left ventricular hypertrophy were exclusion criteria. All patients included were assessed for enzyme α-galactosidase A activity using dry spot testing. Genetic study was performed whenever the enzyme activity was decreased. A total of 47 patients with a mean left ventricular mass index of 141.1 g/m2 (± 28.5; 99.2 to 228.5 g/m2] were included. Most of the patients were females (51.1%). Nine (19.1%) showed decreased α-galactosidase A activity, but only one positive genetic test - [GLA] c.785G>T; p.W262L (exon 5), a mutation not previously described in the literature. This clinical investigation was able to establish the association between the mutation and the clinical presentation. In a population of patients with left ventricular hypertrophy, we documented a Fabry disease prevalence of 2.1%. This novel case was defined in the sequence of a mutation of unknown meaning in the GLA gene with further pathogenicity study. Thus, this study permitted the definition of a novel causal mutation for Fabry disease - [GLA] c.785G>T; p.W262L (exon 5).

  19. Cardiomyopathy and response to enzyme replacement therapy in a male mouse model for Fabry disease.

    PubMed

    Nguyen Dinh Cat, Aurelie; Escoubet, Brigitte; Agrapart, Vincent; Griol-Charhbili, Violaine; Schoeb, Trenton; Feng, Wenguang; Jaimes, Edgar; Warnock, David G; Jaisser, Frederic

    2012-01-01

    Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, (predominately globotriaosylceramide; GL-3) in lysosomes, as well as other cellular compartments and the extracellular space. Our aim was to characterize the cardiac phenotype of male knock-out mice that are deficient in alpha-galactosidase A activity, as a model for Fabry disease and test the efficacy of Enzyme Replacement Therapy with agalsidase-beta. Male mice (3-4 months of age) were characterized with awake blood pressure and heart rate measurements, cardiac echocardiography and electrocardiography measurements under light anesthesia, histological studies and molecular studies with real-time polymerase chain reaction. The Fabry knock-out mouse has bradycardia and lower blood pressure than control wild type (CB7BL/6J) mice. In Fabry knock-out mice, the cardiomyopathy associated mild hypertrophy at echography with normal systolic LV function and mild diastolic dysfunction. Premature atrial contractions were more frequent in without conduction defect. Heart weight normalized to tibial length was increased in Fabry knock-out mice. Ascending aorta dilatation was observed. Molecular studies were consistent with early stages of cardiac remodeling. A single dose of agalsidase-beta (3 mg/kg) did not affect the LV hypertrophy, function or heart rate, but did improve the mRNA signals of early cardiac remodeling. In conclusion, the alpha-galactosidase A deficient mice at 3 to 4 months of age have cardiac and vascular alterations similar to that described in early clinical stage of Fabry disease in children and adolescents. Enzyme replacement therapy affects cardiac molecular remodeling after a single dose.

  20. Cardiomyopathy and Response to Enzyme Replacement Therapy in a Male Mouse Model for Fabry Disease

    PubMed Central

    Nguyen Dinh Cat, Aurelie; Escoubet, Brigitte; Agrapart, Vincent; Griol-Charhbili, Violaine; Schoeb, Trenton; Feng, Wenguang; Jaimes, Edgar; Warnock, David G.; Jaisser, Frederic

    2012-01-01

    Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, (predominately globotriaosylceramide; GL-3) in lysosomes, as well as other cellular compartments and the extracellular space. Our aim was to characterize the cardiac phenotype of male knock-out mice that are deficient in alpha-galactosidase A activity, as a model for Fabry disease and test the efficacy of Enzyme Replacement Therapy with agalsidase-beta. Male mice (3–4 months of age) were characterized with awake blood pressure and heart rate measurements, cardiac echocardiography and electrocardiography measurements under light anesthesia, histological studies and molecular studies with real-time polymerase chain reaction. The Fabry knock-out mouse has bradycardia and lower blood pressure than control wild type (CB7BL/6J) mice. In Fabry knock-out mice, the cardiomyopathy associated mild hypertrophy at echography with normal systolic LV function and mild diastolic dysfunction. Premature atrial contractions were more frequent in without conduction defect. Heart weight normalized to tibial length was increased in Fabry knock-out mice. Ascending aorta dilatation was observed. Molecular studies were consistent with early stages of cardiac remodeling. A single dose of agalsidase-beta (3 mg/kg) did not affect the LV hypertrophy, function or heart rate, but did improve the mRNA signals of early cardiac remodeling. In conclusion, the alpha-galactosidase A deficient mice at 3 to 4 months of age have cardiac and vascular alterations similar to that described in early clinical stage of Fabry disease in children and adolescents. Enzyme replacement therapy affects cardiac molecular remodeling after a single dose. PMID:22574107

  1. Surges in proteinuria are associated with plasma GL-3 elevations in a young patient with classic Fabry disease.

    PubMed

    Kanai, Takahiro; Ito, Takane; Odaka, Jun; Saito, Takashi; Aoyagi, Jun; Betsui, Hiroyuki; Yamagata, Takanori

    2016-03-01

    Fabry disease is an X-linked glycosphingolipidosis caused by deficient synthesis of the enzyme α-galactosidase A, which results in accumulations of globotriaosylceramide (GL-3) in systemic tissues. Nephropathy is a dominant feature of Fabry disease. It still remains unclear how the nephropathy progresses. Recombinant agalsidase replacement therapy is currently the only approved, specific therapy for Fabry disease. The optimal dose of replacement enzyme also still remains unclear. The worldwide shortage of agalsidase-β in 2009 forced dose reduction of administration. It showed that the proteinuria emerged like surges, followed by temporary plasma GL-3 elevations in the early stages of classic Fabry disease. Additionally, it also showed that 1 mg/kg of agalsidase-β every other week could clear the GL-3 accumulations from podocytes and was required to maintain negative proteinuria and normal plasma GL-3 levels. This observation of a young patient with classic Fabry disease about 5 years reveals that the long-term, low-dose agalsidase-β caused proteinuria surges, but not persistent proteinuria, followed by temporary plasma GL-3 elevations, and agalsidase-β at 1 mg/kg every other week could clear accumulated GL-3 from podocytes and was required to maintain normal urinalysis and plasma GL-3 levels.

  2. MALDI-TOF and cluster-TOF-SIMS imaging of Fabry disease biomarkers

    NASA Astrophysics Data System (ADS)

    Touboul, David; Roy, Sandrine; Germain, Dominique P.; Chaminade, Pierre; Brunelle, Alain; Laprevote, Olivier

    2007-02-01

    Fabry disease is an X-linked disorder of glycosphingolipid metabolism, in which a partial or total deficiency of [alpha]-galactosidase A, a lysosomal enzyme, results in the progressive accumulation of neutral glycosphingolipids (globotriaosylceramide and digalactosylceramide) in most fluids and tissues of the body. Few information is available about the composition and distribution in tissues of the accumulated glycosphingolipids species. Mass spectrometry imaging is an innovative technique, which can provide pieces of information about the distribution of numerous biological compounds, such as lipids, directly on the tissue sections. MALDI-TOF and cluster-TOF-SIMS imaging approaches were used to study the localization of lipids (cholesterol, cholesterol sulfate, vitamin E, glycosphingolipids ...) on skin and kidney sections of patients affected by the Fabry disease. Numerous information on pathophysiology were enlightened by both techniques.

  3. [Heart involvement in Anderson-Fabry disease: Italian recommendations for diagnostic, follow-up and therapeutic management].

    PubMed

    Pieruzzi, Federico; Pieroni, Maurizio; Zachara, Elisabetta; Marziliano, Nicola; Morrone, Amelia; Cecchi, Franco

    2015-11-01

    Anderson-Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations of the GLA gene that encodes alpha-galactosidase A. It is characterized by a multisystemic involvement: the renal, neurological, heart, cochleovestibular and cutaneous systems are the most damaged. Morbidity and mortality of Anderson-Fabry disease depend on renal insufficiency, heart failure and nervous system involvement. Left ventricular hypertrophy is the most common cardiac manifestation followed by conduction system disease, valve dysfunction, and arrhythmias. Mild to moderate left ventricular hypertrophy may simulate a non-obstructive hypertrophic cardiomyopathy. Management of Anderson-Fabry disease starting from the diagnosis of cardiac involvement, the prevention of complications, the therapeutic aspects, up to appropriate clinical follow-up, requires a multidisciplinary approach. According to recent management guidelines, only few evidence-based data are available to guide the clinical and therapeutic approach to this rare disease. An Italian Board, composed by nephrologists, cardiologists, geneticists, pediatricians and neurologists has been established in order to approve by consensus a diagnostic and therapeutic management protocol. The authors report the results of this cardiologic management consensus.

  4. Gastrointestinal manifestations of Fabry disease: clinical response to enzyme replacement therapy.

    PubMed

    Banikazemi, Maryam; Ullman, Thomas; Desnick, Robert J

    2005-08-01

    Gastrointestinal symptoms are often an early and prominent manifestation of Fabry disease, an X-linked inborn error of metabolism caused by the deficient activity of the lysosomal enzyme, alpha-galactosidase A. This enzyme deficiency results in the progressive accumulation of globotriaosylceramide and other glycosphingolipids in tissue lysosomes throughout the body. In classically affected patients, glycosphingolipid accumulation in the vascular endothelium eventually culminates in life-threatening renal, cardiac, and cerebrovascular disease. In addition, over 50% of patients experience post-prandial abdominal pain and diarrhea that interferes with the ability to work and quality of life. Here, we describe four males aged 17-40 years with classic Fabry disease and severe gastrointestinal symptoms who participated in clinical trials of enzyme replacement therapy with agalsidase beta (Fabrazyme, 1 mg/kg every 2 weeks). Before therapy, the three adult patients experienced post-prandial abdominal pain, bloating, and severe diarrhea with 7-10 bowel movements per day every day and the 17-year-old had weekly episodes of diarrhea with six bowel movements per day. Other symptoms included vomiting, food intolerance, and poor weight gain. All patients took medications for these symptoms (diphenoxylate-atropine [Lomotil], ranitidine hydrochloride [Zantac], or sulfasalazine). After 6-7 months of agalsidase beta therapy, all patients reported "no or only occasional" abdominal pain or diarrhea, had discontinued their gastrointestinal medications, and had gained 3-8 kg. These marked improvements in gastrointestinal symptoms have persisted for over 3 years of treatment. In such patients, enzyme replacement at 1 mg/kg effects an early and significant clinical improvement in the gastrointestinal manifestations of Fabry disease.

  5. Fabry disease in children: correlation between ocular manifestations, genotype and systemic clinical severity.

    PubMed

    Allen, L E; Cosgrave, E M; Kersey, J P; Ramaswami, U

    2010-12-01

    Fabry disease is an X linked lysosomal disorder associated with severe multiorgan failure and premature death. This study aims to determine the prevalence of ophthalmic manifestations in children with the condition and investigate the correlation with genotype and systemic disease severity. The records of 26 children from 18 pedigrees with Fabry disease undergoing regular ophthalmic and systemic examination were reviewed. All pedigrees underwent GLA gene sequencing to determine genotype. Correlations between ocular and systemic phenotype and genotype were investigated. Corneal verticillata occurred in 50% of the children in this study (95% CI, 29% to 79%). Children with ophthalmic manifestations were more likely to have loss-of-function GLA mutations (p=0.003). Retinal vascular tortuosity was seen in seven children (27%), all of whom had systemic symptoms suggestive of autonomic neuropathy, such as diarrhoea and syncope. These symptoms seemed less prevalent in children without retinal vascular changes, although this did not reach statistical significance (p=0.134). Ophthalmic manifestations of Fabry disease are common even in young children with loss-of-function GLA gene mutations. Although the limited sample size possibly prevented statistical significance, systemic symptoms of autonomic neuropathy often coexist with retinal vascular changes and may share the same pathogenesis.

  6. Modelling the resource implications of managing adults with Fabry disease in Italy.

    PubMed

    Guest, Julian F; Concolino, Daniela; Di Vito, Raffaele; Feliciani, Claudio; Parini, Rossella; Zampetti, Anna

    2011-07-01

    This study estimated the resource implications and budget impact of managing adults with Fabry disease in Italy, from the perspective of the Servizio Sanitario Nazionale (SSN). A decision model was constructed using published clinical outcomes and clinician-derived resource utilisation estimates depicting the management of adults with Fabry disease in Italy. The expected annual cost of managing 220 existing and 20 new Fabry patients in Italy was estimated to be €28·3 million. In an average year, patients receiving enzyme replacement therapy (ERT) with 0·2 mg kg(-1) agalsidase alfa (Replagal; Shire Human Genetic Therapies, Basingstoke, Hampshire, UK) or 1·0 mg kg(-1) agalsidase beta (Fabrazyme; Genzyme Europe BV, Naarden, The Netherlands) are collectively expected to make 4500 hospital attendances to a day ward for infusions, which equates to 2000 eight-h days on the day ward associated with ERT. If all ERT-treated patients received their infusions at home, there would be a marginal reduction in the annual health care cost to manage these patients, and the total annual number of days on the day ward associated with ERT in the second year could potentially be reduced from a mean 2000 to zero, thereby releasing substantial hospital resources for use by non-Fabry patients. Currently, only agalsidase alfa is licensed for home treatment in Italy; hence, only patients receiving this enzyme could be offered home treatment. Use of agalsidase alfa (0·2 mg kg(-1) ) instead of agalsidase beta (1·0 mg kg(-1)) has the potential to reduce health care costs and release hospital resources in different specialities for alternative use by non-Fabry patients, thereby improving the efficiency of the public health care system in Italy. © 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.

  7. Significant improvement in Fabry disease podocytopathy after 3 years of treatment with agalsidase beta.

    PubMed

    Ito, Shuichi; Ogura, Masao; Kamei, Koichi; Matsuoka, Kentaro; Warnock, David G

    2016-08-01

    Fabry disease is an X-linked lysosomal disorder caused by decreased activity of α-galactosidase A (GLA). Consequent accumulation of globotriaosylceramide (GL-3) in lysosomes results in damage to a variety of organs, including the kidneys. Enzyme replacement therapy (ERT) is an effective treatment, but whether it should be started before organ damage is evident is a matter of debate. A 10-year-old boy who complained of severe sole pain for 3 years had been misdiagnosed with juvenile idiopathic arthritis. Further investigations revealed decreased GLA activity and a M1T mutation in the GLA gene causing protein truncation, suggestive of Fabry disease. Despite normal renal function and urinalysis, renal biopsy showed abnormal structure, with marked accumulation of GL-3 in podocytes, partial effacement of foot processes and irregularly reduced expression of nephrin in the slit diaphragm. After 1 year of ERT with 1 mg/kg agalsidase beta once every 2 weeks, his pain had resolved with ERT combined with carbamazepine and pregabalin. After 3 years of the ERT, repeat biopsy showed little renal GL-3 deposition, resolution of foot process effacement, and a dramatic improvement in nephrin expression. There may be a window of opportunity in which pain and renal injury can be addressed in the early stages of Fabry disease. Early initiation of ERT should therefore be considered for children with Fabry disease.

  8. A Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometric Assay for the Quantification of Fabry Disease Biomarker Globotriaosylceramide (GB3) in Fabry Model Mouse.

    PubMed

    Shin, Seok-Ho; Park, Min-Ho; Byeon, Jin-Ju; Lee, Byeong Ill; Park, Yuri; Ko, Ah-Ra; Seong, Mi-Ran; Lee, Soyeon; Kim, Mi Ra; Seo, Jinwook; Jung, Myung Eun; Jin, Dong-Kyu; Shin, Young G

    2018-06-07

    Fabry disease is a rare lysosomal storage disorder resulting from the lack of α-Gal A gene activity. Globotriaosylceramide (GB3, ceramide trihexoside) is a novel endogenous biomarker which predicts the incidence of Fabry disease. At the early stage efficacy/biomarker study, a rapid method to determine this biomarker in plasma and in all relevant tissues related to this disease simultaneously is required. However, the limited sample volume, as well as the various levels of GB3 in different matrices makes the GB3 quantitation very challenging. Hereby we developed a rapid method to identify GB3 in mouse plasma and various tissues. Preliminary stability tests were also performed in three different conditions: short-term, freeze-thaw, long-term. The calibration curve was well fitted over the concentration range of 0.042⁻10 μg/mL for GB3 in plasma and 0.082⁻20 μg/g for GB3 in various tissues. This method was successfully applied for the comparison of GB3 levels in Fabry model mice (B6;129-Gla tm1Kul /J), which has not been performed previously to the best of our knowledge.

  9. Enzyme replacement therapy for Anderson-Fabry disease.

    PubMed

    El Dib, Regina; Gomaa, Huda; Carvalho, Raíssa Pierri; Camargo, Samira E; Bazan, Rodrigo; Barretti, Pasqual; Barreto, Fellype C

    2016-07-25

    Anderson-Fabry disease is an X-linked defect of glycosphingolipid metabolism. Progressive renal insufficiency is a major source of morbidity, additional complications result from cardio- and cerebro-vascular involvement. Survival is reduced among affected males and symptomatic female carriers.This is an update of a Cochrane review first published in 2010, and previously updated in 2013. To evaluate the effectiveness and safety of enzyme replacement therapy compared to other interventions, placebo or no interventions, for treating Anderson-Fabry disease. We searched the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register (date of the most recent search: 08 July 2016). We also searched 'Clinical Trials' on The Cochrane Library, MEDLINE, Embase and LILACS (date of the most recent search: 24 September 2015). Randomized controlled trials of agalsidase alfa or beta in participants diagnosed with Anderson-Fabry disease. Two authors selected relevant trials, assessed methodological quality and extracted data. Nine trials comparing either agalsidase alfa or beta in 351 participants fulfilled the selection criteria.Both trials comparing agalsidase alfa to placebo reported on globotriaosylceramide concentration in plasma and tissue; aggregate results were non-significant. One trial reported pain scores measured by the Brief Pain Inventory severity, there was a statistically significant improvement for participants receiving treatment at up to three months, mean difference -2.10 (95% confidence interval -3.79 to -0.41; at up to five months, mean difference -1.90 (95% confidence interval -3.65 to -0.15); and at up to six months, mean difference -2.00 (95% confidence interval -3.66 to -0.34). There was a significant difference in the Brief Pain Inventory pain-related quality of life at over five months and up to six months, mean difference -2.10 (95% confidence interval -3.92 to -0.28) but not at other time points. Death was not an outcome

  10. Identification of a Novel GLA Mutation (L206 P) in a Patient with Fabry Disease.

    PubMed

    Kim, Ji-Hoon; Kim, Gee-Hee; Park, Hoon-Suk; Choi, Jin-A; Bae, Jung-Min; Cho, Uiju

    2017-03-01

    We report a new α-Galactosidase A (αGal-A) mutation in a 39-year-old Korean born, male Fabry disease patient. Fabry disease is a devastating, progressive inborn error of metabolism caused by X-linked genetic mutations. In this case, the first clinical symptom to occur was in childhood consisting of a burning pain originating in the extremities then radiating inwards to the limbs. This patient also stated to have ringing in his ears, angiokeratomas on his trunk, and cornea verticillata. He visited an outpatient cardiologist due to intermittent and atypical chest discomfort at the age of 39. Electrocardiographic and echocardiographic examination showed left ventricular hypertrophy. A physical examination revealed proteinuria without hematuria. The patient's plasma αGal-A activity was markedly lower than the mean value of the controls. After genetic counseling and obtaining written informed consent, we identified one hemizygous mutation in exon 4 of galactosidase alpha, c.617T>C (p.Leu206 Pro). He was eventually diagnosed as having Fabry disease.

  11. Time to treatment benefit for adult patients with Fabry disease receiving agalsidase β: data from the Fabry Registry

    PubMed Central

    Ortiz, Alberto; Abiose, Ademola; Bichet, Daniel G; Cabrera, Gustavo; Charrow, Joel; Germain, Dominique P; Hopkin, Robert J; Jovanovic, Ana; Linhart, Aleš; Maruti, Sonia S; Mauer, Michael; Oliveira, João P; Patel, Manesh R; Politei, Juan; Waldek, Stephen; Wanner, Christoph; Yoo, Han-Wook; Warnock, David G

    2016-01-01

    Background Agalsidase β is a form of enzyme replacement therapy for Fabry disease, a genetic disorder characterised by low α-galactosidase A activity, accumulation of glycosphingolipids and life-threatening cardiovascular, renal and cerebrovascular events. In clinical trials, agalsidase β cleared glycolipid deposits from endothelial cells within 6 months; clearance from other cell types required sustained treatment. We hypothesised that there might be a ‘lag time’ to clinical benefit after initiating agalsidase β treatment, and analysed the incidence of severe clinical events over time in patients receiving agalsidase β. Methods The incidence of severe clinical events (renal failure, cardiac events, stroke, death) was studied in 1044 adult patients (641 men, 403 women) enrolled in the Fabry Registry who received agalsidase β (average dose 1 mg/kg every 2 weeks) for up to 5 years. Results The incidence of all severe clinical events was 111 per 1000 person-years (95% CI 84 to 145) during the first 6 months. After 6 months, the incidence decreased and remained stable within the range of 40–58 events per 1000 patient-years. The largest decrease in incidence rates was among male patients and those aged ≥40 years when agalsidase β was initiated. Conclusions Contrary to the expected increased incidence of severe clinical events with time, adult patients with Fabry disease had decreased incidence of severe clinical events after 6 months treatment with agalsidase β 1 mg/kg every 2 weeks. Trial registration number NCT00196742. PMID:26993266

  12. A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease.

    PubMed

    Lee, Karen; Jin, Xiaoying; Zhang, Kate; Copertino, Lorraine; Andrews, Laura; Baker-Malcolm, Jennifer; Geagan, Laura; Qiu, Huawei; Seiger, Keirsten; Barngrover, Debra; McPherson, John M; Edmunds, Tim

    2003-04-01

    Fabry disease is a lysosomal storage disease arising from deficiency of the enzyme alpha-galactosidase A. Two recombinant protein therapeutics, Fabrazyme (agalsidase beta) and Replagal (agalsidase alfa), have been approved in Europe as enzyme replacement therapies for Fabry disease. Both contain the same human enzyme, alpha-galactosidase A, but they are produced using different protein expression systems and have been approved for administration at different doses. To determine if there is recognizable biochemical basis for the different doses, we performed a comparison of the two drugs, focusing on factors that are likely to influence biological activity and availability. The two drugs have similar glycosylation, both in the type and location of the oligosaccharide structures present. Differences in glycosylation were mainly limited to the levels of sialic acid and mannose-6-phosphate present, with Fabrazyme having a higher percentage of fully sialylated oligosaccharides and a higher level of phosphorylation. The higher levels of phosphorylated oligomannose residues correlated with increased binding to mannose-6-phosphate receptors and uptake into Fabry fibroblasts in vitro. Biodistribution studies in a mouse model of Fabry disease showed similar organ uptake. Likewise, antigenicity studies using antisera from Fabry patients demonstrated that both drugs were indistinguishable in terms of antibody cross-reactivity. Based on these studies and present knowledge regarding the influence of glycosylation on protein biodistribution and cellular uptake, the two protein preparations appear to be functionally indistinguishable. Therefore, the data from these studies provide no rationale for the use of these proteins at different therapeutic doses.

  13. Cilioretinal artery occlusion and anterior ischemic optic neuropathy as the initial presentation in a child female carrier of Fabry disease.

    PubMed

    Ersoz, M Giray; Ture, Gamze

    2018-04-01

    To report the youngest female carrier of Fabry disease, complicated by cilioretinal artery occlusion and anterior ischemic optic neuropathy (AION). Case report. An 11-year-old girl was referred to our clinic with painless, acute loss of vision in her right eye. Posterior segment examination and fluorescein angiography revealed cilioretinal artery occlusion and AION. Systemic evaluations were unremarkable, except for a low blood α-galactosidase A enzyme level of 242.27 pmol/spot*20 h (reference range: 450-2000 pmol/spot*20 h). The patient was diagnosed with female carrier of Fabry disease. Retinal vascular occlusions are rare in childhood, and Fabry disease may present with retinal vascular occlusion. Ophthalmological examinations may be contributing for early detection of the disease. To the best of our knowledge, this is the first report of a child female carrier of Fabry disease, complicated by cilioretinal artery occlusion and AION.

  14. Nano-LC-MS/MS for Quantification of Lyso-Gb3 and Its Analogues Reveals a Useful Biomarker for Fabry Disease

    PubMed Central

    Sueoka, Hideaki; Ichihara, Junji; Tsukimura, Takahiro; Togawa, Tadayasu; Sakuraba, Hitoshi

    2015-01-01

    Biomarkers useful for diagnosis and evaluation of treatment for patients with Fabry disease are urgently needed. Recently, plasma globotriaosylsphingosine (lyso-Gb3) and lyso-Gb3-related analogues have attracted attention as promising biomarkers of Fabry disease. However, the plasma concentrations of lyso-Gb3 and its analogues are extremely low or below the detection limits in some Fabry patients as well as in healthy subjects. In this paper, we introduce the novel application of a nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) system to the measurement of lyso-Gb3 and its analogues in plasma. Nano-LC-MS/MS requires smaller amounts of samples and is more sensitive than conventional techniques. Using this method, we measured the plasma concentrations of lyso-Gb3 and its analogues in 40 healthy subjects, 5 functional variants (males with E66Q), and various Fabry patients (9 classic Fabry males/9 mutations; 7 later-onset Fabry males/5 mutations; and 10 Fabry females/9 mutations). The results revealed that the mean lyso-Gb3 and lyso-Gb3(-2) concentrations in all the Fabry patient subgroups were statistically higher, especially in the classic Fabry males, than those in the functional variants and healthy subjects. The plasma concentrations of lyso-Gb3 and its analogues in healthy subjects, functional variants, and some Fabry patients with specific mutations (R112H and M296I) that cannot be established by conventional techniques were successfully determined by means of nano-LC-MS/MS. The lyso-Gb3 and lyso-Gb3(-2) concentrations in male patients with these mutations were lower than those in most Fabry patients having other mutations, but higher than those in the functional variants and healthy subjects. This new method is expected to be useful for sensitive determination of the plasma concentrations of lyso-Gb3 and its analogues. This study also revealed that not only lyso-Gb3 but also lyso-Gb3(-2) in plasma is a useful biomarker for the diagnosis of

  15. Neuropathic symptoms and findings in women with Fabry disease.

    PubMed

    Laaksonen, Satu M; Röyttä, Matias; Jääskeläinen, Satu K; Kantola, Ilkka; Penttinen, Maila; Falck, Björn

    2008-06-01

    To examine the neurologic and neurophysiologic findings and neurologic symptoms in 12 women with Fabry disease and to study the relationship between the subjective symptoms and the findings on the various tests done. Neurography, vibratory and thermal quantitative sensory testing (QST), skin biopsy for measuring intraepidermal nerve fiber density (IENFD). Heart rate variability (HRV) and sympathetic skin response (SSR) tests for detecting autonomic dysfunction, pain-, depression- and somatic symptom questionnaires and clinical examination. Only two women had no persistent symptoms or signs of polyneuropathy, 10 had symptoms of small fiber neuropathy. Neurological examination was normal in most patients. Five patients had decreased IENFD or thermal hypoesthesia in QST. In QST, Adelta-fiber function for innocuous cold was more often impaired than C-fiber function. Conventional nerve conduction studies were mostly normal. Carpal tunnel syndrome (CTS) incidence was increased, 25% had symptomatic CTS. Heterozygous women carrying the gene for Fabry disease have symptoms and findings of small-fiber polyneuropathy more often than has previously been considered. The prevalence of CTS is also increased. While the clinical diagnosis of small-fiber neuropathy is difficult, the diagnostic yield can be increased using a combination of thermal QST and IENFD measurements.

  16. Altered Dynamics of a Lipid Raft Associated Protein in a Kidney Model of Fabry Disease

    PubMed Central

    Labilloy, Anatália; Youker, Robert T.; Bruns, Jennifer R.; Kukic, Ira; Kiselyov, Kirill; Halfter, Willi; Finegold, David; do Monte, Semiramis Jamil Hadad; Weisz, Ora A.

    2013-01-01

    Accumulation of globotriaosylceramide (Gb3) and other neutral glycosphingolipids with galactosyl residues is the hallmark of Fabry disease, a lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A (α-gal A). These lipids are incorporated into the plasma membrane and intracellular membranes, with a preference for lipid rafts. Disruption of raft mediated cell processes is implicated in the pathogenesis of several human diseases, but little is known about the effects of the accumulation of glycosphingolipids on raft dynamics in the context of Fabry disease. Using siRNA technology, we have generated a polarized renal epithelial cell model of Fabry disease in Madin-Darby canine kidney cells. These cells present increased levels of Gb3 and enlarged lysosomes, and progressively accumulate zebra bodies. The polarized delivery of both raft-associated and raft-independent proteins was unaffected by α-gal A knockdown, suggesting that accumulation of Gb3 does not disrupt biosynthetic trafficking pathways. To assess the effect of α-gal A silencing on lipid raft dynamics, we employed number and brightness (N&B) analysis to measure the oligomeric status and mobility of the model glycosylphosphatidylinositol (GPI)-anchored protein GFP-GPI. We observed a significant increase in the oligomeric size of antibody-induced clusters of GFP-GPI at the plasma membrane of α-gal A silenced cells compared with control cells. Our results suggest that the interaction of GFP-GPI with lipid rafts may be altered in the presence of accumulated Gb3. The implications of our results with respect to the pathogenesis of Fabry disease are discussed. PMID:24215843

  17. Fabry disease presenting as apical left ventricular hypertrophy in a patient carrying the missense mutation R118C.

    PubMed

    Caetano, Francisca; Botelho, Ana; Mota, Paula; Silva, Joana; Leitão Marques, António

    2014-03-01

    Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by abnormalities of the GLA gene, which encodes the enzyme α-galactosidase A. A deficiency of this enzyme leads to the lysosomal accumulation of glycosphingolipids, which may cause left ventricular hypertrophy that is typically concentric and symmetric. We present the case of a 60-year-old woman with symptoms of dyspnea, atypical chest pain and palpitations, in whom a transthoracic echocardiogram revealed an apical variant of hypertrophic cardiomyopathy. Analysis of specific sarcomeric genetic mutations was negative. The patient underwent a screening protocol for Anderson-Fabry disease, using a dried blood spot test, which was standard at our institution for patients with left ventricular hypertrophy. The enzymatic activity assay revealed reduced α-galactosidase A enzymatic activity. Molecular analysis identified a missense point mutation in the GLA gene (p.R118C). This case report shows that Anderson-Fabry disease may cause an apical form of left ventricular hypertrophy. The diagnosis was only achieved because of systematic screening, which highlights the importance of screening for Anderson-Fabry disease in patients with unexplained left ventricular hypertrophy, including those presenting with more unusual patterns, such as apical variants of left ventricular hypertrophy. This case also supports the idea that the missense mutation R118C is indeed a true pathogenic mutation of Anderson-Fabry disease. Copyright © 2012 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  18. Metabolomic Discovery of Novel Urinary Galabiosylceramide Analogs as Fabry Disease Biomarkers

    NASA Astrophysics Data System (ADS)

    Boutin, Michel; Auray-Blais, Christiane

    2015-03-01

    Fabry disease is an X-linked, complex, multisystemic lysosomal storage disorder presenting marked phenotypic and genotypic variability among affected male and female patients. Glycosphingolipids, mainly globotriaosylceramide (Gb3) isoforms/analogs, globotriaosylsphingosine (lyso-Gb3) and analogs, as well as galabiosylceramide (Ga2) isoforms/analogs accumulate in the vascular endothelium, nerves, cardiomyocytes, renal glomerular and tubular epithelial cells, and biological fluids. The search for biomarkers reflecting disease severity and progression is still on-going. A metabolomic study using quadrupole time-of-flight mass spectrometry has revealed 22 galabiosylceramide isoforms/analogs in urine of untreated Fabry patients classified in seven groups according to their chemical structure: (1) Saturated fatty acid; (2) one extra double bond; (3) two extra double bonds; (4) hydroxylated saturated fatty acid; (5) hydroxylated fatty acid and one extra double bond; (6) hydrated sphingosine and hydroxylated fatty acid; (7) methylated amide linkage. Relative quantification of both Ga2 and Gb3 isoforms/analogs was performed. All these biomarkers are significantly more abundant in urine samples from untreated Fabry males compared with healthy male controls. A significant amount of Ga2 isoforms/analogs, accounting for 18% of all glycosphingolipids analyzed (Ga2 + Gb3 and respective isoforms/analogs), were present in urine of Fabry patients. Gb3 isoforms containing saturated fatty acids are the most abundant (60.9%) compared with 26.3% for Ga2. A comparison between Ga2 isoforms/analogs and their Gb3 counterparts also showed that the proportion of analogs with hydroxylated fatty acids is significantly greater for Ga2 (35.8%) compared with Gb3 (1.9%). These results suggest different biological pathways involved in the synthesis and/or degradation of Gb3 and Ga2 metabolites.

  19. Time to treatment benefit for adult patients with Fabry disease receiving agalsidase β: data from the Fabry Registry.

    PubMed

    Ortiz, Alberto; Abiose, Ademola; Bichet, Daniel G; Cabrera, Gustavo; Charrow, Joel; Germain, Dominique P; Hopkin, Robert J; Jovanovic, Ana; Linhart, Aleš; Maruti, Sonia S; Mauer, Michael; Oliveira, João P; Patel, Manesh R; Politei, Juan; Waldek, Stephen; Wanner, Christoph; Yoo, Han-Wook; Warnock, David G

    2016-07-01

    Agalsidase β is a form of enzyme replacement therapy for Fabry disease, a genetic disorder characterised by low α-galactosidase A activity, accumulation of glycosphingolipids and life-threatening cardiovascular, renal and cerebrovascular events. In clinical trials, agalsidase β cleared glycolipid deposits from endothelial cells within 6 months; clearance from other cell types required sustained treatment. We hypothesised that there might be a 'lag time' to clinical benefit after initiating agalsidase β treatment, and analysed the incidence of severe clinical events over time in patients receiving agalsidase β. The incidence of severe clinical events (renal failure, cardiac events, stroke, death) was studied in 1044 adult patients (641 men, 403 women) enrolled in the Fabry Registry who received agalsidase β (average dose 1 mg/kg every 2 weeks) for up to 5 years. The incidence of all severe clinical events was 111 per 1000 person-years (95% CI 84 to 145) during the first 6 months. After 6 months, the incidence decreased and remained stable within the range of 40-58 events per 1000 patient-years. The largest decrease in incidence rates was among male patients and those aged ≥40 years when agalsidase β was initiated. Contrary to the expected increased incidence of severe clinical events with time, adult patients with Fabry disease had decreased incidence of severe clinical events after 6 months treatment with agalsidase β 1 mg/kg every 2 weeks. NCT00196742. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  20. Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer

    PubMed Central

    Takahashi, Hiroshi; Hirai, Yukihiko; Migita, Makoto; Seino, Yoshihiko; Fukuda, Yuh; Sakuraba, Hitoshi; Kase, Ryoichi; Kobayashi, Toshihide; Hashimoto, Yasuhiro; Shimada, Takashi

    2002-01-01

    Fabry disease is a systemic disease caused by genetic deficiency of a lysosomal enzyme, α-galactosidase A (α-gal A), and is thought to be an important target for enzyme replacement therapy. We studied the feasibility of gene-mediated enzyme replacement for Fabry disease. The adeno-associated virus (AAV) vector containing the α-gal A gene was injected into the right quadriceps muscles of Fabry knockout mice. A time course study showed that α-gal A activity in plasma was increased to ≈25% of normal mice and that this elevated activity persisted for up to at least 30 weeks without development of anti-α-gal A antibodies. The α-gal A activity in various organs of treated Fabry mice remained 5–20% of those observed in normal mice. Accumulated globotriaosylceramide in these organs was completely cleared by 25 weeks after vector injection. Reduction of globotriaosylceramide levels was also confirmed by immunohistochemical and electronmicroscopic analyses. Echocardiographic examination of treated mice demonstrated structural improvement of cardiac hypertrophy 25 weeks after the treatment. AAV vector-mediated muscle-directed gene transfer provides an efficient and practical therapeutic approach for Fabry disease. PMID:12370426

  1. Cardiovascular testing in Fabry disease: exercise capacity reduction, chronotropic incompetence and improved anaerobic threshold after enzyme replacement.

    PubMed

    Lobo, T; Morgan, J; Bjorksten, A; Nicholls, K; Grigg, L; Centra, E; Becker, G

    2008-06-01

    The aim of this study was to document exercise capacity and serial electrocardiogram and echocardiograph findings in a cohort of Australian patients with Fabry disease, in relation to their history of enzyme replacement therapy (ERT). Fabry disease has multifactorial effects on the cardiovascular system. Most previous studies have focused on electrocardiographic and echocardiographic parameters. Exercise capacity can be used as an integrated measure of cardiovascular function and allows the effects of treatment to be monitored. A total of 38 patients (30 men and 8 women) with Fabry disease were monitored by 12-lead electrocardiograms every 6-12 months, and by annual standardized-protocol echocardiograms. Bicycle stress tests with VO(2) max measurement and once-only 6 minutes' walk tests were also carried out in subsets of patients whose general health status allowed testing. Seventy per cent of patients met electrocardiogram criteria for left ventricular hypertrophy. Left ventricular hypertrophy on echocardiograph was present in 64% of patients (80% of men). Exercise capacity was reduced in patients with Fabry disease compared with that predicted from normative population data. Mild improvement in anaerobic threshold was seen in the first year of ERT (14.1 +/- 3.0 to 15.8 +/- 3.0, P = 0.02), but no consistent further increase was seen beyond the first year. Most patients had resting bradycardia, with impaired ability to increase heart rate during exercise. Serial testing on ERT showed an improvement in anaerobic threshold but no significant change in VO(2) max. Male patients with Fabry disease were unable to attain predicted maximal heart rate on exercise or to achieve normal exercise levels. ERT was associated with a small improvement in anaerobic threshold over the first year.

  2. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease.

    PubMed

    Germain, Dominique P; Charrow, Joel; Desnick, Robert J; Guffon, Nathalie; Kempf, Judy; Lachmann, Robin H; Lemay, Roberta; Linthorst, Gabor E; Packman, Seymour; Scott, C Ronald; Waldek, Stephen; Warnock, David G; Weinreb, Neal J; Wilcox, William R

    2015-05-01

    Fabry disease results from deficient α-galactosidase A activity and globotriaosylceramide accumulation causing renal insufficiency, strokes, hypertrophic cardiomyopathy and early demise. We assessed the 10-year outcome of recombinant α-galactosidase A therapy. The outcomes (severe clinical events, renal function, cardiac structure) of 52/58 patients with classic Fabry disease from the phase 3 clinical trial and extension study, and the Fabry Registry were evaluated. Disease progression rates for patients with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline were assessed. 81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period. Ten patients reported a total of 16 events. Patients classified as LRI started therapy 13 years younger than HRI (mean 25 years vs 38 years). Mean slopes for estimated glomerular filtration rate for LRI and HRI were -1.89 mL/min/1.73 m(2)/year and -6.82 mL/min/1.73 m(2)/year, respectively. Overall, the mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal. Patients who initiated treatment at age ≥ 40 years exhibited significant increase in left ventricular posterior wall thickness and interventricular septum thickness. Mean plasma globotriaosylceramide normalised within 6 months. This 10-year study documents the effectiveness of agalsidase beta (1 mg/kg/2 weeks) in patients with Fabry disease. Most patients remained alive and event-free. Patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy. Patients who initiated treatment at older ages and/or had advanced renal disease experienced disease progression. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  3. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease

    PubMed Central

    Germain, Dominique P; Charrow, Joel; Desnick, Robert J; Guffon, Nathalie; Kempf, Judy; Lachmann, Robin H; Lemay, Roberta; Linthorst, Gabor E; Packman, Seymour; Scott, C Ronald; Waldek, Stephen; Warnock, David G; Weinreb, Neal J; Wilcox, William R

    2015-01-01

    Background Fabry disease results from deficient α-galactosidase A activity and globotriaosylceramide accumulation causing renal insufficiency, strokes, hypertrophic cardiomyopathy and early demise. We assessed the 10-year outcome of recombinant α-galactosidase A therapy. Methods The outcomes (severe clinical events, renal function, cardiac structure) of 52/58 patients with classic Fabry disease from the phase 3 clinical trial and extension study, and the Fabry Registry were evaluated. Disease progression rates for patients with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline were assessed. Results 81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period. Ten patients reported a total of 16 events. Patients classified as LRI started therapy 13 years younger than HRI (mean 25 years vs 38 years). Mean slopes for estimated glomerular filtration rate for LRI and HRI were −1.89 mL/min/1.73 m2/year and −6.82 mL/min/1.73 m2/year, respectively. Overall, the mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal. Patients who initiated treatment at age ≥40 years exhibited significant increase in left ventricular posterior wall thickness and interventricular septum thickness. Mean plasma globotriaosylceramide normalised within 6 months. Conclusions This 10-year study documents the effectiveness of agalsidase beta (1 mg/kg/2 weeks) in patients with Fabry disease. Most patients remained alive and event-free. Patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy. Patients who initiated treatment at older ages and/or had advanced renal disease experienced disease progression. PMID:25795794

  4. Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study.

    PubMed

    Germain, Dominique P; Brand, Eva; Burlina, Alessandro; Cecchi, Franco; Garman, Scott C; Kempf, Judy; Laney, Dawn A; Linhart, Aleš; Maródi, László; Nicholls, Kathy; Ortiz, Alberto; Pieruzzi, Federico; Shankar, Suma P; Waldek, Stephen; Wanner, Christoph; Jovanovic, Ana

    2018-04-12

    The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3%). p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males. © 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

  5. Genetic polymorphisms of vitamin D receptor (VDR) in Fabry disease.

    PubMed

    Teitcher, Michael; Weinerman, Sarah; Whybra, Catharina; Beck, Michael; Sharon, Nir; Elstein, Deborah; Altarescu, Gheona

    2008-11-01

    Fabry disease, an X-linked inborn error of metabolism, is characterized by multi-organ involvement including cardiac signs of left ventricular hypertrophy and abnormal intima-medial (IMT) thickening of arteries, progressive renal failure, neurological involvement, and more. The vitamin D receptor (VDR) and an enzyme producing vitamin D3 result in an autocrine loop with direct effects on blood vessels. The purpose of this study is to assess VDR polymorphisms (BsmI, FokI, ApaI, and TaqI) relative to clinically important disease parameters using a disease-specific severity score (MSSI) and haplotype analysis. There were statistically significant differences between females (43% of 74 patients) and males in MSSI total scores, and in general and neurologic sub-scores. There appears to be a protective effect of the TaqI tt genotype so that there were significantly lower scores in clinical categories between those with the tt genotype versus those with the TT genotype. Multivariate models of haplotypes with MSSI scores reveal that T-A-f-B and t-a-F-b haplotypes of the VDR gene polymorphisms are significantly associated with variation in the Fabry phenotype. Despite the limitations of using the MSSI score as a clinical correlate, these results are provocative and further studies in larger cohorts with more males are recommended.

  6. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel

    PubMed Central

    2011-01-01

    Background Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. Methods An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. Results We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e.g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. Conclusions Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be

  7. The effect of enzyme replacement therapy on clinical outcomes in paediatric patients with Fabry disease - A systematic literature review by a European panel of experts.

    PubMed

    Spada, Marco; Baron, Ralf; Elliott, Perry M; Falissard, Bruno; Hilz, Max J; Monserrat, Lorenzo; Tøndel, Camilla; Tylki-Szymańska, Anna; Wanner, Christoph; Germain, Dominique P

    2018-04-26

    Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase, resulting in progressive accumulation of globotriaosylceramide (GL-3). The disease can manifest early during childhood and adolescence. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase is the first specific treatment for Fabry disease and has been available in Europe since 2001. This paper presents the findings of a systematic literature review of clinical outcomes with ERT in paediatric patients with Fabry disease. A comprehensive systematic review of published literature on ERT in Fabry disease was conducted in January 2017. The literature analysis included all original articles reporting outcomes of ERT in paediatric patients. Treatment-related outcomes in the paediatric population were reported in six publications derived from open-label clinical trials and in 10 publications derived from observational or registry-based studies. ERT was shown to significantly reduce plasma and urine GL-3 levels in paediatric patients with Fabry disease. The effect of ERT on GL-3 clearance from renal podocytes appeared to be agalsidase dose-dependent. ERT relieved pain and improved gastrointestinal symptoms and quality of life. Based on the published literature, the use of ERT in paediatric patients can significantly clear GL-3 accumulation, ameliorate the early symptoms of Fabry disease, and improve quality of life. Treatment with ERT in paediatric patients with Fabry disease may be important to prevent further disease progression and overt organ damage. Copyright © 2018. Published by Elsevier Inc.

  8. Long-Term Dose-Dependent Agalsidase Effects on Kidney Histology in Fabry Disease.

    PubMed

    Skrunes, Rannveig; Tøndel, Camilla; Leh, Sabine; Larsen, Kristin Kampevold; Houge, Gunnar; Davidsen, Einar Skulstad; Hollak, Carla; van Kuilenburg, André B P; Vaz, Frédéric M; Svarstad, Einar

    2017-09-07

    Dose-dependent clearing of podocyte globotriaosylceramide has previously been shown in patients with classic Fabry disease treated with enzyme replacement. Our study evaluates the dose-dependent effects of agalsidase therapy in serial kidney biopsies of patients treated for up to 14 years. Twenty patients with classic Fabry disease (12 men) started enzyme replacement therapy at a median age of 21 (range =7-62) years old. Agalsidase- α or - β was prescribed for a median of 9.4 (range =5-14) years. The lower fixed dose group received agalsidase 0.2 mg/kg every other week throughout the follow-up period. The higher dose group received a range of agalsidase doses (0.2-1.0 mg/kg every other week). Dose changes were made due to disease progression, suboptimal effect, or agalsidase- β shortage. Serial kidney biopsies were performed along with clinical assessment and biomarkers and scored according to recommendations from the International Study Group of Fabry Nephropathy. No statistical differences were found in baseline or final GFR or albuminuria. Kidney biopsies showed significant reduction of podocyte globotriaosylceramide in both the lower fixed dose group (-1.39 [SD=1.04]; P =0.004) and the higher dose group (-3.16 [SD=2.39]; P =0.002). Podocyte globotriaosylceramide (Gb3) reduction correlated with cumulative agalsidase dose ( r =0.69; P =0.001). Arterial/arteriolar intima Gb3 cleared significantly in the higher dose group, all seven patients with baseline intimal Gb3 cleared the intima, one patient gained intimal Gb3 inclusions ( P =0.03), and medial Gb3 did not change statistically in either group. Residual plasma globotriaosylsphingosine levels remained higher in the lower fixed dose group (20.1 nmol/L [SD=11.9]) compared with the higher dose group (10.4 nmol/L [SD=8.4]) and correlated with cumulative agalsidase dose in men ( r =0.71; P =0.01). Reduction of podocyte globotriaosylceramide was found in patients with classic Fabry disease treated with long

  9. Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease.

    PubMed

    Goker-Alpan, Ozlem; Gambello, Michael J; Maegawa, Gustavo H B; Nedd, Khan J; Gruskin, Daniel J; Blankstein, Larry; Weinreb, Neal J

    2016-01-01

    Agalsidase alfa and agalsidase beta, recombinant enzyme preparations for treatment of Fabry disease (FD), have different approved dosing schedules: 0.2 mg/kg and 1.0 mg/kg every other week (EOW), respectively. This open-label, multicenter, exploratory phase 4 study evaluated plasma globotriaosylsphingosine (lyso-GL-3) and plasma and urine globotriaosylceramide (GL-3) levels at baseline and 2, 4, and 6 months after the switch from agalsidase alfa (0.2 mg/kg EOW for ≥12 months) to agalsidase beta (1.0 mg/kg EOW) in 15 male patients with FD. Immunoglobulin (Ig)G antidrug antibody titers were assessed, and safety was monitored throughout the study. Plasma lyso-GL-3 concentrations decreased significantly within 2 months after switch and reductions continued through month 6 (mean absolute changes, -12.8, -16.1, and -16.7 ng/mL at 2, 4, and 6 months, respectively; all P < 0.001). The mean percentage reduction from baseline was 39.5% (P < 0.001) at month 6. For plasma GL-3, the mean absolute change from baseline (-0.9 μg/mL) and percentage reduction (17.9%) at month 6 were both significant (P < 0.05). Urine GL-3 measurements showed intra-patient variability and changes from baseline were not significant. No clinical outcomes were assessed in this 6-month study, and, therefore, no conclusions can be drawn regarding the correlation of observed reductions in glycosphingolipid concentrations with clinically relevant outcomes. There were no differences in IgG antidrug antibody titers between the two enzymes. The switch from agalsidase alfa to agalsidase beta was well tolerated. Plasma lyso-GL-3 and GL-3 levels reduced after switching from agalsidase alfa to agalsidase beta, indicating that agalsidase beta has a greater pharmacodynamic effect on these markers at the recommended dose. These data further support the use of agalsidase beta 1.0 mg/kg EOW as enzyme replacement therapy in FD.

  10. Effects of enzyme replacement therapy for cardiac-type Fabry patients with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A)

    PubMed Central

    Lin, Hsiang-Yu; Liu, Hao-Chuan; Huang, Yu-Hsiu; Liao, Hsuan-Chieh; Hsu, Ting-Rong; Shen, Chia-I; Li, Shao-Tzu; Li, Cheng-Fang; Lee, Li-Hong; Lee, Pi-Chang; Huang, Chun-Kai; Chiang, Chuan-Chi; Lin, Ching-Yuang; Lin, Shuan-Pei; Niu, Dau-Ming

    2013-01-01

    Objective Current studies of newborn screening for Fabry disease in Taiwan have revealed a remarkably high prevalence of cardiac-type Fabry disease with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A). Design Retrospective cohort study. Setting Tertiary medical centre. Participants 21 patients with cardiac-type Fabry disease (15 men and 6 women) as well as 15 patients with classic Fabry disease (4 men and 11 women) treated with biweekly intravenous infusions of agalsidase β (1 mg/kg) or agalsidase α (0.2 mg/kg) for at least 6 months. Outcome measures These data were collected at the time before enzyme replacement therapy (ERT) began and followed up after ERT for at least 6 months, including patient demographics, medical history, parameter changes of cardiac status and renal functions, plasma globotriaosylsphingosine (lyso-Gb3) and Mainz Severity Score Index. Results After 6–39 months of ERT, plasma lyso-Gb3 was found to be reduced in 89% (17/19) and 93% (14/15) of patients with cardiac-type and classic Fabry disease, respectively, which indicated an improvement of disease severity. For patients with cardiac-type Fabry disease, echocardiography revealed the reduction or stabilisation of left ventricular mass index (LVMI), the thicknesses of intraventricular septum (IVS) and left posterior wall (LPW) in 83% (15/18), 83% (15/18) and 67% (12/18) of patients, respectively, as well as 77% (10/13), 73% (11/15) and 60% (9/15) for those with classic type. Most patients showed stable renal function after ERT. There were statistically significant improvements (p<0.05) between the data at baseline and those after ERT for values of plasma lyso-Gb3, LVMI, IVS, LPW and Mainz Severity Score Index. No severe clinical events were reported during the treatment. Conclusions ERT is beneficial and appears to be safe for Taiwanese patients with cardiac-type Fabry disease, as well as for those with the classic type. PMID:23864212

  11. [Enzyme replacement therapy in patients with Fabry disease: state of the art and review of the literature].

    PubMed

    Riccio, Eleonora; Capuano, Ivana; Visciano, Bianca; Marchetiello, Cristina; Petrillo, Fortunato; Pisani, Antonio

    2013-01-01

    Anderson-Fabry disease is a hereditary X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha galactosidase A. It results in the accumulation of the glycosphingolypid globotrioasoyl ceramide (Gb3 in different cells and organs, resulting in a multi-system pathology including end organ failure. Patients with Fabry disease present clinically with cardiac, renal and neurological involvement; both life expectancy and quality of life are severely compromised. The current causal treatment for Fabry disease is enzyme replacement therapy (ERT), available since 2001. The two recombinant preparations available for ERT are agalsidase alfa (Replagal) and agalsidase beta (Fabrazyme). They have both been showed to have positive effect on kidney and heart, on the symptoms of pain and quality of life. Few data to date are available on comparison of the two preparations of ERT. This article reviews evidence of the literature and shows our personal experience about the safety and efficacy of ERT.

  12. A thermodynamic assay to test pharmacological chaperones for Fabry disease.

    PubMed

    Andreotti, Giuseppina; Citro, Valentina; Correra, Antonella; Cubellis, Maria Vittoria

    2014-03-01

    The majority of the disease-causing mutations affect protein stability, but not functional sites and are amenable, in principle, to be treated with pharmacological chaperones. These drugs enhance the thermodynamic stability of their targets. Fabry disease, a disorder caused by mutations in the gene encoding lysosomal alpha-galactosidase, represents an excellent model system to develop experimental protocols to test the efficiency of such drugs. The stability of lysosomal alpha-galactosidase under different conditions was studied by urea-induced unfolding followed by limited proteolysis and Western blotting. We measured the concentration of urea needed to obtain half-maximal unfolding because this parameter represents an objective indicator of protein stability. Urea-induced unfolding is a versatile technique that can be adapted to cell extracts containing tiny amounts of wild-type or mutant proteins. It allows testing of protein stability as a function of pH, in the presence or in the absence of drugs. Results are not influenced by the method used to express the protein in transfected cells. Scarce and dispersed populations pose a problem for the clinical trial of drugs for rare diseases. This is particularly true for pharmacological chaperones that must be tested on each mutation associated with a given disease. Diverse in vitro tests are needed. We used a method based on chemically induced unfolding as a tool to assess whether a particular Fabry mutation is responsive to pharmacological chaperones, but, by no means is our protocol limited to this disease. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

  13. Comprehensive and differential long-term characterization of the alpha-galactosidase A deficient mouse model of Fabry disease focusing on the sensory system and pain development

    PubMed Central

    Biko, Lydia; Hose, Dorothea; Hofmann, Lukas; Sommer, Claudia

    2016-01-01

    Background Fabry disease is an X-linked lysosomal storage disorder due to impaired activity of alpha-galactosidase A with intracellular accumulation of globotriaosylceramide. Associated small fiber pathology leads to characteristic pain in Fabry disease. We systematically assessed sensory system, physical activity, metabolic parameters, and morphology of male and female mice with alpha-galactosidase A deficiency (Fabry ko) from 2 to 27 months of age and compared results with those of age- and gender-matched wild-type littermates of C57Bl/6J background. Results From the age of two months, male and female Fabry mice showed mechanical hypersensitivity (p < 0.001 each) compared to wild-type littermates. Young Fabry ko mice of both genders were hypersensitive to heat stimulation (p < 0.01) and developed heat hyposensitivity with aging (p < 0.05), while cold hyposensitivity was present constantly in young (p < 0.01) and old (p < 0.05) Fabry ko mice compared to wild-type littermates. Stride angle increased only in male Fabry ko mice with aging (p < 0.01) in comparison to wild-type littermates. Except for young female mice, male (p < 0.05) and female (p < 0.01) Fabry ko mice had a higher body weight than wild-type littermates. Old male Fabry ko mice were physically less active than their wild-type littermates (p < 0.05), had lower chow intake (p < 0.001), and lost more weight (p < 0.001) in a one-week treadmill experiment than wild-type littermates. Also, Fabry ko mice showed spontaneous pain protective behavior and developed orofacial dysmorphism resembling patients with Fabry disease. Conclusions Mice with alpha-galactosidase A deficiency show age-dependent and distinct deficits of the sensory system. alpha-galactosidase A-deficient mice seem to model human Fabry disease and may be helpful when studying the pathophysiology of Fabry-associated pain. PMID:27145802

  14. Modelling the resource implications of managing adults with Fabry disease in Norway favours home infusion.

    PubMed

    Guest, Julian F; Jenssen, Trond; Houge, Gunnar; Aaseboe, Willy; Tøndel, Camilla; Svarstad, Einar

    2010-12-01

    The aim of this study was to estimate the resource implications and budget impact of managing adults with Fabry disease in Norway, from the perspective of the publicly funded healthcare system. A decision model was constructed using published clinical outcomes and clinician-derived resource utilization estimates. The model was used to estimate the annual healthcare cost of managing a cohort of 64 adult Fabry patients in an average year. The expected annual cost of managing 60 existing Fabry patients and four new patients in Norway each year was estimated to be NOK 55·8 million (€6·7 million). In an average year, patients receiving enzyme replacement therapy (ERT) with agalsidase alfa (Replagal(®)) at 0·2 mg kg⁻¹ or agalsidase beta (Fabrazyme(®)) at 1·0 mg kg⁻¹ are collectively expected to make 586 attendances to their family practitioner's office for their infusions, which equates to 128 eight-hour days associated with ERT. Encouraging more patients to undergo home-based infusions has substantial potential to free-up community-based resources. In comparison, the community-related benefit that can be obtained by switching from agalsidase beta (1·0 mg kg⁻¹) to agalsidase alpha (0·2 mg kg⁻¹) is marginal, and dependent on the two doses being clinically equivalent. Maximizing the proportion of adults with Fabry disease undergoing home-based infusions has the potential to release community-based resources for alternative use by non-Fabry patients, thereby improving the efficiency of the publicly funded healthcare system in Norway. © 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.

  15. Cost-effectiveness of enzyme replacement therapy for Fabry disease.

    PubMed

    Rombach, Saskia M; Hollak, Carla E M; Linthorst, Gabor E; Dijkgraaf, Marcel G W

    2013-02-19

    The cost-effectiveness of enzyme replacement therapy (ERT) compared to standard medical care was evaluated in the Dutch cohort of patients with Fabry disease. Cost-effectiveness analysis was performed using a life-time state-transition model. Transition probabilities, effectiveness data and costs were derived from retrospective data and prospective follow-up of the Dutch study cohort consisting of males and females aged 5-78 years. Intervention with ERT (either agalsidase alfa or agalsidase beta) was compared to the standard medical care. The main outcome measures were years without end organ damage (renal, cardiac en cerebrovascular complications), quality adjusted life years (QALYs), and costs. Over a 70 year lifetime, an untreated Fabry patient will generate 55.0 years free of end-organ damage (53.5 years in males, 56.9 years in females) and 48.6 QALYs (47.8 in males, 49.7 in females). Starting ERT in a symptomatic patient increases the number of years free of end-organ damage by 1.5 year (1.6 in males, 1.3 in females), while the number of QALYs gained increases by a similar amount (1.7 in males, 1.4 in females). The costs of ERT starting in the symptomatic stage are between €9 - €10 million (£ 7.9 - £ 8.8 million, $13.0- $14.5 million) during a patient's lifetime. Consequently, the extra costs per additional year free of end-organ damage and the extra costs per additional QALY range from €5.5 - €7.5 million (£ 4.8 - £ 6.6 million, $ 8.0 - $ 10.8 million), undiscounted. In symptomatic patients with Fabry disease, ERT has limited effect on quality of life and progression to end organ damage. The pharmaco-economic evaluation shows that this modest effectiveness drives the costs per QALY and the costs per year free of end-organ damage to millions of euros. Differentiation of patients who may benefit from ERT should be improved to enhance cost-effectiveness.

  16. Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease

    PubMed Central

    Ashe, Karen M; Budman, Eva; Bangari, Dinesh S; Siegel, Craig S; Nietupski, Jennifer B; Wang, Bing; Desnick, Robert J; Scheule, Ronald K; Leonard, John P; Cheng, Seng H; Marshall, John

    2015-01-01

    Fabry disease, an X-linked glycosphingolipid storage disorder, is caused by the deficient activity of α-galactosidase A (α-Gal A). This results in the lysosomal accumulation in various cell types of its glycolipid substrates, including globotriaosylceramide (GL-3) and lysoglobotriaosylceramide (globotriaosyl lysosphingolipid, lyso-GL-3), leading to kidney, heart, and cerebrovascular disease. To complement and potentially augment the current standard of care, biweekly infusions of recombinant α-Gal A, the merits of substrate reduction therapy (SRT) by selectively inhibiting glucosylceramide synthase (GCS) were examined. Here, we report the development of a novel, orally available GCS inhibitor (Genz-682452) with pharmacological and safety profiles that have potential for treating Fabry disease. Treating Fabry mice with Genz-682452 resulted in reduced tissue levels of GL-3 and lyso-GL-3 and a delayed loss of the thermal nociceptive response. Greatest improvements were realized when the therapeutic intervention was administered to younger mice before they developed overt pathology. Importantly, as the pharmacologic profiles of α-Gal A and Genz-682452 are different, treating animals with both drugs conferred the greatest efficacy. For example, because Genz-682452, but not α-Gal A, can traverse the blood–brain barrier, levels of accumulated glycosphingolipids were reduced in the brain of Genz-682452–treated but not α-Gal A–treated mice. These results suggest that combining substrate reduction and enzyme replacement may confer both complementary and additive therapeutic benefits in Fabry disease. PMID:25938659

  17. Myocardial fibrosis as the first sign of cardiac involvement in a male patient with Fabry disease: report of a clinical case and discussion on the utility of the magnetic resonance in Fabry pathology.

    PubMed

    Sechi, Annalisa; Nucifora, Gaetano; Piccoli, Gianluca; Dardis, Andrea; Bembi, Bruno

    2014-07-16

    Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) imaging is increasingly used to assess myocardial involvement in patients with Fabry disease, an X linked lipid storage disorder. However, it is often proposed as an optional tool. A different cardiomyopathic disease progression between male and female patients was hypothesised in previous studies, as in female myocardial fibrosis was found without left ventricular (LV) hypertrophy, while myocardial fibrosis was always detected in association to LV hypertrophy in men. A male Caucasian patient, 19 years old, diagnosed through a family-based molecular screening, presented with LGE of the LV inferolateral wall evidenced at the CMR, without LV hypertrophy, or other clinical signs of the disease. This is the first report of cardiac fibrosis as the first sign of organ involvement in a male patient with Fabry disease. This finding stresses the importance of performing CMR with LGE imaging for the initial staging and monitoring of Fabry patients of both genders.

  18. Myocardial fibrosis as the first sign of cardiac involvement in a male patient with Fabry disease: report of a clinical case and discussion on the utility of the magnetic resonance in Fabry pathology

    PubMed Central

    2014-01-01

    Background Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) imaging is increasingly used to assess myocardial involvement in patients with Fabry disease, an X linked lipid storage disorder. However, it is often proposed as an optional tool. A different cardiomyopathic disease progression between male and female patients was hypothesised in previous studies, as in female myocardial fibrosis was found without left ventricular (LV) hypertrophy, while myocardial fibrosis was always detected in association to LV hypertrophy in men. Case presentation A male Caucasian patient, 19 years old, diagnosed through a family-based molecular screening, presented with LGE of the LV inferolateral wall evidenced at the CMR, without LV hypertrophy, or other clinical signs of the disease. Conclusion This is the first report of cardiac fibrosis as the first sign of organ involvement in a male patient with Fabry disease. This finding stresses the importance of performing CMR with LGE imaging for the initial staging and monitoring of Fabry patients of both genders. PMID:25026990

  19. Frequency of unrecognized Fabry disease among young European-American and African-American men with first ischemic stroke.

    PubMed

    Wozniak, Marcella A; Kittner, Steven J; Tuhrim, Stanley; Cole, John W; Stern, Barney; Dobbins, Mark; Grace, Marie E; Nazarenko, Irina; Dobrovolny, Robert; McDade, Eric; Desnick, Robert J

    2010-01-01

    The cause of initial ischemic stroke in up to 30% of young patients remains unclear. Fabry disease, due to deficient alpha-galactosidase A (alpha-Gal A) activity, is a vascular endothelial glycosphingolipid storage disease typically presenting in childhood. With advancing age, patients develop renal, cardiac, and cerebrovascular disease and die prematurely. A European study suggested an increased prevalence of unrecognized Fabry disease in patients with cryptogenic stroke. We hypothesized that alpha-Gal A deficiency is a rare cause of initial early-onset ischemic stroke in men. The Stroke Prevention in Young Men Study enrolled >550 men (15 to 49 years) with first ischemic stroke in the Baltimore-Washington area in 2004 to 2007. Frozen plasma samples were assayed for alpha-Gal A activity, and DNA from patients with consistently low plasma alpha-Gal A activities were sequenced. The study sample consisted of 558 men (42% African-American; median age 44 years). Stroke was cryptogenic in 154 men (40% African-American). In 10 patients with low plasma alpha-Gal A activities, DNA sequencing identified alterations in the alpha-Gal A gene in 2 patients. The polymorphism, D313Y, which results in low plasma enzyme activity, but near normal levels of cellular activity was seen in one European-American male. The Fabry disease-causing A143T mutation was seen in an African-American male with cryptogenic stroke (0.18% of all strokes: upper 95% CI=0.53%; 0.65% of cryptogenic strokes: upper 95% CI=1.92%). In this biracial population, unrecognized Fabry disease is a rare but treatable cause of initial ischemic stroke in young men.

  20. Enzyme replacement therapy in Japanese Fabry disease patients: the results of a phase 2 bridging study.

    PubMed

    Eto, Y; Ohashi, T; Utsunomiya, Y; Fujiwara, M; Mizuno, A; Inui, K; Sakai, N; Kitagawa, T; Suzuki, Y; Mochizuki, S; Kawakami, M; Hosoya, T; Owada, M; Sakuraba, H; Saito, H

    2005-01-01

    Fabry Disease (alpha-galactosidase A deficiency) is an X-linked hereditary disorder leading to the pathological accumulation of globotriaosylceramide (GL-3) in lysosomes, particularly in the vascular endothelium of the kidney, heart and brain. We report the results of an open-label phase 2 study that was undertaken to evaluate whether ethnic differences exist that would affect agalsidase beta (Fabrazyme) treatment of Fabry patients in the Japanese population, relative to safety and efficacy. The study design mirrored the design of the completed phase 3 clinical trial that led to approval of the product agalsidase beta. The 13 Japanese, male Fabry patients enrolled in the study received the enzyme replacement therapy over a period of 20 weeks as biweekly infusions. All selected efficacy end points showed improvements that were comparable with findings from the phase 3 study. These improvements included reductions of GL-3 accumulation in both kidney and skin capillary endothelial cells to (near) normal levels (92% of patients). Kidney and plasma GL-3 levels decreased by 51.9% and 100%, respectively, by ELISA. Renal function remained normal. Fabry-associated pain, and quality of life, showed improvement over baseline in multiple categories. Related adverse events were mild or moderate in intensity and mostly infusion-associated (fever and rigors). As expected, IgG antibody formation was observed in 85% of the patients, but had no effect on treatment response. These results suggest that treatment with agalsidase beta is safe and effective in Japanese patients with Fabry disease. With regard to safety and efficacy, no differences were observed as compared to the caucasian population.

  1. Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation.

    PubMed

    Abe, A; Gregory, S; Lee, L; Killen, P D; Brady, R O; Kulkarni, A; Shayman, J A

    2000-06-01

    We used a potent inhibitor of glucosylceramide synthase to test whether substrate deprivation could lower globotriaosylceramide levels in alpha-galactosidase A (alpha-gal A) knockout mice, a model of Fabry disease. C57BL/6 mice treated twice daily for 3 days with D-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidi no-propanol (D-t-EtDO-P4) showed a concentration-dependent decrement in glucosylceramide levels in kidney, liver, and spleen. A single intraperitoneal injection of D-t-EtDO-P4 resulted in a 55% reduction in renal glucosylceramide, consistent with rapid renal glucosylceramide metabolism. A concentration-dependent decrement in renal and hepatic globotriaosylceramide levels was observed in alpha-Gal A(-) males treated for 4 weeks with D-t-EtDO-P4. When 8-week-old alpha-Gal A(-) males were treated for 8 weeks with 10 mg/kg twice daily, renal globotriaosylceramide fell to below starting levels, consistent with an alpha-galactosidase A-independent salvage pathway for globotriaosylceramide degradation. Complications observed with another glucosylceramide synthase inhibitor, N-butyldeoxynojirimycin, including weight loss and acellularity of lymphatic organs, were not observed with D-t-EtDO-P4. These data suggest that Fabry disease may be amenable to substrate deprivation therapy.

  2. Enzyme replacement therapy with agalsidase beta in kidney transplant patients with Fabry disease: a pilot study.

    PubMed

    Mignani, Renzo; Panichi, Vincenzo; Giudicissi, Antonio; Taccola, Daniele; Boscaro, Francesca; Feletti, Carlo; Moneti, Gloriano; Cagnoli, Leonardo

    2004-04-01

    We sought to assess the safety and efficacy of enzyme replacement therapy (ERT) with recombinant human-alpha-galactosidase A (rh-alpha-Gal A) in kidney transplant recipients with Fabry disease, a previously unstudied population. Three male kidney transplant recipients with biochemically, genetically, and histologically confirmed Fabry disease and documented Fabry myocardiopathy received the rh-alpha-Gal A, agalsidase beta, 1 mg/kg of body weight every 2 weeks by intravenous infusion and were monitored biochemically, clinically, and electrocardiographically and echocardiographically for 18 months. Patients showed biochemical, clinical/functional, and morphologic response to ERT. Plasma globotriaosylceramide decreased 23% to 50%. Extremity pain resolved within 2 months in the patient with this manifestation. On echocardiography, left ventricular mass, end diastolic diameter (EDD), and cardiac contractility, shown by ejection fraction (EF), improved in 2 of the 3 patients receiving essentially all planned infusions. EDD and EF remained basically stable, but cardiac morphologic abnormalities progressed in the other patient, who had a 5-month interruption in ERT after the initial month. Mild mitral insufficiency persisted in all patients, as did atrial fibrillation in the affected individual. After a combined total of 116 infusions, no treatment-related adverse event, intolerance, or seroconversion was seen. Renal function remained stable and the immunosuppression regimen unchanged in all patients. Our pilot study provides preliminary evidence that ERT with agalsidase beta, 1 mg/kg every 2 weeks, is safe and often effective against extra-renal manifestations in kidney transplant patients with Fabry disease. Studies with longer courses of this and higher doses of ERT are merited in this population.

  3. Cardiac energy metabolism is disturbed in Fabry disease and improves with enzyme replacement therapy using recombinant human galactosidase A.

    PubMed

    Machann, Wolfram; Breunig, Frank; Weidemann, Frank; Sandstede, Jörn; Hahn, Dietbert; Köstler, Herbert; Neubauer, Stefan; Wanner, Christoph; Beer, Meinrad

    2011-03-01

    In vitro studies have shown impairment of energy metabolism in cardiac fibroblasts from Fabry patients. A recent in vivo study reported an association between cardiac energy metabolism and increased myocardial mass in Fabry patients. We therefore assessed possible disturbances of cardiac energy metabolism in Fabry patients by in vivo (31)P-MR-spectroscopy. Additionally, the effect of enzyme replacement therapy (ERT) on cardiac energetics was tested. Twenty-three patients (41 ± 9 years; 10 females) with genetically proven Fabry disease were examined with a 1.5 T Scanner, and compared with an age-matched healthy control group. Eight patients underwent ERT and had follow-up examinations after 3 and 14 months. The high-energy phosphate molecules phosphocreatine (PCr) and adenosine triphosphate (ATP) were quantified in localized 31P-spectra by SLOOP (spectral localization with optimum point spread function). Cine- and late gadolinium enhancement (LGE) studies were also performed. When compared with healthy controls, Fabry patients demonstrated reduced PCr- (6.1 ± 1.9 vs. 8.8 ± 2.6 mmol/kg; P = 0.003) and ATP concentrations (3.9 ± 1.5 vs. 4.6 ± 1.0 mmol/kg; P = 0.048). During ERT, PCr concentrations increased (7.1 ± 1.5 mmol/kg vs. 6.1 ± 1.9; P < 0.05) and left ventricular mass decreased (215 ± 55 vs. 185 ± 45 g; P = 0.012). Disturbances in cardiac energetics were not correlated to the presence or absence of cardiac fibrosis on LGE. Cardiac energy metabolism is disturbed in Fabry disease; this may play an important role in the pathogenesis of Fabry cardiomyopathy. Enzyme replacement therapy ameliorates energetic depression.

  4. Fabry Disease: prevalence of affected males and heterozygotes with pathogenic GLA mutations identified by screening renal, cardiac and stroke clinics, 1995-2017.

    PubMed

    Doheny, Dana; Srinivasan, Ram; Pagant, Silvere; Chen, Brenden; Yasuda, Makiko; Desnick, Robert J

    2018-04-01

    Fabry Disease (FD), an X linked lysosomal storage disease due to pathogenic α-galactosidase A ( GLA ) mutations, results in two major subtypes, the early-onset Type 1 'Classic' and the Type 2 'Later-Onset' phenotypes. To identify previously unrecognised patients, investigators screened cardiac, renal and stroke clinics by enzyme assays. However, some screening studies did not perform confirmatory GLA mutation analyses, and many included recently recognised 'benign/likely-benign' variants, thereby inflating prevalence estimates. Online databases were searched for all FD screening studies in high-risk clinics (1995-2017). Studies reporting GLA mutations were re-analysed for pathogenic mutations, sex and phenotype. Phenotype-specific and sex-specific prevalence rates were determined. Of 67 studies, 63 that screened 51363patients (33943M and 17420F) and provided GLA mutations were reanalysed for disease-causing mutations. Of reported GLA mutations, benign variants occurred in 47.9% of males and 74.1% of females. The following were the revised prevalence estimates: among 36820 (23954M and 12866F) haemodialysis screenees, 0.21% males and 0.15% females; among 3074 (2031M and 1043F) renal transplant screenees, 0.25% males and no females; among 5491 (4054M and 1437F) cardiac screenees, 0.94% males and 0.90% females; and among 5978 (3904M and 2074F) stroke screenees, 0.13% males and 0.14% females. Among male and female screenees with pathogenic mutations, the type 1 Classic phenotype was predominant (~60%), except more male cardiac patients (75%) had type 2 Later-Onset phenotype. Compared with previous findings, reanalysis of 63 studies increased the screenee numbers (~3.4-fold), eliminated 20 benign/likely benign variants, and provided more accurate sex-specific and phenotype-specific prevalence estimates, ranging from ~0.13% of stroke to ~0.9% of cardiac male or female screenees. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article

  5. Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies

    PubMed Central

    2012-01-01

    Background Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day. Methods Two open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. Results Compared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients’ increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated. Conclusions Migalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing. Trial registration Clinicaltrial.gov: NCT00283959 and NCT00283933 PMID:23176611

  6. Clinical observations on enzyme replacement therapy in patients with Fabry disease and the switch from agalsidase beta to agalsidase alfa.

    PubMed

    Lin, Hsiang-Yu; Huang, Yu-Hsiu; Liao, Hsuan-Chieh; Liu, Hao-Chuan; Hsu, Ting-Rong; Shen, Chia-I; Li, Shao-Tzu; Li, Cheng-Fang; Lee, Li-Hong; Lee, Pi-Chang; Huang, Chun-Kai; Chiang, Chuan-Chi; Lin, Shuan-Pei; Niu, Dau-Ming

    2014-04-01

    Fabry disease is an X-linked inherited lysosomal storage disease that can be treated with the enzymes of agalsidase beta (Fabrazyme) and agalsidase alfa (Replagal). Since June 2009, viral contamination of Genzyme's production facility has resulted in a worldwide shortage of agalsidase beta, leading to the switch to agalsidase alfa for patients with Fabry disease in Taiwan. The medical records were retrospectively reviewed for nine male patients with Fabry disease from the start of agalsidase beta treatment until the switch to agalsidase alfa for at least 1 year. After 12-112 months of enzyme replacement therapy (ERT), decreased plasma globotriaosylsphingosine (lyso-Gb3) was found in five out of seven patients, indicating improvement in disease severity. Among the six patients with available echocardiographic data at baseline and after ERT, all six experienced reductions of left ventricular mass index. Renal function, including microalbuminuria and estimated glomerular filtration rate, showed stability after ERT. Mainz Severity Score Index scores revealed that all nine patients remained stable at 12 months after switching to agalsidase alfa. ERT improved or stabilized cardiac status and stabilized renal function, while reducing plasma lyso-Gb3. ERT was well tolerated, even among the three patients who had hypersensitivity reactions. The switch of ERT from agalsidase beta to agalsidase alfa appears to be safe after 1 year of follow-up for Taiwanese patients with Fabry disease. Copyright © 2013. Published by Elsevier B.V.

  7. Comparison of the effects of agalsidase alfa and agalsidase beta on cultured human Fabry fibroblasts and Fabry mice.

    PubMed

    Sakuraba, Hitoshi; Murata-Ohsawa, Mai; Kawashima, Ikuo; Tajima, Youichi; Kotani, Masaharu; Ohshima, Toshio; Chiba, Yasunori; Takashiba, Minako; Jigami, Yoshifumi; Fukushige, Tomoko; Kanzaki, Tamotsu; Itoh, Kohji

    2006-01-01

    We compared two recombinant alpha-galactosidases developed for enzyme replacement therapy for Fabry disease, agalsidase alfa and agalsidase beta, as to specific alpha-galactosidase activity, stability in plasma, mannose 6-phosphate (M6P) residue content, and effects on cultured human Fabry fibroblasts and Fabry mice. The specific enzyme activities of agalsidase alfa and agalsidase beta were 1.70 and 3.24 mmol h(-1) mg protein(-1), respectively, and there was no difference in stability in plasma between them. The M6P content of agalsidase beta (3.6 mol/mol protein) was higher than that of agalsidase alfa (1.3 mol/mol protein). The administration of both enzymes resulted in marked increases in alpha-galactosidase activity in cultured human Fabry fibroblasts, and Fabry mouse kidneys, heart, spleen and liver. However, the increase in enzyme activity in cultured fibroblasts, kidneys, heart and spleen was higher when agalsidase beta was used. An immunocytochemical analysis revealed that the incorporated recombinant enzyme degraded the globotriaosyl ceramide accumulated in cultured Fabry fibroblasts in a dose-dependent manner, with the effect being maintained for at least 7 days. Repeated administration of agalsidase beta apparently decreased the number of accumulated lamellar inclusion bodies in renal tubular cells of Fabry mice.

  8. A novel mutation of α-galactosidase A gene causes Fabry disease mimicking primary erythromelalgia in a Chinese family.

    PubMed

    Ge, Wei; Wei, Bin; Zhu, Hao; Miao, Zhigang; Zhang, Weimin; Leng, Cuihua; Li, Jizhen; Zhang, Dan; Sun, Miao; Xu, Xingshun

    2017-05-01

    Fabry disease is an X-linked genetic disorder caused by the mutations of α-galactosidase A (GLA, MIM 300644) gene presenting with various clinical symptoms including small-fiber peripheral neuropathy and limb burning pain. Here, we reported a Chinese pedigree with the initial diagnosis of primary erythromelalgia in an autosomal dominant (AD)-inherited pattern. Mutation analysis of SCN9A and GLA genes by direct sequencing and functional analysis of a novel mutation of GLA in cells were performed. Our data did not show any pathological mutations in SCN9A gene; however, a novel missense mutation c.139T>C (p.W47R) of GLA was identified in a male proband as well as two female carriers in this family. Enzyme assay of α-galactosidase A activity showed deficient enzyme activity in male patients and female carriers, further confirming the diagnosis of Fabry disease. Finally, a functional analysis indicated that the replacement of the 47th amino acid tryptophan (W47) with arginine (W47R) or glycine (W47G) led to reduced activity of α-galactosidase A in 293T cells. Therefore, these findings demonstrated that the novel mutation p.W47R of GLA is the cause of Fabry disease. Because Fabry disease and primary erythromelalgia share similar symptoms, it is a good strategy for clinical physicians to perform genetic mutation screenings on both SCN9A and GLA genes in those patients with limb burning pain but without a clear inheritant pattern.

  9. [Clinical and histological findings in Fabry nephropathy].

    PubMed

    Pieruzzi, Federico; Salerno, Fabio; Di Giacomo, Antonella; Torti, Giacomo; Ferrario, Franco; Pagni, Fabio; Stella, Andrea

    2013-01-01

    Fabry disease is a complex pathology, requiring a multidisciplinar approach both in the diagnostic workout and in the management of therapy. Clinical criteria able to predict its morbidity have not yet been found. The wide variability of clinical signs and symptoms requires an individual approach based on the single patient, in order to achieve an optimal management. Enzyme replacement therapy (ERT) has been introduced in the clinical setting for over ten years, but its ability to change the course of the disease has not yet been clearly proved. Recently the hypothesis that ERT may be ineffective in patients with severe organ involvement has emerged. The clinical course of Fabry disease is usually slower in eterozygous women than emizygous men, but can be frequently associated to severe organ failure and premature death in both cases. In this review we discuss the histological aspects of Fabry nephropathy in relation to diagnosis, prognosis, therapy and its effectiveness.

  10. [Court-ordered access to treatment of rare genetic diseases: Fabry Disease in the state of Rio Grande do Sul, Brazil].

    PubMed

    Sartori Junior, Dailor; Leivas, Paulo Gilberto Cogo; Souza, Mônica Vinhas de; Krug, Bárbara Corrêa; Balbinotto, Giacomo; Schwartz, Ida Vanessa Doederlein

    2012-10-01

    Court-ordered access to high-cost drugs for rare genetic diseases, such as Fabry Disease (alpha-galactosidase-A deficiency), is a growing phenomenon as yet lacking systematic study. An observational, cross-sectional and retrospective study was conducted to characterize the lawsuits related to access to treatment for Fabry Disease by Enzyme Replacement Therapy in the State of Rio Grande do Sul prior to 2007. The study identified 13 lawsuits and 17 plaintiffs, 11 requesting alfa and 6 betagalsidase. The State of RS, the Federal Government, and 5 municipalities figured as defendants, in the form of joinder of parties or otherwise. There were 13 requests for interlocutory relief of which 12 were granted, and 2 sentences were handed down, both favorable. "Risk of death" was alleged by doctors in 4 prescriptions and by lawyers in the 13 lawsuits. The data suggest the lack of discussions combining aspects of medical efficacy and safety, cost-effectiveness, economic impact, and legal and constitutional arguments, which requires a specific policy for rare genetic diseases to standardize access to treatment.

  11. Clinical observation of patients with Fabry disease after switching from agalsidase beta (Fabrazyme) to agalsidase alfa (Replagal).

    PubMed

    Tsuboi, Kazuya; Yamamoto, Hiroshi

    2012-09-01

    Fabry disease is a rare, X-linked, inherited lysosomal storage disorder that can be treated with the enzymes agalsidase alfa (Replagal) and agalsidase beta (Fabrazyme). Currently, there is a global shortage of agalsidase beta, and this has increased global demand for agalsidase alfa. We assess the feasibility of switching patients on agalsidase beta treatment to agalsidase alfa instead. This analysis is part of an ongoing observational study involving 11 patients with Fabry disease in whom the treatment was switched from agalsidase beta (1 mg/kg every other week) to agalsidase alfa (0.2 mg/kg every other week). Data were collected for a minimum of 36 months: 24 months before and 12 months after the switch. Serial data were evaluated with respect to renal function, cardiac mass, pain, quality of life, and tolerability/safety. Indexes of renal function (estimated glomerular filtration rate) and cardiac mass (left-ventricular mass index), pain (Brief Pain Inventory), and quality of life (EuroQoL-Dimensions) clearly showed that, in patients switched to agalsidase alfa, Fabry disease stabilized during the 12 months of follow-up. Despite the limitations of this preliminary observational study, it was found that all the patients maintained disease stability when treated with agalsidase alfa, as evidenced by estimated glomerular filtration rate, left-ventricular mass index, pain scores, and quality-of-life indexes, throughout 12 months of follow-up.

  12. Clinical observation of patients with Fabry disease after switching from agalsidase beta (Fabrazyme) to agalsidase alfa (Replagal).

    PubMed

    Tsuboi, Kazuya; Yamamoto, Hiroshi

    2012-09-01

    Fabry disease is a rare, X-linked, inherited lysosomal storage disorder that can be treated with the enzymes agalsidasealfa (Replagal) and agalsidase beta (Fabrazyme). Currently, there is a global shortage of agalsidase beta, and this has increased global demand for agalsidase alfa. We assess the feasibility of switching patients on agalsidase beta treatment to agalsidase alfa instead. This analysis is part of an ongoing observational study involving 11 patients with Fabry disease in whom the treatment was switched from agalsidase beta (1 mg/kg every other week) to agalsidase alfa (0.2 mg/kg every other week). Data were collected for a minimum of 36 months: 24 months before and 12 months after the switch. Serial data were evaluated with respect to renal function, cardiac mass, pain, quality of life, and tolerability/safety. Indexes of renal function (estimated glomerular filtration rate) and cardiac mass (left-ventricular mass index), pain (Brief Pain Inventory), and quality of life (EuroQoL-Dimensions) clearly showed that, in patients switched to agalsidase alfa, Fabry disease stabilized during the 12 months of follow-up. Despite the limitations of this preliminary observational study, it was found that all the patients maintained disease stability when treated with agalsidase alfa, as evidenced by estimated glomerular filtration rate, left-ventricular mass index,pain scores, and quality-of-life indexes, throughout 12 months of follow-up.

  13. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.

    PubMed

    Banikazemi, Maryam; Bultas, Jan; Waldek, Stephen; Wilcox, William R; Whitley, Chester B; McDonald, Marie; Finkel, Richard; Packman, Seymour; Bichet, Daniel G; Warnock, David G; Desnick, Robert J

    2007-01-16

    Fabry disease (alpha-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement. To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease. Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial. 41 referral centers in 9 countries. 82 adults with mild to moderate kidney disease; 74 of whom were protocol-adherent. Intravenous infusion of agalsidase beta (1 mg per kg of body weight) or placebo every 2 weeks for up to 35 months (median, 18.5 months). The primary end point was the time to first clinical event (renal, cardiac, or cerebrovascular event or death). Six patients withdrew before reaching an end point: 3 to receive commercial therapy and 3 due to positive or inconclusive serum IgE or skin test results. Three patients assigned to agalsidase beta elected to transition to open-label treatment before reaching an end point. Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). Secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.034). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, 0.19 [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or

  14. Agalsidase beta treatment is associated with improved quality of life in patients with Fabry disease: findings from the Fabry Registry.

    PubMed

    Watt, Torquil; Burlina, Alessandro P; Cazzorla, Chiara; Schönfeld, Dorothee; Banikazemi, Maryam; Hopkin, Robert J; Martins, Ana Maria; Sims, Katherine; Beitner-Johnson, Dana; O'Brien, Fanny; Feldt-Rasmussen, Ulla

    2010-11-01

    To evaluate the effect of agalsidase beta on longitudinal health-related quality of life in patients with Fabry disease. The SF-36® Health Survey was used to measure health-related quality of life in Fabry Registry patients. Seventy-one men and 59 women who were treated with agalsidase beta (median dose: 1.0 mg/kg/² weeks) and who had baseline and at least 2 yearly posttreatment health-related quality of life measurements were included in these analyses. A repeated measures model was used to analyze change in score from baseline. Men improved in the physical component summary and in all eight scales of the SF-36 after 1 and 2 years and in the mental component summary after 1 year of agalsidase beta treatment (P < 0.05). Women improved in the mental component summary and in six of the eight scales after 1 and/or 2 years of treatment. Patients whose baseline SF-36 scores were below the median showed the greatest improvements. These responses were comparable with or greater than the published effects of various treatments for multiple sclerosis, rheumatoid arthritis, central neuropathic pain, and Gaucher disease. Long-term treatment with agalsidase beta resulted in substantial improvements in health-related quality of life in both men and women; the effect was more pronounced in men.

  15. Infrared imaging microscopy of bone: illustrations from a mouse model of Fabry disease.

    PubMed

    Boskey, Adele L; Goldberg, Michel; Kulkarni, Ashok; Gomez, Santiago

    2006-07-01

    Bone is a complex tissue whose composition and properties vary with age, sex, diet, tissue type, health and disease. In this review, we demonstrate how infrared spectroscopy and infrared spectroscopic imaging can be applied to the study of these variations. A specific example of mice with Fabry disease (a lipid storage disease) is presented in which it is demonstrated that the bones of these young animals, while showing typical spatial variation in mineral content, mineral crystal size, and collagen maturity, do not differ from the bones of age- and sex-matched wild type animals.

  16. Auditing the frequency and the clinical and economic impact of testing for Fabry disease in patients under the age of 70 with a stroke admitted to Saint Vincent's University Hospital over a 6-month period.

    PubMed

    Lambe, J; Noone, I; Lonergan, R; Tubridy, N

    2018-02-01

    Fabry disease is an X-linked recessive lysosomal storage disorder that provokes multi-organ morbidity, including early-onset stroke. Worldwide prevalence may be greater than previously estimated, with many experiencing first stroke prior to diagnosis of Fabry disease. The aim of this study is to screen a cohort of stroke patients under 70 years of age, evaluating the clinical and economic efficacy of such a broad screening programme for Fabry disease. All stroke patients under 70 years of age who were entered into the Saint Vincent's University Hospital stroke database over a 6-month period underwent enzyme analysis and/or genetic testing as appropriate for Fabry disease. Patients' past medical histories were analysed for clinical signs suggestive of Fabry disease. Cost-effectiveness analysis of testing was performed and compared to overall economic impact of young stroke in Ireland. Of 22 patients tested for Fabry disease, no new cases were detected. Few clinical indicators of Fabry disease were identified at the time of testing. Broad screening programmes for Fabry disease are highly unlikely to offset the cost of testing. The efficacy of future screening programmes will depend on careful selection of an appropriate patient cohort of young stroke patients with multi-organ morbidity and a positive family history.

  17. Cognitive Impairments and Subjective Cognitive Complaints in Fabry Disease: A Nationwide Study and Review of the Literature.

    PubMed

    Loeb, Josefine; Feldt-Rasmussen, Ulla; Madsen, Christoffer Valdorff; Vogel, Asmus

    2018-04-14

    Fabry disease is a rare progressive X-linked lysosomal storage disorder which leads to neuropathic pain, organ dysfunction and cerebral pathology. Few studies have investigated cognitive impairment in Fabry disease and these previous studies are difficult to compare due to heterogeneous methodological designs and small cohorts. The objective was to investigate the frequency of cognitive impairment in the Danish nationwide cohort of Fabry patients. Further, we examined if subjective cognitive complaints were associated with objective cognitive performances in this patient group. Neuropsychological tests (17 measures) and evaluation of subjective complaints with the Perceived Deficits Questionnaire (PDQ) were applied in 41 of 63 patients. According to an a priori definition, 12 patients (29.3%) were cognitively impaired. Tests tapping psychomotor speed, attention and executive functions had the highest frequency of impairment. In general, disease related variables as Mainz Severity Score Index, enzyme activity and years since onset and depression did not have a significant impact on the categorisation of patients as being cognitively impaired or non-impaired. Thus, cognitive impairment in Fabry disease does not seem to occur solely by having symptoms for many years or by having high disease burden. However, impaired neuropsychological test results were significantly more common in patients with cerebrovascular disease. Only three patients had scores in the abnormal range of the PDQ scale and subjective perceptions of cognition were not associated with cognitive performances. The levels of subjective cognitive complaints were generally very low in the studied patients demonstrating that the absence of subjective cognitive complaints does not exclude the presence of objective cognitive problems.

  18. Clinical observation of patients with Fabry disease after switching from agalsidase beta (Fabrazyme) to agalsidase alfa (Replagal)

    PubMed Central

    Tsuboi, Kazuya; Yamamoto, Hiroshi

    2012-01-01

    Purpose: Fabry disease is a rare, X-linked, inherited lysosomal storage disorder that can be treated with the enzymes agalsidase alfa (Replagal) and agalsidase beta (Fabrazyme). Currently, there is a global shortage of agalsidase beta, and this has increased global demand for agalsidase alfa. We assess the feasibility of switching patients on agalsidase beta treatment to agalsidase alfa instead. Methods: This analysis is part of an ongoing observational study involving 11 patients with Fabry disease in whom the treatment was switched from agalsidase beta (1 mg/kg every other week) to agalsidase alfa (0.2 mg/kg every other week). Data were collected for a minimum of 36 months: 24 months before and 12 months after the switch. Serial data were evaluated with respect to renal function, cardiac mass, pain, quality of life, and tolerability/safety. Results: Indexes of renal function (estimated glomerular filtration rate) and cardiac mass (left-ventricular mass index), pain (Brief Pain Inventory), and quality of life (EuroQoL-Dimensions) clearly showed that, in patients switched to agalsidase alfa, Fabry disease stabilized during the 12 months of follow-up. Conclusion: Despite the limitations of this preliminary observational study, it was found that all the patients maintained disease stability when treated with agalsidase alfa, as evidenced by estimated glomerular filtration rate, left-ventricular mass index, pain scores, and quality-of-life indexes, throughout 12 months of follow-up. PMID:22498845

  19. Recommendations for the inclusion of Fabry disease as a rare febrile condition in existing algorithms for fever of unknown origin.

    PubMed

    Manna, Raffaele; Cauda, Roberto; Feriozzi, Sandro; Gambaro, Giovanni; Gasbarrini, Antonio; Lacombe, Didier; Livneh, Avi; Martini, Alberto; Ozdogan, Huri; Pisani, Antonio; Riccio, Eleonora; Verrecchia, Elena; Dagna, Lorenzo

    2017-10-01

    Fever of unknown origin (FUO) is a rather rare clinical syndrome representing a major diagnostic challenge. The occurrence of more than three febrile attacks with fever-free intervals of variable duration during 6 months of observation has recently been proposed as a subcategory of FUO, Recurrent FUO (RFUO). A substantial number of patients with RFUO have auto-inflammatory genetic fevers, but many patients remain undiagnosed. We hypothesize that this undiagnosed subgroup may be comprised of, at least in part, a number of rare genetic febrile diseases such as Fabry disease. We aimed to identify key features or potential diagnostic clues for Fabry disease as a model of rare genetic febrile diseases causing RFUO, and to develop diagnostic guidelines for RFUO, using Fabry disease as an example of inserting other rare diseases in the existing FUO algorithms. An international panel of specialists in recurrent fevers and rare diseases, including internists, infectious disease specialists, rheumatologists, gastroenterologists, nephrologists, and medical geneticists convened to review the existing diagnostic algorithms, and to suggest recommendations for arriving at accurate diagnoses on the basis of available literature and clinical experience. By combining specific features of rare diseases with other diagnostic considerations, guidelines have been designed to raise awareness and identify rare diseases among other causes of FUO. The proposed guidelines may be useful for the inclusion of rare diseases in the diagnostic algorithms for FUO. A wide spectrum of patients will be needed to validate the algorithm in different clinical settings.

  20. Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation

    PubMed Central

    Ortiz, Alberto; Mauer, Michael; Linthorst, Gabor E.; Oliveira, João P.; Serra, Andreas L.; Maródi, László; Mignani, Renzo; Vujkovac, Bojan; Beitner-Johnson, Dana; Lemay, Roberta; Cole, J.Alexander; Svarstad, Einar; Waldek, Stephen; Germain, Dominique P.; Wanner, Christoph

    2012-01-01

    Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of –0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of –6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4–3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2–184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope –4.4 mL/min/1.73m2/year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes. PMID:21804088

  1. Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation.

    PubMed

    Warnock, David G; Ortiz, Alberto; Mauer, Michael; Linthorst, Gabor E; Oliveira, João P; Serra, Andreas L; Maródi, László; Mignani, Renzo; Vujkovac, Bojan; Beitner-Johnson, Dana; Lemay, Roberta; Cole, J Alexander; Svarstad, Einar; Waldek, Stephen; Germain, Dominique P; Wanner, Christoph

    2012-03-01

    The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m(2)/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m(2)/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m(2)/year). Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.

  2. High-Risk Screening for Fabry Disease: Analysis by Tandem Mass Spectrometry of Globotriaosylceramide (Gb3 ) in Urine Collected on Filter Paper.

    PubMed

    Auray-Blais, Christiane; Lavoie, Pamela; Boutin, Michel; Abaoui, Mona

    2017-04-06

    Fabry disease is a complex, panethnic lysosomal storage disorder. It is characterized by the accumulation of glycosphingolipids in tissues, organs, the vascular endothelium, and biological fluids. The reported incidence in different populations is quite variable, ranging from 1:1400 to 1:117,000. Its complexity lies in the marked genotypic and phenotypic heterogeneity. Despite the fact that it is an X-linked disease, more than 600 mutations affect both males and females. In fact, some females may be affected as severely as males. The purpose of this protocol is to focus on the high-risk screening of patients who might have Fabry disease using a simple, rapid, non-invasive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for urinary globotriaosylceramide (Gb 3 ) analysis. Urine filter paper samples are easily collected at home by patients and sent by regular mail. This method has been successfully used for high-risk screening of patients with ophthalmologic manifestations and in an on-going study for high-risk screening of Fabry disease in patients with chronic kidney diseases. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

  3. Effects of enzyme-replacement therapy in patients with Anderson-Fabry disease: a prospective long-term cardiac magnetic resonance imaging study.

    PubMed

    Imbriaco, M; Pisani, A; Spinelli, L; Cuocolo, A; Messalli, G; Capuano, E; Marmo, M; Liuzzi, R; Visciano, B; Cianciaruso, B; Salvatore, M

    2009-07-01

    Anderson-Fabry disease is a multisystem X linked disorder of lipid metabolism frequently associated with cardiac symptoms, including left ventricular (LV) hypertrophy gradually impairing cardiac function. Evidence showing that enzyme-replacement therapy (ERT) can be effective in reducing LV hypertrophy and improving myocardial function in the long term is limited. This study aimed to assess the long-term effects of ERT with recombinant alpha-galactosidase A (agalsidase beta, Fabrazyme) on LV function and myocardial signal intensity in 11 patients with Anderson-Fabry disease. Eleven patients (eight males, three females) with varying stages of genetically confirmed Anderson-Fabry disease were examined by means of physical examination and magnetic resonance imaging before ERT with agalsidase beta at 1 mg/kg every other week (study 1) and after a mean treatment duration of 45 months (study 2). At 45 months of treatment, LV mass and LV wall thickness had significantly reduced: 188 (SD 60) g versus 153 (47) g, and 16 (4) mm versus 14 (4) mm, respectively. Furthermore, a significant reduction in myocardial T2 relaxation times was noted in all myocardial regions, that is, interventricular septum 80 (5) ms versus 66 (8) ms, apex 79 (10) ms versus 64 (10) ms, and lateral wall 80 (8) ms versus 65 (16) ms. Changes in LV ejection fraction were not significant. Amelioration of clinical symptoms was observed in all patients. Long-term therapy with agalsidase beta at 1 mg/kg every 2 weeks was effective in significantly reducing LV hypertrophy, improving overall cardiac performance and ameliorating clinical symptoms in patients with Anderson-Fabry disease.

  4. Infrared imaging microscopy of bone: Illustrations from a mouse model of Fabry disease

    PubMed Central

    Boskey, Adele L.; Goldberg, Michel; Kulkarni, Ashok; Gomez, Santiago

    2006-01-01

    Bone is a complex tissue whose composition and properties vary with age, sex, diet, tissue type, health and disease. In this review, we demonstrate how infrared spectroscopy and infrared spectroscopic imaging can be applied to the study of these variations. A specific example of mice with Fabry disease (a lipid storage disease) is presented in which it is demonstrated that the bones of these young animals, while showing typical spatial variation in mineral content, mineral crystal size, and collagen maturity, do not differ from the bones of age- and sex-matched wild type animals. PMID:16697974

  5. Globotriaosylsphingosine (lyso-Gb3) might not be a reliable marker for monitoring the long-term therapeutic outcomes of enzyme replacement therapy for late-onset Fabry patients with the Chinese hotspot mutation (IVS4+919G>A)

    PubMed Central

    2014-01-01

    Background In Taiwan, DNA-based newborn screening showed a surprisingly high incidence (1/875 in males and 1/399 in females) of a cardiac Fabry mutation (IVS4 + 919G > A). However, the natural course, long-term treatment outcomes and suitable biomarkers for monitoring the therapeutic outcomes of these patients are largely unknown. Methods Fabry disease (FD) patients who had received enzyme replacement therapy (ERT) for more than 1 year were enrolled in this study from December 2008 to April 2013. Periodic echocardiography and serum globotriaosylsphingosine (lyso-Gb3) analysis were carried out. Before and after ERT, left ventricular mass index (LVMI) and serum lyso-Gb3 level were compared and the correlation between the change of LVMI and the change of serum lyso-Gb3 were also analyzed. Results Thirty-six patients, in four patient groups, were enrolled: (1) 16 males with IVS4 + 919G > A mutation; (2) 7 females with IVS4 + 919G > A mutation; (3) 2 males with classical mutations; and (4) 11 females with classical mutations. The follow-up period was 13–46 months. There were significant LVMI reductions after ERT in all four groups after excluding confounding factors. However, interestingly, serum lyso-Gb3 decreased significantly in the early period after ERT in all groups, but increased gradually after an average of 11.1 months after ERT in late-onset male and female Fabry groups, even when their LVMI still decreased or remained stable. Furthermore, there was no correlation between the change of serum lyso-Gb3 and the change of LVMI in both classical and IVS4 + 919G > A FD patients. Conclusion Although lyso-Gb3 has a high diagnostic sensitivity in late-onset Fabry patients and has a good response to ERT during the early stages, it might not be a reliable marker for monitoring the long-term therapeutic outcomes of ERT for late-onset Fabry patients with the Chinese hotspot mutation (IVS4 + 919G > A). PMID:25047006

  6. Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.

    PubMed

    Maruyama, Hiroki; Miyata, Kaori; Mikame, Mariko; Taguchi, Atsumi; Guili, Chu; Shimura, Masaru; Murayama, Kei; Inoue, Takeshi; Yamamoto, Saori; Sugimura, Koichiro; Tamita, Koichi; Kawasaki, Toshihiro; Kajihara, Jun; Onishi, Akifumi; Sugiyama, Hitoshi; Sakai, Teiko; Murata, Ichijiro; Oda, Takamasa; Toyoda, Shigeru; Hanawa, Kenichiro; Fujimura, Takeo; Ura, Shigehisa; Matsumura, Mimiko; Takano, Hideki; Yamashita, Satoshi; Matsukura, Gaku; Tazawa, Ryushi; Shiga, Tsuyoshi; Ebato, Mio; Satoh, Hiroshi; Ishii, Satoshi

    2018-03-15

    PurposePlasma globotriaosylsphingosine (lyso-Gb3) is a promising secondary screening biomarker for Fabry disease. Here, we examined its applicability as a primary screening biomarker for classic and late-onset Fabry disease in males and females.MethodsBetween 1 July 2014 and 31 December 2015, we screened 2,360 patients (1,324 males) referred from 169 Japanese specialty clinics (cardiology, nephrology, neurology, and pediatrics), based on clinical symptoms suggestive of Fabry disease. We used the plasma lyso-Gb3 concentration, α-galactosidase A (α-Gal A) activity, and analysis of the α-Gal A gene (GLA) for primary and secondary screens, respectively.ResultsOf 8 males with elevated lyso-Gb3 levels (≥2.0 ng ml -1 ) and low α-Gal A activity (≤4.0 nmol h -1  ml -1 ), 7 presented a GLA mutation (2 classic and 5 late-onset). Of 15 females with elevated lyso-Gb3, 7 displayed low α-Gal A activity (5 with GLA mutations; 4 classic and 1 late-onset) and 8 exhibited normal α-Gal A activity (1 with a classic GLA mutation and 3 with genetic variants of uncertain significance).ConclusionPlasma lyso-Gb3 is a potential primary screening biomarker for classic and late-onset Fabry disease probands.Genet Med advance online publication, 15 March 2018; doi:10.1038/gim.2018.31.

  7. Identification of novel mutations in the α-galactosidase A gene in patients with Fabry disease: pitfalls of mutation analyses in patients with low α-galactosidase A activity.

    PubMed

    Yoshimitsu, Makoto; Higuchi, Koji; Miyata, Masaaki; Devine, Sean; Mattman, Andre; Sirrs, Sandra; Medin, Jeffrey A; Tei, Chuwa; Takenaka, Toshihiro

    2011-05-01

    Fabry disease is an X-linked lysosomal storage disorder caused by mutations of the α-galactosidase A (GLA) gene, and the disease is a relatively prevalent cause of left ventricular hypertrophy followed by conduction abnormalities and arrhythmias. Mutation analysis of the GLA gene is a valuable tool for accurate diagnosis of affected families. In this study, we carried out molecular studies of 10 unrelated families diagnosed with Fabry disease. Genetic analysis of the GLA gene using conventional genomic sequencing was performed in 9 hemizygous males and 6 heterozygous females. In patients with no mutations in coding DNA sequence, multiplex ligation-dependent probe amplification (MLPA) and/or cDNA sequencing were performed. We identified a novel exon 2 deletion (IVS1_IVS2) in a heterozygous female by MLPA, which was undetectable by conventional sequencing methods. In addition, the g.9331G>A mutation that has previously been found only in patients with cardiac Fabry disease was found in 3 unrelated, newly-diagnosed, cardiac Fabry patients by sequencing GLA genomic DNA and cDNA. Two other novel mutations, g.8319A>G and 832delA were also found in addition to 4 previously reported mutations (R112C, C142Y, M296I, and G373D) in 6 other families. We could identify GLA gene mutations in all hemizygotes and heterozygotes from 10 families with Fabry disease. Mutations in 4 out of 10 families could not be identified by classical genomic analysis, which focuses on exons and the flanking region. Instead, these data suggest that MLPA analysis and cDNA sequence should be considered in genetic testing surveys of patients with Fabry disease. Copyright © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  8. Patients with Fabry Disease after Enzyme Replacement Therapy Dose Reduction and Switch-2-Year Follow-Up.

    PubMed

    Lenders, Malte; Canaan-Kühl, Sima; Krämer, Johannes; Duning, Thomas; Reiermann, Stefanie; Sommer, Claudia; Stypmann, Jörg; Blaschke, Daniela; Üçeyler, Nurcan; Hense, Hans-Werner; Brand, Stefan-Martin; Wanner, Christoph; Weidemann, Frank; Brand, Eva

    2016-03-01

    Because of the shortage of agalsidase-β supply between 2009 and 2012, patients with Fabry disease either were treated with reduced doses or were switched to agalsidase-α. In this observational study, we assessed end organ damage and clinical symptoms with special focus on renal outcome after 2 years of dose-reduction and/or switch to agalsidase-α. A total of 89 adult patients with Fabry disease who had received agalsidase-β (1.0 mg/kg body wt) for >1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=24), to receive a reduced dose of 0.3-0.5 mg/kg and a subsequent switch to 0.2 mg/kg agalsidase-α (dose-reduction-switch group, n=28), or to directly switch to 0.2 mg/kg agalsidase-α (switch group, n=37) and were followed-up for 2 years. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD), changes in cardiac and renal function, Fabry-related symptoms (pain, hypohidrosis, diarrhea), and disease severity scores. Determination of renal function by creatinine and cystatin C-based eGFR revealed decreasing eGFRs in the dose-reduction-switch group and the switch group. The Mainz Severity Score Index increased significantly in these two groups (P=0.02 and P<0.001, respectively), and higher frequencies of gastrointestinal pain occurred during follow-up. In conclusion, after 2 years of observation, all groups showed a stable clinical disease course with respect to serious clinical events. However, patients under agalsidase-β dose-reduction and switch or a direct switch to agalsidase-α showed a decline of renal function independent of the eGFR formula used. Copyright © 2016 by the American Society of Nephrology.

  9. Patients with Fabry Disease after Enzyme Replacement Therapy Dose Reduction and Switch–2-Year Follow-Up

    PubMed Central

    Lenders, Malte; Canaan-Kühl, Sima; Krämer, Johannes; Duning, Thomas; Reiermann, Stefanie; Sommer, Claudia; Stypmann, Jörg; Blaschke, Daniela; Üçeyler, Nurcan; Hense, Hans-Werner; Brand, Stefan-Martin; Wanner, Christoph; Weidemann, Frank

    2016-01-01

    Because of the shortage of agalsidase-β supply between 2009 and 2012, patients with Fabry disease either were treated with reduced doses or were switched to agalsidase-α. In this observational study, we assessed end organ damage and clinical symptoms with special focus on renal outcome after 2 years of dose-reduction and/or switch to agalsidase-α. A total of 89 adult patients with Fabry disease who had received agalsidase-β (1.0 mg/kg body wt) for >1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=24), to receive a reduced dose of 0.3–0.5 mg/kg and a subsequent switch to 0.2 mg/kg agalsidase-α (dose-reduction-switch group, n=28), or to directly switch to 0.2 mg/kg agalsidase-α (switch group, n=37) and were followed-up for 2 years. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD), changes in cardiac and renal function, Fabry-related symptoms (pain, hypohidrosis, diarrhea), and disease severity scores. Determination of renal function by creatinine and cystatin C–based eGFR revealed decreasing eGFRs in the dose-reduction-switch group and the switch group. The Mainz Severity Score Index increased significantly in these two groups (P=0.02 and P<0.001, respectively), and higher frequencies of gastrointestinal pain occurred during follow-up. In conclusion, after 2 years of observation, all groups showed a stable clinical disease course with respect to serious clinical events. However, patients under agalsidase-β dose-reduction and switch or a direct switch to agalsidase-α showed a decline of renal function independent of the eGFR formula used. PMID:26185201

  10. Functional and pharmacological evaluation of novel GLA variants in Fabry disease identifies six (two de novo) causative mutations and two amenable variants to the chaperone DGJ.

    PubMed

    Ferri, Lorenzo; Malesci, Duccio; Fioravanti, Antonella; Bagordo, Gaia; Filippini, Armando; Ficcadenti, Anna; Manna, Raffaele; Antuzzi, Daniela; Verrecchia, Elena; Donati, Ilaria; Mignani, Renzo; Cavicchi, Catia; Guerrini, Renzo; Morrone, Amelia

    2018-06-01

    Allelic heterogeneity is an important feature of the GLA gene for which almost 900 known genetic variants have been discovered so far. Pathogenetic GLA variants cause alpha-galactosidase A (α-Gal A) enzyme deficiency leading to the X-linked lysosomal storage disorder Fabry disease (FD). Benign GLA intronic and exonic variants (e.g. pseudodeficient p.Asp313Tyr) have also been described. Some GLA missense variants, previously deemed to be pathogenetic (e.g. p.Glu66Gln and p.Arg118Cys), they have been reclassified as benign after re-evaluation by functional and population studies. Hence, the functional role of novel GLA variants should be investigated to assess their clinical relevance. We identified six GLA variants in 4 males and 2 females who exhibited symptoms of FD: c.159C>G p.(Asn53Lys), c.400T>C p.(Tyr134His), c.680G>C (p.Arg227Pro), c.815A>T p.(Asn272Ile), c.907A>T p.(Ile303Phe) and c.1163_1165delTCC (p.Leu388del). We evaluated their impact on the α-Gal A protein by bioinformatic analysis and homology modelling, by analysis of the GLA mRNA, and by site-directed mutagenesis and in vitro expression studies. We also measured their responsiveness to the pharmacological chaperone DGJ. The six detected GLA variants cause deficient α-Gal A activity and impairment or loss of the protein wild-type structure. We found p.Asn53Lys and p.Ile303Phe variants to be susceptible to DGJ. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  11. Enzyme replacement therapy in patients with Fabry disease: state of the art and review of the literature.

    PubMed

    Pisani, Antonio; Visciano, Bianca; Roux, Graciana Diez; Sabbatini, Massimo; Porto, Caterina; Parenti, Giancarlo; Imbriaco, Massimo

    2012-11-01

    Anderson-Fabry disease is an X-linked lysosomal storage disorder resulting from the deficiency of the hydrolytic enzyme alpha galactosidase A, with consequent accumulation of globotrioasoyl ceramide in cells and tissues of the body, resulting in a multi-system pathology including end organ failure. In the classical phenotype, cardiac failure, renal failure and stroke result in a reduced median life expectancy. The current causal treatment for Fabry disease is the enzyme replacement therapy (ERT): two different products, Replagal (agalsidase alfa) and Fabrazyme (agalsidase beta), have been commercially available in Europe for almost 10 years and they are both indicated for long-term treatment. In fact, clinical trials, observational studies and registry data have provided many evidences for safety and efficacy of ERT in improving symptoms of pain, gastrointestinal disturbances, hypohidrosis, left ventricular mass index, glomerular filtration rate and quality of life. Few data are available on comparison of the two treatments and on the clinical course of the disease. This article reviews the published evidence for clinical efficacy of the two available enzyme preparations. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Home-based infusion therapy for patients with Fabry disease.

    PubMed

    Cousins, A; Lee, P; Rorman, D; Raas-Rothschild, A; Banikazemi, M; Waldek, S; Thompson, L

    Fabry disease is an inherited, progressive, life-threatening disease; therefore, lifelong therapy is needed. By replacing the deficient enzyme, disease progression may be delayed or halted, thereby avoiding serious complications. Hospital-based agalsidase therapy is generally perceived as inconvenient and home-based infusion therapy is greatly appreciated by patients, their families and healthcare professionals. Patients can get familiar with infusion therapy in a hospital setting and, if specific requirements are fulfilled, routine nurse-assisted infusion, or self-care, at the patient's home can be organized. A stable patient who tolerates the infusion and a suitable home environment are prerequisites for home therapy. The authors' clinical experiences underscore the safety and practicality of home therapy. In addition to a major positive impact on the patient's quality of life, home infusion therapy may reduce the constraints of hospital resources. This article reviews the collective experiences with agalsidase beta home infusion therapy and outlines how safe, patient-centred homecare can be organized. Home infusion therapy with Fabrazyme should not be withheld from patients considered eligible according to the proposed criteria. Similar approaches to other enzyme therapies are also possible.

  13. Kidney transplantation from a mother with unrecognized Fabry disease to her son with low α-galactosidase A activity: A 14-year follow-up without enzyme replacement therapy.

    PubMed

    Odani, Keiko; Okumi, Masayoshi; Honda, Kazuho; Ishida, Hideki; Tanabe, Kazunari

    2016-07-01

    We report a case of kidney transplantation from mother to son, both of whom were likely to have had an unrecognized renal variant phenotype of Fabry disease. The patient was a 54-year-old man, with an unknown primary cause of end stage renal disease. He had no notable past medical history, other than end stage renal disease. He underwent living-related kidney transplantation from his mother at age 40 years. Foam cells in the glomeruli were identified on histology assessment of a 0-hour allograft biopsy, with zebra bodies identified in the glomerular visceral epithelial cells by electron microscopy. These findings were indicative of Fabry disease in the donated kidney. As a definitive diagnosis of Fabry's disease could not be confirmed, enzyme replacement therapy was not initiated. Thirteen years after kidney transplantation, the patient underwent left nephrectomy for a left renal tumour, with pathological findings of clear cell carcinoma, foam cells and zebra bodies in the native kidney. Detailed examinations identified low α-galactosidase A activity and mutation of the α-Gal A gene, confirming a diagnosis of a renal variant phenotype of Fabry disease. Histology of several allograft biopsies performed over the 14 years from the time of kidney transplantation revealed only moderate interstitial fibrosis and tubular atrophy, with no evidence of disease progression on electron microscopy, despite the presence of zebra bodies in the glomerular visceral epithelial cells. © 2016 Asian Pacific Society of Nephrology.

  14. Fabry disease: multidisciplinary evaluation after 10 years of treatment with agalsidase Beta.

    PubMed

    Juan, Politei; Hernan, Amartino; Beatriz, Schenone Andrea; Gustavo, Cabrera; Antonio, Michref; Eduardo, Tanus; Raul, Dominguez; Margarita, Larralde; Mariana, Blanco; Daniela, Gaggioli; Marina, Szlago

    2014-01-01

    Fabry disease is an X linked disorder of metabolism due to deficient α-galactosidase A activity. Enzyme replacement therapy (ERT) with agalsidase Beta was approved by EMA in 2001 and FDA in 2003. Six patients were enrolled. Baseline data was measured for renal, cardiac, and cerebrovascular functioning. We compared baseline quality of life scales with the current results. These parameters were assessed during the 10 years of follow-up period. Before ERT four patients showed normal eGFR, one stage 2 of CKD, and one hyperfiltration stage. All presented microalbuminuria and just two cases showed proteinuria. After 10 years of ERT, no patient showed decrease in renal functioning. One patient decreased from proteinuria to microalbuminuria range. Before treatment one case showed left ventricular (LV) hypertrophy and LV Mass Index was abnormal in two female patients. After 10 years echocardiographic values did not present progression to LVH and one female showed regression to normal values of LV posterior wall and interventricular septum. Brain MRI showed ischemic lesions in one female and vertebrobasilar dolichoectasia in one male. From baseline and during the follow-up period MRI did not progress to new ischemic lesions and there were no clinical signs of cerebrovascular damage. After 10 years quality of life showed improvement in all domains measured. Early treatment of agalsidase Beta is related to a better outcome regarding stability and regression of signs and symptoms in Fabry disease. Our results in patients with mild organ involvement showed good outcomes and support an early and continuous ERT.

  15. Role of cardiac MRI in evaluating patients with Anderson-Fabry disease: assessing cardiac effects of long-term enzyme replacement therapy.

    PubMed

    Messalli, G; Imbriaco, M; Avitabile, G; Russo, R; Iodice, D; Spinelli, L; Dellegrottaglie, S; Cademartiri, F; Salvatore, M; Pisani, A

    2012-02-01

    Anderson-Fabry disease is a multisystemic disorder of lipid metabolism secondary to X-chromosome alterations and is frequently associated with cardiac manifestations such as left ventricular (LV) hypertrophy, gradually leading to an alteration in cardiac performance. The purpose of this study was to monitor, using magnetic resonance imaging (MRI), any changes produced by enzyme replacement therapy with agalsidase beta at the cardiac level in patients with Anderson-Fabry disease. Sixteen (ten men, six women) patients with genetically confirmed Anderson-Fabry disease underwent cardiac MRI before starting enzyme replacement therapy (baseline study) and after 48 months of treatment with agalsidase beta at the dose of 1 mg/kg (follow-up study). After 48 months of treatment, a significant reduction in LV mass and wall thickness was observed: 187±59 g vs. 149±44 g, and 16±3 mm vs. 13±3 mm, respectively. A significant reduction in T2 relaxation time was noted at the level of the interventricular septum (81±3 ms vs. 67±7 ms), at the apical level (80±8 ms vs. 63±6 ms) and at the level of the lateral wall (82±8 ms vs. 63±10 ms) (p<0.05). No significant variation was observed in ejection fraction between the two studies (65±3% vs. 64±2%; p>0.05) (mean bias 1.0); however, an improvement was noted in the New York Heart Association (NYHA) class of the majority of patients (12/16) (p<0.05). In patients with Anderson-Fabry disease undergoing enzyme replacement therapy with agalsidase beta, MRI documented a significant reduction in myocardial T2 relaxation time, a significant decrease in maximal myocardial thickness and in total LV mass. MRI did not reveal significant improvements in LV global systolic function; however, improvement in NYHA functional class was noted, consistent with improved diastolic function.

  16. Enzyme replacement therapy in a patient with Fabry disease and the development of IgE antibodies against agalsidase beta but not agalsidase alpha.

    PubMed

    Tanaka, Akemi; Takeda, Taisuke; Hoshina, Takao; Fukai, Kazuyoshi; Yamano, Tsunekazu

    2010-12-01

    Fabry disease is an X-linked inherited lysosomal storage disorder caused by an inborn deficiency of the enzyme α-galactosidase A. Enzyme replacement therapy (ERT) with agalsidase alpha or beta isozymes is an effective treatment. Cross-reactivity of immunoglobulin G (IgG) antibodies with agalsidase alpha and beta has been reported, but no such reaction has been recorded for IgE antibodies. We present the case of a patient with Fabry disease who developed antiagalsidase beta IgE antibodies without cross-reactivity to agalsidase alpha. A 17-year-old boy with Fabry disease had suffered from severe atopic dermatitis since infancy, and he complained for several years of peripheral pain during the summer months and when exercising. Fabry disease was confirmed by family history and a positive enzyme test, and ERT was commenced. Following infusion of agalsidase beta (1.0 mg/kg), the patient complained of a high temperature in his hands and feet, and purulent eczema developed. The infusion dose was reduced to 0.2 mg/kg, but the hyperthermia did not change, although its duration decreased. After three infusions, eosinophilia developed (9.4%; 573 cells/μl blood) and remained unresolved after four infusions with agalsidase beta. Treatment with this enzyme was discontinued, and agalsidase alpha (0.2 mg/kg) started. This produced immediate resolution of the eosinophilia, which has been maintained during follow-up. In conclusion, this patient developed IgE antibodies against agalsidase beta, which demonstrated no cross-reactivity to agalsidase alpha. These findings emphasize the importance of analyzing IgE antibodies against both enzymes when patients exhibit severe infusion-related events.

  17. Mutant α-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin

    PubMed Central

    Ishii, Satoshi; Chang, Hui-Hwa; Kawasaki, Kunito; Yasuda, Kayo; Wu, Hui-Li; Garman, Scott C.; Fan, Jian-Qiang

    2007-01-01

    Fabry disease is a lysosomal storage disorder caused by the deficiency of α-Gal A (α-galactosidase A) activity. In order to understand the molecular mechanism underlying α-Gal A deficiency in Fabry disease patients with residual enzyme activity, enzymes with different missense mutations were purified from transfected COS-7 cells and the biochemical properties were characterized. The mutant enzymes detected in variant patients (A20P, E66Q, M72V, I91T, R112H, F113L, N215S, Q279E, M296I, M296V and R301Q), and those found mostly in mild classic patients (A97V, A156V, L166V and R356W) appeared to have normal Km and Vmax values. The degradation of all mutants (except E59K) was partially inhibited by treatment with kifunensine, a selective inhibitor of ER (endoplasmic reticulum) α-mannosidase I. Metabolic labelling and subcellular fractionation studies in COS-7 cells expressing the L166V and R301Q α-Gal A mutants indicated that the mutant protein was retained in the ER and degraded without processing. Addition of DGJ (1-deoxygalactonojirimycin) to the culture medium of COS-7 cells transfected with a large set of missense mutant α-Gal A cDNAs effectively increased both enzyme activity and protein yield. DGJ was capable of normalizing intracellular processing of mutant α-Gal A found in both classic (L166V) and variant (R301Q) Fabry disease patients. In addition, the residual enzyme activity in fibroblasts or lymphoblasts from both classic and variant hemizygous Fabry disease patients carrying a variety of missense mutations could be substantially increased by cultivation of the cells with DGJ. These results indicate that a large proportion of mutant enzymes in patients with residual enzyme activity are kinetically active. Excessive degradation in the ER could be responsible for the deficiency of enzyme activity in vivo, and the DGJ approach may be broadly applicable to Fabry disease patients with missense mutations. PMID:17555407

  18. Enzyme therapy in Fabry disease: severe adverse events associated with anti-agalsidase cross-reactive IgG antibodies.

    PubMed

    Tesmoingt, Chloe; Lidove, Olivier; Reberga, Axele; Thetis, Marguerite; Ackaert, Chloe; Nicaise, Pascale; Arnaud, Philippe; Papo, Thomas

    2009-11-01

    To report a severe adverse event related to enzyme replacement therapy with agalsidase in an hemizygous male patient treated for Fabry disease. Retrospective analysis of clinical, radiological and biochemical data in a patient who suffered adverse events related to both agalsidase alfa and agalsidase beta treatments. A hemizygous male patient was first treated for Fabry disease with agalsidase alfa. After more than 1 year of therapy, infusion-related symptoms necessitated systemic steroids and antihistaminic therapy. Decline in kidney function prompted a switch for agalsidase beta. Anaphylactoid shock occurred after the second infusion. No serum IgE antibodies were disclosed. Skin-test reactivity to agalsidase beta was negative. Following a published rechallenge infusion protocol, agalsidase beta was reintroduced, leading to a second anaphylactoid shock episode. Enzyme replacement therapy was stopped and the patient was treated with symptomatic therapy only. This case was referred to the pharmacovigilance department. The negativity of immunological tests (specific anti-agalsidase IgE antibodies and skin tests) does not rule out the risk of repeated anaphylactoid shock following agalsidase infusion.

  19. Enzyme therapy in Fabry disease: severe adverse events associated with anti-agalsidase cross-reactive IgG antibodies

    PubMed Central

    Tesmoingt, Chloe; Lidove, Olivier; Reberga, Axele; Thetis, Marguerite; Ackaert, Chloe; Nicaise, Pascale; Arnaud, Philippe; Papo, Thomas

    2009-01-01

    AIMS To report a severe adverse event related to enzyme replacement therapy with agalsidase in an hemizygous male patient treated for Fabry disease. METHODS Retrospective analysis of clinical, radiological and biochemical data in a patient who suffered adverse events related to both agalsidase alfa and agalsidase beta treatments. RESULTS A hemizygous male patient was first treated for Fabry disease with agalsidase alfa. After more than 1 year of therapy, infusion-related symptoms necessitated systemic steroids and antihistaminic therapy. Decline in kidney function prompted a switch for agalsidase beta. Anaphylactoid shock occurred after the second infusion. No serum IgE antibodies were disclosed. Skin-test reactivity to agalsidase beta was negative. Following a published rechallenge infusion protocol, agalsidase beta was reintroduced, leading to a second anaphylactoid shock episode. Enzyme replacement therapy was stopped and the patient was treated with symptomatic therapy only. This case was referred to the pharmacovigilance department. CONCLUSION The negativity of immunological tests (specific anti-agalsidase IgE antibodies and skin tests) does not rule out the risk of repeated anaphylactoid shock following agalsidase infusion. PMID:19917001

  20. [Fabry nephropathy in a female with superposed IgA glomerulonephritis].

    PubMed

    Pisani, A; Sessa, A; Sabbatini, M; Andreucci, M V; Fusco, C; Balletta, M; Cianciaruso, B

    2005-01-01

    In Anderson-Fabry disease (AFd), the kidney is affected in all hemizygous males and in some heterozygous females. Female carriers can present subtle renal abnormalities due to glycosphingolipid (GSL) accumulation within renal cells. Renal biopsy is rarely performed in female Fabry patients because clinical renal manifestations are usually lacking. However, female carriers can accumulate GSL in their renal cells despite the absence of clinically evident kidney disease. We performed a kidney biopsy in a 52-year-old female patient, a Fabry disease carrier. The patient showed normal glomerular filtration rate, persistent microhematuria and proteinuria (about 1.7 g/24 hr), cornea "verticillata", and evident left ventricular hypertrophy. The molecular study documented a missense mutation R227Q in exon 5 of the alpha-galactosidase A gene. Optical microscopy showed electron-dense mesangial deposits due IgA glomerulonephritis, as confirmed by immunofluorescence. We decided to start therapy with angiotensin-converting enzyme inhibitors (ACE-I). After 8 months of treatment, the patient demonstrated proteinuria of 0.9 g/24 hr. To decide when to start treatment using enzyme replacement therapy (ERT) with human recombinant GAL A (Fabrazyme), we decided to perform an electron microscopy study of the renal biopsy. The renal ultrastructural findings were typical GSL inclusions in all kinds of glomerular cells, in tubular epithelial cells and in endothelial cells of interstitial capillaries, confirming the hypothesis of Fabry nephropathy. Consequently, Fabrazyme was given at a standard dose of 1 mg/kg every 2 weeks. After 24 months of combined treatment (ACE-I-Fabrazyme), proteinuria decreased to 0.2 g/24 hr. The importance of performing the ultrastructural examination of the kidney biopsy is stressed, especially in heterozygous Fabry patients to evaluate the need to treat them with ERT and to evaluate the degree of renal involvement.

  1. The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in a patient with Anderson-Fabry disease.

    PubMed

    Moon, James C; Sheppard, Mary; Reed, Emma; Lee, Phillip; Elliott, Perry M; Pennell, Dudley J

    2006-01-01

    Anderson-Fabry Disease (AFD) is a storage disease that mimics hypertrophic cardiomyopathy. Late gadolinium enhancement (LGE) by cardiovascular magnetic resonance occurs in approximately 50% of patients in the basal inferolateral LV wall, but how an intracellular storage disease causes focal LGE is unknown. We present a whole-heart histological validation that LGE is caused by focal myocardial collagen scarring. This scarring may be the substrate for electrical re-entry and sudden arrhythmic death. The reasons for this distribution of fibrosis are unclear, but may reflect inhomogeneous left ventricular wall stress.

  2. Glycosphingolipid storage in Fabry mice extends beyond globotriaosylceramide and is affected by ABCB1 depletion

    PubMed Central

    Kamani, Mustafa A; Provençal, Philippe; Boutin, Michel; Pacienza, Natalia; Fan, Xin; Novak, Anton; Huang, Tonny C; Binnington, Beth; Au, Bryan C; Auray-Blais, Christiane; Lingwood, Clifford A; Medin, Jeffrey A

    2016-01-01

    Aim: Fabry disease is caused by α-galactosidase A deficiency leading to accumulation of globotriaosylceramide (Gb3) in tissues. Clinical manifestations do not appear to correlate with total Gb3 levels. Studies examining tissue distribution of specific acyl chain species of Gb3 and upstream glycosphingolipids are lacking. Material & methods/Results: Thorough characterization of the Fabry mouse sphingolipid profile by LC-MS revealed unique Gb3 acyl chain storage profiles. Storage extended beyond Gb3; all Fabry tissues also accumulated monohexosylceramides. Depletion of ABCB1 had a complex effect on glycosphingolipid storage. Conclusion: These data provide insights into how specific sphingolipid species correlate with one another and how these correlations change in the α-galactosidase A-deficient state, potentially leading to the identification of more specific biomarkers of Fabry disease. PMID:28116130

  3. Antiproteinuric therapy and fabry nephropathy: sustained reduction of proteinuria in patients receiving enzyme replacement therapy with agalsidase-beta.

    PubMed

    Tahir, Hindia; Jackson, Leslie L; Warnock, David G

    2007-09-01

    This report describes an open-label, nonrandomized, prospective evaluation of the effects of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapy on patients who have Fabry disease and also received enzyme replacement therapy with agalsidase-beta, given at 1 mg/kg body wt every 2 wk. Previous placebo-controlled phase III and phase IV trials with agalsidase-beta demonstrated clearing of globotriaosylceramide from vascular endothelia but little effect on proteinuria or progressive loss of kidney function in patients with Fabry disease and severe chronic kidney disease marked by overt proteinuria and/or estimated GFR <60 ml/min per 1.73 m2. Angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker therapy is the standard of care for patients with proteinuric kidney diseases, but their use is challenging in patients with Fabry disease and low or low-normal baseline systemic BP. A group of patients with Fabry disease were treated with antiproteinuric therapy, in conjunction with agalsidase-beta; sustained reductions in proteinuria with stabilization of kidney function were achieved in a group of six patients who had severe Fabry nephropathy; the progression rate was -0.23 +/- 1.12 ml/min per 1.73 m2 per yr with 30 mo of follow-up.

  4. Multiplex newborn screening for Pompe, Fabry, Hunter, Gaucher, and Hurler diseases using a digital microfluidic platform.

    PubMed

    Sista, Ramakrishna S; Wang, Tong; Wu, Ning; Graham, Carrie; Eckhardt, Allen; Winger, Theodore; Srinivasan, Vijay; Bali, Deeksha; Millington, David S; Pamula, Vamsee K

    2013-09-23

    New therapies for lysosomal storage diseases (LSDs) have generated interest in screening newborns for these conditions. We present performance validation data on a digital microfluidic platform that performs multiplex enzymatic assays for Pompe, Fabry, Hunter, Gaucher, and Hurler diseases. We developed an investigational disposable digital microfluidic cartridge that uses a single dried blood spot (DBS) punch for performing a 5-plex fluorometric enzymatic assay on up to 44 DBS samples. Precision and linearity of the assays were determined by analyzing quality control DBS samples; clinical performance was determined by analyzing 600 presumed normal and known affected samples (12 for Pompe, 7 for Fabry and 10 each for Hunter, Gaucher and Hurler). Overall coefficient of variation (CV) values between cartridges, days, instruments, and operators ranged from 2 to 21%; linearity correlation coefficients were ≥0.98 for all assays. The multiplex enzymatic assay performed from a single DBS punch was able to discriminate presumed normal from known affected samples for 5 LSDs. Digital microfluidic technology shows potential for rapid, high-throughput screening for 5 LSDs in a newborn screening laboratory environment. Sample preparation to enzymatic activity on each cartridge is less than 3h. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Wilhelm Fabry's 1614 report on a giant condyloma of the penis.

    PubMed

    Marx, F J; Karenberg, A

    2012-02-01

    For many years it has been the work of Buschke and Löwenstein that has justified calling the exophytic, locally destructive tumour of the anogenital mucosal surface 'giant condyloma of Buschke and Löwenstein' or GCBL. In order to investigate the early history of this rare disease we examined the writings of the barber-surgeon Wilhelm Fabry (1560-1634) who had a serious interest in dermatological disorders and their treatment. We analysed Fabry's 600 Latin case reports and identified the case of a 'monstrous penile tumour'. We then translated this text into English and compared it point by point with later publications. This was followed by a cursory review of surgical treatises from the 16th to the 18th centuries. In 1614 Fabry described and depicted a tumour of the penis; the clinical characteristics (gradual formation of a warty lesion, considerable size, invasive growth, absence of metastases) indicated it was a giant condyloma. His mention of the urethral fistulization enables discrimination from 'common' condylomata acuminata, and the survival period of 10 years after amputation allows exclusion of a 'true' carcinoma. This report is singular among 17th-century case histories. The neoplasias described 300 years later are most probably biologically identical. Thus, Fabry's is the first clinical report; the histological classification, however, belongs to Buschke and Löwenstein. From now on the disease should be designated with the eponym giant condyloma of Fabry-Buschke-Löwenstein or GCFBL. © 2011 The Authors. BJD © 2011 British Association of Dermatologists.

  6. Development and Analytical Characterization of Pegunigalsidase Alfa, a Chemically Cross-Linked Plant Recombinant Human α-Galactosidase-A for Treatment of Fabry Disease.

    PubMed

    Ruderfer, Ilya; Shulman, Avidor; Kizhner, Tali; Azulay, Yaniv; Nataf, Yakir; Tekoah, Yoram; Shaaltiel, Yoseph

    2018-05-16

    The current treatment of Fabry disease by enzyme replacement therapy with commercially available recombinant human α-Galactosidase A shows a continuous deterioration of the disease patients. Human recombinant α-Galactosidase A is a homodimer with noncovalently bound subunits and is expressed in the ProCellEx plant cell-based protein expression platform to produce pegunigalsidase alfa. The effect of covalent bonding between two α-Galactosidase A subunits by PEG-based cross-linkers of various lengths was evaluated in this study. The results show that cross-linking by a bifunctional PEG polymer of 2000 Da produces a more stable protein with improved pharmacokinetic and biodistribution properties. The chemical modification did not influence the tertiary protein structure but led to an increased thermal stability and showed partial masking of immune epitopes. The developed pegunigalsidase alfa is currently tested in phase III clinical trials and has a potential to show superior efficacy versus the currently used enzyme replacement therapies in the treatment of Fabry disease patients.

  7. A Pharmacogenetic Approach to Identify Mutant Forms of α-Galactosidase A that Respond to a Pharmacological Chaperone for Fabry Disease

    PubMed Central

    Wu, Xiaoyang; Katz, Evan; Valle, Maria Cecilia Della; Mascioli, Kirsten; Flanagan, John J; Castelli, Jeffrey P; Schiffmann, Raphael; Boudes, Pol; Lockhart, David J; Valenzano, Kenneth J; Benjamin, Elfrida R

    2011-01-01

    Fabry disease is caused by mutations in the gene (GLA) that encodes α-galactosidase A (α-Gal A). The iminosugar AT1001 (GR181413A, migalastat hydrochloride, 1-deoxygalactonojirimycin) is a pharmacological chaperone that selectively binds and stabilizes α-Gal A, increasing total cellular levels and activity for some mutant forms (defined as “responsive”). In this study, we developed a cell-based assay in cultured HEK-293 cells to identify mutant forms of α-Gal A that are responsive to AT1001. Concentration-dependent increases in α-Gal A activity in response to AT1001 were shown for 49 (60%) of 81 mutant forms. The responses of α-Gal A mutant forms were generally consistent with the responses observed in male Fabry patient-derived lymphoblasts. Importantly, the HEK-293 cell responses of 19 α-Gal A mutant forms to a clinically achievable concentration of AT1001 (10 µM) were generally consistent with observed increases in α-Gal A activity in peripheral blood mononuclear cells from male Fabry patients orally administered AT1001 during Phase 2 clinical studies. This indicates that the cell-based responses can identify mutant forms of α-Gal A that are likely to respond to AT1001 in vivo. Thus, the HEK-293 cell-based assay may be a useful aid in the identification of Fabry patients with AT1001-responsive mutant forms. Hum Mutat 32:1–13, 2011. © 2011 Wiley-Liss, Inc. PMID:21598360

  8. A prospective 10-year study of individualized, intensified enzyme replacement therapy in advanced Fabry disease.

    PubMed

    Schiffmann, Raphael; Swift, Caren; Wang, Xuan; Blankenship, Derek; Ries, Markus

    2015-11-01

    To test the hypothesis that more frequent enzyme replacement therapy (ERT) slows the decline in kidney function in adult patients with Fabry disease. A single center open label 10-year prospective clinical trial of 12 patients with advanced Fabry disease who, after having experienced an ongoing decline in renal function after 2-4 years of receiving ERT at the approved dose of 0.2 mg/kg agalsidase alfa every other week (EOW), were switched to weekly (EW) ERT at the same dose. We used linear regression to fit each individual patient's longitudinal estimated glomerular filtration rate (eGFR) record in order to compare the deterioration rates between EOW and EW ERT. For the entire group, mean slope on agalsidase alfa every 2 weeks was -7.92 ± 2.88 ml/min/1.73 m(2)/year and 3.84 ± 4.08 ml/min/1.73 m(2)/year on weekly enzyme infusions (p = 0.01, two-tailed paired t test). Three patients (25 %) completed the entire study with relatively preserved renal function while 50 % of patients reached end-stage renal disease (ESRD) during the 10 years of this study. The estimated average delay to ESRD was 13.8 years [n = 11; 95 % CI 0.66, 27]. One patient had a positive eGFR slope on weekly infusions while the patient with the highest antibody titer had a steeper slope after switching. Mean globotriaosylceramide concentrations in urine and plasma as well as urine protein excretion remained unchanged. Weekly enzyme infusions slow the decline of renal function in a subgroup of more severe patients thus showing that existing ERT can be further optimized.

  9. Clinical course of patients with Fabry disease who were switched from agalsidase-β to agalsidase-α.

    PubMed

    Tsuboi, Kazuya; Yamamoto, Hiroshi

    2014-10-01

    Between 2009 and 2012, there was a worldwide shortage of agalsidase-β for the treatment of Fabry disease. Therefore, alternative treatments were needed, including switching to a different enzyme-replacement therapy. This is an ongoing observational study assessing the effects of switching from agalsidase-β (1.0 mg/kg every other week) to agalsidase-α (0.2 mg/kg every other week) in 11 patients with Fabry disease. Clinical data were collected for 5 years-2 years before switching and 3 years after switching. Measures of renal function such as estimated glomerular filtration rate remained stable during the 3 years after switching to agalsidase-α. Improvements in cardiac mass were recorded in both male and female patients 12 months after switching to agalsidase-α, and the benefit was maintained during 36 months of follow-up. There was no significant difference in the severity of pain experienced by patients before and after switching enzyme-replacement therapy, and no difference in quality-of-life parameters. Agalsidase-α was generally well tolerated, and no patients experienced allergy or developed antibodies to agalsidase-α. This observational study supports the safety of switching from agalsidase-β to agalsidase-α at the approved doses, with no loss of efficacy. It also suggests that if an infusion-related allergic reaction occurs in a patient receiving agalsidase-β, switching to agalsidase-α may be a viable option.

  10. Progressive renal failure despite long-term biweekly enzyme replacement therapy in a patient with Fabry disease secondary to a new α-galactosidase mutation of Leu311Arg (L311R).

    PubMed

    Suzuki, Keisuke; Miura, Naoto; Kitagawa, Wataru; Suzuki, Shinkichi; Komatsuda, Atsushi; Nishikawa, Kazuhiro; Watanabe, Daisuke; Imai, Hirokazu

    2011-12-01

    A 37-year-old Japanese man affected by Fabry disease secondary to a novel mutation of Leu311Arg (L311R) in α-galactosidase demonstrated progressive renal failure despite biweekly enzyme replacement therapy (ERT) for approximately 10 years. Kidney biopsy revealed foamy glomerular epithelial cells, compatible with the typical pathologic features of Fabry disease. The patient entered a phase III study of Replagal (agalsidase alfa) in 2001, allowing him to continue ERT with biweekly dosing for almost 10 years. During 2 years of that period, he was continued on Fabrazyme (agalsidase beta) biweekly dosing. His estimated GFR was calculated to decrease by 9.9 mL/min/1.73 m(2) per year. Patients with Fabry disease have been reported to have a mean decrease in GFR of 12.2 ± 8.1 mL/min/1.73 m(2) per year. This result suggests that biweekly ERT is only mildly effective at preventing loss of kidney function.

  11. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study.

    PubMed

    Hughes, Derralynn A; Nicholls, Kathleen; Shankar, Suma P; Sunder-Plassmann, Gere; Koeller, David; Nedd, Khan; Vockley, Gerard; Hamazaki, Takashi; Lachmann, Robin; Ohashi, Toya; Olivotto, Iacopo; Sakai, Norio; Deegan, Patrick; Dimmock, David; Eyskens, François; Germain, Dominique P; Goker-Alpan, Ozlem; Hachulla, Eric; Jovanovic, Ana; Lourenco, Charles M; Narita, Ichiei; Thomas, Mark; Wilcox, William R; Bichet, Daniel G; Schiffmann, Raphael; Ludington, Elizabeth; Viereck, Christopher; Kirk, John; Yu, Julie; Johnson, Franklin; Boudes, Pol; Benjamin, Elfrida R; Lockhart, David J; Barlow, Carrolee; Skuban, Nina; Castelli, Jeffrey P; Barth, Jay; Feldt-Rasmussen, Ulla

    2017-04-01

    Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant ( amenable ) forms of α-Gal to facilitate normal lysosomal trafficking. The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed. Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m 2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated. Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations. NCT00925301; Pre-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  12. Evaluation of a low dose, after a standard therapeutic dose, of agalsidase beta during enzyme replacement therapy in patients with Fabry disease.

    PubMed

    Lubanda, Jean-Claude; Anijalg, Ene; Bzdúch, Vladimír; Thurberg, Beth L; Bénichou, Bernard; Tylki-Szymanska, Anna

    2009-04-01

    Fabry disease, a genetic deficiency of alpha-galactosidase A, is characterized by pathogenic cellular accumulation of globotriaosylceramide. During clinical trials, recombinant human alpha-galactosidase A (agalsidase beta; Fabrazyme, Genzyme Corporation, Cambridge, MA), infused intravenously at 1.0 mg/kg every 2 weeks for 6 months, cleared or reduced globotriaosylceramide in renal, cardiac, and dermal microvascular endothelia and other cells, with results sustained for up to 5 years in most patients evaluated. This study explored whether a lower dose could maintain globotriaosylceramide clearance achieved with 1.0 mg/kg. Cellular globotriaosylceramide levels were assessed histologically in kidney and skin biopsies from 21 adult Fabry males treated for 6 months at 1.0 mg/kg/2 weeks followed by 18 months at 0.3 mg/kg/2 weeks. In kidney interstitial capillary endothelium, the primary endpoint, globotriaosylceramide clearance was achieved in 100% of patients with 1.0 mg/kg and maintained in 90% with 0.3 mg/kg. In seven other renal cell types and superficial dermal capillary endothelium, globotriaosylceramide reduction or clearance was maintained with 0.3 mg/kg in approximately 70% of patients. A lower dose of agalsidase beta may be sufficient in some, but not all, patients with Fabry disease to maintain the cellular globotriaosylceramide clearance achieved with 1.0 mg/kg/2 weeks. Long-term clinical effects of transitioning to the lower dose have not been evaluated.

  13. Focal Reduction in Cardiac 123I-Metaiodobenzylguanidine Uptake in Patients With Anderson-Fabry Disease.

    PubMed

    Yamamoto, Saori; Suzuki, Hideaki; Sugimura, Koichiro; Tatebe, Shunsuke; Aoki, Tatsuo; Miura, Masanobu; Yaoita, Nobuhiro; Sato, Haruka; Kozu, Katuya; Ota, Hideki; Takanami, Kentaro; Takase, Kei; Shimokawa, Hiroaki

    2016-11-25

    It remains to be elucidated whether cardiac sympathetic nervous activity is impaired in patients with Anderson-Fabry disease (AFD).Methods and Results:We performed 123 I-meta-iodobenzylguanidine (MIBG) scintigraphy and gadolinium-enhanced cardiovascular magnetic resonance (CMR) in 5 AFD patients. MIBG uptake in the inferolateral wall, where wall thinning and delayed enhancement were noted on CMR, was significantly lower compared with the anteroseptal wall. The localized reduction in MIBG uptake was also noted in 2 patients with no obvious abnormal findings on CMR. Cardiac sympathetic nervous activity is impaired in AFD before development of structural myocardial abnormalities. (Circ J 2016; 80: 2550-2551).

  14. Clinical course of patients with Fabry disease who were switched from agalsidase-β to agalsidase-α

    PubMed Central

    Tsuboi, Kazuya; Yamamoto, Hiroshi

    2014-01-01

    Background: Between 2009 and 2012, there was a worldwide shortage of agalsidase-β for the treatment of Fabry disease. Therefore, alternative treatments were needed, including switching to a different enzyme-replacement therapy. Purpose: This is an ongoing observational study assessing the effects of switching from agalsidase-β (1.0 mg/kg every other week) to agalsidase-α (0.2 mg/kg every other week) in 11 patients with Fabry disease. Methods: Clinical data were collected for 5 years—2 years before switching and 3 years after switching. Results: Measures of renal function such as estimated glomerular filtration rate remained stable during the 3 years after switching to agalsidase-α. Improvements in cardiac mass were recorded in both male and female patients 12 months after switching to agalsidase-α, and the benefit was maintained during 36 months of follow-up. There was no significant difference in the severity of pain experienced by patients before and after switching enzyme-replacement therapy, and no difference in quality-of-life parameters. Agalsidase-α was generally well tolerated, and no patients experienced allergy or developed antibodies to agalsidase-α. Conclusion: This observational study supports the safety of switching from agalsidase-β to agalsidase-α at the approved doses, with no loss of efficacy. It also suggests that if an infusion-related allergic reaction occurs in a patient receiving agalsidase-β, switching to agalsidase-α may be a viable option. PMID:24651606

  15. Switch from agalsidase beta to agalsidase alfa in the enzyme replacement therapy of patients with Fabry disease in Latin America.

    PubMed

    Ripeau, Diego; Amartino, Hernán; Cedrolla, Martín; Urtiaga, Luis; Urdaneta, Bella; Cano, Marilis; Valdez, Rita; Antongiovanni, Norberto; Masllorens, Francisca

    2017-01-01

    There are currently two available enzyme replacement therapies for Fabry disease and little information regarding efficacy and safety of switching therapies. Between 2009 and 2012 there was a worldwide shortage of agalsidase beta and patients on that enzyme were switched to agalsidase alfa. This retrospective observational study assessed a 2-year period of efficacy and safety in a population of Fabry patients, in Argentina (30 patients) and Venezuela (3 patients), who switched therapies from algasidase beta to agalsidase alfa. Thirty-three patients completed 24-months follow-up after the switch (age 32.4 ± 2.0, range 10.0-55.9 years; male: female 23:10). Measures of renal function such as estimated glomerular filtration rate remained almost unchanged in 31 patients without end stage renal disease over the 2 years after switching and urine protein excretion continued stable. Cardiac functional parameters: left ventricular mass index, interventricular septum, left ventricular posterior wall showed no significant change from baseline in the 33 patients. Quality of life, pain and disease severity scores were mostly unchanged after 24-months and agalsidase alfa was generally well tolerated. Our findings showed there is no significant change in the efficacy measured through the renal or cardiac function, quality of life, pain, disease severity scoring and safety for at least 2 years after switching from agalsidase beta to agalsidase alfa.

  16. A Novel Rapid MALDI-TOF-MS-Based Method for Measuring Urinary Globotriaosylceramide in Fabry Patients

    NASA Astrophysics Data System (ADS)

    Alharbi, Fahad J.; Geberhiwot, Tarekegn; Hughes, Derralynn A.; Ward, Douglas G.

    2016-04-01

    Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of α-galactosidase A, resulting in the accumulation of glycosphingolipids in various organs. Globotriaosylceramide (Gb3) and its isoforms and analogues have been identified and quantified as biomarkers of disease severity and treatment efficacy. The current study aimed to establish rapid methods for urinary Gb3 extraction and quantitation. Urine samples from 15 Fabry patients and 21 healthy control subjects were processed to extract Gb3 by mixing equal volumes of urine, methanol containing an internal standard, and chloroform followed by sonication and centrifugation. Thereafter, the lower phase was analyzed by MALDI-TOF MS and the relative peak areas of the internal standard and four major species of Gb3 determined. The results showed high reproducibility with intra- and inter-assay coefficients variation of 9.9% and 13.7%, respectively. The limit of detection was 0.15 ng/μL and the limit of quantitation was 0.30 ng/μL. Total urinary Gb3 levels in both genders of classic Fabry patients were significantly higher than in healthy controls (p < 0.0001). Gb3 levels in Fabry males were higher than in Fabry females (p = 0.08). We have established a novel assay for urinary total Gb3 that takes less than 15 min from start to finish.

  17. Successful management of enzyme replacement therapy in related fabry disease patients with severe adverse events by switching from agalsidase Beta (fabrazyme(®)) to agalsidase alfa (replagal (®)).

    PubMed

    Tsuboi, Kazuya; Yamamoto, Hiroshi; Somura, Fuji; Goto, Hiromi

    2015-01-01

    Enzyme replacement therapy (ERT) is the only approved therapy for Fabry disease. In June 2009, there was a worldwide shortage of agalsidase beta, necessitating dose reductions or switching to agalsidase alfa in some patients. We present two cases of Fabry disease (a parent and a child) who received agalsidase beta for 27 months at the licensed dose and 10 months at a reduced dose, followed by a switch to agalsidase alfa for 28 months. Case 1, a 26-year-old male had severe coughing and fatigue during ERT with agalsidase beta requiring antitussive and asthmatic drug therapy. After switching to agalsidase alfa, the coughing gradually resolved completely. Case 2, a 62-year-old female had advanced cardiac manifestations at the time of diagnosis. Despite receiving ERT with the approved dose of agalsidase beta, she experienced aggravation of congestive heart failure and was hospitalized. After switching to agalsidase alfa with standard care in heart disease, BNP level, echocardiographic parameters, eGFR rate and lyso-Gb3 levels were improved or stabilized. We report on two Fabry disease patients who experienced severe adverse events while on approved and/or reduced doses of agalsidase beta. Switching to agalsidase alfa associated with standard care in heart disease led to resolution or improvement in the cardiorespiratory status. And reduction in dose associated with standard care in respiratory disease was useful for decrease in cough and fatigue. Plasma BNP level was useful for monitoring heart failure and the effects of ERT.

  18. The use of high resolution melting analysis to detect Fabry mutations in heterozygous females via dry bloodspots.

    PubMed

    Tai, Chang-Long; Liu, Mei-Ying; Yu, Hsiao-Chi; Chiang, Chiang-Chuan; Chiang, Hung; Suen, Jeng-Hung; Kao, Shu-Min; Huang, Yu-Hsiu; Wu, Tina Jui-Ting; Yang, Chia-Feng; Tsai, Fang-Chih; Lin, Ching-Yuang; Chang, Jan-Gowth; Chen, Hong-Duo; Niu, Dau-Ming

    2012-02-18

    As an X-linked genetic disorder, Fabry disease was first thought to affect males only, and females were generally considered to be asymptomatic carriers. However, recent research suggests that female carriers of Fabry disease may still develop vital organ damage causing severe morbidity and mortality. In the previous newborn screening, from 299,007 newborns, we identified a total of 20 different Fabry mutations and 121 newborns with Fabry mutations. However, we found that most female carriers are not detected by enzyme assays. A streamlined method for high resolution melting (HRM) analysis was designed to screen for GLA gene mutations using a same PCR and melting program. Primer sets were designed to cover the 7 exons and the Chinese common intronic mutation, IVS4+919G>A of GLA gene. The HRM analysis was successful in identifying heterozygous and hemizygous patients with the 20 surveyed mutations. We were also successful in using this method to test dry blood spots of newborns afflicted with Fabry mutations without having to determine DNA concentration before PCR amplification. The results of this study show that HRM could be a reliable and sensitive method for use in the rapid screening of females for GLA mutations. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. 21 CFR 74.340 - FD&C Red No. 40.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.340 FD&C Red No. 40. (a) Identity. (1) The color additive FD&C...-naphthalenesulfonic acid. (2) Color additive mixtures for food use (including dietary supplements) made with FD&C Red...

  20. 21 CFR 74.203 - FD&C Green No. 3.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.203 FD&C Green No. 3. (a) Identity. (1) The color additive FD... mixtures for coloring food. (b) Specifications. The color additive FD&C Green No. 3 shall conform to the...

  1. 21 CFR 74.203 - FD&C Green No. 3.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.203 FD&C Green No. 3. (a) Identity. (1) The color additive FD... mixtures for coloring food. (b) Specifications. The color additive FD&C Green No. 3 shall conform to the...

  2. 21 CFR 74.340 - FD&C Red No. 40.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.340 FD&C Red No. 40. (a) Identity. (1) The color additive FD&C...-naphthalenesulfonic acid. (2) Color additive mixtures for food use (including dietary supplements) made with FD&C Red...

  3. 21 CFR 74.340 - FD&C Red No. 40.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.340 FD&C Red No. 40. (a) Identity. (1) The color additive FD&C...-naphthalenesulfonic acid. (2) Color additive mixtures for food use (including dietary supplements) made with FD&C Red...

  4. 21 CFR 74.203 - FD&C Green No. 3.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.203 FD&C Green No. 3. (a) Identity. (1) The color additive FD... mixtures for coloring food. (b) Specifications. The color additive FD&C Green No. 3 shall conform to the...

  5. 21 CFR 74.706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.706 FD&C Yellow No. 6. (a) Identity. (1) The color additive FD...) Color additive mixtures for food use made with FD&C Yellow No. 6 may contain only those diluents that...

  6. 21 CFR 74.705 - FD&C Yellow No. 5.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.705 FD&C Yellow No. 5. (a) Identity. (1) The color additive FD... salt. (2) Color additive mixtures for food use made with FD&C Yellow No. 5 may contain only those...

  7. 21 CFR 74.706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.706 FD&C Yellow No. 6. (a) Identity. (1) The color additive FD...) Color additive mixtures for food use made with FD&C Yellow No. 6 may contain only those diluents that...

  8. 21 CFR 74.706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.706 FD&C Yellow No. 6. (a) Identity. (1) The color additive FD...) Color additive mixtures for food use made with FD&C Yellow No. 6 may contain only those diluents that...

  9. 21 CFR 74.706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.706 FD&C Yellow No. 6. (a) Identity. (1) The color additive FD...) Color additive mixtures for food use made with FD&C Yellow No. 6 may contain only those diluents that...

  10. 21 CFR 74.705 - FD&C Yellow No. 5.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.705 FD&C Yellow No. 5. (a) Identity. (1) The color additive FD... salt. (2) Color additive mixtures for food use made with FD&C Yellow No. 5 may contain only those...

  11. 21 CFR 74.706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.706 FD&C Yellow No. 6. (a) Identity. (1) The color additive FD...) Color additive mixtures for food use made with FD&C Yellow No. 6 may contain only those diluents that...

  12. 21 CFR 74.705 - FD&C Yellow No. 5.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.705 FD&C Yellow No. 5. (a) Identity. (1) The color additive FD... salt. (2) Color additive mixtures for food use made with FD&C Yellow No. 5 may contain only those...

  13. A retrospective analysis of the potential impact of IgG antibodies to agalsidase beta on efficacy during enzyme replacement therapy for Fabry disease.

    PubMed

    Bénichou, Bernard; Goyal, Sunita; Sung, Crystal; Norfleet, Andrea M; O'Brien, Fanny

    2009-01-01

    Fabry disease results from a genetic deficiency of alpha-galactosidase A (alpha GAL) and the impaired catabolism of globotriasoylceramide (GL-3) and other glycosphingolipid substrates, which then accumulate pathogenically within most cells. Enzyme replacement therapy (ERT) with agalsidase beta (Fabrazyme), one of two available forms of recombinant human alpha GAL, involves regular intravenous infusions of the therapeutic protein. Immunoglobulin G (IgG) antibodies to recombinant alpha GAL develop in the majority of patients upon repeated infusion. To explore whether anti-alpha GAL IgG interferes with therapeutic efficacy, retrospective analyses were conducted using data obtained from a total of 134 adult male and female patients with Fabry disease who were treated with agalsidase beta at 1mg/kg every 2 weeks for up to 5 years during placebo-controlled trials and the corresponding open-label extension studies. The analyses did not reveal a correlation between anti-alpha GAL IgG titers and the onset of clinical events or the rate of change in estimated GFR during treatment, and no statistically significant association was found between anti-alpha GAL IgG titers and abnormal elevations in plasma GL-3 during treatment. However, a statistically significant association was found between anti-alpha GAL IgG titers and observation of some GL-3 deposition in the dermal capillary endothelial cells of skin during treatment, suggesting that GL-3 clearance may be partially impaired in some patients with high antibody titers. Determination of the long-term impact of circulating anti-alpha GAL IgG antibodies on clinical outcomes will require continued monitoring, and serology testing is recommended as part of the routine care of Fabry disease patients during ERT.

  14. 21 CFR 74.2203 - FD&C Green No. 3.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2203 FD&C Green No. 3. (a) Identity and specifications. The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements of § 74.203(a)(1) and (b). (b) Uses and restrictions. The color additive FD&C Green No. 3 may be...

  15. 21 CFR 74.1303 - FD&C Red No. 3.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1303 FD&C Red No. 3. (a) Identity and specifications. (1) The color additive FD&C Red No. 3 shall conform in identity and specifications to the requirements of § 74.303(a)(1) and (b). (2) Color additive mixtures for ingested drug used made with FD&C Red No. 3 may...

  16. 21 CFR 74.2203 - FD&C Green No. 3.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2203 FD&C Green No. 3. (a) Identity and specifications. The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements of § 74.203(a)(1) and (b). (b) Uses and restrictions. The color additive FD&C Green No. 3 may be...

  17. 21 CFR 74.1303 - FD&C Red No. 3.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1303 FD&C Red No. 3. (a) Identity and specifications. (1) The color additive FD&C Red No. 3 shall conform in identity and specifications to the requirements of § 74.303(a)(1) and (b). (2) Color additive mixtures for ingested drug used made with FD&C Red No. 3 may...

  18. 21 CFR 74.2203 - FD&C Green No. 3.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2203 FD&C Green No. 3. (a) Identity and specifications. The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements of § 74.203(a)(1) and (b). (b) Uses and restrictions. The color additive FD&C Green No. 3 may be...

  19. 21 CFR 74.1303 - FD&C Red No. 3.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1303 FD&C Red No. 3. (a) Identity and specifications. (1) The color additive FD&C Red No. 3 shall conform in identity and specifications to the requirements of § 74.303(a)(1) and (b). (2) Color additive mixtures for ingested drug used made with FD&C Red No. 3 may...

  20. 21 CFR 74.2203 - FD&C Green No. 3.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2203 FD&C Green No. 3. (a) Identity and specifications. The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements of § 74.203(a)(1) and (b). (b) Uses and restrictions. The color additive FD&C Green No. 3 may be...

  1. 21 CFR 74.1303 - FD&C Red No. 3.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1303 FD&C Red No. 3. (a) Identity and specifications. (1) The color additive FD&C Red No. 3 shall conform in identity and specifications to the requirements of § 74.303(a)(1) and (b). (2) Color additive mixtures for ingested drug used made with FD&C Red No. 3 may...

  2. Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease.

    PubMed

    Germain, Dominique P; Waldek, Stephen; Banikazemi, Maryam; Bushinsky, David A; Charrow, Joel; Desnick, Robert J; Lee, Philip; Loew, Thomas; Vedder, Anouk C; Abichandani, Rekha; Wilcox, William R; Guffon, Nathalie

    2007-05-01

    Fabry disease, an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human alpha-galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase beta and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase beta for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n = 8) maintained complete GL-3 clearance in renal capillary endothelial cells and multiple cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n = 41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time. Long-term agalsidase beta therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.

  3. An Archetype Semi-Ring Fabry-Perot (SRFP) Resonator

    NASA Technical Reports Server (NTRS)

    Taghavi-Larigani, Shervin; VanZyl, Jakob

    2009-01-01

    We introduce and demonstrate the generation of a novel resonator, termed Semi-Ring Fabry-Perot (SRFP), that exhibits unique features, such as, its use of one plane mirror, allowing the SRFP to be easily fabricated as a symmetrical device. In addition to its unique features, it exhibits advantages of ring and Fabry-Perot resonators: 1) compared to a ring resonator that only allows a transmitted intensity, the Semi-Ring Fabry-Perot (SRFP) supports standing waves, allowing both a reflected and transmitted intensity; 2) the reflected light spectrum of the SRFP resonator is much narrower than similar Fabry-Perot, implying higher finesse.

  4. 21 CFR 74.1101 - FD&C Blue No. 1

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1101 FD&C Blue No. 1 (a) Identity. (1) For ingested drugs, the color additive FD&C Blue No. 1 shall conform in identity to the requirements of § 74.101(a)(1). (2) For externally applied drugs, the color additive FD&C Blue No. 1 shall conform in identity to the requirements of...

  5. 21 CFR 74.1101 - FD&C Blue No. 1

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FD&C Blue No. 1 74.1101 Section 74.1101 Food and... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1101 FD&C Blue No. 1 (a) Identity. (1) For ingested drugs, the color additive FD&C Blue No. 1 shall conform in identity to the requirements of § 74.101(a)(1). (2) For...

  6. 21 CFR 82.102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FD&C Blue No. 2. 82.102 Section 82.102 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.102 FD&C Blue No. 2. The color additive FD&C Blue No. 2 shall conform in identity and specifications to the requirements of § 74.102(a)(1...

  7. 21 CFR 82.101 - FD&C Blue No. 1.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FD&C Blue No. 1. 82.101 Section 82.101 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.101 FD&C Blue No. 1. The color additive FD&C Blue No. 1 shall conform in identity and specifications to the requirements of § 74.101(a)(1...

  8. 21 CFR 74.1102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FD&C Blue No. 2. 74.1102 Section 74.1102 Food and... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1102 FD&C Blue No. 2. (a) Identity. (1) The color additive FD&C Blue No. 2 shall conform in identity to the requirements of § 74.102(a)(1). (2) Color additive...

  9. 21 CFR 74.1101 - FD&C Blue No. 1

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FD&C Blue No. 1 74.1101 Section 74.1101 Food and... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1101 FD&C Blue No. 1 (a) Identity. (1) For ingested drugs, the color additive FD&C Blue No. 1 shall conform in identity to the requirements of § 74.101(a)(1). (2) For...

  10. 21 CFR 82.102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FD&C Blue No. 2. 82.102 Section 82.102 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.102 FD&C Blue No. 2. The color additive FD&C Blue No. 2 shall conform in identity and specifications to the requirements of § 74.102(a)(1...

  11. 21 CFR 74.1102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FD&C Blue No. 2. 74.1102 Section 74.1102 Food and... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1102 FD&C Blue No. 2. (a) Identity. (1) The color additive FD&C Blue No. 2 shall conform in identity to the requirements of § 74.102(a)(1). (2) Color additive...

  12. 21 CFR 74.1101 - FD&C Blue No. 1

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FD&C Blue No. 1 74.1101 Section 74.1101 Food and... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1101 FD&C Blue No. 1 (a) Identity. (1) For ingested drugs, the color additive FD&C Blue No. 1 shall conform in identity to the requirements of § 74.101(a)(1). (2) For...

  13. 21 CFR 82.101 - FD&C Blue No. 1.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FD&C Blue No. 1. 82.101 Section 82.101 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.101 FD&C Blue No. 1. The color additive FD&C Blue No. 1 shall conform in identity and specifications to the requirements of § 74.101(a)(1...

  14. 21 CFR 82.102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Blue No. 2. 82.102 Section 82.102 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.102 FD&C Blue No. 2. The color additive FD&C Blue No. 2 shall conform in identity and specifications to the requirements of § 74.102(a)(1...

  15. 21 CFR 82.101 - FD&C Blue No. 1.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FD&C Blue No. 1. 82.101 Section 82.101 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.101 FD&C Blue No. 1. The color additive FD&C Blue No. 1 shall conform in identity and specifications to the requirements of § 74.101(a)(1...

  16. 21 CFR 82.102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FD&C Blue No. 2. 82.102 Section 82.102 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.102 FD&C Blue No. 2. The color additive FD&C Blue No. 2 shall conform in identity and specifications to the requirements of § 74.102(a)(1...

  17. 21 CFR 82.102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FD&C Blue No. 2. 82.102 Section 82.102 Food and... PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.102 FD&C Blue No. 2. The color additive FD&C Blue No. 2 shall conform in identity and specifications to the requirements of § 74.102(a)(1...

  18. 21 CFR 74.1102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FD&C Blue No. 2. 74.1102 Section 74.1102 Food and... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1102 FD&C Blue No. 2. (a) Identity. (1) The color additive FD&C Blue No. 2 shall conform in identity to the requirements of § 74.102(a)(1). (2) Color additive...

  19. Two novel mutations in the alpha-galactosidase gene in Japanese classical hemizygotes with Fabry disease.

    PubMed

    Okumiya, T; Takenaka, T; Ishii, S; Kase, R; Kamei, S; Sakuraba, H

    1996-09-01

    Four alpha-galactosidase gene mutations were identified in Japanese male patients with Fabry disease who had no detectable alpha-galactosidase activity. Two of them were novel mutations, an 11-bp deletion in exon 2 and a g-1 to t substitution at the 3' end of the splice acceptor site in intron 1. The former caused a frameshift and led to the creation of a new stop codon at codon 118. The latter was predicted to provoke aberrant mRNA splicing followed by accelerated degradation of the mRNA. A nonsense mutation, R301X, and a 2-bp deletion starting at nucleotide position 718, which were reported previously, were also identified in unrelated patients.

  20. Antibody Epitope of Human α-Galactosidase A Revealed by Affinity Mass Spectrometry: A Basis for Reversing Immunoreactivity in Enzyme Replacement Therapy of Fabry Disease.

    PubMed

    Kukacka, Zdenek; Iurascu, Marius; Lupu, Loredana; Rusche, Hendrik; Murphy, Mary; Altamore, Lorenzo; Borri, Fabio; Maeser, Stefan; Papini, Anna Maria; Hennermann, Julia; Przybylski, Michael

    2018-05-08

    α-Galactosidase (αGal) is a lysosomal enzyme that hydrolyses the terminal α-galactosyl moiety from glycosphingolipids. Mutations in the encoding genes for αGal lead to defective or misfolded enzyme, which results in substrate accumulation and subsequent organ dysfunction. The metabolic disease caused by a deficiency of human α-galactosidase A is known as Fabry disease or Fabry-Anderson disease, and it belongs to a larger group known as lysosomal storage diseases. An effective treatment for Fabry disease has been developed by enzyme replacement therapy (ERT), which involves infusions of purified recombinant enzyme in order to increase enzyme levels and decrease the amounts of accumulated substrate. However, immunoreactivity and IgG antibody formation are major, therapy-limiting, and eventually life-threatening complications of ERT. The present study focused on the epitope determination of human α-galactosidase A against its antibody formed. Here we report the identification of the epitope of human αGal(309-332) recognized by a human monoclonal anti-αGal antibody, using a combination of proteolytic excision of the immobilized immune complex and surface plasmon resonance biosensing mass spectrometry. The epitope peptide, αGal(309-332), was synthesized by solid-phase peptide synthesis. Determination of its affinity by surface plasmon resonance analysis revealed a high binding affinity for the antibody (K D =39×10 -9  m), which is nearly identical to that of the full-length enzyme (K D =16×10 -9  m). The proteolytic excision affinity mass spectrometry method is shown here to be an efficient tool for epitope identification of an immunogenic lysosomal enzyme. Because the full-length αGal and the antibody epitope showed similar binding affinities, this provides a basis for reversing immunogenicity upon ERT by: 1) treatment of patients with the epitope peptide to neutralize antibodies, or 2) removal of antibodies by apheresis, and thus significantly

  1. Reaccumulation of globotriaosylceramide in podocytes after agalsidase dose reduction in young Fabry patients.

    PubMed

    Skrunes, Rannveig; Svarstad, Einar; Kampevold Larsen, Kristin; Leh, Sabine; Tøndel, Camilla

    2017-05-01

    Agalsidase-α 0.2 mg/kg every other week (eow) and agalsidase-β 1.0 mg/kg/eow are licensed in Europe as equipotent treatment of the α-galactosidase deficiency in Fabry disease. This case series describes the effects of agalsidase dose adjustments in serial kidney biopsies in switch patients. All treatment-naïve patients with classical Fabry disease in our centre started on agalsidase-β 1.0 mg/kg/eow and subsequently switched to agalsidase-α 0.2 mg/kg/eow were included ( n = 3). The median age at enzyme replacement therapy start was 11 (range 7-18) years. Kidney biopsies were performed at baseline, after 5 years of agalsidase-β 1.0 mg/kg/eow and after 3 subsequent years of agalsidase-α 0.2 mg/kg/eow. One patient was re-biopsied 2 years after reswitch to agalsidase-β 1.0 mg/kg/eow. The scoring system of the International Scoring Group of Fabry Nephropathy was used. The patients completely cleared globotriaosylceramide (GL3) from mesangial and endothelial cells and partly cleared podocytes on agalsidase-β 1.0 mg/kg/eow. Reaccumulation of GL3 in podocytes, but not in the mesangium or endothelium, occurred after 3 years of agalsidase-α 0.2 mg/kg/eow. Subsequent reduction of podocyte GL3 was observed in the single patient rebiopsied 2 years after reswitch to agalsidase-β 1.0 mg/kg/eow. Partial clearance, reaccumulation and renewed partial clearance of podocyte GL3 deposits in serial kidney biopsies over 8-10 years were seen in parallel with agalsidase dose adjustments. Repeated kidney biopsies may impact therapeutic choices in Fabry disease. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  2. FD-CHIRP: hosted payload system engineering lessons

    NASA Astrophysics Data System (ADS)

    Schueler, Carl F.

    2012-10-01

    The Commercially Hosted Infrared Payload (CHIRP) Flight Demonstration (FD-CHIRP) launched 21 Sept 2011 was designated a "resounding success" as the first Wide Field-of-View (WFOV) staring infrared (IR) sensor flown in geostationary earth orbit (GEO) with a primary mission of Missile Warning (MW). FD-CHIRP was an Air Force research and development project initiated in July 2008 via an unsolicited industry proposal aimed to mature and reduce the risk of WFOV sensors and ground processing technologies. Unlike the Defense Support Program (DSP) and the Space Based Infrared System (SBIRS) which were acquired via traditional integrated sensor and satellite design, FDCHIRP was developed using the "commercially hosted" approach. The FD-CHIRP host spacecraft and sensor were independently designed, creating significant development risk to the industry proposer, especially under a Firm Fixed Price contract. Yet, within 39 months of contract initiation, FD-CHIRP was launched and successfully operated in GEO to 30 June 2012 at a total cost of 111M including the 82.9M CHIRP commercial-hosting contract and a $28M sensor upgrade. The commercial-hosting contract included sensor and spacecraft modifications, integration and test, design and development of secure Mission Operations and Analysis Centers, launch, and nearly a year of GEO operations with 70 Mbps secure data acquisition. The Air Force extended the contract for six months to continue operations through the end of calendar 2012. This paper outlines system engineering challenges FD-CHIRP overcame and key lessons to smooth development of future commercially hosted missions.

  3. Strained layer Fabry-Perot device

    DOEpatents

    Brennan, Thomas M.; Fritz, Ian J.; Hammons, Burrell E.

    1994-01-01

    An asymmetric Fabry-Perot reflectance modulator (AFPM) consists of an active region between top and bottom mirrors, the bottom mirror being affixed to a substrate by a buffer layer. The active region comprises a strained-layer region having a bandgap and thickness chosen for resonance at the Fabry-Perot frequency. The mirrors are lattice matched to the active region, and the buffer layer is lattice matched to the mirror at the interface. The device operates at wavelengths of commercially available semiconductor lasers.

  4. Agalsidase Benefits Renal Histology in Young Patients with Fabry Disease

    PubMed Central

    Bostad, Leif; Larsen, Kristin Kampevold; Hirth, Asle; Vikse, Bjørn Egil; Houge, Gunnar; Svarstad, Einar

    2012-01-01

    The effect of early-onset enzyme replacement therapy on renal morphologic features in Fabry disease is largely unknown. Here, we evaluated the effect of 5 years of treatment with agalsidase alfa or agalsidase beta in 12 consecutive patients age 7–33 years (median age, 16.5 years). We performed renal biopsies at baseline and after 5 years of enzyme replacement therapy; 7 patients had additional biopsies after 1 and 3 years. After a median of 65 months, biopsy findings from all patients showed total clearance of glomerular endothelial and mesangial cell inclusions, and findings from 2 patients showed complete clearance of inclusions from epithelial cells of the distal tubule. The 4 patients who received the highest dose of agalsidase exhibited substantial clearance of podocyte inclusions, and the youngest patient had nearly complete clearance of these inclusions. Linear regression analysis showed a highly significant correlation between podocyte globotriaocylceramide clearance and cumulative agalsidase dose (r=0.804; P=0.002). Microalbuminuria normalized in five patients. In summary, long-term enzyme replacement therapy in young patients can result in complete globotriaocylceramide clearance of mesangial and glomerular endothelial cells across all dosage regimens, and clearance of podocyte inclusions is dose-dependent. PMID:23274955

  5. Treatment of Fabry disease with different dosing regimens of agalsidase: effects on antibody formation and GL-3.

    PubMed

    Vedder, Anouk C; Breunig, Frank; Donker-Koopman, Wilma E; Mills, Kevin; Young, Elisabeth; Winchester, Bryan; Ten Berge, Ineke J M; Groener, Johanna E M; Aerts, Johannes M F G; Wanner, Christoph; Hollak, Carla E M

    2008-07-01

    Two different enzyme preparations are used for the treatment of Fabry disease patients, agalsidase alpha (Replagal, Shire) and agalsidase beta (Fabrazyme, Genzyme). Therapeutic efficacy of both products has been variable probably due to differences in gender, severity, age and other patient characteristics. We studied the occurrence of alpha-Gal A antibodies and their effect on urinary and plasma globotriaosylceramide (GL-3), plasma chitotriosidase and clinical outcome in 52 patients after 12 months of treatment with either 0.2mg/kg agalsidase alppha (10 males, 8 females) or beta (8 males, 5 females) or 1.0mg/kg agalsidase beta (10 males, 11 females). Antibodies were detected in 18/28 male patients after 6 months. None of the females developed antibodies. Following 12 months of 0.2mg/kg treatment, urinary GL-3 decreased in antibody negative (AB-) but increased in antibody positive (AB+) patients. Treatment with 1.0mg/kg gave a reduction in urinary GL-3 in both AB- and AB+ patients. Levels of plasma GL-3 and chitotriosidase decreased in all patient groups. Twelve months of 0.2mg/kg treatment did not change renal function or left ventricular mass. Further, no change in renal function was seen following 1.0mg/kg treatment and left ventricular mass decreased in both AB- and AB+ patients. In summary, alpha-Gal A antibodies frequently develop in male Fabry disease patients and interfere with urinary GL-3 excretion. Infusion of a dose of 1.0mg/kg results in a more robust decline in GL-3, less impact, if any of antibodies, stable renal function and reduction of LVMass.

  6. Exposure estimate for FD&C colour additives for the US population.

    PubMed

    Doell, Diana L; Folmer, Daniel E; Lee, Hyoung S; Butts, Kyla M; Carberry, Susan E

    2016-05-01

    Dietary exposures to the seven food, drug, and cosmetic (FD&C) colour additives that are approved for general use in food in the United States were estimated for the US population (aged 2 years and older), children (aged 2-5 years) and teenage boys (aged 13-18 years) based on analytical levels of the FD&C colour additives in foods. Approximately 600 foods were chosen for analysis, based on a survey of product labels, for the levels of FD&C colour additives. Dietary exposure was estimated using both 2-day food consumption data from the combined 2007-10 National Health and Nutrition Examination Survey (NHANES) and 10-14-day food consumption data from the 2007-10 NPD Group, Inc. National Eating Trends - Nutrient Intake Database (NPD NET-NID). Dietary exposure was estimated at the mean and 90th percentile using three different exposure scenarios: low exposure, average exposure and high exposure, to account for the range in the amount of each FD&C colour additive for a given food. For all populations and all exposure scenarios, the highest cumulative eaters-only exposures in food were determined for FD&C Red No. 40, FD&C Yellow No. 5 and FD&C Yellow No. 6. In addition, the eaters-only exposure was estimated for individual food categories in order to determine which food categories contributed the most to the exposure for each FD&C colour additive. Breakfast Cereal, Juice Drinks, Soft Drinks, and Frozen Dairy Desserts/Sherbet (also referred to as Ice Cream, Frozen Yogurt, Sherbet (including Bars, Sticks, Sandwiches)) were the major contributing food categories to exposure for multiple FD&C colour additives for all three populations.

  7. Cognitive Style FD/I: An Important Learner Characteristic for Educational Technologists.

    ERIC Educational Resources Information Center

    Chinien, Chris A.; Boutin, France

    1993-01-01

    Reviews the literature on the cognitive style field dependent/field independent (FD/FI) and suggests implications for educational technologists in their efforts to address individual differences among learners during the instructional design process that would narrow the differential learning gain between FD and FI learners. Testing for FD/FI is…

  8. Exposure estimate for FD&C colour additives for the US population

    PubMed Central

    Folmer, Daniel E.; Lee, Hyoung S.; Butts, Kyla M.; Carberry, Susan E.

    2016-01-01

    Dietary exposures to the seven food, drug, and cosmetic (FD&C) colour additives that are approved for general use in food in the United States were estimated for the US population (aged 2 years and older), children (aged 2–5 years) and teenage boys (aged 13–18 years) based on analytical levels of the FD&C colour additives in foods. Approximately 600 foods were chosen for analysis, based on a survey of product labels, for the levels of FD&C colour additives. Dietary exposure was estimated using both 2-day food consumption data from the combined 2007–10 National Health and Nutrition Examination Survey (NHANES) and 10–14-day food consumption data from the 2007–10 NPD Group, Inc. National Eating Trends – Nutrient Intake Database (NPD NET-NID). Dietary exposure was estimated at the mean and 90th percentile using three different exposure scenarios: low exposure, average exposure and high exposure, to account for the range in the amount of each FD&C colour additive for a given food. For all populations and all exposure scenarios, the highest cumulative eaters-only exposures in food were determined for FD&C Red No. 40, FD&C Yellow No. 5 and FD&C Yellow No. 6. In addition, the eaters-only exposure was estimated for individual food categories in order to determine which food categories contributed the most to the exposure for each FD&C colour additive. Breakfast Cereal, Juice Drinks, Soft Drinks, and Frozen Dairy Desserts/Sherbet (also referred to as Ice Cream, Frozen Yogurt, Sherbet (including Bars, Sticks, Sandwiches)) were the major contributing food categories to exposure for multiple FD&C colour additives for all three populations. PMID:27092991

  9. Availability of and access to orphan drugs: an international comparison of pharmaceutical treatments for pulmonary arterial hypertension, Fabry disease, hereditary angioedema and chronic myeloid leukaemia.

    PubMed

    Blankart, Carl Rudolf; Stargardt, Tom; Schreyögg, Jonas

    2011-01-01

    Market authorization does not guarantee patient access to any given drug. This is particularly true for costly orphan drugs because access depends primarily on co-payments, reimbursement policies and prices. The objective of this article is to identify differences in the availability of orphan drugs and in patient access to them in 11 pharmaceutical markets: Australia, Canada, England, France, Germany, Hungary, the Netherlands, Poland, Slovakia, Switzerland and the US. Four rare diseases were selected for analysis: pulmonary arterial hypertension (PAH), Fabry disease (FD), hereditary angioedema (HAE) and chronic myeloid leukaemia (CML). Indicators for availability were defined as (i) the indications for which orphan drugs had been authorized in the treatment of these diseases; (ii) the application date; and (iii) the date upon which these drugs received market authorization in each country. Indicators of patient access were defined as (i) the outcomes of technology appraisals; (ii) the extent of coverage provided by healthcare payers; and (iii) the price of the drugs in each country. For PAH we analysed bosentan, iloprost, sildenafil, treprostinil (intravenous and inhaled) as well as sitaxentan and ambrisentan; for FD we analysed agalsidase alfa and agalsidase beta; for HAE we analysed icatibant, ecallantide and two complement C1s inhibitors; for CML we analysed imatinib, dasatinib and nilotinib. Most drugs included in this study had received market authorization in all countries, but the range of indications for which they had been authorized differed by country. The broadest range of indications was found in Australia, and the largest variations in indications were found for PAH drugs. Authorization process speed (the time between application and market authorization) was fastest in the US, with an average of 362 days, followed by the EU (394 days). The highest prices for the included drugs were found in Germany and the US, and the lowest in Canada, Australia and

  10. 21 CFR 74.2706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... COLOR ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2706 FD&C Yellow No. 6. (a) Identity and specifications. The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the... coloring cosmetics generally in amounts consistent with current good manufacturing practice. (c) Labeling...

  11. 21 CFR 74.2706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... COLOR ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2706 FD&C Yellow No. 6. (a) Identity and specifications. The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the... coloring cosmetics generally in amounts consistent with current good manufacturing practice. (c) Labeling...

  12. 21 CFR 74.2706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... COLOR ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2706 FD&C Yellow No. 6. (a) Identity and specifications. The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the... coloring cosmetics generally in amounts consistent with current good manufacturing practice. (c) Labeling...

  13. 21 CFR 74.2706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... COLOR ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2706 FD&C Yellow No. 6. (a) Identity and specifications. The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the... coloring cosmetics generally in amounts consistent with current good manufacturing practice. (c) Labeling...

  14. Safety and efficacy of enzyme replacement therapy with agalsidase beta: an international, open-label study in pediatric patients with Fabry disease.

    PubMed

    Wraith, J Edmond; Tylki-Szymanska, Anna; Guffon, Nathalie; Lien, Y Howard; Tsimaratos, Michel; Vellodi, Ashok; Germain, Dominique P

    2008-04-01

    To evaluate the safety and explore the efficacy of enzyme replacement therapy with agalsidase beta (recombinant human alpha-galactosidase A; Fabrazyme [Genzyme Corporation, Cambridge, MA]) in pediatric patients with Fabry disease, a genetic disorder in which deficient endogenous enzyme causes pathogenic tissue accumulation of globotriaosylceramide (GL-3). Fourteen male and 2 female patients, 8 to 16 years old, were treated in this open-label study. A 12-week observation period to collect baseline data preceded the 48-week treatment period when agalsidase beta (1 mg/kg) was infused intravenously every 2 weeks. No primary efficacy end point was specified. Before treatment, results of skin biopsies from 12 male patients showed moderate or severe GL-3 accumulation in superficial dermal capillary endothelial cells; with treatment, these cells were completely cleared of GL-3 in week-24 biopsies from all 12 male patients and in all available week-48 biopsies. With treatment, reports of gastrointestinal symptoms declined steadily. Patient diaries documented significant reductions in school absences due to sickness. Agalsidase beta was generally well tolerated; most treatment-related adverse events were mild or moderate infusion-associated reactions involving rigors, fever, or rhinitis. Agalsidase beta safely and effectively reduced the GL-3 accumulation in dermal endothelium already evident in children with Fabry disease. Early intervention may prevent irreversible end-organ damage from chronic GL-3 deposition.

  15. 21 CFR 74.101 - FD&C Blue No. 1.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.101 FD&C Blue No. 1. (a) Identity. (1) The color additive FD&C...] (o-sulfobenzyl) ammonium hydroxide inner salt. (2) Color additive mixtures for food use (including...

  16. 21 CFR 74.101 - FD&C Blue No. 1.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.101 FD&C Blue No. 1. (a) Identity. (1) The color additive FD&C...] (o-sulfobenzyl) ammonium hydroxide inner salt. (2) Color additive mixtures for food use (including...

  17. 21 CFR 74.101 - FD&C Blue No. 1.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.101 FD&C Blue No. 1. (a) Identity. (1) The color additive FD&C...] (o-sulfobenzyl) ammonium hydroxide inner salt. (2) Color additive mixtures for food use (including...

  18. 21 CFR 74.1203 - FD&C Green No. 3.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... manufacturing practice. (c) Labeling. The label of the color additive and any mixtures prepared therefrom... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1203 FD&C Green No. 3. (a) Identity and specifications. (1) The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements...

  19. 21 CFR 74.1706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... manufacturing practice. (c) Labeling requirements. (1) The label of the color additive and any mixtures intended... COLOR ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1706 FD&C Yellow No. 6. (a) Identity and specifications. (1) The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the...

  20. 21 CFR 74.2304 - FD&C Red No. 4.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2304 FD&C Red No. 4. (a) Identity and specifications. The color additive FD&C Red No. 4 shall conform in identity and specifications to the requirements of § 74... externally applied cosmetics in amounts consistent with good manufacturing practice. (c) Labeling. The label...

  1. 21 CFR 74.2304 - FD&C Red No. 4.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2304 FD&C Red No. 4. (a) Identity and specifications. The color additive FD&C Red No. 4 shall conform in identity and specifications to the requirements of § 74... externally applied cosmetics in amounts consistent with good manufacturing practice. (c) Labeling. The label...

  2. 21 CFR 74.1706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... manufacturing practice. (c) Labeling requirements. (1) The label of the color additive and any mixtures intended... COLOR ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1706 FD&C Yellow No. 6. (a) Identity and specifications. (1) The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the...

  3. 21 CFR 74.2304 - FD&C Red No. 4.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2304 FD&C Red No. 4. (a) Identity and specifications. The color additive FD&C Red No. 4 shall conform in identity and specifications to the requirements of § 74... externally applied cosmetics in amounts consistent with good manufacturing practice. (c) Labeling. The label...

  4. 21 CFR 74.1203 - FD&C Green No. 3.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... manufacturing practice. (c) Labeling. The label of the color additive and any mixtures prepared therefrom... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1203 FD&C Green No. 3. (a) Identity and specifications. (1) The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements...

  5. 21 CFR 74.1706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... manufacturing practice. (c) Labeling requirements. (1) The label of the color additive and any mixtures intended... COLOR ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1706 FD&C Yellow No. 6. (a) Identity and specifications. (1) The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the...

  6. 21 CFR 74.1706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... manufacturing practice. (c) Labeling requirements. (1) The label of the color additive and any mixtures intended... COLOR ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1706 FD&C Yellow No. 6. (a) Identity and specifications. (1) The color additive FD&C Yellow No. 6 shall conform in identity and specifications to the...

  7. 21 CFR 74.2304 - FD&C Red No. 4.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2304 FD&C Red No. 4. (a) Identity and specifications. The color additive FD&C Red No. 4 shall conform in identity and specifications to the requirements of § 74... externally applied cosmetics in amounts consistent with good manufacturing practice. (c) Labeling. The label...

  8. 21 CFR 74.1203 - FD&C Green No. 3.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... manufacturing practice. (c) Labeling. The label of the color additive and any mixtures prepared therefrom... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1203 FD&C Green No. 3. (a) Identity and specifications. (1) The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements...

  9. 21 CFR 74.1203 - FD&C Green No. 3.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... manufacturing practice. (c) Labeling. The label of the color additive and any mixtures prepared therefrom... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1203 FD&C Green No. 3. (a) Identity and specifications. (1) The color additive FD&C Green No. 3 shall conform in identity and specifications to the requirements...

  10. 21 CFR 74.1340 - FD&C Red No. 40.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... amounts consistent with current good manufacturing practice. (c) Labeling. The label of the color additive... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of § 74...

  11. 21 CFR 74.2340 - FD&C Red No. 40.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... manufacturing practice. (2) The color additive shall not be exposed to oxidizing or reducing agents that may... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of...

  12. 21 CFR 74.2340 - FD&C Red No. 40.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... manufacturing practice. (2) The color additive shall not be exposed to oxidizing or reducing agents that may... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of...

  13. 21 CFR 74.2340 - FD&C Red No. 40.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... manufacturing practice. (2) The color additive shall not be exposed to oxidizing or reducing agents that may... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of...

  14. 21 CFR 74.1340 - FD&C Red No. 40.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... amounts consistent with current good manufacturing practice. (c) Labeling. The label of the color additive... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of § 74...

  15. 21 CFR 74.2340 - FD&C Red No. 40.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... manufacturing practice. (2) The color additive shall not be exposed to oxidizing or reducing agents that may... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of...

  16. 21 CFR 74.1340 - FD&C Red No. 40.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... amounts consistent with current good manufacturing practice. (c) Labeling. The label of the color additive... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of § 74...

  17. 21 CFR 74.2340 - FD&C Red No. 40.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... manufacturing practice. (2) The color additive shall not be exposed to oxidizing or reducing agents that may... ADDITIVES SUBJECT TO CERTIFICATION Cosmetics § 74.2340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of...

  18. 21 CFR 74.1340 - FD&C Red No. 40.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... amounts consistent with current good manufacturing practice. (c) Labeling. The label of the color additive... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1340 FD&C Red No. 40. (a) Identity and specifications. (1) The color additive FD&C Red No. 40 shall conform in identity and specifications to the requirements of § 74...

  19. 21 CFR 74.303 - FD&C Red No. 3.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.303 FD&C Red No. 3. (a) Identity. (1) The color additive FD&C... are listed in part 73 of this chapter as safe for use in color additive mixtures for coloring foods...

  20. 21 CFR 74.303 - FD&C Red No. 3.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.303 FD&C Red No. 3. (a) Identity. (1) The color additive FD&C... are listed in part 73 of this chapter as safe for use in color additive mixtures for coloring foods...

  1. 21 CFR 74.303 - FD&C Red No. 3.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR ADDITIVES SUBJECT TO CERTIFICATION Foods § 74.303 FD&C Red No. 3. (a) Identity. (1) The color additive FD&C... are listed in part 73 of this chapter as safe for use in color additive mixtures for coloring foods...

  2. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium.

    PubMed

    Moon, James C C; Sachdev, Bhavesh; Elkington, Andrew G; McKenna, William J; Mehta, Atul; Pennell, Dudley J; Leed, Philip J; Elliott, Perry M

    2003-12-01

    Anderson-Fabry Disease (AFD), an X-linked disorder of sphingolipid metabolism, is a cause of idiopathic left ventricular hypertrophy but the mechanism of hypertrophy is poorly understood. Gadolinium enhanced cardiovascular magnetic resonance can detect focal myocardial fibrosis. We hypothesised that hyperenhancement would be present in AFD. Eighteen males (mean 43+/-14 years) and eight female heterozygotes (mean 48+/-12 years) with AFD underwent cine and late gadolinium cardiovascular magnetic resonance. Nine male (50%) had myocardial hyperenhancement ranging from 3.4% to 20.6% (mean 7.7+/-5.7%) of total myocardium; in males, percentage hyperenhancement related to LV mass index (r=0.78, P=0.0002) but not to ejection fraction or left ventricular volumes. Lesser hyperenhancement was also found in four (50%) heterozygous females (mean 4.6%). In 12 (92%) patients with abnormal gadolinium uptake, hyperenhancement occurred in the basal infero-lateral wall where, unlike myocardial infarction, it was not sub-endocardial. In two male patients with severe LVH (left ventricular hypertrophy) and systolic impairment there was additional hyperenhancement in other myocardial segments. These observations suggests that myocardial fibrosis occurs in AFD and may contribute to the hypertrophy and the natural history of the disease.

  3. Successful reinstitution of agalsidase beta therapy in Fabry disease patients with previous IgE-antibody or skin-test reactivity to the recombinant enzyme.

    PubMed

    Bodensteiner, David; Scott, C Ronald; Sims, Katherine B; Shepherd, Gillian M; Cintron, Rebecca D; Germain, Dominique P

    2008-05-01

    To determine if enzyme replacement therapy, involving intravenous infusions of recombinant human alpha-galactosidase A (agalsidase beta; Fabrazyme), could be safely continued in patients with Fabry disease who had been withdrawn from a previous clinical trial as a precautionary, protocol-specified measure due to detection of serum IgE antibodies or skin-test reactivity to agalsidase beta. The rechallenge infusion protocol specified strict patient monitoring conditions and graded dosing and infusion-rate schemes that were adjusted according to each patient's tolerance to the infusion. Six males (age: 26-66 years) were enrolled. During rechallenge, five patients received between 4 and 27 infusions; one patient voluntarily withdrew after one infusion because of recurrence of infusion-associated reactions. No anaphylactic reactions occurred. All adverse events, including four serious adverse events, were mild or moderate in intensity. Most treatment-related adverse events occurred during infusions (most commonly urticaria, vomiting, nausea, chills, pruritus, hypertension) and were resolved by infusion rate reductions and/or medication. After participation in the study, all patients, including the one who withdrew after one infusion, transitioned to commercial drug. Agalsidase beta therapy can be successfully reinstated in patients with Fabry disease who have developed IgE antibodies or skin test reactivity to the recombinant enzyme.

  4. 21 CFR 74.1706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Yellow No. 6. 74.1706 Section 74.1706 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF... safe for use in color additive mixtures for coloring drugs. (b) Uses and restrictions. FD&C Yellow No...

  5. 21 CFR 74.1102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Blue No. 2. 74.1102 Section 74.1102 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... coloring drugs. (b) The color additive FD&C Blue No. 2 for use in coloring ingested drugs shall conform to...

  6. 21 CFR 74.2304 - FD&C Red No. 4.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Red No. 4. 74.2304 Section 74.2304 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR....1304(a)(1) and (b). (b) Uses and restrictions. FD&C Red No. 4 may be safely used for coloring...

  7. 21 CFR 74.1203 - FD&C Green No. 3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Green No. 3. 74.1203 Section 74.1203 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... use in color additive mixtures for coloring drugs. (b) Uses and restrictions. The color additive FD&C...

  8. 21 CFR 74.1303 - FD&C Red No. 3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Red No. 3. 74.1303 Section 74.1303 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... use in color additive mixtures for coloring ingested drugs. (b) Uses and restrictions. FD&C Red No. 3...

  9. 21 CFR 74.1101 - FD&C Blue No. 1

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Blue No. 1 74.1101 Section 74.1101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... mixtures for coloring drugs. (b) Specifications. (1) The color additive FD&C Blue No. 1 for use in coloring...

  10. 21 CFR 82.101 - FD&C Blue No. 1.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Blue No. 1. 82.101 Section 82.101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF CERTIFIED PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.101 FD&C Blue No. 1. The color...

  11. 21 CFR 82.101 - FD&C Blue No. 1.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FD&C Blue No. 1. 82.101 Section 82.101 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF CERTIFIED PROVISIONALLY LISTED COLORS AND SPECIFICATIONS Foods, Drugs, and Cosmetics § 82.101 FD&C Blue No. 1. The color...

  12. Brainstem Involvement as a Cause of Central Sleep Apnea: Pattern of Microstructural Cerebral Damage in Patients with Cerebral Microangiopathy

    PubMed Central

    Duning, Thomas; Deppe, Michael; Brand, Eva; Stypmann, Jörg; Becht, Charlotte; Heidbreder, Anna; Young, Peter

    2013-01-01

    Background The exact underlying pathomechanism of central sleep apnea with Cheyne-Stokes respiration (CSA-CSR) is still unclear. Recent studies have demonstrated an association between cerebral white matter changes and CSA. A dysfunction of central respiratory control centers in the brainstem was suggested by some authors. Novel MR-imaging analysis tools now allow far more subtle assessment of microstructural cerebral changes. The aim of this study was to investigate whether and what severity of subtle structural cerebral changes could lead to CSA-CSR, and whether there is a specific pattern of neurodegenerative changes that cause CSR. Therefore, we examined patients with Fabry disease (FD), an inherited, lysosomal storage disease. White matter lesions are early and frequent findings in FD. Thus, FD can serve as a "model disease" of cerebral microangiopathy to study in more detail the impact of cerebral lesions on central sleep apnea. Patients and Methods Genetically proven FD patients (n = 23) and age-matched healthy controls (n = 44) underwent a cardio-respiratory polysomnography and brain MRI at 3.0 Tesla. We applied different MR-imaging techniques, ranging from semiquantitative measurement of white matter lesion (WML) volumes and automated calculation of brain tissue volumes to VBM of gray matter and voxel-based diffusion tensor imaging (DTI) analysis. Results In 5 of 23 Fabry patients (22%) CSA-CSR was detected. Voxel-based DTI analysis revealed widespread structural changes in FD patients when compared to the healthy controls. When calculated as a separate group, DTI changes of CSA-CSR patients were most prominent in the brainstem. Voxel-based regression analysis revealed a significant association between CSR severity and microstructural DTI changes within the brainstem. Conclusion Subtle microstructural changes in the brainstem might be a neuroanatomical correlate of CSA-CSR in patients at risk of WML. DTI is more sensitive and specific than

  13. Treatment of Fabry Disease: Outcome of a Comparative Trial with Agalsidase Alfa or Beta at a Dose of 0.2 mg/kg

    PubMed Central

    Vedder, Anouk C.; Linthorst, Gabor E.; Houge, Gunnar; Groener, Johannna E.M.; Ormel, Els E.; Bouma, Berto J.; Aerts, Johannes M.F.G.; Hirth, Asle; Hollak, Carla E.M.

    2007-01-01

    Background Two different enzyme preparations, agalsidase alfa (ReplagalTM, Shire) and beta (FabrazymeTM, Genzyme), are registered for treatment of Fabry disease. We compared the efficacy of and tolerability towards the two agalsidase preparations administered at identical protein dose in a randomized controlled open label trial. Methodology/Principal Findings Thirty-four Fabry disease patients were treated with either agalsidase alfa or agalsidase beta at equal dose of 0.2 mg/kg biweekly. Primary endpoint was reduction in left ventricular mass after 12 and 24 months of treatment. Other endpoints included occurrence of treatment failure (defined as progression of cardiac, renal or cerebral disease), glomerular filtration rate, pain, anti-agalsidase antibodies, and globotriaosylceramide levels in plasma and urine. After 12 and 24 months of treatment no reduction in left ventricular mass was seen, which was not different between the two treatment groups. Also, no differences in glomerular filtration rate, pain and decline in globotriaosylceramide levels were found. Antibodies developed only in males (4/8 in the agalsidase alfa group and 6/8 in the agalsidase beta group). Treatment failure within 24 months of therapy was seen in 8/34 patients: 6 male patients (3 in each treatment group) and 2 female patients (both agalsidase alfa). The occurrence of treatment failures did not differ between the two treatment groups; χ2 = 0.38 p = 0.54. Conclusion Our study revealed no difference in reduction of left ventricular mass or other disease parameters after 12 and 24 months of treatment with either agalsidase alfa or beta at a dose of 0.2 mg/kg biweekly. Treatment failure occurred frequently in both groups and seems related to age and severe pre-treatment disease. Trial Registration International Standard Randomized Clinical Trial ISRCTN45178534 PMID:17622343

  14. Treatment of Fabry disease: outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg.

    PubMed

    Vedder, Anouk C; Linthorst, Gabor E; Houge, Gunnar; Groener, Johannna E M; Ormel, Els E; Bouma, Berto J; Aerts, Johannes M F G; Hirth, Asle; Hollak, Carla E M

    2007-07-11

    Two different enzyme preparations, agalsidase alfa (Replagal(TM), Shire) and beta (Fabrazyme(TM), Genzyme), are registered for treatment of Fabry disease. We compared the efficacy of and tolerability towards the two agalsidase preparations administered at identical protein dose in a randomized controlled open label trial. Thirty-four Fabry disease patients were treated with either agalsidase alfa or agalsidase beta at equal dose of 0.2 mg/kg biweekly. Primary endpoint was reduction in left ventricular mass after 12 and 24 months of treatment. Other endpoints included occurrence of treatment failure (defined as progression of cardiac, renal or cerebral disease), glomerular filtration rate, pain, anti-agalsidase antibodies, and globotriaosylceramide levels in plasma and urine. After 12 and 24 months of treatment no reduction in left ventricular mass was seen, which was not different between the two treatment groups. Also, no differences in glomerular filtration rate, pain and decline in globotriaosylceramide levels were found. Antibodies developed only in males (4/8 in the agalsidase alfa group and 6/8 in the agalsidase beta group). Treatment failure within 24 months of therapy was seen in 8/34 patients: 6 male patients (3 in each treatment group) and 2 female patients (both agalsidase alfa). The occurrence of treatment failures did not differ between the two treatment groups; chi(2) = 0.38 p = 0.54. Our study revealed no difference in reduction of left ventricular mass or other disease parameters after 12 and 24 months of treatment with either agalsidase alfa or beta at a dose of 0.2 mg/kg biweekly. Treatment failure occurred frequently in both groups and seems related to age and severe pre-treatment disease. International Standard Randomized Clinical Trial ISRCTN45178534 [http://www.controlled-trials.com/ISRCTN45178534].

  15. The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat.

    PubMed

    Benjamin, Elfrida R; Della Valle, Maria Cecilia; Wu, Xiaoyang; Katz, Evan; Pruthi, Farhana; Bond, Sarah; Bronfin, Benjamin; Williams, Hadis; Yu, Julie; Bichet, Daniel G; Germain, Dominique P; Giugliani, Roberto; Hughes, Derralynn; Schiffmann, Raphael; Wilcox, William R; Desnick, Robert J; Kirk, John; Barth, Jay; Barlow, Carrolee; Valenzano, Kenneth J; Castelli, Jeff; Lockhart, David J

    2017-04-01

    Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of α-galactosidase A to restore lysosomal activity. A pharmacogenetic assay was used to identify the α-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease-causing mutations were expressed in HEK-293 (HEK) cells; increases in α-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies. Comparison of the GLP HEK assay results in in vivo white blood cell α-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (≥0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay. The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat.Genet Med 19 4, 430-438.

  16. 21 CFR 74.1102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... ADDITIVES SUBJECT TO CERTIFICATION Drugs § 74.1102 FD&C Blue No. 2. (a) Identity. (1) The color additive FD&C Blue No. 2 shall conform in identity to the requirements of § 74.102(a)(1). (2) Color additive... suitable and that are listed in part 73 of this chapter as safe for use in color additive mixtures for...

  17. Clinical benefit in Fabry patients given enzyme replacement therapy--a case series.

    PubMed

    Guffon, N; Fouilhoux, A

    2004-01-01

    Fabry disease is a rare lysosomal storage disorder resulting from deficient activity of alpha-galactosidase A and subsequent pathological accumulation of glycosphingolipids throughout the body. Traditionally, Fabry disease was managed symptomatically, but the introduction of enzyme replacement therapies (ERTs) (agalsidase beta (Fabrazyme); agalsidase alfa (Replagal)) has transformed treatment of this disorder. Clinical studies of both compounds have demonstrated clearance of glycosphingolipds from key tissues. To explore whether substrate clearance translates into clinical benefit, a retrospective survey of 17 patients (mean age 34.7 years) treated with agalsidase beta (1 mg/kg every 2 weeks) was undertaken, using an eight-item retrospective questionnaire developed specifically to assess the effect of ERT on the symptoms of Fabry disease. Pain severity, heat tolerance, physical activity, fatigue and psychological status were scored using a 10-point visual analogue scale (e.g. for pain severity: 1=none, 10=strong). Answers to all other questions were quantitative. Changes in mean scores were 4.69 to 2.25 (p =0.012) for pain severity; 4.38 to 2.21 (p =0.019) for number of pain crises per month; 8.69 to 2.98 (p =0.097) for duration of pain crises in hours; 2.76 to 5.76 (p =0.002) for heat tolerance; 3.28 to 2.51 (p =0.058) for bowel movements per day; 2.47 to 4.47 (p =0.007) for frequency of physical activity; 5.53 to 3.71 (p =0.046) for fatigue, and 5.82 to 8.12 (p =0.005) for psychological status. All patients improved in at least one aspect, although the degree of improvement across patients and aspects varied widely; reasons for this remain unclear. Despite the inherent bias involved in retrospective questionnaires, we believe that the findings are encouraging. A prospective version of the questionnaire is currently under validation.

  18. Detection of Anderson-Fabry cardiomyopathy with CMR in a patient with chest pain and elevated cardiac biomarkers.

    PubMed

    Albin, Glenn; Ryan, Michael; Heltne, Carl

    2006-01-01

    This case illustrates the utility of CMR in evaluating a patient with undiagnosed Anderson-Fabry disease who presented with chest pain, elevated cardiac biomarkers, normal coronary arteries, and an abnormal echocardiogram.

  19. Different renal phenotypes in related adult males with Fabry disease with the same classic genotype.

    PubMed

    Mignani, Renzo; Moschella, Mariarita; Cenacchi, Giovanna; Donati, Ilaria; Flachi, Marta; Grimaldi, Daniela; Cerretani, Davide; Giovanni, Paola De; Montevecchi, Marcello; Rigotti, Angelo; Ravasio, Alessandro

    2017-07-01

    Fabry disease related patients with classical mutation usually exhibit similar severe phenotype especially concerning renal manifestation. A dry blood spot screening (DBS) and the DNA analysis has been performed in a 48-year-old man (Patient 1) because of paresthesia. The DBS revealed absent leukocyte α -Gal A enzyme activity while DNA analysis identified the I354K mutation. Serum creatinine and e-GFR were in normal range and also albuminuria and proteinuria were absent. The brain MRI showed ischemic lesions and a diffuse focus of gliosis in the white matter, while the echocardiogram showed a left ventricular hypertrophy. The renal biopsy performed in the case index showed a massive deposition of zebra bodies. By a familiar investigation, it was recognized that his brother (Patient 2) died 2 years before from sudden death syndrome at the age of 49. He had suffered sporadic and undiagnosed pain at the extremities, a prior cataract, bilateral neurosensorial hearing loss and left ventricular hypertrophy on Echocardiogram. His previous laboratory examinations revealed a normal serum creatinine and the absence of proteinuria. Pedigree analysis of the brothers revealed a high disease burden among family members, with an affected cousin (Patient 3) who progressed early to end-stage renal disease (ESRD) that required renal transplantation. Here we describe the clinical history of three adult male members of the same family with the same genotype who manifested different presentation and progression of the disease, particularly concerning the renal involvement.

  20. Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

    PubMed Central

    Ferreira, Susana; Auray-Blais, Christiane; Boutin, Michel; Lavoie, Pamela; Nunes, José Pedro; Martins, Elisabete; Garman, Scott; Oliveira, João Paulo

    2016-01-01

    Recent data have shown that lyso-Gb3, the deacylated derivative of globotriaosylceramide (Gb3), is possibly involved in the pathogenesis of Fabry disease (FD) and might be a clinically useful biomarker of its metabolic load. To test this hypothesis, we assayed Gb3 and lyso-Gb3 and related analogs in plasma and/or urine samples of 12 clinically well-characterized subjects carrying several different GLA variant alleles associated with a wide range of residual α-galactosidase A activities. Urinary Gb3 was measured by HPLC–MS/MS; plasma and urinary lyso-Gb3 and related analogs were measured by UPLC–MS/MS. Individual profiles of Gb3 and lyso-Gb3 and related analogs closely correlated with the phenotypic data for each subject, discerning the classical FD patient from the two patients carrying cardiac variants as well as these from all the others without FD. The lyso-Gb3 analog at m/z 836 was found at increased levels only in patients manifesting clinically severe heart disease, irrespective of the pathogenicity of the GLA variant they carried. This finding suggests that this lyso-Gb3 analog might be an earlier biomarker of progressive heart disease, non-specific of the FD cardiomyopathy. The possibility that urinary Gb3 is a specific marker of kidney involvement in FD deserves further study. PMID:26070511

  1. Miniature fiber Fabry-Perot sensors based on fusion splicing

    NASA Astrophysics Data System (ADS)

    Zhu, Jia-li; Wang, Ming; Yang, Chun-di; Wang, Ting-ting

    2013-03-01

    Fiber-optic Fabry-Perot (F-P) sensors are widely investigated because they have several advantages over conventional sensors, such as immunity to electromagnetic interference, ability to operate under bad environments, high sensitivity and the potential for multiplexing. A new method to fabricate micro-cavity Fabry-Perot interferometer is introduced, which is fusion splicing a section of conventional single-mode fiber (SMF) and a section of hollow core or solid core photonic crystal fiber (PCF) together to form a micro-cavity at the splice joint. The technology of fusion splicing is discussed, and two miniature optical fiber sensors based on Fabry-Perot interference using fusion splicing are presented. The two sensors are completely made of fused silica, and have good high-temperature capability.

  2. Consequences of a global enzyme shortage of agalsidase beta in adult Dutch Fabry patients.

    PubMed

    Smid, Bouwien E; Rombach, Saskia M; Aerts, Johannes M F G; Kuiper, Symen; Mirzaian, Mina; Overkleeft, Hermen S; Poorthuis, Ben J H M; Hollak, Carla E M; Groener, Johanna E M; Linthorst, Gabor E

    2011-10-31

    Enzyme replacement therapy is currently the only approved therapy for Fabry disease. From June 2009 on, viral contamination of Genzyme's production facility resulted in a worldwide shortage of agalsidase beta leading to involuntary dose reductions (approved dose 1 mg/kg/eow, reduced dose 0.5 mg/kg/m), or switch to agalsidase alpha (administered dose 0.2 mg/kg/eow). An assessment report from the European Medicines Agency (EMA) raised serious concerns about an increase in adverse events at lower dosages of agalsidase beta. We determined the influence of the shortage on clinical event incidence and the most sensitive biochemical marker (lysoGb3) in Dutch Fabry patients. The incidence of clinical events per person per year was calculated from start of agalsidase beta treatment until the shortage, and was compared to the incidence of clinical events during the shortage period. In addition, plasma lysoGb3, eGFR, quality of life (SF-36) and brief pain inventory (BPI) questionnaires were analysed. All thirty-five Dutch Fabry patients using agalsidase beta (17 males) were included. Mean clinical event incidence was unchanged: 0.15 events per person per year before versus 0.15 during the shortage (p = 0.68). In total 28 clinical events occurred in 14 patients during 4.6 treatment years, compared to 7 events in 6 patients during the 1.3 year shortage period. eGFR and BPI scores were not significantly altered. Two SF-36 subscales were significantly but minimally reduced in females. In males, lysoGb3 increased with a median of 8.1 nM (range 2.5-29.2) after 1 year of shortage (p = 0.001). Increases in lysoGb3 were found in both patients switching to agalsidase alpha and on a reduced agalsidase beta dose. Antibody status, treatment duration or clinical event incidence showed no clear correlation to lysoGb3 increases. No increase in clinical event incidence was found in the adult Dutch Fabry cohort during the agalsidase beta shortage. Increases in lysoGb3, however, suggest

  3. fd3: Spectral disentangling of double-lined spectroscopic binary stars

    NASA Astrophysics Data System (ADS)

    Ilijić, Saša

    2017-05-01

    The spectral disentangling technique can be applied on a time series of observed spectra of a spectroscopic double-lined binary star (SB2) to determine the parameters of orbit and reconstruct the spectra of component stars, without the use of template spectra. fd3 disentangles the spectra of SB2 stars, capable also of resolving the possible third companion. It performs the separation of spectra in the Fourier space which is faster, but in several respects less versatile than the wavelength-space separation. (Wavelength-space separation is implemented in the twin code CRES.) fd3 is written in C and is designed as a command-line utility for a Unix-like operating system. fd3 is a new version of FDBinary (ascl:1705.011), which is now deprecated.

  4. Simultaneous measurement of temperature and pressure with cascaded extrinsic Fabry-Perot interferometer and intrinsic Fabry-Perot interferometer sensors

    NASA Astrophysics Data System (ADS)

    Zhang, Yinan; Huang, Jie; Lan, Xinwei; Yuan, Lei; Xiao, Hai

    2014-06-01

    This paper presents an approach for simultaneous measurement of temperature and pressure using miniaturized fiber inline sensors. The approach utilizes the cascaded optical fiber inline intrinsic Fabry-Perot interferometer and extrinsic Fabry-Perot interferometer as temperature and pressure sensing elements, respectively. A CO2 laser was used to create a loss between them to balance their reflection power levels. The multiplexed signals were demodulated using a Fast Fourier transform-based wavelength tracking method. Experimental results showed that the sensing system could measure temperature and pressure unambiguously in a pressure range of 0 to 6.895×105 Pa and a temperature range from 20°C to 700°C.

  5. Micromachined Tunable Fabry-Perot Filters for Infrared Astronomy

    NASA Technical Reports Server (NTRS)

    Barclay, Richard; Bier, Alexander; Chen, Tina; DiCamillo, Barbara; Deming, Drake; Greenhouse, Matthew; Henry, Ross; Hewagama, Tilak; Jacobson, Mindy; Loughlin, James; hide

    2002-01-01

    Micromachined Fabry-Perot tunable filters with a large clear aperture (12.5 to 40 mm) are being developed as an optical component for wide-field imaging 1:1 spectroscopy. This program applies silicon micromachining fabrication techniques to miniaturize Fabry-Perot filters for astronomical science instruments. The filter assembly consists of a stationary etalon plate mated to a plate in which the etalon is free to move along the optical axis on silicon springs attached to a stiff silicon support ring. The moving etalon is actuated electrostatically by electrode pairs on the fixed and moving etalons. To reduce mass, both etalons are fabricated by applying optical coatings to a thin freestanding silicon nitride film held flat in drumhead tension rather than to a thick optical substrate. The design, electro-mechanical modeling, fabrication, and initial results will be discussed. The potential application of the miniature Fabry-Perot filters will be briefly discussed with emphasis on the detection of extra-solar planets.

  6. Review of FD-TD numerical modeling of electromagnetic wave scattering and radar cross section

    NASA Technical Reports Server (NTRS)

    Taflove, Allen; Umashankar, Korada R.

    1989-01-01

    Applications of the finite-difference time-domain (FD-TD) method for numerical modeling of electromagnetic wave interactions with structures are reviewed, concentrating on scattering and radar cross section (RCS). A number of two- and three-dimensional examples of FD-TD modeling of scattering and penetration are provided. The objects modeled range in nature from simple geometric shapes to extremely complex aerospace and biological systems. Rigorous analytical or experimental validatons are provided for the canonical shapes, and it is shown that FD-TD predictive data for near fields and RCS are in excellent agreement with the benchmark data. It is concluded that with continuing advances in FD-TD modeling theory for target features relevant to the RCS problems and in vector and concurrent supercomputer technology, it is likely that FD-TD numerical modeling will occupy an important place in RCS technology in the 1990s and beyond.

  7. Interconversion of the Specificities of Human Lysosomal Enzymes Associated with Fabry and Schindler Diseases

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tomasic, Ivan B.; Metcalf, Matthew C.; Guce, Abigail I.

    2010-09-03

    The human lysosomal enzymes {alpha}-galactosidase ({alpha}-GAL, EC 3.2.1.22) and {alpha}-N-acetylgalactosaminidase ({alpha}-NAGAL, EC 3.2.1.49) share 46% amino acid sequence identity and have similar folds. The active sites of the two enzymes share 11 of 13 amino acids, differing only where they interact with the 2-position of the substrates. Using a rational protein engineering approach, we interconverted the enzymatic specificity of {alpha}-GAL and {alpha}-NAGAL. The engineered {alpha}-GAL (which we call {alpha}-GALSA) retains the antigenicity of {alpha}-GAL but has acquired the enzymatic specificity of {alpha}-NAGAL. Conversely, the engineered {alpha}-NAGAL (which we call {alpha}-NAGAL{sup EL}) retains the antigenicity of {alpha}-NAGAL but has acquired themore » enzymatic specificity of the {alpha}-GAL enzyme. Comparison of the crystal structures of the designed enzyme {alpha}-GAL{sup SA} to the wild-type enzymes shows that active sites of {alpha}-GAL{sup SA} and {alpha}-NAGAL superimpose well, indicating success of the rational design. The designed enzymes might be useful as non-immunogenic alternatives in enzyme replacement therapy for treatment of lysosomal storage disorders such as Fabry disease.« less

  8. Confocal Fabry-Perot interferometer for frequency stabilization of laser

    NASA Astrophysics Data System (ADS)

    Pan, H.-J.; Ruan, P.; Wang, H.-W.; Li, F.

    2011-02-01

    The frequency shift of laser source of Doppler lidar is required in the range of a few megahertzs. To satisfy this demand, a confocal Fabry-Perot (F-P) interferometer was manufactured as the frequency standard for frequency stabilization. After analyzing and contrasting the center frequency shift of confocal Fabry-Perot interferometers that are made of three different types of material with the change of temperature, the zerodur material was selected to fabricate the interferometer, and the cavity mirrors were optically contacted onto the end of spacer. The confocal Fabry-Perot interferometer was situated within a double-walled chamber, and the change of temperature in the chamber was less than 0.01 K. The experimental results indicate that the free spectral range is 500 MHz, the full-width at half maximum is 3.33 MHz, and the finesse is 150.

  9. Rapid Immunochromatographic Detection of Serum Anti-α-Galactosidase A Antibodies in Fabry Patients after Enzyme Replacement Therapy.

    PubMed

    Nakano, Sachie; Tsukimura, Takahiro; Togawa, Tadayasu; Ohashi, Toya; Kobayashi, Masahisa; Takayama, Katsuyoshi; Kobayashi, Yukuharu; Abiko, Hiroshi; Satou, Masatsugu; Nakahata, Tohru; Warnock, David G; Sakuraba, Hitoshi; Shibasaki, Futoshi

    2015-01-01

    We developed an immunochromatography-based assay for detecting antibodies against recombinant α-galactosidase A proteins in serum. The evaluation of 29 serum samples from Fabry patients, who had received enzyme replacement therapy with agalsidase alpha and/or agalsidase beta, was performed by means of this assay method, and the results clearly revealed that the patients exhibited the same level of antibodies against both agalsidase alpha and agalsidase beta, regardless of the species of recombinant α-galactosidase A used for enzyme replacement therapy. A conventional enzyme-linked immunosorbent assay supported the results. Considering these, enzyme replacement therapy with agalsidase alpha or agalsidase beta would generate antibodies against the common epitopes in both agalsidase alpha and agalsidase beta. Most of the patients who showed immunopositive reaction exhibited classic Fabry phenotype and harbored gene mutations affecting biosynthesis of α-galactosidase A. As immunochromatography is a handy and simple assay system which can be available at bedside, this assay method would be extremely useful for quick evaluation or first screening of serum antibodies against agalsidase alpha or agalsidase beta in Fabry disease with enzyme replacement therapy.

  10. High-temperature fiber-optic Fabry-Perot interferometric sensors.

    PubMed

    Ding, Wenhui; Jiang, Yi; Gao, Ran; Liu, Yuewu

    2015-05-01

    A photonic crystal fiber (PCF) based high-temperature fiber-optic sensor is proposed and experimentally demonstrated. The sensor head is a Fabry-Perot cavity manufactured with a short section of endless single-mode photonic crystal fiber (ESM PCF). The interferometric spectrum of the Fabry-Perot interferometer is collected by a charge coupled device linear array based micro spectrometer. A high-resolution demodulation algorithm is used to interrogate the peak wavelengths. Experimental results show that the temperature range of 1200 °C and the temperature resolution of 1 °C are achieved.

  11. High-temperature fiber-optic Fabry-Perot interferometric sensors

    NASA Astrophysics Data System (ADS)

    Ding, Wenhui; Jiang, Yi; Gao, Ran; Liu, Yuewu

    2015-05-01

    A photonic crystal fiber (PCF) based high-temperature fiber-optic sensor is proposed and experimentally demonstrated. The sensor head is a Fabry-Perot cavity manufactured with a short section of endless single-mode photonic crystal fiber (ESM PCF). The interferometric spectrum of the Fabry-Perot interferometer is collected by a charge coupled device linear array based micro spectrometer. A high-resolution demodulation algorithm is used to interrogate the peak wavelengths. Experimental results show that the temperature range of 1200 °C and the temperature resolution of 1 °C are achieved.

  12. Endomyocardial biopsies in patients with left ventricular hypertrophy and a common Chinese later-onset fabry mutation (IVS4 + 919G > A)

    PubMed Central

    2014-01-01

    Background In Taiwan, DNA-based newborn screening showed a surprisingly high incidence of a cardiac Fabry mutation (IVS4 + 919G > A). The prevalence of this mutation is too high to be believed that it is a real pathogenic mutation. The purpose of this study is to identify the cardiac pathologic characteristics in patients with left ventricular hypertrophy and this mutation Methods and results Endomyocardial biopsies were obtained in 22 patients (Median age: 61, males: 17; females: 5) with left ventricular hypertrophy and the IVS4 + 919G > A mutation; five patients had not received enzyme replacement therapy (ERT) before biopsy, while the other 17 patients had received ERT from 8 months to 51 months. Except for three patients who had received ERT for more than 3 years, all other patients showed significant pathological change and globotriaosylceramide (Gb3) accumulation in their cardiomyocytes. In contrast to classical Fabry patients, no Gb3 accumulation was found in the capillary endothelial cells of any of our patients. Fourteen patients (63.6%) were found to have myofibrillolysis. Conclusions All of the untreated and most of the treated IVS4 + 919G > A patients showed typical pathological changes of Fabry disease in their cardiomyocytes. No endothelial accumulation of Gb3 was found, which is similar to the findings of several previous reports regarding later-onset Fabry disease. This result highly suggests that the IVS4 + 919G > A is a real pathogenic later-onset Fabry mutation. PMID:24980630

  13. Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors

    PubMed Central

    Biegstraaten, Marieke; Hughes, Derralynn A.; Mehta, Atul; Elliott, Perry M.; Oder, Daniel; Watkinson, Oliver T.; Vaz, Frédéric M.; van Kuilenburg, André B. P.; Wanner, Christoph; Hollak, Carla E. M.

    2017-01-01

    Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease course (clinical events, progression of cardiac and renal disease) we retrospectively evaluated 293 treated patients from three international centers of excellence. As expected, age, sex and phenotype were important predictors of event rate. Clinical events before enzyme replacement therapy, cardiac mass and eGFR at baseline predicted an increased event rate. eGFR was the most important predictor: hazard ratios increased from 2 at eGFR <90 ml/min/1.73m2 to 4 at eGFR <30, compared to patients with an eGFR >90. In addition, men with classical disease and a baseline eGFR <60 ml/min/1.73m2 had a faster yearly decline (-2.0 ml/min/1.73m2) than those with a baseline eGFR of >60. Proteinuria was a further independent risk factor for decline in eGFR. Increased cardiac mass at baseline was associated with the most robust decrease in cardiac mass during treatment, while presence of cardiac fibrosis predicted a stronger increase in cardiac mass (3.36 gram/m2/year). Of other cardiovascular risk factors, hypertension significantly predicted the risk for clinical events. In conclusion, besides increasing age, male sex and classical phenotype, faster disease progression while on enzyme replacement therapy is predicted by renal function, proteinuria and to a lesser extent cardiac fibrosis and hypertension. PMID:28763515

  14. A Novel Fabry-Perot Cavity Fiber Sensor

    NASA Astrophysics Data System (ADS)

    Lin, Chun; Huang, Yuan Qing; Lei, Wang; Ye, Xiao Juan

    Fabry-Perot (F-P) cavity fiber sensors are often used in acceleration, vibration and pressure measurement. When the structure of sensors are similar, there are the same disadvantages exist. A novel design of Fabry-Perot (F-P) cavity fiber sensor is described in this paper, which is composed by a non-coating end-face and a holophote. Triple beams interference is formed in the sensor and shows higher sensitivity. In order to demodulate interference signal in great background noise, two photodiodes are connected in series to form short circuit current which delimits the common mode signal. Experimental results are described for the sensor signal responding to the vibration excited by PZT.^p

  15. Consequences of a global enzyme shortage of agalsidase beta in adult Dutch Fabry patients

    PubMed Central

    2011-01-01

    Background Enzyme replacement therapy is currently the only approved therapy for Fabry disease. From June 2009 on, viral contamination of Genzyme's production facility resulted in a worldwide shortage of agalsidase beta leading to involuntary dose reductions (approved dose 1 mg/kg/eow, reduced dose 0.5 mg/kg/m), or switch to agalsidase alpha (administered dose 0.2 mg/kg/eow). An assessment report from the European Medicines Agency (EMA) raised serious concerns about an increase in adverse events at lower dosages of agalsidase beta. We determined the influence of the shortage on clinical event incidence and the most sensitive biochemical marker (lysoGb3) in Dutch Fabry patients. Methods The incidence of clinical events per person per year was calculated from start of agalsidase beta treatment until the shortage, and was compared to the incidence of clinical events during the shortage period. In addition, plasma lysoGb3, eGFR, quality of life (SF-36) and brief pain inventory (BPI) questionnaires were analysed. Results All thirty-five Dutch Fabry patients using agalsidase beta (17 males) were included. Mean clinical event incidence was unchanged: 0.15 events per person per year before versus 0.15 during the shortage (p = 0.68). In total 28 clinical events occurred in 14 patients during 4.6 treatment years, compared to 7 events in 6 patients during the 1.3 year shortage period. eGFR and BPI scores were not significantly altered. Two SF-36 subscales were significantly but minimally reduced in females. In males, lysoGb3 increased with a median of 8.1 nM (range 2.5 - 29.2) after 1 year of shortage (p = 0.001). Increases in lysoGb3 were found in both patients switching to agalsidase alpha and on a reduced agalsidase beta dose. Antibody status, treatment duration or clinical event incidence showed no clear correlation to lysoGb3 increases. Conclusions No increase in clinical event incidence was found in the adult Dutch Fabry cohort during the agalsidase beta shortage

  16. Distributed torsion sensor based on cascaded coaxial cable Fabry-Perot interferometers

    NASA Astrophysics Data System (ADS)

    Cheng, Baokai; Zhu, Wenge; Hua, Liwei; Liu, Jie; Li, Yurong; Nygaard, Runar; Xiao, Hai

    2016-07-01

    Cascaded coaxial cable Fabry-Perot interferometers (FPI) are studied and demonstrated for distributed torsion measurement. Multiple weak reflectors are implemented on a coaxial cable so that any two consecutive reflectors can form a Fabry-Perot cavity. By fixing the cable sensor in a helical form on a shaft, the distributed torsion of the shaft can be measured by the cascaded Fabry-Perot cavities. A test on a single section shows that the sensor has a linear response with a sensitivity of 1.834 MHz (rad/m)-1 in the range of twisted rate from 0 to 8.726 rad m-1. The distributed torsion sensing capability is useful in drilling process monitoring, structure health monitoring and machine failure detection.

  17. Simple Common Plane contact detection algorithm for FE/FD methods

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Vorobiev, O

    2006-07-19

    Common-plane (CP) algorithm is widely used in Discrete Element Method (DEM) to model contact forces between interacting particles or blocks. A new simple contact detection algorithm is proposed to model contacts in FE/FD methods which is similar to the CP algorithm. The CP is defined as a plane separating interacting faces of FE/FD mesh instead of blocks or particles in the original CP method. The method does not require iterations. It is very robust and easy to implement both in 2D and 3D case.

  18. Clinical and genetic predictors of major cardiac events in patients with Anderson-Fabry Disease.

    PubMed

    Patel, Vimal; O'Mahony, Constantinos; Hughes, Derralynn; Rahman, Mohammad Shafiqur; Coats, Caroline; Murphy, Elaine; Lachmann, Robin; Mehta, Atul; Elliott, Perry M

    2015-06-01

    Anderson-Fabry Disease (AFD) is an X linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Some mutations are associated with prominent and, in many cases, exclusive cardiac involvement. The primary aims of this study were to determine the incidence of major cardiac events in AFD and to identify clinical and genetic predictors of adverse outcomes. We studied 207 patients with AFD (47% male, mean age 44 years, mean follow-up 7.1 years). Fifty-eight (28%) individuals carried mutations that have been previously associated with a cardiac predominant phenotype. Twenty-one (10%) developed severe heart failure (New York Heart Association functional class (NYHA) ≥3), 13 (6%) developed atrial fibrillation (AF), 13 (6%) received devices for the treatment of bradycardia; there were a total of 7 (3%) cardiac deaths. The incidence of the primary endpoint (a composite of new onset AF, NYHA ≥ 3 symptoms, device insertion for bradycardia and cardiac death) was 2.64 per 100 person-years (CI 1.78 to 3.77). Age (HR 1.04, CI 1.01 to 1.08, p=0.004), Mainz Severity Score Index score (HR 1.05, CI 1.01 to 1.09, p=0.012) and QRS duration (HR 1.03, CI 1.00 to 1.05, p=0.020) were significant independent predictors of the primary endpoint. The presence of a cardiac genetic variant did not predict the primary end point. AFD is associated with a high burden of cardiac morbidity and mortality. Adverse cardiac outcomes are associated with age, global disease severity and advanced cardiac disease but not the presence of cardiac genetic variants. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  19. Long-Term Safety and Efficacy of Enzyme Replacement Therapyfor Fabry Disease

    PubMed Central

    Wilcox, William R.; Banikazemi, Maryam; Guffon, Nathalie; Waldek, Stephen; Lee, Philip; Linthorst, Gabor E.; Desnick, Robert J.; Germain, Dominique P.

    2004-01-01

    Elsewhere, we reported the safety and efficacy results of a multicenter phase 3 trial of recombinant human α-galactosidase A (rh-αGalA) replacement in patients with Fabry disease. All 58 patients who were enrolled in the 20-wk phase 3 double-blind, randomized, and placebo-controlled study received subsequently 1 mg/kg of rh-αGalA (agalsidase beta, Fabrazyme, Genzyme Corporation) biweekly in an ongoing open-label extension study. Evidence of long-term efficacy, even in patients who developed IgG antibodies against rh-αGalA, included the continuously normal mean plasma globotriaosylceramide (GL-3) levels during 30 mo of the extension study and the sustained capillary endothelial GL-3 clearance in 98% (39/40) of patients who had a skin biopsy taken after treatment for 30 mo (original placebo group) or 36 mo (original enzyme-treated group). The mean serum creatinine level and estimated glomerular filtration rate also remained stable after 30–36 mo of treatment. Infusion-associated reactions decreased over time, as did anti-rh-αGalA IgG antibody titers. Among seroconverted patients, after 30–36 mo of treatment, seven patients tolerized (no detectable IgG antibody), and 59% had ⩾4-fold reductions in antibody titers. As of 30 mo into the extension trial, three patients were withdrawn from the study because of positive serum IgE or skin tests; however, all have been rechallenged successfully at the time of this report. Thus, enzyme replacement therapy for 30–36 mo with agalsidase beta resulted in continuously decreased plasma GL-3 levels, sustained endothelial GL-3 clearance, stable kidney function, and a favorable safety profile. PMID:15154115

  20. Fiber optic, Fabry-Perot high temperature sensor

    NASA Technical Reports Server (NTRS)

    James, K.; Quick, B.

    1984-01-01

    A digital, fiber optic temperature sensor using a variable Fabry-Perot cavity as the sensor element was analyzed, designed, fabricated, and tested. The fiber transmitted cavity reflection spectra is dispersed then converted from an optical signal to electrical information by a charged coupled device (CCD). A microprocessor-based color demodulation system converts the wavelength information to temperature. This general sensor concept not only utilizes an all-optical means of parameter sensing and transmitting, but also exploits microprocessor technology for automated control, calibration, and enhanced performance. The complete temperature sensor system was evaluated in the laboratory. Results show that the Fabry-Perot temperature sensor has good resolution (0.5% of full seale), high accuracy, and potential high temperature ( 1000 C) applications.

  1. Rapid Immunochromatographic Detection of Serum Anti-α-Galactosidase A Antibodies in Fabry Patients after Enzyme Replacement Therapy

    PubMed Central

    Nakano, Sachie; Tsukimura, Takahiro; Togawa, Tadayasu; Ohashi, Toya; Kobayashi, Masahisa; Takayama, Katsuyoshi; Kobayashi, Yukuharu; Abiko, Hiroshi; Satou, Masatsugu; Nakahata, Tohru; Warnock, David G.; Sakuraba, Hitoshi; Shibasaki, Futoshi

    2015-01-01

    We developed an immunochromatography-based assay for detecting antibodies against recombinant α-galactosidase A proteins in serum. The evaluation of 29 serum samples from Fabry patients, who had received enzyme replacement therapy with agalsidase alpha and/or agalsidase beta, was performed by means of this assay method, and the results clearly revealed that the patients exhibited the same level of antibodies against both agalsidase alpha and agalsidase beta, regardless of the species of recombinant α-galactosidase A used for enzyme replacement therapy. A conventional enzyme-linked immunosorbent assay supported the results. Considering these, enzyme replacement therapy with agalsidase alpha or agalsidase beta would generate antibodies against the common epitopes in both agalsidase alpha and agalsidase beta. Most of the patients who showed immunopositive reaction exhibited classic Fabry phenotype and harbored gene mutations affecting biosynthesis of α-galactosidase A. As immunochromatography is a handy and simple assay system which can be available at bedside, this assay method would be extremely useful for quick evaluation or first screening of serum antibodies against agalsidase alpha or agalsidase beta in Fabry disease with enzyme replacement therapy. PMID:26083343

  2. Simple Common Plane contact algorithm for explicit FE/FD methods

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Vorobiev, O

    2006-12-18

    Common-plane (CP) algorithm is widely used in Discrete Element Method (DEM) to model contact forces between interacting particles or blocks. A new simple contact algorithm is proposed to model contacts in FE/FD methods which is similar to the CP algorithm. The CP is defined as a plane separating interacting faces of FE/FD mesh instead of blocks or particles used in the original CP method. The new method does not require iterations even for very stiff contacts. It is very robust and easy to implement both in 2D and 3D parallel codes.

  3. Functional Characterization of Phalaenopsis aphrodite Flowering Genes PaFT1 and PaFD

    PubMed Central

    Jang, Seonghoe; Choi, Sang-Chul; Li, Hsing-Yi; An, Gynheung; Schmelzer, Elmon

    2015-01-01

    We show that the key flowering regulators encoded by Phalaenopsis aphrodite FLOWERING LOCUS T1 (PaFT1) and PaFD share high sequence homologies to these from long-day flowering Arabidopsis and short-day flowering rice. Interestingly, PaFT1 is specifically up-regulated during flowering inductive cooling treatment but is not subjected to control by photoperiod in P. aphrodite. Phloem or shoot apex-specific expression of PaFT1 restores the late flowering of Arabidopsis ft mutants. Moreover, PaFT1 can suppress the delayed flowering caused by SHORT VEGATATIVE PHASE (SVP) overexpression as well as an active FRIGIDA (FRI) allele, indicating the functional conservation of flowering regulatory circuit in different plant species. PaFT1 promoter:GUS in Arabidopsis showed similar staining pattern to that of Arabidopsis FT in the leaves and guard cells but different in the shoot apex. A genomic clone or heat shock-inducible expression of PaFT1 is sufficient to the partial complementation of the ft mutants. Remarkably, ectopic PaFT1 expression also triggers precocious heading in rice. To further demonstrate the functional conservation of the flowering regulators, we show that PaFD, a bZIP transcription factor involved in flowering promotion, interacts with PaFT1, and PaFD partially complemented Arabidopsis fd mutants. Transgenic rice expressing PaFD also flowered early with increased expression of rice homologues of APETALA1 (AP1). Consistently, PaFT1 knock-down Phalaenopsis plants generated by virus-induced gene silencing exhibit delayed spiking. These studies suggest functional conservation of FT and FD genes, which may have evolved and integrated into distinct regulatory circuits in monopodial orchids, Arabidopsis and rice that promote flowering under their own inductive conditions. PMID:26317412

  4. Enzyme replacement therapy for Fabry disease: lessons from two alpha-galactosidase A orphan products and one FDA approval.

    PubMed

    Desnick, Robert J

    2004-07-01

    Two virtually identical products have been developed for enzyme replacement therapy for the treatment of Fabry disease, which is a rare and debilitating genetic disease caused by decreased activity of the lysosomal enzyme alpha-galactosidase A. Lack of this enzyme results in progressive tissue accumulation of globotriaosylceramide (GL-3), resulting in life-threatening renal, cardiac and cerebrovascular complications. Both enzyme replacement products, agalsidase alfa (Replagal; Transkaryotic Therapies, Cambridge, MA, USA) and agalsidase beta (Fabrazyme; Genzyme Corporation, Cambridge, MA, USA), were approved by the European Agency for the Evaluation of Medicinal Products in 2001; agalsidase alfa at a recommended dose of 0.2 mg/kg and agalsidase beta at a recommended dose of 1 mg/kg. In the US, however, orphan drug laws dictated that only one of these products could be approved. In April 2003, after a rigorous evaluation of both products by the US FDA, this approval was granted to agalsidase beta. This decision reflected clinical trial design, how dosages were determined, antibody effects and the ability of each product to demonstrate either clinical efficacy or reduction of tissue storage of GL-3 in major organs of pathology when administered at the recommended dosage. The process also highlighted important issues in the evaluation of drugs to treat life-threatening genetic diseases for which the pathological basis is well-defined.

  5. A Demonstration of TIA Using FD-SOI CMOS OPAMP for Far-Infrared Astronomy

    NASA Astrophysics Data System (ADS)

    Nagase, Koichi; Wada, Takehiko; Ikeda, Hirokazu; Arai, Yasuo; Ohno, Morifumi; Hanaoka, Misaki; Kanada, Hidehiro; Oyabu, Shinki; Hattori, Yasuki; Ukai, Sota; Suzuki, Toyoaki; Watanabe, Kentaroh; Baba, Shunsuke; Kochi, Chihiro; Yamamoto, Keita

    2016-07-01

    We are developing a fully depleted silicon-on-insulator (FD-SOI) CMOS readout integrated circuit (ROIC) operated at temperatures below ˜ 4 K. Its application is planned for the readout circuit of high-impedance far-infrared detectors for astronomical observations. We designed a trans-impedance amplifier (TIA) using a CMOS operational amplifier (OPAMP) with FD-SOI technique. The TIA is optimized to readout signals from a germanium blocked impurity band (Ge BIB) detector which is highly sensitive to wavelengths of up to ˜ 200 \\upmu m. For the first time, we demonstrated the FD-SOI CMOS OPAMP combined with the Ge BIB detector at 4.5 K. The result promises to solve issues faced by conventional cryogenic ROICs.

  6. FdC1 and Leaf-Type Ferredoxins Channel Electrons From Photosystem I to Different Downstream Electron Acceptors.

    PubMed

    Guan, Xiaoqian; Chen, Shuai; Voon, Chia Pao; Wong, Kam-Bo; Tikkanen, Mikko; Lim, Boon L

    2018-01-01

    Plant-type ferredoxins in Arabidopsis transfer electrons from the photosystem I to multiple redox-driven enzymes involved in the assimilation of carbon, nitrogen, and sulfur. Leaf-type ferredoxins also modulate the switch between the linear and cyclic electron routes of the photosystems. Recently, two novel ferredoxin homologs with extra C-termini were identified in the Arabidopsis genome (AtFdC1, AT4G14890; AtFdC2, AT1G32550). FdC1 was considered as an alternative electron acceptor of PSI under extreme ferredoxin-deficient conditions. Here, we showed that FdC1 could interact with some, but not all, electron acceptors of leaf-type Fds, including the ferredoxin-thioredoxin reductase (FTR), sulfite reductase (SiR), and nitrite reductase (NiR). Photoreduction assay on cytochrome c and enzyme assays confirmed its capability to receive electrons from PSI and donate electrons to the Fd-dependent SiR and NiR but not to the ferredoxin-NADP + oxidoreductase (FNR). Hence, FdC1 and leaf-type Fds may play differential roles by channeling electrons from photosystem I to different downstream electron acceptors in photosynthetic tissues. In addition, the median redox potential of FdC1 may allow it to receive electrons from FNR in non-photosynthetic plastids.

  7. FdC1 and Leaf-Type Ferredoxins Channel Electrons From Photosystem I to Different Downstream Electron Acceptors

    PubMed Central

    Guan, Xiaoqian; Chen, Shuai; Voon, Chia Pao; Wong, Kam-Bo; Tikkanen, Mikko; Lim, Boon L.

    2018-01-01

    Plant-type ferredoxins in Arabidopsis transfer electrons from the photosystem I to multiple redox-driven enzymes involved in the assimilation of carbon, nitrogen, and sulfur. Leaf-type ferredoxins also modulate the switch between the linear and cyclic electron routes of the photosystems. Recently, two novel ferredoxin homologs with extra C-termini were identified in the Arabidopsis genome (AtFdC1, AT4G14890; AtFdC2, AT1G32550). FdC1 was considered as an alternative electron acceptor of PSI under extreme ferredoxin-deficient conditions. Here, we showed that FdC1 could interact with some, but not all, electron acceptors of leaf-type Fds, including the ferredoxin-thioredoxin reductase (FTR), sulfite reductase (SiR), and nitrite reductase (NiR). Photoreduction assay on cytochrome c and enzyme assays confirmed its capability to receive electrons from PSI and donate electrons to the Fd-dependent SiR and NiR but not to the ferredoxin-NADP+ oxidoreductase (FNR). Hence, FdC1 and leaf-type Fds may play differential roles by channeling electrons from photosystem I to different downstream electron acceptors in photosynthetic tissues. In addition, the median redox potential of FdC1 may allow it to receive electrons from FNR in non-photosynthetic plastids. PMID:29670639

  8. Levitated optomechanics with a fiber Fabry-Perot interferometer

    NASA Astrophysics Data System (ADS)

    Pontin, A.; Mourounas, L. S.; Geraci, A. A.; Barker, P. F.

    2018-02-01

    In recent years, quantum phenomena have been experimentally demonstrated on variety of optomechanical systems ranging from micro-oscillators to photonic crystals. Since single photon couplings are quite small, most experimental approaches rely on the realization of high finesse Fabry-Perot cavities in order to enhance the effective coupling. Here we show that by exploiting a, long path, low finesse fiber Fabry-Perot interferometer ground state cooling can be achieved. We model a 100 m long cavity with a finesse of 10 and analyze the impact of additional noise sources arising from the fiber. As a mechanical oscillator we consider a levitated microdisk but the same approach could be applied to other optomechanical systems.

  9. All-fiber, long-active-length Fabry-Perot strain sensor.

    PubMed

    Pevec, Simon; Donlagic, Denis

    2011-08-01

    This paper presents a high-sensitivity, all-silica, all-fiber Fabry-Perot strain-sensor. The proposed sensor provides a long active length, arbitrary length of Fabry-Perot cavity, and low intrinsic temperature sensitivity. The sensor was micro-machined from purposely-developed sensor-forming fiber that is etched and directly spliced to the lead-in fiber. This manufacturing process has good potential for cost-effective, high-volume production. Its measurement range of over 3000 µε, and strain-resolution better than 1 µε were demonstrated by the application of a commercial, multimode fiber-based signal processor.

  10. Identification and assessment of Anderson-Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping.

    PubMed

    Sado, Daniel M; White, Steven K; Piechnik, Stefan K; Banypersad, Sanjay M; Treibel, Thomas; Captur, Gabriella; Fontana, Marianna; Maestrini, Viviana; Flett, Andrew S; Robson, Matthew D; Lachmann, Robin H; Murphy, Elaine; Mehta, Atul; Hughes, Derralynn; Neubauer, Stefan; Elliott, Perry M; Moon, James C

    2013-05-01

    Anderson-Fabry disease (AFD) is a rare but underdiagnosed intracellular lipid disorder that can cause left ventricular hypertrophy (LVH). Lipid is known to shorten the magnetic resonance imaging parameter T1. We hypothesized that noncontrast T1 mapping by cardiovascular magnetic resonance would provide a novel and useful measure in this disease with potential to detect early cardiac involvement and distinguish AFD LVH from other causes. Two hundred twenty-seven subjects were studied: patients with AFD (n=44; 55% with LVH), healthy volunteers (n=67; 0% with LVH), patients with hypertension (n=41; 24% with LVH), patients with hypertrophic cardiomyopathy (n=34; 100% with LVH), those with severe aortic stenosis (n=21; 81% with LVH), and patients with definite amyloid light-chain (AL) cardiac amyloidosis (n=20; 100% with LVH). T1 mapping was performed using the shortened modified Look-Locker inversion sequence on a 1.5-T magnet before gadolinium administration with primary results derived from the basal and midseptum. Compared with health volunteers, septal T1 was lower in AFD and higher in other diseases (AFD versus healthy volunteers versus other patients, 882±47, 968±32, 1018±74 milliseconds; P<0.0001). In patients with LVH (n=105), T1 discriminated completely between AFD and other diseases with no overlap. In AFD, T1 correlated inversely with wall thickness (r=-0.51; P=0.0004) and was abnormal in 40% of subjects who did not have LVH. Segmentally, AFD showed pseudonormalization or elevation of T1 in the left ventricular inferolateral wall, correlating with the presence or absence of late gadolinium enhancement (1001±82 versus 891±38 milliseconds; P<0.0001). Noncontrast T1 mapping shows potential as a unique and powerful measurement in the imaging assessment of LVH and AFD.

  11. A randomised, double-blind, placebo-controlled, crossover study to assess the efficacy and safety of three dosing schedules of agalsidase alfa enzyme replacement therapy for Fabry disease.

    PubMed

    Hughes, D A; Deegan, P B; Milligan, A; Wright, N; Butler, L H; Jacobs, A; Mehta, A B

    2013-07-01

    Anecdotal reports suggest that the currently approved dosing interval of agalsidase alfa (0.2 mg/kg/2 weeks) for Fabry disease treatment is too long. This randomised, double-blind, placebo-controlled, crossover study investigated three altered dosing intervals. 18 Fabry patients received three agalsidase alfa dosing schedules, each for four weeks (A: 0.2 mg/kg∗2 weeks, B: 0.1 mg/kg/week, C: 0.2 mg/kg/week). Health state, pain levels, sweat volume and latency and plasma and urinary globotriaosylceramide levels were recorded throughout the study. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores. A trend toward increased sweat volume on QSART testing, and reduced urine globotriaosylceramide concentration were seen with treatment schedule C. Agalsidase alfa was safe and well tolerated with all schedules. In conclusion, the primary analyses did not find weekly infusions of agalsidase alfa to be statistically better than the approved dosing schedule however the data indicates that further studies with more patients over a longer period are required to more accurately determine the optimum dose and schedule. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Crescent shaped Fabry-Perot fiber cavity for ultra-sensitive strain measurement.

    PubMed

    Liu, Ye; Wang, D N; Chen, W P

    2016-12-02

    Optical Fabry-Perot interferometer sensors based on inner air-cavity is featured with compact size, good robustness and high strain sensitivity, especially when an ultra-thin air-cavity is adopted. The typical shape of Fabry-Perot inner air-cavity with reflection mode of operation is elliptic, with minor axis along with and major axis perpendicular to the fiber length. The first reflection surface is diverging whereas the second one is converging. To increase the visibility of the output interference pattern, the length of major axis should be large for a given cavity length. However, the largest value of the major axis is limited by the optical fiber diameter. If the major axis length reaches the fiber diameter, the robustness of the Fabry-Perot cavity device would be decreased. Here we demonstrate an ultra-thin crescent shaped Fabry-Perot cavity for strain sensing with ultra-high sensitivity and low temperature cross-sensitivity. The crescent-shape cavity consists of two converging reflection surfaces, which provide the advantages of enhanced strain sensitivity when compared with elliptic or D-shaped FP cavity. The device is fabricated by fusion splicing an etched multimode fiber with a single mode fiber, and hence is simple in structure and economic in cost.

  13. Crescent shaped Fabry-Perot fiber cavity for ultra-sensitive strain measurement

    NASA Astrophysics Data System (ADS)

    Liu, Ye; Wang, D. N.; Chen, W. P.

    2016-12-01

    Optical Fabry-Perot interferometer sensors based on inner air-cavity is featured with compact size, good robustness and high strain sensitivity, especially when an ultra-thin air-cavity is adopted. The typical shape of Fabry-Perot inner air-cavity with reflection mode of operation is elliptic, with minor axis along with and major axis perpendicular to the fiber length. The first reflection surface is diverging whereas the second one is converging. To increase the visibility of the output interference pattern, the length of major axis should be large for a given cavity length. However, the largest value of the major axis is limited by the optical fiber diameter. If the major axis length reaches the fiber diameter, the robustness of the Fabry-Perot cavity device would be decreased. Here we demonstrate an ultra-thin crescent shaped Fabry-Perot cavity for strain sensing with ultra-high sensitivity and low temperature cross-sensitivity. The crescent-shape cavity consists of two converging reflection surfaces, which provide the advantages of enhanced strain sensitivity when compared with elliptic or D-shaped FP cavity. The device is fabricated by fusion splicing an etched multimode fiber with a single mode fiber, and hence is simple in structure and economic in cost.

  14. Sapphire Fabry-Perot high-temperature sensor study

    NASA Astrophysics Data System (ADS)

    Yao, Yi-qiang; Liang, Wei-long; Gui, Xinwang; Fan, Dian

    2017-04-01

    A new structure sapphire fiber Fabry-Perot (F-P) high-temperature sensor based on sapphire wafer was proposed and fabricated. The sensor uses the sapphire fiber as a transmission waveguide, the sapphire wafer as an Fabry-Perot (F-P) interferometer and the new structure of "Zirconia ferrule-Zirconia tube" as the sensor fixing structure of the sensor. The reflection spectrum of the interferometer was demodulated by a serial of data processing including FIR bandpass filter, FFT (Fast Fourier Transformation) estimation and LSE (least squares estimation) compensation to obtain more precise OPD. Temperature measurement range is from 20 to 1000°C in experiment. The experimental results show that the sensor has the advantages of small size, low cost, simple fabrication and high repeatability. It can be applied for longterm, stable and high-precision high temperature measurement in harsh environments.

  15. Solid, 3-Mirror Fabry-Perot Etalon

    NASA Technical Reports Server (NTRS)

    Stephen, Mark; Fahey, Molly; Miller, Ian

    2017-01-01

    We present modeling and performance of a solid, fused silica, 3-mirror Fabry-Perot-type etalon. We show the optical cavity design and construction of the new etalon and show >95% peak transmission, improved passband shape and 20 dB better out of band rejection than a similar 2-mirror etalon.

  16. Three-stage Fabry-Perot liquid crystal tunable filter with extended spectral range.

    PubMed

    Zheng, Zhenrong; Yang, Guowei; Li, Haifeng; Liu, Xu

    2011-01-31

    A method to extend spectral range of tunable optical filter is proposed in this paper. Two same tunable Fabry-Perot filters and an additional tunable filter with different free spectral range are cascaded to extend spectral range and reduce sidelobes. Over 400 nm of free spectral range and 4 nm of full width at half maximum of the filter were achieved. Design procedure and simulation are described in detail. An experimental 3-stage tunable Fabry-Perot filter with visible and infrared spectra is demonstrated. The experimental results and the theoretical analysis are presented in detail to verify this method. The results revealed that a compact and extended tunable spectral range of Fabry-Perot filter can be easily attainable by this method.

  17. Use of PZT's for adaptive control of Fabry-Perot etalon plate figure

    NASA Technical Reports Server (NTRS)

    Skinner, WIlbert; Niciejewski, R.

    2005-01-01

    A Fabry Perot etalon, consisting of two spaced and reflective glass flats, provides the mechanism by which high resolution spectroscopy may be performed over narrow spectral regions. Space based applications include direct measurements of Doppler shifts of airglow absorption and emission features and the Doppler broadening of spectral lines. The technique requires a high degree of parallelism between the two flats to be maintained through harsh launch conditions. Monitoring and adjusting the plate figure by illuminating the Fabry Perot interferometer with a suitable monochromatic source may be performed on orbit to actively control of the parallelism of the flats. This report describes the use of such a technique in a laboratory environment applied to a piezo-electric stack attached to the center of a Fabry Perot etalon.

  18. 21 CFR 74.3102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... copolymer of adipic acid and hexamethylene diamine) surgical sutures for use in general surgery subject to... Food, Drug, and Cosmetic Act with respect to the medical device in which the color additive FD&C Blue...

  19. 21 CFR 74.3102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... copolymer of adipic acid and hexamethylene diamine) surgical sutures for use in general surgery subject to... Food, Drug, and Cosmetic Act with respect to the medical device in which the color additive FD&C Blue...

  20. 21 CFR 74.3102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... copolymer of adipic acid and hexamethylene diamine) surgical sutures for use in general surgery subject to... Food, Drug, and Cosmetic Act with respect to the medical device in which the color additive FD&C Blue...

  1. 21 CFR 74.3102 - FD&C Blue No. 2.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... copolymer of adipic acid and hexamethylene diamine) surgical sutures for use in general surgery subject to... Food, Drug, and Cosmetic Act with respect to the medical device in which the color additive FD&C Blue...

  2. Hemodynamic Changes Caused by Flow Diverters in Rabbit Aneurysm Models: Comparison of Virtual and Realistic FD Deployments Based on Micro-CT Reconstruction

    PubMed Central

    Fang, Yibin; Yu, Ying; Cheng, Jiyong; Wang, Shengzhang; Wang, Kuizhong; Liu, Jian-Min; Huang, Qinghai

    2013-01-01

    Adjusting hemodynamics via flow diverter (FD) implantation is emerging as a novel method of treating cerebral aneurysms. However, most previous FD-related hemodynamic studies were based on virtual FD deployment, which may produce different hemodynamic outcomes than realistic (in vivo) FD deployment. We compared hemodynamics between virtual FD and realistic FD deployments in rabbit aneurysm models using computational fluid dynamics (CFD) simulations. FDs were implanted for aneurysms in 14 rabbits. Vascular models based on rabbit-specific angiograms were reconstructed for CFD studies. Real FD configurations were reconstructed based on micro-CT scans after sacrifice, while virtual FD configurations were constructed with SolidWorks software. Hemodynamic parameters before and after FD deployment were analyzed. According to the metal coverage (MC) of implanted FDs calculated based on micro-CT reconstruction, 14 rabbits were divided into two groups (A, MC >35%; B, MC <35%). Normalized mean wall shear stress (WSS), relative residence time (RRT), inflow velocity, and inflow volume in Group A were significantly different (P<0.05) from virtual FD deployment, but pressure was not (P>0.05). The normalized mean WSS in Group A after realistic FD implantation was significantly lower than that of Group B. All parameters in Group B exhibited no significant difference between realistic and virtual FDs. This study confirmed MC-correlated differences in hemodynamic parameters between realistic and virtual FD deployment. PMID:23823503

  3. CIV Polarization Measurements using a Vacuum Ultraviolet Fabry-Perot Interferometer

    NASA Technical Reports Server (NTRS)

    West, Edward; Gary, G. Allen; Cirtain, Jonathan; David, John; Kobayashi, Ken; Pietraszewski, Chris

    2009-01-01

    Marshall Space Flight Center's (MSFC) is developing a Vacuum Ultraviolet (VUV) Fabry-P rot Interferometer that will be launched on a sounding rocket for high throughput, high-cadence, extended field of view CIV (155nm) measurements. These measurements will provide (i) Dopplergrams for studies of waves, oscillations, explosive events, and mass motions through the transition region, and, (ii), polarization measurements to study the magnetic field in the transition region. This paper will describe the scientific goals of the instrument, a brief description of the optics and the polarization characteristics of the VUV Fabry P rot.

  4. The beneficial effects of long-term enzyme replacement therapy on cardiac involvement in Japanese Fabry patients.

    PubMed

    Hongo, Kenichi; Ito, Keiichi; Date, Taro; Anan, Ikuko; Inoue, Yasunori; Morimoto, Satoshi; Ogawa, Kazuo; Kawai, Makoto; Kobayashi, Hiroshi; Kobayashi, Masahisa; Ida, Hiroyuki; Ohashi, Toya; Taniguchi, Ikuo; Yoshimura, Michihiro; Eto, Yoshikatsu

    2018-06-01

    Fabry disease is a hereditary disorder that occurs due to the reduction or absence of alpha-galactosidase A activity, which leads to cardiac involvement including left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) provides better patient outcomes by preventing serious complications. However, there have been very few studies on the long-term effects of ERT on the cardiac manifestations in Japanese Fabry patients. We retrospectively analyzed the data from the medical records of 42 Fabry patients (male, n = 17; female, n = 25) who were followed at Jikei University Hospital, and in whom the long-term effects of ERT could be evaluated (median follow-up period: male, 11 years; female, 8 years). The slope of the left ventricular mass (LVM) increase was 3.02 ± 3.41 g/m 2 /year in males and 1.69 ± 2.73 g/m 2 /year in females. In a subgroup analysis, the slopes of males with and without LVH did not differ to a statistically significant extent; however, the slope in female patients without LVH was significantly smaller than that of female patients with LVH. We then compared our data to the natural historical data that have previously been reported. In comparison to the previously reported data, we found a significant reduction in the LVM changes (g/height 2.7 /year) of patients who received long-term ERT (male, 4.07 ± 1.03 to 1.25 ± 1.39; female, 2.31 ± 0.81 to 0.78 ± 1.23). Long-term ERT effectively prevents LVH in Fabry patients. This effect was also observed in the patients with LVH prior to the initiation of ERT. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.

    PubMed

    Wilcox, William R; Banikazemi, Maryam; Guffon, Nathalie; Waldek, Stephen; Lee, Philip; Linthorst, Gabor E; Desnick, Robert J; Germain, Dominique P

    2004-07-01

    Elsewhere, we reported the safety and efficacy results of a multicenter phase 3 trial of recombinant human alpha -galactosidase A (rh-alpha GalA) replacement in patients with Fabry disease. All 58 patients who were enrolled in the 20-wk phase 3 double-blind, randomized, and placebo-controlled study received subsequently 1 mg/kg of rh-alpha GalA (agalsidase beta, Fabrazyme, Genzyme Corporation) biweekly in an ongoing open-label extension study. Evidence of long-term efficacy, even in patients who developed IgG antibodies against rh- alpha GalA, included the continuously normal mean plasma globotriaosylceramide (GL-3) levels during 30 mo of the extension study and the sustained capillary endothelial GL-3 clearance in 98% (39/40) of patients who had a skin biopsy taken after treatment for 30 mo (original placebo group) or 36 mo (original enzyme-treated group). The mean serum creatinine level and estimated glomerular filtration rate also remained stable after 30-36 mo of treatment. Infusion-associated reactions decreased over time, as did anti-rh- alpha GalA IgG antibody titers. Among seroconverted patients, after 30-36 mo of treatment, seven patients tolerized (no detectable IgG antibody), and 59% had > or =4-fold reductions in antibody titers. As of 30 mo into the extension trial, three patients were withdrawn from the study because of positive serum IgE or skin tests; however, all have been rechallenged successfully at the time of this report. Thus, enzyme replacement therapy for 30-36 mo with agalsidase beta resulted in continuously decreased plasma GL-3 levels, sustained endothelial GL-3 clearance, stable kidney function, and a favorable safety profile.

  6. Nematic Fabry-Perot etalons for ground- and space-based atmospheric remote sensing

    NASA Astrophysics Data System (ADS)

    Noto, John; Schneller, Kristin E.; Schneller, William J.; Kerr, Robert B.; Doe, R. A.

    1997-10-01

    Birefringent, nematic liquid crystals (LC) have been laminated between the substrates of several Fabry-Perot etalons. The application of an electric field allows the effective index of refraction of the LC to be varied. A polymer alignment layer is used to align the crystals perpendicular to the optical axis of the Fabry-Perot etalon. An oscillating electric field is used to rotate the crystal around the optical axis of the etalon, effectively changing the index of refraction. This change in index is used to tune the Fabry-Perot etalon in a manner similar to traditional pressure and mechanical tuning systems. However, the approach described here has the advantage of producing a solid-state etalon that is tunable without needing a bulky pressure system or environmentally sensitive piezo-electric stacks. A two etalon spectrometer consisting of two Fabry- Perot etalons coupled to a CID detector has been developed. A suppression etalon with a gap of 10 micrometers , and a LC wit a refractive index of 1.63 are used in conjunction with a high resolution etalon to produce an instrument ideal for observing the atomic spectra of hot, light neutral species and the molecular bands in the atmosphere. Several other etalons have been constructed to further develop this technology. Clear apertures greater than 2 inches have been achieved, and a hybrid spacer technique has been developed to allow for etalons with spacings of up to 1 cm. Fabry- Perot partial reflective coatings capable of operation from the visible to the NIR will also be discussed.

  7. Inhibition of cell signaling by the combi-nitrosourea FD137 in the androgen independent DU145 prostate cancer cell line.

    PubMed

    Qiu, Qiyu; Dudouit, Fabienne; Banerjee, Ranjita; McNamee, James P; Jean-Claude, Bertrand J

    2004-04-01

    FD137, a nitrosourea appended to a quinazoline ring, was designed to simultaneously block epidermal growth factor receptor (EGFR)-mediated signaling and damage genomic DNA in refractory EGF-dependent prostate tumors. The mixed inhibition of cell signaling and DNA damage by FD137 were determined by Western blotting, RT-PCR, flow cytometry, sulforhodamine B (SRB), and comet assay. FD137 and its metabolite FD110 induced a dose-dependent increase in inhibition of EGF-stimulated EGFR autophosphorylation and this translated into blockade of c-fos gene expression in DU145 cells. FD137 induced significant levels of DNA damage and showed 150-fold greater anti-proliferative activity than BCNU, a classical nitrosourea. In contrast to BCNU, complete inhibition of EGF-induced cell transition to S-phase was observed at concentrations of FD137 as low as 3 microM. FD137 could not only damage DNA, but also significantly block downstream EGFR-mediated signaling. The superior activity of FD137 may be imputable to the combined effect of its mixed EGFR/DNA targeting properties. This novel strategy may well represent a new approach to target nitrosoureas to EGFR-overexpressing carcinomas of the prostate. Copyright 2004 Wiley-Liss, Inc.

  8. Rayleigh Scattering Measurements Using a Tunable Liquid Crystal Fabry-Perot Interferometer

    NASA Technical Reports Server (NTRS)

    Mielke-Fagan, Amy F.; Clem, Michelle M.; Elam, Kristie A.

    2010-01-01

    Spectroscopic Rayleigh scattering is an established flow diagnostic that has the ability to provide simultaneous density, velocity, and temperature measurements. The Fabry-Perot interferometer or etalon is a commonly employed instrument for resolving the spectrum of molecular Rayleigh scattered light for the purpose of evaluating these flow properties. This paper investigates the use of a tunable liquid crystal (LC) Fabry-Perot etalon in Rayleigh scattering experiments at NASA Glenn Research Center. The LC etalon provides a robust interferometry system that can be tuned rapidly by adjusting the voltage applied to the liquid crystal interface. Tuning the interferometer is often necessary to control the physical locations of the concentric interference fringes when Rayleigh light is imaged through the LC etalon. The LC etalon diagnostic system was tested in a 1-cm diameter nozzle flow in two different scattering configurations to evaluate its usefulness for Rayleigh measurements compared to a traditional non-tunable fused silica Fabry-Perot etalon.

  9. Fiber optic microphone with large dynamic range based on bi-fiber Fabry-Perot cavity

    NASA Astrophysics Data System (ADS)

    Cheng, Jin; Lu, Dan-feng; Gao, Ran; Qi, Zhi-mei

    2017-10-01

    In this paper, we report a fiber optic microphone with a large dynamic range. The probe of microphone consists of bi-fiber Fabry-Perot cavity architecture. The wavelength of the working laser is about 1552.05nm. At this wavelength, the interference spectroscopies of these two fiber Fabry-Perot cavities have a quadrature shift. So the outputs of these two fiber Fabry-Perot sensors are orthogonal signal. By using orthogonal signal demodulation method, this microphone can output a signal of acoustic wave. Due to no relationship between output signal and the linear region on interference spectroscopy, the microphones have a large maximum acoustic pressure above 125dB.

  10. Switch to agalsidase alfa after shortage of agalsidase beta in Fabry disease: a systematic review and meta-analysis of the literature.

    PubMed

    Pisani, Antonio; Bruzzese, Dario; Sabbatini, Massimo; Spinelli, Letizia; Imbriaco, Massimo; Riccio, Eleonora

    2017-03-01

    In 2009, the agalsidase beta shortage resulted in switching to agalsidase alfa treatment for many Fabry disease patients, offering the unique opportunity to compare the effects of the two drugs. Because single studies describing effects of switching on the disease course are limited and inconclusive, we performed a systematic review and meta-analysis of existing data. Relevant studies were identified in the PubMed, Cochrane, ISI Web, and SCOPUS databases from July 2009 to September 2015. The following parameters were analyzed: clinical events, changes in organ function or structure, disease-related symptoms, lyso-Gb3 plasma levels, and adverse effects. The nine studies (217 patients) included in our systematic review showed only marginal differences in most of the evaluated parameters. Seven of these studies were included in the meta-analysis (176 patients). The pooled incidence rate of major adverse events was reported for five studies (150 patients) and was equal to 0.04 events per person-year. No significant change was observed after the shift in glomerular filtration rate, whereas left ventricular mass index, left ventricular posterior wall dimension, and ejection fraction were significantly reduced over time. Our data showed that the switch to agalsidase alfa was well tolerated and associated with stable clinical conditions.Genet Med 19 3, 275-282.

  11. In-fiber Fabry-Perot refractometer assisted by a long-period grating.

    PubMed

    Mosquera, L; Sáez-Rodriguez, D; Cruz, J L; Andrés, M V

    2010-02-15

    We present an optical fiber refractometer based on a Fabry-Perot interferometer defined by two fiber Bragg gratings and an intracavity long-period grating that makes the light confined in the resonator interact with the surrounding medium. The external refractive index is monitored by the resonant frequencies of the Fabry-Perot interferometer, which can be measured either in transmission or in reflection. In this first experiment, wavelength shifts measured with a resolution of 0.1 pm have allowed one to establish a refractive index detection limit of 2.1x10(-5).

  12. Variations on the "Blue-Bottle" Demonstration Using Food Items That Contain FD&C Blue #1

    ERIC Educational Resources Information Center

    Staiger, Felicia A.; Peterson, Joshua P.; Campbell, Dean J.

    2015-01-01

    Erioglaucine dye (FD&C Blue #1) can be used instead of methylene blue in the classic "blue-bottle" demonstration. Food items containing FD&C Blue #1 and reducing species such as sugars can therefore be used at the heart of this demonstration, which simply requires the addition of strong base such as sodium hydroxide lye.

  13. Fabry disease and enzyme replacement therapy in classic patients with same mutation: different formulations--different outcome?

    PubMed

    Politei, J; Schenone, A B; Cabrera, G; Heguilen, R; Szlago, M

    2016-01-01

    We describe the results of the multidisciplinary evaluation in patients with Fabry disease and the same genetic mutation and their outcomes using different approved enzyme replacement therapy (ERT). We measured baseline data and serial results of neuropathic pain assessment and renal, cardiac and cerebrovascular functioning. Pain scale showed improvement in all male cases treated with agalsidasa beta. A mild improvement was detected in agalsidasa alfa-treated patients after 1 year with posterior increase. During the agalsidase beta shortage, two male patients were switched to agalsidasa alfa, after 1 year both cases presented an increase in scale values. Renal evolution showed a tendency toward a decrease in proteinuria in patients using agalsidase beta and worsening with agalsidase alfa. We found improvement in two females using agalsidase beta and no changes in the other cases regarding cardiac functioning. Brain magnetic resonance imaging (MRI) showed increase of white matter lesions in four patients. Improvement and stabilization in neuropathic pain, renal and cardiac functioning and brain MRI were found mainly in patients treated with agalsidase beta. Following the reported recommendations on reintroduction of agalsidase beta after the enzyme shortage, we decided to switch all patients to agalsidase beta. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Zn2+ selectively stabilizes FdU-substituted DNA through a unique major groove binding motif

    PubMed Central

    Ghosh, Supratim; Salsbury, Freddie R.; Horita, David A.; Gmeiner, William H.

    2011-01-01

    We report, based on semi-empirical calculations, that Zn2+ binds duplex DNA containing consecutive FdU–dA base pairs in the major groove with distorted trigonal bipyramidal geometry. In this previously uncharacterized binding motif, O4 and F5 on consecutive FdU are axial ligands while three water molecules complete the coordination sphere. NMR spectroscopy confirmed Zn2+ complexation occurred with maintenance of base pairing while a slight hypsochromic shift in circular dichroism (CD) spectra indicated moderate structural distortion relative to B-form DNA. Zn2+ complexation inhibited ethidium bromide (EtBr) intercalation and stabilized FdU-substituted duplex DNA (ΔTm > 15°C). Mg2+ neither inhibited EtBr complexation nor had as strong of a stabilizing effect. DNA sequences that did not contain consecutive FdU were not stabilized by Zn2+. A lipofectamine preparation of the Zn2+–DNA complex displayed enhanced cytotoxicity toward prostate cancer cells relative to the individual components prepared as lipofectamine complexes indicating the potential utility of Zn2+–DNA complexes for cancer treatment. PMID:21296761

  15. Comprehensive clinical evaluation of a large Spanish family with Anderson-Fabry disease, novel GLA mutation and severe cardiac phenotype.

    PubMed

    San Román-Monserrat, Irene; Moreno-Flores, Victoria; López-Cuenca, David; Rodríguez-González-Herrero, Elena; Guillén-Navarro, Encarna; Rodríguez-González-Herrero, Beatriz; Alegría-Fernández, Marisol; Poza-Cisneros, Gabriela; Piñero-Fernández, Juan A; Sornichero-Martínez, Javier; Gimeno-Blanes, Juan R

    2014-06-06

    Fabry disease is an X-linked multisystemic lysosomal-storage condition. We describe a large family with a novel GLA mutation: p.M187R/g7219 T>G. Anamnesis/physical-exam, blood/urine analysis, α-Gal-A activity and/or genetic study of at-risk individuals and multidisciplinary evaluation in confirmed cases. 4 males and 13 heterozygous-females displayed the mutation. Cardiac/renal/neurological disease was diagnosed at a mean age of 41/29/39 years in males and 51/56/46 years in females. Onset mean age was 20 years versus 42 years. 9/15 had cardiomyopathy. Delta wave suggestive of accessory pathway was identified in 1 male and 2 females. 1 female had cardiac arrest (ventricular fibrillation, 61 years). 2 females and 1 male died suddenly (63, 64 and 57 years). Cardiac-subscore of Mainz Severity-Score-Index was severe for males and females over 40 years. 4/15(26%) developed early renal disease. 2 males needed dialysis. 1 male died at 69 years in spite of kidney-heart transplant. We describe the largest genetically confirmed Spanish family using multidisciplinary evaluation and MSSI calculation. The novel mutation p.M187R/g7219 T>G is associated with a particularly malignant cardiac phenotype in males and females over 40 years. Severity was higher than that of the largest Spanish FOS-cohort. Short-PR with delta is being reported for the first time. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  16. 21 CFR 74.2101 - FD&C Blue No. 1.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...-[(ethylphenylamino)methyl] benzenesulfonic acid, and smaller amounts of 4-[(ethylphenylamino)methyl] benzenesulfonic acid and 2-[(ethylphenylamino)methyl] benzenesulfonic acid to form the leuco base. The leuco base is... inner salt. Additionally, FD&C Blue No. 1 is manufactured by the acid catalyzed condensation of one mole...

  17. 21 CFR 74.2101 - FD&C Blue No. 1.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...-[(ethylphenylamino)methyl] benzenesulfonic acid, and smaller amounts of 4-[(ethylphenylamino)methyl] benzenesulfonic acid and 2-[(ethylphenylamino)methyl] benzenesulfonic acid to form the leuco base. The leuco base is... inner salt. Additionally, FD&C Blue No. 1 is manufactured by the acid catalyzed condensation of one mole...

  18. 21 CFR 74.2101 - FD&C Blue No. 1.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...-[(ethylphenylamino)methyl] benzenesulfonic acid, and smaller amounts of 4-[(ethylphenylamino)methyl] benzenesulfonic acid and 2-[(ethylphenylamino)methyl] benzenesulfonic acid to form the leuco base. The leuco base is... inner salt. Additionally, FD&C Blue No. 1 is manufactured by the acid catalyzed condensation of one mole...

  19. Analysis of left ventricular mass in untreated men and in men treated with agalsidase-β: data from the Fabry Registry.

    PubMed

    Germain, Dominique P; Weidemann, Frank; Abiose, Ademola; Patel, Manesh R; Cizmarik, Marta; Cole, J Alexander; Beitner-Johnson, Dana; Benistan, Karelle; Cabrera, Gustavo; Charrow, Joel; Kantola, Ilkka; Linhart, Ales; Nicholls, Kathy; Niemann, Markus; Scott, C Ronald; Sims, Katherine; Waldek, Stephen; Warnock, David G; Strotmann, Jörg

    2013-12-01

    The aim of this study was to evaluate the progression of left ventricular hypertrophy in untreated men with Fabry disease and to assess the effects of agalsidase-β (recombinant human α-galactosidase A) on left ventricular hypertrophy. Longitudinal Fabry Registry data were analyzed from 115 men treated with agalsidase-β (1 mg/kg/2 weeks) and 48 untreated men. Measurements included baseline left-ventricular mass and at least one additional left-ventricular mass assessment over ≥ 2 years. Patients were grouped into quartiles, based on left-ventricular mass slopes. Multivariate logistic regression analyses identified factors associated with left ventricular hypertrophy progression. For men in whom treatment was initiated at the age of 18 to <30 years, mean left ventricular mass slope was -3.6 g/year (n = 31) compared with +9.5 g/year in untreated men of that age (n = 15) (P < 0.0001). Untreated men had a 3.4-fold higher risk of having faster increases in left-ventricular mass compared with treated men (odds ratio: 3.43; 95% confidence interval: 1.05-11.22; P = 0.0415). A baseline age of ≥ 40 years was also associated with left--ventricular hypertrophy progression (odds ratio: 5.03; 95% confidence interval: 1.03-24.49; P = 0.0457) compared with men younger than 30 years. Agalsidase-β treatment for ≥2 years may improve or stabilize left-ventricular mass in men with Fabry disease. Further investigations may determine whether early intervention and stabilization of LVM are correlated with clinical outcomes.

  20. Band-pass Fabry-Pèrot magnetic tunnel junctions

    NASA Astrophysics Data System (ADS)

    Sharma, Abhishek; Tulapurkar, Ashwin. A.; Muralidharan, Bhaskaran

    2018-05-01

    We propose a high-performance magnetic tunnel junction by making electronic analogs of optical phenomena such as anti-reflections and Fabry-Pèrot resonances. The devices we propose feature anti-reflection enabled superlattice heterostructures sandwiched between the fixed and the free ferromagnets of the magnetic tunnel junction structure. Our predictions are based on non-equilibrium Green's function spin transport formalism coupled self-consistently with the Landau-Lifshitz-Gilbert-Slonczewski equation. Owing to the physics of bandpass spin filtering in the bandpass Fabry-Pèrot magnetic tunnel junction device, we demonstrate an ultra-high boost in the tunnel magneto-resistance (≈5 × 104%) and nearly 1200% suppression of spin transfer torque switching bias in comparison to a traditional trilayer magnetic tunnel junction device. The proof of concepts presented here can lead to next-generation spintronic device design harvesting the rich physics of superlattice heterostructures and exploiting spintronic analogs of optical phenomena.

  1. FD/DAMA Scheme For Mobile/Satellite Communications

    NASA Technical Reports Server (NTRS)

    Yan, Tsun-Yee; Wang, Charles C.; Cheng, Unjeng; Rafferty, William; Dessouky, Khaled I.

    1992-01-01

    Integrated-Adaptive Mobile Access Protocol (I-AMAP) proposed to allocate communication channels to subscribers in first-generation MSAT-X mobile/satellite communication network. Based on concept of frequency-division/demand-assigned multiple access (FD/DAMA) where partition of available spectrum adapted to subscribers' demands for service. Requests processed, and competing requests resolved according to channel-access protocol, or free-access tree algorithm described in "Connection Protocol for Mobile/Satellite Communications" (NPO-17735). Assigned spectrum utilized efficiently.

  2. 21 CFR 74.2706 - FD&C Yellow No. 6.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Yellow No. 6. 74.2706 Section 74.2706 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF... coloring cosmetics generally in amounts consistent with current good manufacturing practice. (c) Labeling...

  3. 21 CFR 74.340 - FD&C Red No. 40.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... more than 0.3 percent. 4-Amino-5-methoxy-o- toluenesulfonic acid, not more than 0.2 percent. Disodium... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...-naphthalenesulfonic acid. (2) Color additive mixtures for food use (including dietary supplements) made with FD&C Red...

  4. 21 CFR 74.340 - FD&C Red No. 40.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... more than 0.3 percent. 4-Amino-5-methoxy-o- toluenesulfonic acid, not more than 0.2 percent. Disodium... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...-naphthalenesulfonic acid. (2) Color additive mixtures for food use (including dietary supplements) made with FD&C Red...

  5. Forkhead Transcription Factor Fd3F Cooperates with Rfx to Regulate a Gene Expression Program for Mechanosensory Cilia Specialization

    PubMed Central

    Newton, Fay G.; zur Lage, Petra I.; Karak, Somdatta; Moore, Daniel J.; Göpfert, Martin C.; Jarman, Andrew P.

    2012-01-01

    Summary Cilia have evolved hugely diverse structures and functions to participate in a wide variety of developmental and physiological processes. Ciliary specialization requires differences in gene expression, but few transcription factors are known to regulate this, and their molecular function is unclear. Here, we show that the Drosophila Forkhead box (Fox) gene, fd3F, is required for specialization of the mechanosensory cilium of chordotonal (Ch) neurons. fd3F regulates genes for Ch-specific axonemal dyneins and TRPV ion channels, which are required for sensory transduction, and retrograde transport genes, which are required to differentiate their distinct motile and sensory ciliary zones. fd3F is reminiscent of vertebrate Foxj1, a motile cilia regulator, but fd3F regulates motility genes as part of a broader sensory regulation program. Fd3F cooperates with the pan-ciliary transcription factor, Rfx, to regulate its targets directly. This illuminates pathways involved in ciliary specialization and the molecular mechanism of transcription factors that regulate them. PMID:22698283

  6. Effect and Tolerability of Agalsidase Alfa in Patients with Fabry Disease Who Were Treatment Naïve or Formerly Treated with Agalsidase Beta or Agalsidase Alfa.

    PubMed

    Goker-Alpan, Ozlem; Nedd, Khan; Shankar, Suma P; Lien, Yeong-Hau H; Weinreb, Neal; Wijatyk, Anna; Chang, Peter; Martin, Rick

    2015-01-01

    In a multicenter, open-label, treatment protocol (HGT-REP-059; NCT01031173), clinical effects and tolerability of agalsidase alfa (agalα; 0.2 mg/kg every other week) were evaluated in patients with Fabry disease who were treatment naïve or switched from agalsidase beta (switch). Over 24 months, data were collected on the safety profile; renal and cardiac parameters were assessed using estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMI), and midwall fractional shortening (MFS). Enrolled patients included 71 switch (median [range] age, 46.6 [5-84] years; male to female [M:F], 40:31) and 29 treatment naïve (38.7 [12-74] years; M:F, 14:15). Adverse events (AEs) were consistent with the known safety profile of agalα. Two switch patients had hospitalization due to possibly/probably drug-related serious AEs (one with transient ischemic attack, one with infusion-related AEs). One switch and two treatment-naïve patients discontinued treatment because of AEs. Three patients (one each switch, treatment naïve, and previous agalα) died; no deaths were considered drug-related. There was no significant change from baseline in LVMI or MFS in either group. Similarly, eGFR remained stable; mean ± standard error annualized change in eGFR (mL/min/1.73 m(2)) was -2.40 ± 1.04 in switch and -1.68 ± 2.21 in treatment-naïve patients. This is the largest cohort of patients with Fabry disease who were started on or switched to agalα in an FDA-accepted protocol during a worldwide supply shortage of agalsidase beta. Because this protocol was primarily designed to provide access to agalα, there were limitations, including not having stringent selection criteria and the lack of a placebo group.

  7. Effects of switching from agalsidase Beta to agalsidase alfa in 10 patients with anderson-fabry disease.

    PubMed

    Pisani, A; Spinelli, L; Visciano, B; Capuano, I; Sabbatini, M; Riccio, E; Messalli, G; Imbriaco, M

    2013-01-01

    Anderson-Fabry disease (AFD) is a multiorgan X-linked lysosomal storage disease that particularly affects the heart, kidneys, and cerebrovascular system. Current treatment is enzyme replacement therapy (ERT) with agalsidase beta (Fabrazyme(®), Genzyme Corporation, Cambridge, MA, USA) or agalsidase alfa (Replagal(®), Shire Human Genetic Therapies AB, Lund, Sweden). It was recommended that patients switch to agalsidase alfa due to a manufacturing shortage of agalsidase beta beginning in June 2009. This study assessed the effect of switching to agalsidase alfa on clinical outcomes in patients with AFD previously treated with agalsidase beta. Ten patients (seven male, three female) with genetically confirmed AFD and at least 48 months' continuous data collected during treatment with agalsidase beta 1 mg/kg every other week were switched to agalsidase alfa 0.2 mg/kg every other week for at least 20 months, with prospective clinical evaluations every 6 months. Pre-switch data was collected retrospectively from patient charts. Cardiac functional parameters were assessed using magnetic resonance imaging. Results showed that renal function was normal (estimated glomerular filtration rate ≥90 mL/min/1.73 m(2)) in 8 of 10 patients prior to agalsidase alfa and generally remained stable after the switch. Cardiac mass decreased significantly (p < 0.05 vs pre-ERT) after agalsidase beta and remained unchanged after switching to agalsidase alfa. Symptoms of pain and health status scores did not deteriorate during agalsidase alfa therapy. Adverse events were mostly mild and infusion related. In conclusion, switching to agalsidase alfa was relatively well tolerated and associated with stable clinical status and preserved renal and cardiac function.

  8. 21 CFR 74.2203 - FD&C Green No. 3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Green No. 3. 74.2203 Section 74.2203 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... safely used for coloring cosmetics generally in amounts consistent with current good manufacturing...

  9. Miniaturized fiber inline Fabry-Perot interferometer for chemical sensing.

    DOT National Transportation Integrated Search

    2010-01-01

    This paper demonstrates the chemical sensing capability of a miniaturized fiber inline Fabry-Prot sensor fabricated by femtosecond : laser. Its accessible cavity enables the device to measure the refractive index within the cavity. The refractive i...

  10. Demonstrations Using a Fabry-Perot. I. Multiple-Slit Interference

    ERIC Educational Resources Information Center

    Roychoudhuri, Chandrasekhar

    1975-01-01

    Describes a demonstration technique for showing multiple-slit interference patterns with the use of a Fabry-Perot etalon and a laser beam. A simple derivation of the analytical expression for such fringes is presented. (Author/CP)

  11. Power-ratio tunable dual-wavelength laser using linearly variable Fabry-Perot filter as output coupler.

    PubMed

    Wang, Xiaozhong; Wang, Zhongfa; Bu, Yikun; Chen, Lujian; Cai, Guoxiong; Huang, Wencai; Cai, Zhiping; Chen, Nan

    2016-02-01

    For a linearly variable Fabry-Perot filter, the peak transmission wavelengths change linearly with the transverse position shift of the substrate. Such a Fabry-Perot filter is designed and fabricated and used as an output coupler of a c-cut Nd:YVO4 laser experimentally in this paper to obtain a 1062 and 1083 nm dual-wavelength laser. The peak transmission wavelengths are gradually shifted from 1040.8 to 1070.8 nm. The peak transmission wavelength of the Fabry-Perot filter used as the output coupler for the dual-wavelength laser is 1068 nm and resides between 1062 and 1083 nm, which makes the transmissions of the desired dual wavelengths change in opposite slopes with the transverse shift of the filter. Consequently, powers of the two wavelengths change in opposite directions. A branch power, oppositely tunable 1062 and 1083 nm dual-wavelength laser is successfully demonstrated. Design principles of the linear variable Fabry-Perot filter used as an output coupler are discussed. Advantages of the method are summarized.

  12. Fabry-Perot Interferometer-Based Electrooptic Modulator using LiNbO3 and Organic Thin Films

    NASA Technical Reports Server (NTRS)

    Banks, C.; Frazier, D.; Penn, B.; Abdeldayem, H.; Sharma, A.; Yelleswarapu, C.; Leyderman, Alexander; Correa, Margarita; Curreri, Peter A. (Technical Monitor)

    2002-01-01

    We report the study of a Fabry-Perot electro-optical modulator using thin crystalline film NPP, and Crystalline LiNbO3. We are able to observe 14, and 60 percent degree of modulation. Measurements were carried using a standard lock-in amplifier with a silicon detector. The proposal to design a Fabry-Perot electro-optic modulator with an intracavity electro-optically active organic material was based on the initial results using poled polymer thin films. The main feature of the proposed device is the observation that in traditional electrooptic modulators like a Packets cell, it requires few kilovolts of driving voltage to cause a 3 dB modulation even in high figure-of-merit electrooptic materials like LiNbO3. The driving voltage for the modulator can be reduced to as low as 10 volts by introducing the electrooptic material inside die resonant cavity of a Fabry-Perot modulator. This is because the transmission of the Fabry-Perot cavity varies nonlinearly with the change of refractive index or phase of light due to applied electric field.

  13. CO2 flux monitoring using Continuous Timeseries-Forced Diffusion (CT-FD): Development, Validation

    NASA Astrophysics Data System (ADS)

    McArthur, G. S.; Risk, D. A.; Nickerson, N. R.; Creelman, C. A.; Beltrami, H.

    2009-12-01

    Land-based CO2 flux measurements are a key indicator of the biological, chemical and physical processes occurring in the soil. While highly dense temporal flux measurements can be acquired using Eddy Covariance towers, or flux chambers, the challenge of gathering data that is rich both temporally and spatially persists. Over the past two years we have developed a new technique for measuring soil CO2 fluxes, called continuous timeseries-forced diffusion (CT-FD) attempts to satisfy the need for spatially and temporally rich data. The CT-FD probe consists of a Vaisala CO2 sensor, embodied in a PVC casing, with tear/UV resistant Tyvek membranes at both the inlet and outlet. The probe delivers continuous flux data and can be inexpensively replicated across the landscape.The CT-FD technique works by forcing a known diffusive regime between the soil and the atmosphere, allowing the calculation of fluxes across the soil/atmosphere boundary to be made from; the internal concentration of a CT-FD probe placed at the soil surface; and a common reference probe designed to capture the atmospheric CO2. For every concentration measurement, the difference between the probe and the reference concentration is indicative of a unique flux value. Here we examine properties of the instrument and method, as documented by a long series of developmental studies involving numerical gas transport modeling, laboratory and field experiments. A suite of 1D and 3D modeling experiments were needed to optimize embodiment and geometries of the probe. These show that the probe should have a relatively long collar, with relatively high diffusivity made possible by having large, highly diffusive membranes, both of which help to induce 1D movement of gases into the probe and reduce the lateral diffusion around the probe. Modeling also shows that correction for lateral diffusion is feasible. As for error, sensor error transfers linearly to errors in the flux, and that the sensor can be used in non free

  14. 21 CFR 74.303 - FD&C Red No. 3.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... are listed in part 73 of this chapter as safe for use in color additive mixtures for coloring foods... coloring foods generally (including dietary supplements) in amounts consistent with good manufacturing... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FD&C Red No. 3. 74.303 Section 74.303 Food and...

  15. 21 CFR 74.303 - FD&C Red No. 3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... are listed in part 73 of this chapter as safe for use in color additive mixtures for coloring foods... coloring foods generally (including dietary supplements) in amounts consistent with good manufacturing... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Red No. 3. 74.303 Section 74.303 Food and...

  16. 21 CFR 74.1340 - FD&C Red No. 40.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Red No. 40. 74.1340 Section 74.1340 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR... additive mixtures for coloring drugs. (3) The listing of this color additive includes lakes prepared as...

  17. 21 CFR 74.1304 - FD&C Red No. 4.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...-insoluble matter, not more than 0.2 percent. 5-Amino-2,4-dimethyl-1-benzenesulfonic acid, sodium salt, not... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...-naphthalenesulfonic acid. (2) Color additive mixtures for use in externally applied drugs made with FD&C Red No. 4 may...

  18. 21 CFR 74.1304 - FD&C Red No. 4.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...-insoluble matter, not more than 0.2 percent. 5-Amino-2,4-dimethyl-1-benzenesulfonic acid, sodium salt, not... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF COLOR...-naphthalenesulfonic acid. (2) Color additive mixtures for use in externally applied drugs made with FD&C Red No. 4 may...

  19. Fabry disease under enzyme replacement therapy-new insights in efficacy of different dosages.

    PubMed

    Krämer, Johannes; Lenders, Malte; Canaan-Kühl, Sima; Nordbeck, Peter; Üçeyler, Nurcan; Blaschke, Daniela; Duning, Thomas; Reiermann, Stefanie; Stypmann, Jörg; Brand, Stefan-Martin; Gottschling, Timo; Störk, Stefan; Wanner, Christoph; Sommer, Claudia; Brand, Eva; Weidemann, Frank

    2017-11-23

    Fabry patients on reduced dose of agalsidase-beta or after switch to agalsidase-alfa show a decline in estimated glomerular filtration rate (eGFR) and an increase of the Mainz Severity Score Index. In this prospective observational study, we assessed end-organ damage and clinical symptoms in 112 patients who had received agalsidase-beta (1.0 mg/kg) for >1 year, who were (i) non-randomly assigned to continue this treatment regime (regular-dose group, n = 37); (ii) received a reduced dose of agalsidase-beta and subsequent switch to agalsidase-alfa (0.2 mg/kg) or a direct switch to 0.2 mg/kg agalsidase-alfa (switch group, n = 38); or (iii) were re-switched to agalsidase-beta after receiving agalsidase-alfa for at least 12 months (re-switch group, n = 37) with a median follow-up of 53 (38-57) months. eGFR of patients in the regular-dose group remained stable. Patients in the switch group showed an annual eGFR loss of - 4.6  ±  9.1 mL/min/1.73 m2 (P < 0.05). Patients in the re-switch group also had an eGFR loss of - 2.2  ±  4.4 mL/min/1.73 m2 after re-switch to agalsidase-beta, but to a lower degree compared with the switch group (P < 0.05). Patients in the re-switch group suffered less frequently from diarrhoea (relative risk 0.42; 95% confidence interval 0.19-0.93; P = 0.02). Lyso-Gb3 remained stable in the switch (P = 0.97) and the regular-dose (P = 0.48) groups, but decreased in the re-switch group after change of the therapy regimen (P < 0.05). After switch to agalsidase-alfa, Fabry patients experienced a continuous decline in eGFR, while this decline was attenuated in patients who were re-switched to agalsidase-beta. Decreasing lyso-Gb3 levels may indicate a better treatment response in the latter group. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  20. Characterization of Ferredoxin-Dependent Glutamine-Oxoglutarate Amidotransferase (Fd-GOGAT) Genes and Their Relationship with Grain Protein Content QTL in Wheat

    PubMed Central

    2014-01-01

    Background In higher plants, inorganic nitrogen is assimilated via the glutamate synthase cycle or GS-GOGAT pathway. GOGAT enzyme occurs in two distinct forms that use NADH (NADH-GOGAT) or Fd (Fd-GOGAT) as electron carriers. The goal of the present study was to characterize wheat Fd-GOGAT genes and to assess the linkage with grain protein content (GPC), an important quantitative trait controlled by multiple genes. Results We report the complete genomic sequences of the three homoeologous A, B and D Fd-GOGAT genes from hexaploid wheat (Triticum aestivum) and their localization and characterization. The gene is comprised of 33 exons and 32 introns for all the three homoeologues genes. The three genes show the same exon/intron number and size, with the only exception of a series of indels in intronic regions. The partial sequence of the Fd-GOGAT gene located on A genome was determined in two durum wheat (Triticum turgidum ssp. durum) cvs Ciccio and Svevo, characterized by different grain protein content. Genomic differences allowed the gene mapping in the centromeric region of chromosome 2A. QTL analysis was conducted in the Svevo×Ciccio RIL mapping population, previously evaluated in 5 different environments. The study co-localized the Fd-GOGAT-A gene with the marker GWM-339, identifying a significant major QTL for GPC. Conclusions The wheat Fd-GOGAT genes are highly conserved; both among the three homoeologous hexaploid wheat genes and in comparison with other plants. In durum wheat, an association was shown between the Fd-GOGAT allele of cv Svevo with increasing GPC - potentially useful in breeding programs. PMID:25099972

  1. Does football cause an increase in degenerative disease of the lumbar spine?

    PubMed

    Gerbino, Peter G; d'Hemecourt, Pierre A

    2002-02-01

    Degenerative disease of the lumbar spine is exceedingly common. Whether any specific activity increases the likelihood of developing degenerative disc disease (DDD) or facet degeneration (FD) has enormous implications. Within the field of occupational medicine there are specific activities, occupations, and morphologic characteristics that have been related to low back pain. Several specific risk factors have been conclusively linked to low back pain, and in particular DDD and FD. Within the sport of American football, there has long been the feeling that many athletes have or will develop low back pain, DDD, and FD. Proving that certain risk factors present in football will predictably lead to an increase in LBP, DDD, and FD is more difficult. At this time, it can be said that football players, in general, increase their risk of developing low back pain, DDD, and FD as their years of involvement with their sport increase. Because specific spine injuries like fracture, disc herniation, and spondylolysis are more frequent in football players, the resulting DDD and FD are greater than that of the general population. The weightlifting and violent hyperextension that are part of American football are independent risk factors for degenerative spine disease.

  2. Development of the Fabry-Perot Spectrometer Application

    NASA Technical Reports Server (NTRS)

    Browne, Kathryn

    2015-01-01

    Methane is a greenhouse gas with global warming effects 20 times more detrimental than carbon dioxide. Currently, only aircraft missions measure methane and do not provide continuous monitoring, This presentation will cover the Fabry-Perot spectrometer which will provide continuous monitoring of methane. It will also cover the development of the software used to extract and process the data the spectrometer collects.

  3. 21 CFR 74.2705 - FD&C Yellow No. 5.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FD&C Yellow No. 5. 74.2705 Section 74.2705 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF... ethyl ester, or a salt of this carboxylic acid. The resulting dye is purified and isolated as the sodium...

  4. 21 CFR 74.2705 - FD&C Yellow No. 5.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FD&C Yellow No. 5. 74.2705 Section 74.2705 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF... ethyl ester, or a salt of this carboxylic acid. The resulting dye is purified and isolated as the sodium...

  5. 21 CFR 74.2705 - FD&C Yellow No. 5.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FD&C Yellow No. 5. 74.2705 Section 74.2705 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF... ethyl ester, or a salt of this carboxylic acid. The resulting dye is purified and isolated as the sodium...

  6. 21 CFR 74.2705 - FD&C Yellow No. 5.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FD&C Yellow No. 5. 74.2705 Section 74.2705 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF... ethyl ester, or a salt of this carboxylic acid. The resulting dye is purified and isolated as the sodium...

  7. BIMOS transistor solutions for ESD protection in FD-SOI UTBB CMOS technology

    NASA Astrophysics Data System (ADS)

    Galy, Philippe; Athanasiou, S.; Cristoloveanu, S.

    2016-01-01

    We evaluate the Electro-Static Discharge (ESD) protection capability of BIpolar MOS (BIMOS) transistors integrated in ultrathin silicon film for 28 nm Fully Depleted SOI (FD-SOI) Ultra Thin Body and BOX (UTBB) high-k metal gate technology. Using as a reference our measurements in hybrid bulk-SOI structures, we extend the BIMOS design towards the ultrathin silicon film. Detailed study and pragmatic evaluations are done based on 3D TCAD simulation with standard physical models using Average Current Slope (ACS) method and quasi-static DC stress (Average Voltage Slope AVS method). These preliminary 3D TACD results are very encouraging in terms of ESD protection efficiency in advanced FD-SOI CMOS.

  8. Multimode excitation-induced phase shifts in intrinsic Fabry-Perot interferometric fiber sensor spectra.

    PubMed

    Ma, Cheng; Wang, Anbo

    2010-09-01

    We report the modal analysis of optical fiber single-mode-multimode-single-mode intrinsic Fabry-Perot interferometer sensors. The multimode nature of the Fabry-Perot cavity gives rise to an additional phase term in the spectrogram due to intermodal dispersion-induced wavefront distortion, which could significantly affect the cavity length demodulation accuracy. By using an exact model to analyze the modal behavior, this phase term is explained by employing a rotating vector approach. Comparison of the theoretical analysis with experimental results is presented.

  9. A Case of Infantile Kyrle-Flegel Disease in a 6-Year-Old Yemeni Girl.

    PubMed

    Alshami, Mohammad Ali; Mohana, Mona Jameel

    2016-01-01

    Kyrle disease (KD) and Flegel disease (FD) are rare variants of primary perforating dermatoses, characterized by transepidermal elimination of abnormal endogenous materials. We describe a 6-year-old Yemeni girl with a 2-year history of generalized asymptomatic, small, reddish-brown keratotic papules with a lenticular central keratotic plug. Although these features are synonymous with FD, the histology of a punch biopsy was consistent with KD. The patient was otherwise healthy, and no family members had a history of similar diseases. The patient was diagnosed with KD-FD, owing to the manifestation of features associated with both diseases.

  10. A Case of Infantile Kyrle-Flegel Disease in a 6-Year-Old Yemeni Girl

    PubMed Central

    Alshami, Mohammad Ali; Mohana, Mona Jameel

    2016-01-01

    Kyrle disease (KD) and Flegel disease (FD) are rare variants of primary perforating dermatoses, characterized by transepidermal elimination of abnormal endogenous materials. We describe a 6-year-old Yemeni girl with a 2-year history of generalized asymptomatic, small, reddish-brown keratotic papules with a lenticular central keratotic plug. Although these features are synonymous with FD, the histology of a punch biopsy was consistent with KD. The patient was otherwise healthy, and no family members had a history of similar diseases. The patient was diagnosed with KD-FD, owing to the manifestation of features associated with both diseases. PMID:26933407

  11. Nitrogen-doped diamond thin films: potential application in Fabry-Pérot interferometer

    NASA Astrophysics Data System (ADS)

    Kosowska, M.; Majchrowicz, D.; Sankaran, K. J.; Ficek, M.; Jedrzejewska-Szczerska, M.; Haenen, M. K.

    2018-04-01

    In this paper we present results of preliminary research of using nitrogen-doped diamond (NDD) films as reflective layer in Fabry-Pérot interferometer. NDD films were deposited on Si substrates by Microwave Plasma Enhanced Chemical Vapor Deposition (MPECVD) with the use of CH4, H2 and N2 gas mixtures. During deposition process methane flow rate varied while nitrogen flow was constant. We performed series of measurements which showed that NDD can be used as a mirror in Fabry-Pérot interferometer. The best signal visibility and repeatability of measurements were obtained for sample made with 3 sccm methane flow rate.

  12. Influence of antibody formation on reduction of globotriaosylceramide (GL-3) in urine from Fabry patients during agalsidase beta therapy.

    PubMed

    Ohashi, Toya; Sakuma, Mio; Kitagawa, Teruo; Suzuki, Ken; Ishige, Nobuyuki; Eto, Yoshikatsu

    2007-11-01

    Two recombinant human agalsidase preparations are available for treatment of Fabry disease. We assayed urinary GL-3 (uGL-3) concentration in seronegative and seropositive patients receiving agalsidase beta (1mg/kg). Antibody formation and residual enzyme activity were strongly correlated. Normalization of uGL-3 was achieved more efficiently in seronegatives. But different from previous reports, reduction of uGL-3 level was observed in some seropositive patients.

  13. Compressible Fabry-Perot refractometer.

    PubMed

    Andersson, M; Eliasson, L; Pendrill, L R

    1987-11-15

    The use of a long, thermally stable Fabry-Perot etalon as a refractometer is considered in detail in this study of the refractive index of air. The etalon consists of two flat plates of fused silica 60 mm in diameter, with a cylindrical spacer made of Zerodur (a polycrystalline glass ceramic of extremely low thermal expansion) 200 mm long. The interferogram of light from a frequency-stabilized He-Ne laser is imaged with large-diameter mirror optics. The principal result is a demonstration of the effects of changes in atmospheric pressure on the etalon. The measured refractive-index values deviate by 2 parts in 10(7) from calculated values. Possible causes of error are considered in detail.

  14. Simplified design of diaphragm-based fiber optic extrinsic Fabry-Perot accelerometer

    NASA Astrophysics Data System (ADS)

    Wang, Zhaogang; Zhang, Wentao; Han, Jing; Huang, Wenzhu; Li, Fang

    2014-11-01

    A fiber optic Fabry-Perot accelerometer (FOFPA) with diaphragm-mass-collimator (DMC) gathered structure is presented. This design makes the structure more compacts and the manufacturing process more controllable. The operation principle based on Fabry-Perot interference is described. Several tests using intensity demodulation scheme which can control the working point of FOFPA were carried out. Experimental results show that: axis sensitivity of the proposed FOFPA is 36.07 dB (re: 0 dB=1 V/g) with a fluctuation less than 0.9 dB in a frequency bandwidth of 10-125 Hz, the resonant frequency is about 350 Hz, measurement range is about 70 dB@100 Hz. which are much close to theoretical values

  15. Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy

    PubMed Central

    Warnock, David G; Thomas, Christie P; Vujkovac, Bojan; Campbell, Ruth C; Charrow, Joel; Laney, Dawn A; Jackson, Leslie L; Wilcox, William R; Wanner, Christoph

    2015-01-01

    Background Nephropathy is an important feature of classical Fabry disease, which results in alpha-galactosidase A deficiency and cellular globotriaosylceramide accumulation. We report the safety and efficacy of antiproteinuric therapy with ACE inhibitors or angiotensin II receptor blockers (ARBs) in a study of classical Fabry patients receiving recombinant agalsidase-beta therapy. Methods and design The goal was maintenance of urine protein to creatinine ratio (UPCR) <0.5 g/g or a 50% reduction in baseline UPCR for 24 patients at eight study sites. The change in estimated glomerular filtration rate (eGFR) was assessed over 21 months of treatment. Results 18 out of 24 patients achieved the UPCR goal with eGFR slopes that were significantly better than six patients who did not achieve the UPCR goal (−3.6 (−4.8 to −1.1) versus −7.0 (−9.0 to −5.6) mL/min/1.73 m2/year, respectively, p=0.018). Despite achieving the UPCR goal, 67% (12/18 patients) still progressed with an eGFR slope <−2 mL/min/1.73 m2/year. Regression analysis showed that increased age at initiation of agalsidase-beta therapy was significantly associated with worsened kidney outcome. Hypotension and hyperkalaemia occurred in seven and eight patients, respectively, which required modification of antiproteinuric therapy but was not associated with serious adverse events. Conclusions This study documents the effectiveness of agalsidase-beta (1 mg/kg/2 weeks) and antiproteinuric therapy with ACE inhibitors and/or ARB in patients with severe Fabry nephropathy. Patients had preservation of kidney function if agalsidase-beta treatment was initiated at a younger age, and UPCR maintained at or below 0.5 g/g with antiproteinuric therapy. Trial registration number NCT00446862. PMID:26490103

  16. Stable CW Single-Frequency Operation of Fabry-Perot Laser Diodes by Self-Injection Phase Locking

    NASA Technical Reports Server (NTRS)

    Duerksen, Gary L.; Krainak, Michael A.

    1999-01-01

    Previously, single-frequency semiconductor laser operation using fiber Bragg gratings has been achieved by two methods: 1) use of the FBG as the output coupler for an anti-reflection-coated semiconductor gain element'; 2) pulsed operation of a gain-switched Fabry-Perot laser diode with FBG-optical and RF-electrical feedback. Here, we demonstrate CW single frequency operation from a non-AR coated Fabry-Perot laser diode using only FBG optical feedback. We coupled a nominal 935 run-wavelength Fabry-Perot laser diode to an ultra narrow band (18 pm) FBG. When tuned by varying its temperature, the laser wavelength is pulled toward the centerline of the Bragg grating, and the spectrum of the laser output is seen to fall into three discrete stability regimes as measured by the side-mode suppression ratio.

  17. Analysis of globotriaosylceramide (Gb3) isoforms/analogs in unfractionated leukocytes, B lymphocytes and monocytes from Fabry patients using ultra-high performance liquid chromatography/tandem mass spectrometry.

    PubMed

    Toupin, Amanda; Lavoie, Pamela; Arthus, Marie-Françoise; Abaoui, Mona; Boutin, Michel; Fortier, Carole; Ménard, Claudia; Bichet, Daniel G; Auray-Blais, Christiane

    2018-07-26

    Fabry disease is an X-linked lysosomal storage disorder with marked variability in the phenotype and genotype. Glycosphingolipids such as globotriaosylceramide (Gb 3 ) isoforms/analogs, globotriaosylsphingosine (lyso-Gb 3 ) and analogs, and galabiosylceramide (Ga 2 ) isoforms/analogs may accumulate in biological fluids and different organs. The aims of this study were to: 1) develop/validate a novel UHPLC-MS/MS method for relative quantitation of Gb 3 in leukocytes (unfractionated white blood cells), B lymphocytes and monocytes; 2) evaluate these biomarkers in a cohort of Fabry patients and healthy controls; and 3) assess correlations between these biomarkers, treatment and genotype. Whole blood, plasma and urine samples from 21 Fabry patients and 20 healthy controls were analyzed. Samples were purified by liquid-liquid extraction and analyzed by UHPLC-MS/MS in positive electrospray ionization. Methylated Gb 3 isoforms were detected, showing that a methylation process occurs at the cellular level. Our results show that there were no significant differences in the distribution of the different Gb 3 isoforms/analogs in blood cells between Fabry patients and healthy controls. In leukocyte, Gb 3 [(d18:1)(C14:0)], Gb 3 [(d18:1)(C16:0)], Gb 3 [(d18:1)(C16:0)]Me, Gb 3 [(d18:1)(C16:1)], Gb 3 [(d18:1)(C18:0)], Gb 3 [(d18:1)(C18:1)], Gb 3 [(d18:1)(C20:1)], Gb 3 [(d18:1)(C24:2)], Gb 3 [(d18:1)(C26:1)] and total Gb 3 allowed good discrimination between male Fabry patients and male controls, patients having higher biomarker levels than controls. Regarding B lymphocytes and monocytes, the same tendency was observed without reaching statistical significance. A positive concordance between mutation types and biomarker levels in white blood cells was established. Our results might provide a deeper mechanistic comprehension of the underlying biochemical processes of Gb 3 biomarkers in white blood cells of Fabry patients. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Fabry disease: Evidence for a regional founder effect of the GLA gene mutation 30delG in Brazilian patients.

    PubMed

    de Alencar, Dayse Oliveira; Netto, Cristina; Ashton-Prolla, Patricia; Giugliani, Roberto; Ribeiro-Dos-Santos, Ândrea; Pereira, Fernanda; Matte, Ursula; Santos, Ney; Santos, Sidney

    2014-01-01

    The Fabry disease is caused by mutations in the gene ( GLA ) that encodes the enzyme α-galactosidase A (α-Gal A). More than 500 pathologic variants of GLA have already been described, most of them are family-specific. In southern Brazil, a frequent single-base deletion ( GLA 30delG) was identified among four families that do not recognize any common ancestral. In order to investigate the history of this mutation (investigate the founder effect, estimate the mutation age and the most likely source), six gene-flanking microsatellite markers of the X chromosome on the mutation carriers and their parents, 150 individuals from the same population and 300 individuals that compose the Brazilian parental populations (Europeans, Africans and Native Americans) were genotyped. A common haplotype to the four families was identified and characterized as founder. The age was estimated with two statistics software (DMLE 2.2 and ESTIAGE) that agreed with 11 to 12 generations old. This result indicates that the mutation GLA 30delG was originated from a single event on the X chromosome of a European immigrant, during the southern Brazil colonization between 1710 and 1740.

  19. The IRAF Fabry-Perot analysis package: Ring fitting

    NASA Technical Reports Server (NTRS)

    Shopbell, P. L.; Bland-Hawthorn, J.; Cecil, G.

    1992-01-01

    As introduced at ADASSI, a Fabry-Perot analysis package for IRAF is currently under development as a joint effort of ourselves and Frank Valdes of the IRAF group. Although additional portions of the package were also implemented, we report primarily on the development of a robust ring fitting task, useful for fitting the calibration rings obtained in Fabry-Perot observations. The general equation of an ellipse is fit to the shape of the rings, providing information on ring center, ellipticity, and position angle. Such parameters provide valuable information on the wavelength response of the etalon and the geometric stability of the system. Appropriate statistical weighting is applied to the pixels to account for increasing numbers with radius, the Lorentzian cross-section, and uneven illumination. The major problems of incomplete, non-uniform, and multiple rings are addressed with the final task capable of fitting rings regardless of center, cross-section, or completion. The task requires only minimal user intervention, allowing large numbers of rings to be fit in an extremely automated manner.

  20. Intrinsic Fabry-Perot Sensors for Magnetic Field Detection

    NASA Astrophysics Data System (ADS)

    Broadway, Christian; Descamps, Frédéric; Kinet, Damien; Caucheteur, Christophe; Mégret, Patrice

    2018-01-01

    Within the context of ensuring stable nuclear fusion, it is important to monitor and control a number of parametersincluding the magnetic field associated with plasma circulation. Optical fibre sensing techniques have seen a surge in promulgation and research advances in recent years, due to their immunity to electromagnetic radiation and compact dimensions. Prior work has shown that fibre Bragg gratings are one method of recovering the induced magnetic field, with the main point of interest being their use as distributed point sensors. However, Bragg grating inscription leads to the creation of linear birefringence that increases detector noise and could obscure a given signal. We have hypothesised that by using an intrinsic Fabry-Perot cavity comprised of two identical Bragg gratings, we could obtain a more accurate detector with the removal of photo-induced birefringence in the detection region. We present a proof of concept optical fibre sensor based on an intrinsic Fabry-Perot cavity that shows spectrally visible amplitude modulation. Finally, we demonstrate faster data processing that allows real time monitoring of a given scenario.

  1. All-optical logic gates and wavelength conversion via the injection locking of a Fabry-Perot semiconductor laser

    NASA Astrophysics Data System (ADS)

    Harvey, E.; Pochet, M.; Schmidt, J.; Locke, T.; Naderi, N.; Usechak, N. G.

    2013-03-01

    This work investigates the implementation of all-optical logic gates based on optical injection locking (OIL). All-optical inverting, NOR, and NAND gates are experimentally demonstrated using two distributed feedback (DFB) lasers, a multi-mode Fabry-Perot laser diode, and an optical band-pass filter. The DFB lasers are externally modulated to represent logic inputs into the cavity of the multi-mode Fabry-Perot slave laser. The input DFB (master) lasers' wavelengths are aligned with the longitudinal modes of the Fabry-Perot slave laser and their optical power is used to modulate the injection conditions in the Fabry-Perot slave laser. The optical band-pass filter is used to select a Fabry- Perot mode that is either suppressed or transmitted given the logic state of the injecting master laser signals. When the input signal(s) is (are) in the on state, injection locking, and thus the suppression of the non-injected Fabry-Perot modes, is induced, yielding a dynamic system that can be used to implement photonic logic functions. Additionally, all-optical photonic processing is achieved using the cavity-mode shift produced in the injected slave laser under external optical injection. The inverting logic case can also be used as a wavelength converter — a key component in advanced wavelength-division multiplexing networks. As a result of this experimental investigation, a more comprehensive understanding of the locking parameters involved in injecting multiple lasers into a multi-mode cavity and the logic transition time is achieved. The performance of optical logic computations and wavelength conversion has the potential for ultrafast operation, limited primarily by the photon decay rate in the slave laser.

  2. All sky imaging Fabry-Perot spectrometer for optical investigation of the upper atmosphere

    NASA Astrophysics Data System (ADS)

    Sekar, R.; Gurubaran, S.; Sridharan, R.

    1993-06-01

    A simple optical design, keeping in view of the available components, has been worked out to develop the 'all sky imaging Fabry-Perot spectrometer' to study the spatial structures in thermospheric winds and temperature. This system comprises three subsystems, namely, (1) field widening front-end optics, (2) high resolution Fabry-Perot spectrometer and (3) a two-dimensional detector. The design details of the above imaging spectrometer that has been commissioned for routine observations from Mt. Abu along with the first results on OI 6300 A airglow emission are presented and discussed.

  3. Impact of enzyme replacement therapy on cardiac morphology and function and late enhancement in Fabry's cardiomyopathy.

    PubMed

    Beer, Meinrad; Weidemann, Frank; Breunig, Frank; Knoll, Anita; Koeppe, Sabrina; Machann, Wolfram; Hahn, Dietbert; Wanner, Christoph; Strotmann, Jörg; Sandstede, Jörn

    2006-05-15

    The present study evaluated the evolution of cardiac morphology, function, and late enhancement as a noninvasive marker of myocardial fibrosis, and their inter-relation during enzyme replacement therapy in patients with Fabry's disease using magnetic resonance imaging and color Doppler myocardial imaging. Late enhancement, which was present in up to 50% of patients, was associated with increased left ventricular mass, the failure of a significant regression of hypertrophy during enzyme replacement therapy, and worse segmental myocardial function. Late enhancement may predict the effect of enzyme replacement therapy on left ventricular mass and cardiac function.

  4. A coaxial cable Fabry-Perot interferometer for sensing applications.

    PubMed

    Huang, Jie; Wang, Tao; Hua, Lei; Fan, Jun; Xiao, Hai; Luo, Ming

    2013-11-07

    This paper reports a novel coaxial cable Fabry-Perot interferometer for sensing applications. The sensor is fabricated by drilling two holes half-way into a coaxial cable. The device physics was described. The temperature and strain responses of the sensor were tested. The measurement error was calculated and analyzed.

  5. Stable CW Single Frequency Operation of Fabry-Perot Laser Diodes by Self-Injection Phase Locking

    NASA Technical Reports Server (NTRS)

    Duerksen, Gary L.; Krainak, Michael A.

    1999-01-01

    Previously, single-frequency semiconductor laser operation using fiber Bragg gratings has been achieved by tWo methods: 1) use of the FBG as the output coupler for an anti-reflection-coated semiconductor gain element'; 2) pulsed operation of a gain-switched Fabry-Perot laser diode with FBG-optical and RF-electrical feedback'. Here, we demonstrate CW single frequency operation from a non-AR coated Fabry-Perot laser diode using only FBG optical feedback.

  6. Stable CW Single-Frequency Operation of Fabry-Perot Laser Diodes by Self-Injection Phase Locking

    NASA Technical Reports Server (NTRS)

    Duerksen, Gary L.; Krainak, Michael A.

    1998-01-01

    Previously, single-frequency semiconductor laser operation using fiber Bragg gratings (FBG) has been achieved by two methods: (1) use of the FBG as the output coupler for an anti-reflection-coated semiconductor gain element; (2) pulsed operation of a gain-switched Fabry-Perot laser diode with FBG-optical and RF-electrical feedback. Here, we demonstrate CW single frequency operation from a non-AR coated Fabry-Perot laser diode using only FBG optical feedback.

  7. Composite-cavity-based Fabry-Perot interferometric strain sensors.

    PubMed

    Zhang, Jianzhong; Peng, G D; Yuan, Libo; Sun, Weimin

    2007-07-01

    A composite-cavity-based Fabry-Perot interferometric strain sensor system is proposed to gain the minimum cross sensitivity to temperature and a high multiplexing capability at the same time. The interrogation of the sensor system is based on a white-light interferometric technology, and the demodulation is achieved by analyzing the coherence spectra. A demonstration system with two sensors is presented and tested.

  8. Fiber-Optic Temperature Sensor Using a Thin-Film Fabry-Perot Interferometer

    NASA Technical Reports Server (NTRS)

    Beheim, Glenn

    1997-01-01

    A fiber-optic temperature sensor was developed that is rugged, compact, stable, and can be inexpensively fabricated. This thin-film interferometric temperature sensor was shown to be capable of providing a +/- 2 C accuracy over the range of -55 to 275 C, throughout a 5000 hr operating life. A temperature-sensitive thin-film Fabry-Perot interferometer can be deposited directly onto the end of a multimode optical fiber. This batch-fabricatable sensor can be manufactured at a much lower cost than can a presently available sensor, which requires the mechanical attachment of a Fabry-Perot interferometer to a fiber. The principal disadvantage of the thin-film sensor is its inherent instability, due to the low processing temperatures that must be used to prevent degradation of the optical fiber's buffer coating. The design of the stable thin-film temperature sensor considered the potential sources of both short and long term drifts. The temperature- sensitive Fabry-Perot interferometer was a silicon film with a thickness of approx. 2 microns. A laser-annealing process was developed which crystallized the silicon film without damaging the optical fiber. The silicon film was encapsulated with a thin layer of Si3N4 over coated with aluminum. Crystallization of the silicon and its encapsulation with a highly stable, impermeable thin-film structure were essential steps in producing a sensor with the required long-term stability.

  9. A Coaxial Cable Fabry-Perot Interferometer for Sensing Applications

    PubMed Central

    Huang, Jie; Wang, Tao; Hua, Lei; Fan, Jun; Xiao, Hai; Luo, Ming

    2013-01-01

    This paper reports a novel coaxial cable Fabry-Perot interferometer for sensing applications. The sensor is fabricated by drilling two holes half-way into a coaxial cable. The device physics was described. The temperature and strain responses of the sensor were tested. The measurement error was calculated and analyzed. PMID:24212121

  10. Optical fiber Fabry-Perot interferometry

    NASA Astrophysics Data System (ADS)

    Wang, Anbo

    2014-06-01

    Fiber Fabry-Perot (FP) interferometry is one of the most important tools for harsh environment sensing because of its great flexibility of sensor material selection, superior long-­-term stability, and nature of remote passive operation. Virginia Tech's Center for Photonics Technology has been involved in the research of this field for many years. After a quick review of the typical methods for the construction of F-P sensors, emphasis will be placed on the whitelight interferometry, which is perhaps the most robust interferometric sensor demodulation technique today. The recent discovery of an additional phase will be presented and its significance to the sensor demodulation will be discussed.

  11. Pulmonary involvement in Fabry disease: effect of plasma globotriaosylsphingosine and time to initiation of enzyme replacement therapy.

    PubMed

    Franzen, Daniel; Haile, Sarah R; Kasper, David C; Mechtler, Thomas P; Flammer, Andreas J; Krayenbühl, Pierre A; Nowak, Albina

    2018-01-01

    Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by mutations of GLA gene leading to reduced α-galactosidase activity and resulting in a progressive accumulation of globotriaosylceramide (Gb3) and its deacylated derivative, globotriaosyl-sphingosine (Lyso-Gb3). Plasma Lyso-Gb3 levels serve as a disease severity and treatment monitoring marker during enzyme replacement therapy (ERT). Adult patients with AFD who had yearly pulmonary function tests between 1999 and 2015 were eligible for this observational study. Primary outcome measures were the change in z-score of forced expiratory volume in the first second (FEV 1 ) and FEV 1 /FVC over time. Plasma Lyso-Gb3 levels and the age of ERT initiation were investigated for their association with lung function decline. Fifty-three patients (42% male, median (range) age at diagnosis of AFD 34 (6-61) years in men, 34 (13-67) in women) were included. The greatest decrease of FEV 1 /FVC z-scores was observed in Classic men (-0.048 per year, 95% CI -0.081 to -0.014), compared with the Later-Onset men (+0.013,95% CI -0.055 to 0.082), Classic women (-0.008, 95% CI -0.035 to +0.020) and Later-Onset women (-0.013, 95% CI -0.084 to +0.058). Cigarette smoking (P=0.022) and late ERT initiation (P=0.041) were independently associated with faster FEV 1 decline. FEV 1 /FVC z-score decrease was significantly reduced after initiation of ERT initiation (-0.045 compared with -0.015, P=0.014). Furthermore, there was a trend towards a relevant influence of Lyso-Gb3 (P=0.098) on airflow limitation with age. Early ERT initiation seems to preserve pulmonary function. Plasma Lyso-Gb3 is maybe a useful predictor for airflow limitation. Classic men need a closer monitoring of the lung function.

  12. An arc tangent function demodulation method of fiber-optic Fabry-Perot high-temperature pressure sensor

    NASA Astrophysics Data System (ADS)

    Ren, Qianyu; Li, Junhong; Hong, Yingping; Jia, Pinggang; Xiong, Jijun

    2017-09-01

    A new demodulation algorithm of the fiber-optic Fabry-Perot cavity length based on the phase generated carrier (PGC) is proposed in this paper, which can be applied in the high-temperature pressure sensor. This new algorithm based on arc tangent function outputs two orthogonal signals by utilizing an optical system, which is designed based on the field-programmable gate array (FPGA) to overcome the range limit of the original PGC arc tangent function demodulation algorithm. The simulation and analysis are also carried on. According to the analysis of demodulation speed and precision, the simulation of different numbers of sampling points, and measurement results of the pressure sensor, the arc tangent function demodulation method has good demodulation results: 1 MHz processing speed of single data and less than 1% error showing practical feasibility in the fiber-optic Fabry-Perot cavity length demodulation of the Fabry-Perot high-temperature pressure sensor.

  13. FIFI: The MPE Garching/UC Berkeley Far-Infrared Imaging Fabry-Perot Interferometer

    NASA Technical Reports Server (NTRS)

    Geis, Norbert; Genzel, Reinhard; Haggerty, M.; Herrmann, F.; Jackson, J.; Madden, Suzanne C.; Nikola, T.; Poglitsch, Albrecht; Rumitz, M.; Stacey, G. J.

    1995-01-01

    We describe the performance characteristics of the MPE Garching/UC Berkeley Far-Infrared Imaging Fabry-Perot Interferometer (FIFI) for the Kuiper Airborne Observatory (KAO). The spectrometer features two or three cryogenic tunable Fabry-Perot filters in series giving spectral resolution R of up to 10(exp 5) in the range of 40 microns less than lambda less than 200 microns, and an imaging 5x5 array of photoconductive detectors with variable focal plane plate scale. The instrument works at background limited sensitivity of up to 2 x 10(exp -19) W cm(exp -2) Hz(exp -1/2) per pixel per resolution element at R = 10(exp 5) on the KAO.

  14. Thin-film-based optical fiber Fabry-Perot interferometer used for humidity sensing.

    PubMed

    Peng, Jiankun; Qu, Yapeng; Wang, Weijia; Sun, Tengpeng; Yang, Minghong

    2018-04-20

    A thin-film-based optical fiber Fabry-Perot interferometer that consists of ZrO 2 and SiO 2 porous thin films is designed and fabricated by electron beam physical vapor deposition. Since the SiO 2 porous thin film has the capability of water adsorption, the proposed Fabry-Perot interferometer is appropriate to detect humidity. Experimental results show that the prepared sensor has a humidity detection range from 0.06% RH to 70% RH. A cycling test shows that the humidity sensor has a responding or recover time of 4 s and good repeatability among different humidity environments. Especially, the proposed humidity sensor is insensitive to temperature variation and suitable for the detection of low relative humidity.

  15. [Non-destructive, preclinical evaluation of root canal anatomy of human teeth with flat-panel detector volume CT (FD-VCT)].

    PubMed

    Heidrich, G; Hassepass, F; Dullin, C; Attin, T; Grabbe, E; Hannig, C

    2005-12-01

    Successful endodontic diagnostics and therapy call for adequate depiction of the root canal anatomy with multimodal diagnostic imaging. The aim of the present study is to evaluate visualization of the endodont with flat-panel detector volume CT (FD-VCT). 13 human teeth were examined with the prototype of a FD-VCT. After data acquisition and generation of volume data sets in volume rendering technology (VRT), the findings obtained were compared to conventional X-rays and cross-section preparations of the teeth. The anatomical structures of the endodont such as root canals, side canals and communications between different root canals as well as denticles could be detected precisely with FD-VCT. The length of curved root canals was also determined accurately. The spatial resolution of the system is around 140 microm. Only around 73 % of the main root canals detected with FD-VCT and 87 % of the roots could be visualized with conventional dental X-rays. None of the side canals, shown with FD-VCT, was detectable on conventional X-rays. In all cases the enamel and dentin of the teeth could be well delineated. No differences in image quality could be discerned between stored and freshly extracted teeth, or between primary and adult teeth. FD-VCT is an innovative diagnostic modality in preclinical and experimental use for non-destructive three-dimensional analysis of teeth. Thanks to the high isotropic spatial resolution compared with conventional X-rays, even the minutest structures, such as side canals, can be detected and evaluated. Potential applications in endodontics include diagnostics and evaluation of all steps of root canal treatment, ranging from trepanation through determination of the length of the root canal to obturation.

  16. Temperature-independent refractometer based on fiber-optic Fabry-Perot interferometer

    NASA Astrophysics Data System (ADS)

    Li, Jiacheng; Qiao, Xueguang; Wang, Ruohui; Rong, Qiangzhou; Bao, Weijia; Shao, Zhihua; Yang, Tingting

    2016-04-01

    A miniature fiber-optic refractometer based on Fabry-Perot interferometer (FPI) has been proposed and experimentally demonstrated. The sensing head consists of a short section of photonics crystal fiber (PCF) spliced to a single mode fiber (SMF), in which the end-face of the PCF is etched to remove holey structure with hydrofluoric (HF) acid. A Fabry-Perot interference spectrum is achieved based on the reflections from the fusion splicing interface and the end-face of the core of PCF. The interference fringe is sensitive to the external refractive index (RI) with an intensity-referenced sensitivity of 358.27 dB/RIU ranging from 1.33 to 1.38. The sensor has also been implemented for the concentration measurement of λ-phage DNA solution. In addition, the dip intensity is insensitive to the ambient temperature variation, making it a good candidate for temperature-independent bio-sensing area.

  17. Exploiting diurnal variations to evaluate the ISCCP-FD flux calculations and radiative-flux-analysis-processed surface observations from BSRN, ARM, and SURFRAD

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, Yuanchong; Long, Charles N.; Rossow, William B.

    2010-01-01

    Based on monthly-3-hourly and 3-hourly mean surface radiative fluxes and their associated meteorological parameters for 2004 from the International Satellite Cloud Climatology Project-FD (ISCCP-FD) and the Radiative Flux Analysis method-Produced Surface Observations (RFA-PSO) for 15 high-quality-controlled surface stations, operated by the Baseline Surface Radiation Network (BSRN), the Atmospheric Radiation Measurement (ARM) and the National Oceanic and Atmospheric Administration's Surface Radiation budget network (SURFRAD), this work, goes beyond the previous validation for FD against surface observation by introducing the Meteorological Similarity Comparison Method (MSCM) to make a more precise, mutual evaluation of both FD and PSO products. The comparison results inmore » substantial uncertainty reduction and provides reasonable physical explanations for the flux differences. This approach compares fluxes for cases where the atmospheric and surface physical properties (specifically, the input parameters for radiative transfer model) are as close as possible to the values determined at the observational sites by matching the RFA-produced cloud fraction (CF) and/or optical thickness (Tau), etc., or alternatively, by directly changing the model input variables for FD to match PSO values, and using such-produced matched sub-datasets to make more accurate comparisons based on more similar meteorological environments between FD and PSO. The crucial part is the availability of flux-associated meteorological parameters from RFA-PSO, which was only recently made available that makes this work possible. For surface downwelling shortwave(SW) flux (SWdn) and its two components, diffuse (Dif) and direct (Dir), uncertainty for monthly mean is 15, 15 and 17 W/m 2, respectively, smaller than the separately estimated uncertainty values from both FD and PSO. When applying MSCM by reducing their CF difference, the differences can be reduced by a factor of 2. The strength of MSCM

  18. Clinical and genetic investigation of a Japanese family with cardiac fabry disease. Identification of a novel α-galactosidase A missense mutation (G195V).

    PubMed

    Nakagawa, Naoki; Maruyama, Hiroki; Ishihara, Takayuki; Seino, Utako; Kawabe, Jun-ichi; Takahashi, Fumihiko; Kobayashi, Motoi; Yamauchi, Atsushi; Sasaki, Yukie; Sakamoto, Naka; Ota, Hisanobu; Tanabe, Yasuko; Takeuchi, Toshiharu; Takenaka, Toshihiro; Kikuchi, Kenjiro; Hasebe, Naoyuki

    2011-01-01

    Fabry disease is an X-linked lysosomal storage disorder caused by mutations of the α-galactosidase A gene (GLA), and the disease is a relatively prevalent cause of left ventricular hypertrophy mimicking idiopathic hypertrophic cardiomyopathy. We assessed clinically 5 patients of a three-generation family and also searched for GLA mutations in 10 family members. The proband had left ventricular hypertrophy with localized thinning in the basal posterior wall and late gadolinium enhancement (LGE) in the near-circumferential wall in cardiovascular magnetic resonance images and her sister had vasospastic angina pectoris without organic stenosis of the coronary arteries. LGE notably appeared in parallel with decreased α-galactosidase A activity and increased NT-pro BNP in our patients. We detected a new GLA missense mutation (G195V) in exon 4, resulting in a glycine-to-valine substitution. Of the 10 family members, 5 family members each were positive and negative for this mutation. These new data extend our clinical and molecular knowledge of GLA gene mutations and confirm that a novel missense mutation in the GLA gene is important not only for a precise diagnosis of heterozygous status, but also for confirming relatives who are negative for this mutation.

  19. First experience of simultaneous PET/MRI for the early detection of cardiac involvement in patients with Anderson-Fabry disease.

    PubMed

    Nappi, Carmela; Altiero, Michele; Imbriaco, Massimo; Nicolai, Emanuele; Giudice, Caterina Anna; Aiello, Marco; Diomiaiuti, Claudio Tommaso; Pisani, Antonio; Spinelli, Letizia; Cuocolo, Alberto

    2015-06-01

    Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder associated with severe multiorgan dysfunction and premature death. Early diagnosis and treatment strategies play a key role in patient outcome. We investigated the potential role of hybrid PET/MR imaging in the assessment of early cardiac involvement in AFD patients. Thirteen AFD patients without cardiac symptoms and with normal left ventricular function underwent simultaneous cardiac PET/MR imaging after administration of (18)F-FDG. Cardiac FDG uptake was quantified by measuring the standardized uptake value in 17 myocardial segments in each subject. The coefficient of variation (COV, i.e. the standard deviation divided by the average) of the uptake of the 17 segments was calculated as an index of heterogeneity in the heart. Six patients exhibited focal late gadolinium enhancement (LGE) indicating intramyocardial fibrosis, and four of these also had positive short inversion time inversion recovery (STIR) sequences. All patients with LGE and positive STIR MR images showed focal FDG uptake in the corresponding myocardial segments indicating inflammation. Of the seven patients with negative LGE and STIR images, five showed homogeneous FDG cardiac uptake and two showed heterogeneous FDG uptake. The COV was significantly greater in patients with focal FDG uptake (0.25 ± 0.02) than in those without (0.14 ± 0.07, p < 0.01). PET/MR imaging is clinically feasible for the early detection of cardiac involvement in patients with AFD. Further studies evaluating the role of hybrid PET/MR imaging in management of the disease in larger patient populations are warranted.

  20. Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase

    PubMed Central

    Warnock, David G.; Bichet, Daniel G.; Holida, Myrl; Goker-Alpan, Ozlem; Nicholls, Kathy; Thomas, Mark; Eyskens, Francois; Shankar, Suma; Adera, Mathews; Sitaraman, Sheela; Khanna, Richie; Flanagan, John J.; Wustman, Brandon A.; Barth, Jay; Barlow, Carrolee; Valenzano, Kenneth J.; Lockhart, David J.; Boudes, Pol; Johnson, Franklin K.

    2015-01-01

    Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified. Trial Registration ClinicalTrials.gov NCT01196871 PMID:26252393

  1. Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase.

    PubMed

    Warnock, David G; Bichet, Daniel G; Holida, Myrl; Goker-Alpan, Ozlem; Nicholls, Kathy; Thomas, Mark; Eyskens, Francois; Shankar, Suma; Adera, Mathews; Sitaraman, Sheela; Khanna, Richie; Flanagan, John J; Wustman, Brandon A; Barth, Jay; Barlow, Carrolee; Valenzano, Kenneth J; Lockhart, David J; Boudes, Pol; Johnson, Franklin K

    2015-01-01

    Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified. ClinicalTrials.gov NCT01196871.

  2. Development FD-SOI MOSFET Amplifiers for Integrated Read-Out Circuit of Superconducting-Tunnel-Junction Single-Photon-Detectors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kiuchi, Kenji; et al.

    We proposed a new high-resolution single-photon infrared spectrometer for search for radiative decay of cosmic neutrino background (CνB). The superconducting-tunnel-junctions(STJs) are used as a single-photon counting device. Each STJ consists of Nb/Al/Al xO y/Al/Nb layers, and their thicknesses are optimized for the operation temperature at 370 mK cooled by a 3He sorption refrigerator. Our STJs achieved the leak current 250 pA, and the measured data implies that a smaller area STJ fulfills our requirement. FD-SOI MOSFETs are employed to amplify the STJ signal current in order to increase signal-to-noise ratio (S/N). FD-SOI MOSFETs can be operated at cryogenic temperature ofmore » 370 mK, which reduces the noise of the signal amplification system. FD-SOI MOSFET characteristics are measured at cryogenic temperature. The Id-Vgs curve shows a sharper turn on with a higher threshold voltage and the Id-Vds curve shows a nonlinear shape in linear region at cryogenic temperature. Taking into account these effects, FD-SOI MOSFETs are available for read-out circuit of STJ detectors. The bias voltage for STJ detectors is 0.4 mV, and it must be well stabilized to deliver high performance. We proposed an FD-SOI MOSFET-based charge integrated amplifier design as a read-out circuit of STJ detectors. The requirements for an operational amplifier used in the amplifier is estimated using SPICE simulation. The op-amp is required to have a fast response (GBW ≥ 100 MHz), and it must have low power dissipation as compared to the cooling power of refrigerator.« less

  3. Differential Radiometers Using Fabry-Perot Interferometric Technique for Remote Sensing of Greenhouse Gases

    NASA Technical Reports Server (NTRS)

    Georgieva, Elena M.; Heaps,William S.; Wilson, Emily L.

    2007-01-01

    A new type of remote sensing radiometer based upon the Fabry-Perot interferometric technique has been developed at NASA's Goddard Space Flight Center and tested from both ground and aircraft platform. The sensor uses direct or reflected sunlight and has channels for measuring column concentration of carbon dioxide at 1570 nm, oxygen lines sensitive to pressure and temperature at 762 and 768 nm, and water vapor (940 nm). A solid Fabry-Perot etalon is used as a tunable narrow bandpass filter to restrict the measurement to the gas of interest's absorption bands. By adjusting the temperature of the etalon, which changes the index of refraction of its material, the transmission fringes can be brought into nearly exact correspondence with absorption lines of the particular species. With this alignment between absorption lines and fringes, changes in the amount of a species in the atmosphere strongly affect the amount of light transmitted by the etalon and can be related to gas concentration. The technique is applicable to different chemical species. We have performed simulations and instrument design studies for CH4, "Cot isotope, and CO detection. Index Terms- Absorbing media, Atmospheric measurements, Fabry-Perot interferometers, Optical interferometry, Remote sensing.

  4. Risk of death in heart disease is associated with elevated urinary globotriaosylceramide.

    PubMed

    Schiffmann, Raphael; Forni, Sabrina; Swift, Caren; Brignol, Nastry; Wu, Xiaoyang; Lockhart, David J; Blankenship, Derek; Wang, Xuan; Grayburn, Paul A; Taylor, Matthew R G; Lowes, Brian D; Fuller, Maria; Benjamin, Elfrida R; Sweetman, Lawrence

    2014-02-04

    Elevated urinary globotriaosylceramide (Gb3) has been considered a hallmark of Fabry disease, an X-linked lysosomal disorder that is a risk factor for most types of heart disease. We screened 1421 consecutive patients with common forms of heart disease for Fabry disease by measuring urinary Gb3 in whole urine using tandem mass spectrometry, α-galactosidase A activity in dried blood spots, and we looked for GLA mutations by parallel sequencing of the whole gene (exons and introns) in pooled genomic DNA samples followed by Sanger sequencing verification. GLA variants were found in 13 patients. In the 1408 patients without GLA mutations, urinary Gb3 levels were significantly higher in heart disease patients compared to 116 apparently healthy controls (median difference=10.0 ng/mL and P<0.001). Urinary lipid profiling showed that levels of 5 other lipids significantly distinguished between urine of patients with Fabry disease (n=7) and heart disease patients with elevated urinary Gb3 (n=6). Sphingomyelin and Gb3 levels were abnormal in the left ventricular wall of patients with ischemic heart failure. Elevated levels of urinary Gb3 were independently associated with increased risk of death in the average follow-up of 17 months (hazard ratio=1.59 for increase in Gb3 of 200, 95% CI=1.36 and 1.87, and P<0.0001). In heart disease patients who do not have Fabry disease or GLA gene mutations, a higher level of urinary Gb3 is positively associated with near-term mortality. The elevation of urinary Gb3 and that of other lipids suggests that heart disease is associated with multiorgan lipid abnormalities. clinicaltrials.gov. Unique Identifier: NCT01019629.

  5. Risk of Death in Heart Disease is Associated With Elevated Urinary Globotriaosylceramide

    PubMed Central

    Schiffmann, Raphael; Forni, Sabrina; Swift, Caren; Brignol, Nastry; Wu, Xiaoyang; Lockhart, David J.; Blankenship, Derek; Wang, Xuan; Grayburn, Paul A.; Taylor, Matthew R. G.; Lowes, Brian D.; Fuller, Maria; Benjamin, Elfrida R.; Sweetman, Lawrence

    2014-01-01

    Background Elevated urinary globotriaosylceramide (Gb3) has been considered a hallmark of Fabry disease, an X‐linked lysosomal disorder that is a risk factor for most types of heart disease. Methods and Results We screened 1421 consecutive patients with common forms of heart disease for Fabry disease by measuring urinary Gb3 in whole urine using tandem mass spectrometry, α‐galactosidase A activity in dried blood spots, and we looked for GLA mutations by parallel sequencing of the whole gene (exons and introns) in pooled genomic DNA samples followed by Sanger sequencing verification. GLA variants were found in 13 patients. In the 1408 patients without GLA mutations, urinary Gb3 levels were significantly higher in heart disease patients compared to 116 apparently healthy controls (median difference=10.0 ng/mL and P<0.001). Urinary lipid profiling showed that levels of 5 other lipids significantly distinguished between urine of patients with Fabry disease (n=7) and heart disease patients with elevated urinary Gb3 (n=6). Sphingomyelin and Gb3 levels were abnormal in the left ventricular wall of patients with ischemic heart failure. Elevated levels of urinary Gb3 were independently associated with increased risk of death in the average follow‐up of 17 months (hazard ratio=1.59 for increase in Gb3 of 200, 95% CI=1.36 and 1.87, and P<0.0001). Conclusions In heart disease patients who do not have Fabry disease or GLA gene mutations, a higher level of urinary Gb3 is positively associated with near‐term mortality. The elevation of urinary Gb3 and that of other lipids suggests that heart disease is associated with multiorgan lipid abnormalities. Clinical Trial Registration URL: clinicaltrials.gov. Unique Identifier: NCT01019629. PMID:24496231

  6. Novel Fabry-Perot fiber optic sensor with multiple applications

    NASA Astrophysics Data System (ADS)

    Chen, Xiaopei; Shen, Fabin; Wang, Anbo; Wang, Zhuang; Zhang, Yan

    2004-12-01

    A novel Intrinsic Fabry-Perot fiber-optic sensor is presented in this paper. The sensors were made through two simple steps: wet chemical etch and fusion splice. Micro air-gaps were generated inside the fibers and functioned as reflective mirrors. This procedure not only provides a simple and cost effective technology for fabricating intrinsic Fabry-Perot Interferometric (IFPI) fiber sensors, but also provides two possible IFPI structures. Both of the fiber cavity between the air-gaps or the air-gap and cleaved fiber end can be used as sensing elements. With these two structures, this sensor can be used to measure the temperature, strain, pressure, refractive index of chemicals and the thin film thickness by itself. Multi-point measurements can also be achieved by multiplexing. Furthermore, it also can be multiplexed with other sensors such as Long Period Gratings (LPG) to provide compensations for other perturbation sensing. Theoretical and experimental studies of two sensor structures are described. Experimental results show that high resolution and high sensitivity can be obtained with appropriate signal processing.

  7. The use of pressure controlled Fabry-Pérot interferometer with linear scanning of data for Brillouin-type experiments

    NASA Astrophysics Data System (ADS)

    Błachowicz, Tomasz

    2000-08-01

    The article presents results from work with Fabry-Pérot interferometers in Brillouin laser light scattering experiments, where optical signals of very low level intensity are observed. The information presented here can be useful in other types of optical experiments where scanning in the Fabry-Pérot interferometer spectral range has to be used. In such situations the shape of spectral lines as well as their relative distances can be detected. The key to the solution presented here is the use of a silicon-membrane pressure sensor coupled to a pressure chamber. It makes it possible to view spectral lines equally spaced after nonlinear flow of air from a chamber where the Fabry-Pérot interferometer is placed. Linear scanning in the spectral range equal to a frequency of about 150 GHz is possible. The method can be applied to Fabry-Pérot's etalons, very frequently produced some years ago. Now it should find new fields of application, in a simple and cost effective way, in student laboratories as well as in other research institutions.

  8. Familial Dysautonomia (FD) Human Embryonic Stem Cell Derived PNS Neurons Reveal that Synaptic Vesicular and Neuronal Transport Genes Are Directly or Indirectly Affected by IKBKAP Downregulation

    PubMed Central

    Kantor, Gal; Cheishvili, David; Even, Aviel; Birger, Anastasya; Turetsky, Tikva; Gil, Yaniv; Even-Ram, Sharona; Aizenman, Einat; Bashir, Nibal; Maayan, Channa; Razin, Aharon; Reubinoff, Benjamim E.; Weil, Miguel

    2015-01-01

    A splicing mutation in the IKBKAP gene causes Familial Dysautonomia (FD), affecting the IKAP protein expression levels and proper development and function of the peripheral nervous system (PNS). Here we found new molecular insights for the IKAP role and the impact of the FD mutation in the human PNS lineage by using a novel and unique human embryonic stem cell (hESC) line homozygous to the FD mutation originated by pre implantation genetic diagnosis (PGD) analysis. We found that IKBKAP downregulation during PNS differentiation affects normal migration in FD-hESC derived neural crest cells (NCC) while at later stages the PNS neurons show reduced intracellular colocalization between vesicular proteins and IKAP. Comparative wide transcriptome analysis of FD and WT hESC-derived neurons together with the analysis of human brains from FD and WT 12 weeks old embryos and experimental validation of the results confirmed that synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKBKAP downregulation in FD neurons. Moreover we show that kinetin (a drug that corrects IKBKAP alternative splicing) promotes the recovery of IKAP expression and these IKAP functional associated genes identified in the study. Altogether, these results support the view that IKAP might be a vesicular like protein that might be involved in neuronal transport in hESC derived PNS neurons. This function seems to be mostly affected in FD-hESC derived PNS neurons probably reflecting some PNS neuronal dysfunction observed in FD. PMID:26437462

  9. 21 CFR 866.5540 - Immunoglobulin G (Fd fragment specific) immunological test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) immunological test system. 866.5540 Section 866.5540 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological Test Systems § 866.5540 Immunoglobulin G (Fd fragment specific) immunological test system. (a...

  10. SSR-CE/FD assessment of Guizhou approved sugarcane cultivars and regional materials

    USDA-ARS?s Scientific Manuscript database

    Twelve sugarcane genotypes (three cultivars and nine clones involved in regional tests) from Guizhou Province, China were analyzed using SSR-capillary electrophoresis/fluorescence detection (SSR-CE/FD) technology to construct the SSR fingerprints and assess the genetic diversity. A total of 131 DNA ...

  11. Deep Fabry-Perot imaging of NGC 6240: Kinematic evidence for merging galaxies

    NASA Technical Reports Server (NTRS)

    Hawthorn, J. Bland; Wilson, A. S.; Tully, R. B.

    1990-01-01

    The authors have observed the superluminous, infrared galaxy NGC 6240 (z = 0.025) at H alpha with the Hawaii Imaging Fabry-Perot Interferometer (HIFI - Bland and Tully 1989). During the past decade, observational evidence from all wavebands indicates that the unusual appearance of NGC 6240 has resulted from a collision between two gas-rich systems, a view which is supported by our spectrophotometric data. However, the origin of the enormous infrared luminosity (4 times 10(exp 11) solar luminosity) detected by the Infrared Astronomy Satellite (IRAS) remains highly controversial, where opinions differ on the relative roles of large-scale shocks, massive star formation or a buried 'active' nucleus. These mechanisms are discussed in the light of the author's Fabry-Perot observations.

  12. A theoretical multi-reflection method for analysis of optomechanical behavior of the Fabry-Perot cavity with moving boundary condition

    NASA Astrophysics Data System (ADS)

    Bahrampour, A. R.; Vahedi, M.; Abdi, M.; Ghobadi, R.; Golshani, M.; Tofighi, S.; Parvin, B.

    2011-09-01

    The opto-mechanical coupling and the generation of Stokes and anti-Stokes frequencies in the in-band and intra-band regimes of operation of the Fabry-Perot cavity with a moving mirror on the basis of multi-reflection method (MRM) are described by a unique theory. The frequency characteristic function of the Fabry-Perot filter is modified. By increasing the amplitude of mirror oscillation the Fabry-Perot bandwidth increases and normal mode splitting occurred. The conversion efficiencies of the Stokes and anti-Stokes frequencies versus the mechanical amplitude of oscillation have an optimum value. Also, the delay function corresponding to the radiation pressure is obtained.

  13. Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy.

    PubMed

    Warnock, David G; Thomas, Christie P; Vujkovac, Bojan; Campbell, Ruth C; Charrow, Joel; Laney, Dawn A; Jackson, Leslie L; Wilcox, William R; Wanner, Christoph

    2015-12-01

    Nephropathy is an important feature of classical Fabry disease, which results in alpha-galactosidase A deficiency and cellular globotriaosylceramide accumulation. We report the safety and efficacy of antiproteinuric therapy with ACE inhibitors or angiotensin II receptor blockers (ARBs) in a study of classical Fabry patients receiving recombinant agalsidase-beta therapy. The goal was maintenance of urine protein to creatinine ratio (UPCR) <0.5 g/g or a 50% reduction in baseline UPCR for 24 patients at eight study sites. The change in estimated glomerular filtration rate (eGFR) was assessed over 21 months of treatment. 18 out of 24 patients achieved the UPCR goal with eGFR slopes that were significantly better than six patients who did not achieve the UPCR goal (-3.6 (-4.8 to -1.1) versus -7.0 (-9.0 to -5.6) mL/min/1.73 m(2)/year, respectively, p=0.018). Despite achieving the UPCR goal, 67% (12/18 patients) still progressed with an eGFR slope <-2 mL/min/1.73 m(2)/year. Regression analysis showed that increased age at initiation of agalsidase-beta therapy was significantly associated with worsened kidney outcome. Hypotension and hyperkalaemia occurred in seven and eight patients, respectively, which required modification of antiproteinuric therapy but was not associated with serious adverse events. This study documents the effectiveness of agalsidase-beta (1 mg/kg/2 weeks) and antiproteinuric therapy with ACE inhibitors and/or ARB in patients with severe Fabry nephropathy. Patients had preservation of kidney function if agalsidase-beta treatment was initiated at a younger age, and UPCR maintained at or below 0.5 g/g with antiproteinuric therapy. NCT00446862. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  14. Solid, 3-mirror Fabry-Perot etalon.

    PubMed

    Stephen, Mark; Fahey, Molly; Miller, Ian

    2017-04-01

    We present modeling and performance of a solid, fused silica, 3-mirror Fabry-Perot-type etalon. 3-mirror etalons have been known for decades to have superior theoretical performance but for the first time we demonstrate an etalon with sufficient quality to realize the benefits of the more complex design. 3-mirror etalons have better passband shape and higher contrast ratio enabling significantly improved wavelength separation. We show the optical cavity design and construction of the new etalon and show >95% peak transmission, improved passband shape and 20 dB better out-of-band rejection than a similar 2-mirror etalon.

  15. Absolute-length determination of a long-baseline Fabry-Perot cavity by means of resonating modulation sidebands.

    PubMed

    Araya, A; Telada, S; Tochikubo, K; Taniguchi, S; Takahashi, R; Kawabe, K; Tatsumi, D; Yamazaki, T; Kawamura, S; Miyoki, S; Moriwaki, S; Musha, M; Nagano, S; Fujimoto, M K; Horikoshi, K; Mio, N; Naito, Y; Takamori, A; Yamamoto, K

    1999-05-01

    A new method has been demonstrated for absolute-length measurements of a long-baseline Fabry-Perot cavity by use of phase-modulated light. This method is based on determination of a free spectral range (FSR) of the cavity from the frequency difference between a carrier and phase-modulation sidebands, both of which resonate in the cavity. Sensitive response of the Fabry-Perot cavity near resonant frequencies ensures accurate determination of the FSR and thus of the absolute length of the cavity. This method was applied to a 300-m Fabry-Perot cavity of the TAMA gravitational wave detector that is being developed at the National Astronomical Observatory, Tokyo. With a modulation frequency of approximately 12 MHz, we successfully determined the absolute cavity length with resolution of 1 microm (3 x 10(-9) in strain) and observed local ground strain variations of 6 x 10(-8).

  16. Enhanced transmission in rolled-up hyperlenses utilizing Fabry-Pérot resonances

    NASA Astrophysics Data System (ADS)

    Kerbst, Jochen; Schwaiger, Stephan; Rottler, Andreas; Koitmäe, Aune; Bröll, Markus; Ehlermann, Jens; Stemmann, Andrea; Heyn, Christian; Heitmann, Detlef; Mendach, Stefan

    2011-11-01

    We experimentally demonstrate that the transmission through rolled-up metal/semiconductor hyperlenses can be enhanced at desired frequencies utilizing Fabry-Pérot resonances. By means of finite difference time domain simulations, we prove that hyperlensing occurs at frequencies of high transmission.

  17. In vivo sweat film layer thickness measured with Fourier-domain optical coherence tomography (FD-OCT)

    NASA Astrophysics Data System (ADS)

    Jonathan, Enock

    2008-06-01

    While human sweat secretion is accepted as a mechanism by which the body cools off, excessive sweating (hyperhidrosis) is now appreciated as a medical condition and the primary site for diagnosis is the palm of the hand. We propose sweat film layer thickness as a potential clinical diagnostic parameter when screening for excessive sweating. In this preliminary study we demonstrate the usefulness of Fourier-domain optical coherence tomography (FD-OCT) for measurement of sweat film thickness in vivo with micron-scale resolution on the hand of a human volunteer. FD-OCT has a superior image acquisition time and identification of active sweat glands, ducts and pores is also possible.

  18. Folded Fabry-Perot quasi-optical ring resonator diplexer Theory and experiment

    NASA Technical Reports Server (NTRS)

    Pickett, H. M.; Chiou, A. E. T.

    1983-01-01

    Performance of folded Fabry-Perot quasi-optical ring resonator diplexers with different geometries of reflecting surfaces is investigated both theoretically and experimentally. Design of optimum surface geometry for minimum diffraction, together with the figure of merit indicating improvement in performance, are given.

  19. A miniature extrinsic fiber Fabry-Perot pressure sensor based on fiber etching

    NASA Astrophysics Data System (ADS)

    Ge, Yixian; Wang, Ming; Yang, Chundi

    2009-10-01

    This paper presents a miniature fiber optic pressure sensor based on Fabry-Perot interference fabricated on the tip of a single mode (SM) fiber. The sensor measures only 125μm in diameter. A Fabry-Perot cavity and a thin silica diaphragm are fabricated by simple techniques involving only fusion splicing, cleaving, and wet chemical etching. Interference pattern of the sensor is analyzed and issues in sensor design are discussed. The overall chemical reaction of the fiber wet etching is specifically represented. Pressure testing system is carried out. By tracing a peak point in the interference spectrum, the gap length of the sensor can be demodulated. The sensor is made entirely of fused silica, whose structure has good stability, cabinet, simple for fabrication and low cost. It may also find uses in medical applications.

  20. A miniature extrinsic fiber Fabry-Perot pressure sensor based on fiber etching

    NASA Astrophysics Data System (ADS)

    Ge, Yixian; Zhou, Junping; Wang, Tingting

    2011-11-01

    A miniature fiber optic pressure sensor based on Fabry-Perot interference fabricated on the tip of a single mode (SM) fiber is presented. The sensor measures only 125μm in diameter. A Fabry-Perot cavity and a thin silica diaphragm are fabricated by simple techniques involving only cleaving, wet chemical etching and fusion splicing. Interference pattern of the sensor is analyzed and issues in sensor design are discussed. The overall chemical reaction of the fiber wet etching is specifically represented. Pressure testing system is carried out. By tracing a peak point in the interference spectrum, the gap length of the sensor can be demodulated. Experimental results show the sensor has a good linearity. The sensor is made entirely of fused silica, whose structure has good stability, cabinet, simple for fabrication and low cost.

  1. A hybrid demodulation method of fiber-optic Fabry-Perot pressure sensor

    NASA Astrophysics Data System (ADS)

    Yu, Le; Lang, Jianjun; Pan, Yong; Wu, Di; Zhang, Min

    2013-12-01

    The fiber-optic Fabry-Perot pressure sensors have been widely applied to measure pressure in oilfield. For multi-well it will take a long time (dozens of seconds) to demodulate downhole pressure values of all wells by using only one demodulation system and it will cost a lot when every well is equipped with one system, which heavily limits the sensor applied in oilfield. In present paper, a new hybrid demodulation method, combining the windowed nonequispaced discrete Fourier Transform (nDFT) method with segment search minimum mean square error estimation (MMSE) method, was developed, by which the demodulation time can be reduced to 200ms, i.e., measuring 10 channels/wells was less than 2s. Besides, experimental results showed the demodulation cavity length of the fiber-optic Fabry-Perot sensor has a maximum error of 0.5 nm and consequently pressure measurement accuracy can reach 0.4% F.S.

  2. Sensing Properties of a Fabry-Perot Dielectric Structure and Dimer Nanoparticles

    DOE PAGES

    Polemi, A.; Shuford, K. L.

    2012-01-01

    We investigate the use of a Fabry-Perot dielectric structure combined with differently shaped nanoparticles for Surface Enhanced Raman Scattering. In particular, we show how an ideal two-layer Fabry-Perot configuration enhances the local surface field of silver nanoparticles positioned on the surface of the structure. We develop the concept using disc dimers and then extend the discussion to bowtie nanoparticles. The structure is excited by a single emitter, which couples to the nanoparticles through the dielectric layers, producing a wide aperture field that can be used to excite multiple dimers. We show how an array of nanoparticles can be properly arrangedmore » in order to increase the total scattering signal generated from the structure. The layered geometry produces robust field properties in between nanoparticles, making the overall sensing characteristics less sensitive to the interparticle seperation distance and incident polarization.« less

  3. Electro-optic Modulation Using a DAST Single-crystal Film in a Fabry-Perot Cavity

    NASA Astrophysics Data System (ADS)

    Kutty, S. P.

    2005-03-01

    In this paper, we report a multiple-pass electro-optic modulator using a single- crystal film of 4'-dimethyamino-N-methyl-4-stilbazolium tosylate (DAST) placed inside a Fabry-Perot cavity. The single-crystal film was prepared using the modified shear method. Electro-optic modulation was achieved at 633 nm using field-induced birefringence in the cross polarized geometry including the Fabry-Perot cavity. The modulation due to the electro-optic effect was recorded as a function of phase while the phase was controlled by moving one of the mirrors in the cavity. The observed modulation was high (80 percent) for a low field (0.5V/micron) applied along the charge transfer axis on the film. Similar modulation using the Fabry-Perot cavity with a lower modulation depth was observed involving electroabsorption at 633 nm. Electroabsorption in the DAST film has been recently reported [1]. These are important results considering applications in photonics. [1] ``Electroabsorption in single-crystal film of a second-order optical material,'' R. K. Swamy, S. P. Kutty, J. Titus, S. Khatavkar, and M. Thakur, APL, Vol. 85, 4025, (2004).

  4. Use of gamma ray radiation to parallel the plates of a Fabry-Perot interferometer

    NASA Technical Reports Server (NTRS)

    Skinner, Wilbert R.; Hays, Paul B.; Anderson, Sally M.

    1987-01-01

    The use of gamma radiation to parallel the plates of a Fabry-Perot etalon is examined. The method for determining the etalon parallelism, and the procedure for irradiating the posts are described. Changes in effective gap for the etalon over the surface are utilized to measure the parallelism of the Fabry-Perot etalon. An example in which this technique is applied to an etalon of fused silica plates, which are 132 mm in diameter and coded with zinc sulfide and cryolite, with Zerodur spaces 2 cm in length. The effect of the irradiation of the posts on the thermal performance of the etalon is investigated.

  5. Diaphragm based long cavity Fabry-Perot fiber acoustic sensor using phase generated carrier

    NASA Astrophysics Data System (ADS)

    Liu, Bin; Lin, Jie; Liu, Huan; Ma, Yuan; Yan, Lei; Jin, Peng

    2017-01-01

    A diaphragm based long cavity Fabry-Perot interferometric fiber acoustic sensor is proposed. The Fabry-Perot cavity is formed by a flat fiber facet and an ultra-thin silver diaphragm with a 6-meter long fiber inserted in the cavity. A narrow-linewidth ring-cavity erbium-doped fiber laser is applied to demodulate the sensing signal in the phase generated carrier algorithm. Experimental results have demonstrated that the phase sensitivity is about -140 dB re 1 rad/μPa at 2 kHz. The noise equivalent acoustic signal level is 60.6 μPa/Hz1/2 and the dynamic range is 65.1 dB-SPL at 2 kHz. The sensor is suitable for sensing of weak acoustic signals.

  6. Application of thin dielectric films in low coherence fiber-optic Fabry-Pérot sensing interferometers: comparative study

    NASA Astrophysics Data System (ADS)

    Hirsch, Marzena; Wierzba, Paweł; Jedrzejewska-Szczerska, Małgorzata

    2016-11-01

    We examine the application of selected thin dielectric films, deposited by atomic layer deposition (ALD), in a low coherence fiber-optic Fabry-Pérot interferometer designed for sensing applications. Such films can be deposited on the end-face of a single mode optical fiber (SMF-28) in order to modify the reflectivity of the Fabry-Pérot cavity, to provide protection of the fibers from aggressive environments or to create a multi-cavity interferometric sensor. Spectral reflectance of films made from zinc oxide (ZnO), titanium dioxide (TiO2), aluminum oxide (Al2O3) and boron nitride (BN) was calculated for various thickness of the films and compared. The results show that the most promising materials for use in fiber-optic Fabry-Pérot interferometer are TiO2 and ZnO, although Al2O3 is also suitable for this application.

  7. A tunable Fabry-Perot filter (λ/18) based on all-dielectric metamaterials

    NASA Astrophysics Data System (ADS)

    Ao, Tianhong; Xu, Xiangdong; Gu, Yu; Jiang, Yadong; Li, Xinrong; Lian, Yuxiang; Wang, Fu

    2018-05-01

    A tunable Fabry-Perot filter composed of two separated all-dielectric metamaterials is proposed and numerically investigated. Different from metallic metamaterials reflectors, the all-dielectric metamaterials are constructed by high-permittivity TiO2 cylinder arrays and exhibit high reflection in a broadband of 2.49-3.08 THz. The high reflection is attributed to the first and second Mie resonances, by which the all-dielectric metamaterials can serve as reflectors in the Fabry-Perot filter. Both the results from phase analysis method and CST simulations reveal that the resonant frequency of the as-proposed filter appears at 2.78 THz, responding to a cavity with λ/18 wavelength thickness. Particularly, the resonant frequency can be adjusted by changing the cavity thickness. This work provides a feasible approach to design low-loss terahertz filters with a thin air cavity.

  8. Designating Additions to the Current List of Tropical Diseases in the Federal Food, Drug, and Cosmetic Act. Final order.

    PubMed

    2015-08-20

    The Federal Food, Drug, and Cosmetic Act (the FD&C Act) authorizes the Food and Drug Administration (FDA or Agency) to award priority review vouchers (PRVs) to tropical disease product applicants when the applications meet certain criteria. The FD&C Act lists the diseases that are considered to be tropical diseases for purposes of obtaining PRVs, and also provides for Agency expansion of that list to include other diseases that satisfy the definition of ``tropical diseases'' as set forth in the FD&C Act. FDA has determined that Chagas disease and neurocysticercosis satisfy this definition, and therefore is adding them to the list of designated tropical diseases whose product applications may result in the award of PRVs. Sponsors submitting certain applications for the treatment of Chagas disease and neurocysticercosis may be eligible to receive a PRV if such applications are approved by FDA.

  9. An RBF-FD closest point method for solving PDEs on surfaces

    NASA Astrophysics Data System (ADS)

    Petras, A.; Ling, L.; Ruuth, S. J.

    2018-10-01

    Partial differential equations (PDEs) on surfaces appear in many applications throughout the natural and applied sciences. The classical closest point method (Ruuth and Merriman (2008) [17]) is an embedding method for solving PDEs on surfaces using standard finite difference schemes. In this paper, we formulate an explicit closest point method using finite difference schemes derived from radial basis functions (RBF-FD). Unlike the orthogonal gradients method (Piret (2012) [22]), our proposed method uses RBF centers on regular grid nodes. This formulation not only reduces the computational cost but also avoids the ill-conditioning from point clustering on the surface and is more natural to couple with a grid based manifold evolution algorithm (Leung and Zhao (2009) [26]). When compared to the standard finite difference discretization of the closest point method, the proposed method requires a smaller computational domain surrounding the surface, resulting in a decrease in the number of sampling points on the surface. In addition, higher-order schemes can easily be constructed by increasing the number of points in the RBF-FD stencil. Applications to a variety of examples are provided to illustrate the numerical convergence of the method.

  10. The MPE/UCB far-infrared imaging Fabry-Perot interferometer (FIFI)

    NASA Technical Reports Server (NTRS)

    Poglitsch, A.; Geis, N.; Genzel, R.; Haggerty, M.; Beeman, J. W.

    1991-01-01

    FIFI, an imaging spectrometer with two or three Fabry-Perot interferometers in a series for astronomical observations in the FIR range, is described. Spectral resolutions of 2 km/s can be obtained with FIFI. Design considerations are discussed as well as optics, the detector array, the transimpedance amplifier array, signal demodulation, data acquisition, and instrument control.

  11. Optimal Design of an Hourglass in-Fiber Air Fabry-Perot Microcavity—Towards Spectral Characteristics and Strain Sensing Technology

    PubMed Central

    Wang, Qi; Yan, Dongchao; Cui, Binbin; Guo, Zixuan

    2017-01-01

    An hourglass in-fiber air microcavity Fabry-Perot interferometer is proposed in this paper, and its second reflecting surface of in-fiber microcavity is designed to be a concave reflector with the best curvature radius in order to improve the spectral characteristics. Experimental results proved that the extinction ratio of Fabry-Perot interferometer with cavity length of 60 μm and concave reflector radius of 60 μm is higher than for a rectangular Fabry-Perot interferometer with cavity length of 60 μm (14 dB: 11 dB). Theory and numerical simulation results show that the strain sensitivity of sensor can be improved by reducing the microcavity wall thickness and microcavity diameter, and when the in-fiber microcavity length is 40 μm, the microcavity wall thickness is 10 μm, the microcavity diameter is 20 μm, and the curvature radius of reflective surface II is 50 μm, the interference fringe contrast of is greater than 0.97, an Axial-pull sensitivity of 20.46 nm/N and resolution of 1 mN can be achieved in the range of 0–1 N axial tension. The results show that the performance of hourglass in-fiber microcavity interferometer is far superior to that of the traditional Fabry-Perot interferometer. PMID:28587221

  12. Matrine in association with FD-2 stimulates F508del-cystic fibrosis transmembrane conductance regulator activity in the presence of corrector VX809

    PubMed Central

    Marengo, Barbara; Speciale, Andrea; Senatore, Lisa; Garibaldi, Silvano; Musumeci, Francesca; Nieddu, Erika; Pollarolo, Benedetta; Pronzato, Maria Adelaide; Schenone, Silvia; Mazzei, Mauro; Domenicotti, Cinzia

    2017-01-01

    Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and the predominant mutation is termed Phe508del (F508del). Therapy for F508del-CFTR patients is based on the use of Orkambi®, a combination of VX809 and VX770. However, though Orkambi leads to an improvement in the lung function of patients, a progressive reduction in its efficacy has been observed. In order to overcome this effect, the aim of the present study was to investigate the role of matrine and the in-house compound FD-2 in increasing the action of VX809 and VX770. Fischer rat thyroid cells overexpressing F508del-CFTR were treated with matrine, VX809 (corrector) and/or with a number of potentiators (VX770, FD-1 and FD-2). The results demonstrated that matrine was able to stimulate CFTR activity and, in association with FD-2, increased the functionality of the channel in the presence of VX809. Based on these results, it may be hypothesized that FD-2 may be a novel and more effective potentiator compared with VX770. PMID:29039559

  13. Phase-demodulation error of a fiber-optic Fabry-Perot sensor with complex reflection coefficients.

    PubMed

    Kilpatrick, J M; MacPherson, W N; Barton, J S; Jones, J D

    2000-03-20

    The influence of reflector losses attracts little discussion in standard treatments of the Fabry-Perot interferometer yet may be an important factor contributing to errors in phase-stepped demodulation of fiber optic Fabry-Perot (FFP) sensors. We describe a general transfer function for FFP sensors with complex reflection coefficients and estimate systematic phase errors that arise when the asymmetry of the reflected fringe system is neglected, as is common in the literature. The measured asymmetric response of higher-finesse metal-dielectric FFP constructions corroborates a model that predicts systematic phase errors of 0.06 rad in three-step demodulation of a low-finesse FFP sensor (R = 0.05) with internal reflector losses of 25%.

  14. Chronology of Fabry-Perot Interferometer Fiber-Optic Sensors and Their Applications: A Review

    PubMed Central

    Islam, Md. Rajibul; Ali, Muhammad Mahmood; Lai, Man-Hong; Lim, Kok-Sing; Ahmad, Harith

    2014-01-01

    Optical fibers have been involved in the area of sensing applications for more than four decades. Moreover, interferometric optical fiber sensors have attracted broad interest for their prospective applications in sensing temperature, refractive index, strain measurement, pressure, acoustic wave, vibration, magnetic field, and voltage. During this time, numerous types of interferometers have been developed such as Fabry-Perot, Michelson, Mach-Zehnder, Sagnac Fiber, and Common-path interferometers. Fabry-Perot interferometer (FPI) fiber-optic sensors have been extensively investigated for their exceedingly effective, simple fabrication as well as low cost aspects. In this study, a wide variety of FPI sensors are reviewed in terms of fabrication methods, principle of operation and their sensing applications. The chronology of the development of FPI sensors and their implementation in various applications are discussed. PMID:24763250

  15. Optical power equalization for upstream traffic with injection-locked Fabry-Perot lasers in TDM-PON

    NASA Astrophysics Data System (ADS)

    Huang, Ting-Tsan; Sheu, Lih-Gen; Chi, Sien

    2010-10-01

    An optical power equalization of upstream traffic in time-division-multiplexed passive optical network (TDM-PON) based on injection-locked Fabry-Perot lasers has been experimentally investigated. The upstream transmitters with stable spectrum are achieved by using an external injection light source in the optical line terminal (OLT). The different upstream powers can be equalized by injection locking a Fabry-Perot laser diode (FP-LD) biased below threshold current in OLT. The dynamic upstream power range from - 8.5 to - 19.5 db m is reduced to a 1.6 dB maximal power variation, when the uplink signal is directly modulated at 1.25 Gb/s.

  16. Composite material embedded fiber-optic Fabry-Perot strain rosette

    NASA Astrophysics Data System (ADS)

    Valis, Thomas; Hogg, Dayle; Measures, Raymond M.

    1990-12-01

    A fiber-optic strain rosette is embedded in Kevlar/epoxy. The individual arms of the rosette are fiber Fabry-Perot interferometers operated in reflection-mode with gauge (i.e., cavity) lengths of approximately 5 mm. Procedures for manufacturing the cavities, and bending the fibers, to form a strain rosette are described. Experimental results showing 2D interlaminar strain-tensor measurement are presented. The sensor is also tested as a surface adhered device.

  17. Fabry-Perot interferometer development for rocket engine plume spectroscopy

    NASA Astrophysics Data System (ADS)

    Bickford, R. L.; Madzsar, G.

    1990-07-01

    This paper describes a new rugged high-resolution Fabry-Perot interferometer (FPI) designed for rocket engine plume spectroscopy, which is capable of detecting spectral signatures of eroding engine components during rocket engine tests and/or flight operations. The FPI system will make it possible to predict and to respond to the incipient rocket engine failures and to indicate the presence of rocket components degradation. The design diagram of the FPI spectrometer is presented.

  18. Fabry-Perot interferometer development for rocket engine plume spectroscopy

    NASA Technical Reports Server (NTRS)

    Bickford, R. L.; Madzsar, G.

    1990-01-01

    This paper describes a new rugged high-resolution Fabry-Perot interferometer (FPI) designed for rocket engine plume spectroscopy, which is capable of detecting spectral signatures of eroding engine components during rocket engine tests and/or flight operations. The FPI system will make it possible to predict and to respond to the incipient rocket engine failures and to indicate the presence of rocket components degradation. The design diagram of the FPI spectrometer is presented.

  19. An electronically tunable, first-order Fabry-Perot infrared filter

    NASA Astrophysics Data System (ADS)

    Knudtson, J. T.; Levy, D. S.; Herr, K. C.

    1995-04-01

    A tunable infrared filter capable of scanning from 8.2 to 12.8 micrometers has been designed, constructed and tested. It is a first order Fabry Perot interferometer with piezoelectrically driven cavity spacing. Multilayer dielectric coatings for the partially transmitting mirrors were designed to minimize the wavelength dependent phase change produced by reflection. The transmission bandwidth ranged from 2.8 to 4.0% across the tuning range. Continuous scanning at 20 Hz rates was demonstrated.

  20. Integration of miniature Fabry-Perot fiber optic sensor with FBG for the measurement of temperature and strain

    NASA Astrophysics Data System (ADS)

    Li, L.; Tong, X. L.; Zhou, C. M.; Wen, H. Q.; Lv, D. J.; Ling, K.; Wen, C. S.

    2011-03-01

    A sensor has been fabricated by the integration of a fiber Bragg gating sensor (FBGs) with a fiber Fabry-Perot (F-P) sensor fabricated by etching method. In the integrated sensor, the FBG was used to measure temperature, while the fiber Fabry-Perot interferometer sensor (FFPIs) was used for strain measurement. Wavelength decoding for FBG and peak tracking for FFPI was employed for demodulation, respectively. The result showed that the temperature and strain sensitivity for the integrated sensor is ~ 2.7 pm/ μɛand ~ 9.3 pm/°C, respectively.

  1. Low-Cost, Single-Frequency Sources for Spectroscopy using Conventional Fabry-Perot Diode Lasers

    NASA Technical Reports Server (NTRS)

    Duerksen, Gary L.; Krainak, Michael A.

    1999-01-01

    Commercial (uncoated) Fabry-Perot laser diodes are converted to single-frequency spectroscopy sources by passively locking the laser frequency to the band edge of a fiber Bragg grating, which phase-locks the laser oscillations through self-injection seeding.

  2. Low-Cost, Single-Frequency Sources for Spectroscopy Using Conventional Fabry-Perot Diode Lasers

    NASA Technical Reports Server (NTRS)

    Krainak, Michael A.; Duerksen, Gary L.

    1999-01-01

    Commercial (uncoated) Fabry-Perot laser diodes are converted to single-frequency spectroscopy sources by passively locking the laser frequency to the band edge of a fiber Bragg grating, which phase-locks the laser oscillations through self-injection seeding.

  3. On-Chip High-Finesse Fabry-Perot Microcavities for Optical Sensing and Quantum Information.

    PubMed

    Bitarafan, Mohammad H; DeCorby, Ray G

    2017-07-31

    For applications in sensing and cavity-based quantum computing and metrology, open-access Fabry-Perot cavities-with an air or vacuum gap between a pair of high reflectance mirrors-offer important advantages compared to other types of microcavities. For example, they are inherently tunable using MEMS-based actuation strategies, and they enable atomic emitters or target analytes to be located at high field regions of the optical mode. Integration of curved-mirror Fabry-Perot cavities on chips containing electronic, optoelectronic, and optomechanical elements is a topic of emerging importance. Micro-fabrication techniques can be used to create mirrors with small radius-of-curvature, which is a prerequisite for cavities to support stable, small-volume modes. We review recent progress towards chip-based implementation of such cavities, and highlight their potential to address applications in sensing and cavity quantum electrodynamics.

  4. On-Chip High-Finesse Fabry-Perot Microcavities for Optical Sensing and Quantum Information

    PubMed Central

    Bitarafan, Mohammad H.; DeCorby, Ray G.

    2017-01-01

    For applications in sensing and cavity-based quantum computing and metrology, open-access Fabry-Perot cavities—with an air or vacuum gap between a pair of high reflectance mirrors—offer important advantages compared to other types of microcavities. For example, they are inherently tunable using MEMS-based actuation strategies, and they enable atomic emitters or target analytes to be located at high field regions of the optical mode. Integration of curved-mirror Fabry-Perot cavities on chips containing electronic, optoelectronic, and optomechanical elements is a topic of emerging importance. Micro-fabrication techniques can be used to create mirrors with small radius-of-curvature, which is a prerequisite for cavities to support stable, small-volume modes. We review recent progress towards chip-based implementation of such cavities, and highlight their potential to address applications in sensing and cavity quantum electrodynamics. PMID:28758967

  5. Intraoperative Diagnosis of Anderson-Fabry Disease in Patients With Obstructive Hypertrophic Cardiomyopathy Undergoing Surgical Myectomy.

    PubMed

    Cecchi, Franco; Iascone, Maria; Maurizi, Niccolò; Pezzoli, Laura; Binaco, Irene; Biagini, Elena; Fibbi, Maria Laura; Olivotto, Iacopo; Pieruzzi, Federico; Fruntelata, Ana; Dorobantu, Lucian; Rapezzi, Claudio; Ferrazzi, Paolo

    2017-10-01

    Diagnostic screening for Anderson-Fabry cardiomyopathy (AFC) is performed in the presence of specific clinical red flags in patients with hypertrophic cardiomyopathy (HCM) older than 25 years. However, left ventricular outflow tract obstruction (LVOTO) has been traditionally considered an exclusion criteria for AFC. To examine a series of patients diagnosed with HCM and severe basal LVOTO undergoing myectomy in whom the diagnosis of AFC was suspected by the cardiac surgeon intraoperatively and confirmed by histological and genetic examinations. This retrospective analysis of patients undergoing surgical septal reduction strategies was conducted in 3 European tertiary referral centers for HCM from July 2013 to December 2016. Patients with a clinical diagnosis of obstructive HCM referred for surgical management of LVOTO were observed for at least 18 months after the procedure (mean [SD] follow-up, 33 [14] months). Etiology of patients with HCM who underwent surgical myectomy. From 2013, 235 consecutive patients with a clinical diagnosis of HCM underwent septal myectomy. The cardiac surgeon suspected a storage disease in 3 patients (1.3%) while inspecting their heart samples extracted from myectomy. The mean (SD) age at diagnosis for these 3 patients was 42 (4) years; all were male. None of the 3 patients presented with extracardiac features suggestive of AFC. All patients showed asymmetrical left ventricular hypertrophy, with maximal left ventricular thickness in the basal septum (19-31 mm), severe basal LVOTO (70-120 mm Hg), and left atrial dilatation (44-57 mm). Only 1 patient presented with late gadolinium enhancement on cardiovascular magnetic resonance at the right ventricle insertion site. The mean (SD) age at surgical procedure was 63 (5) years. On tactile sensation, the surgeon felt a spongy consistency of the surgical samples, different from the usual stony-elastic consistency typical of classic HCM, and this prompted histological examinations. Histology

  6. Microwave radiometric aircraft observations of the Fabry-Perot interference fringes of an ice-water system

    NASA Technical Reports Server (NTRS)

    Harrington, R. F.; Swift, C. T.; Fedors, J. C.

    1980-01-01

    Airborne stepped-frequency microwave radiometer (SFMR) observations of the Fabry-Perot interference fringes of ice-water systems are discussed. The microwave emissivity at normal incidence of a smooth layered dielectric medium over a semi-infinite dielectric medium is examined for the case of ice over water as a function of ice thickness and attenuation coefficient, and the presence of quarter-wavelength oscillations in emissivity as the ice thickness and frequency are varied is pointed out. Experimental observations of pronounced quarter-wavelength oscillations in radiometric brightness temperature due to the Fabry-Perot interference fringes over smooth sea ice and lake ice varying in roughness as the radiometer frequencies were scanned are then presented.

  7. A young woman with visual hallucinations, delusions of persecution and a history of performing arson with possible three-generation Fahr disease.

    PubMed

    Shirahama, M; Akiyoshi, J; Ishitobi, Y; Tanaka, Y; Tsuru, J; Matsushita, H; Hanada, H; Kodama, K

    2010-01-01

    Fahr disease (FD) is a rare neurological and psychiatric disorder. The disease is classified by intracranial calcification of the basal ganglia with the globus pallidus region being particularly affected. We examined a young woman with visual hallucinations, delusions of persecution and a history of performing arson with possible third-generation FD. Case report of third-generation FD. A 23-year-old woman was arrested for two arsons: i) The patient exhibited progressive psychotic symptoms, including visual hallucinations, delusion of injury, irritability, lability of mood, mental retardation and visual disorders and ii) Computed tomography (CT) imaging demonstrated bilateral calcifications of the basal ganglia (globus pallidus) in the patient, her mother and her grandmother. We found a family with a three-generation history of FD who exhibited calcification in the brain and mental retardation. Compared to her mother, the patient described here displayed anticipation of disease onset.

  8. Phase-sensitive reflection technique for characterization of a fabry-perot interferometer.

    PubMed

    Slagmolen, B J; Gray, M B; Baigent, K G; McClelland, D E

    2000-07-20

    Using a radio frequency coherent modulation and demodulation technique, we explicitly measure both the amplitude and the phase response of Fabry-Perot interferometers in reflection. This allows us to differentiate clearly between overcoupled and undercoupled cavities and allows a detailed measurement of the full width at half-maximum, the free spectral range, and the finesse of the cavities.

  9. Metrology of semiconductor structures using novel Fabry Perot fringe stretching system

    NASA Astrophysics Data System (ADS)

    Walecki, Wojtek J.; Pravdivtsev, Alexander

    2017-08-01

    We describe patent pending fiber optic apparatus for measurements of thicknesses and distance employing low resolution spectrometer and etalon. The application of an additional known reference etalon "stretches fringes" and allows us to use Fabry Perot interference to investigate thick samples and large distances which would not be possible when using the low resolution spectrometer alone.

  10. First results from SAM-FP: Fabry-Perot observations with ground-layer adaptive optics - the structure and kinematics of the core of 30 Doradus

    NASA Astrophysics Data System (ADS)

    Mendes de Oliveira, C.; Amram, P.; Quint, Bruno C.; Torres-Flores, S.; Barbá, R.; Andrade, D.

    2017-08-01

    The aim of this paper is to present the first data set obtained with SOAR Adaptive Module-Fabry-Parot (SAM-FP), a Fabry-Perot instrument mounted inside the SOAR telescope Adaptive-Optics Module. This is the only existing imaging Fabry-Perot interferometer using laser-assisted ground-layer adaptive optics. SAM-FP was used to observe the ionized gas, traced by Hα, in the centre of the 30 Doradus starburst (the Tarantula Nebula) in the Large Magellanic Cloud, with high spatial (˜0.6 arcsec, or 0.15 pc) and spectral (R ≃ 11 200) resolution. Radial velocity, velocity dispersion and monochromatic maps were derived. The region displays a mix of narrow, σ ˜ 20 km s-1 profiles and multiple broader profiles with σ ˜ 70-80 km s-1, indicating the complex nature of the nebula kinematics. A comparison with previously obtained VLT/FLAMES spectroscopy demonstrates that the data agree well in the regions of overlap, but the Fabry-Perot data are superior in spatial coverage. A preliminary analysis of the observations finds a new expanding bubble south of R136, with a projected radius of r = 5.6 pc and an expansion velocity of 29 ± 4 km s-1. In addition, the first-time detailed kinematic maps derived here for several complexes and filaments of 30 Doradus allow identification of kinematically independent structures. These data exemplify the power of the combination of a high-order Fabry-Perot with a wide-field imager (3 × 3 arcmin2 GLAO-corrected field of view) for high-resolution spatial and spectral studies. In particular, SAM-FP data cubes are highly advantageous over multifibre or long-slit data sets for nebula structure studies and to search for small-scale bubbles, given their greatly improved spatial coverage. For reference, this paper also presents two appendices with detailed descriptions of the usage of Fabry-Perot devices, including formulae and explanations for understanding Fabry-Perot observations.

  11. Fabry-Perot confocal resonator optical associative memory

    NASA Astrophysics Data System (ADS)

    Burns, Thomas J.; Rogers, Steven K.; Vogel, George A.

    1993-03-01

    A unique optical associative memory architecture is presented that combines the optical processing environment of a Fabry-Perot confocal resonator with the dynamic storage and recall properties of volume holograms. The confocal resonator reduces the size and complexity of previous associative memory architectures by folding a large number of discrete optical components into an integrated, compact optical processing environment. Experimental results demonstrate the system is capable of recalling a complete object from memory when presented with partial information about the object. A Fourier optics model of the system's operation shows it implements a spatially continuous version of a discrete, binary Hopfield neural network associative memory.

  12. Fabry-Perot enhanced Faraday rotation in graphene.

    PubMed

    Ubrig, Nicolas; Crassee, Iris; Levallois, Julien; Nedoliuk, Ievgeniia O; Fromm, Felix; Kaiser, Michl; Seyller, Thomas; Kuzmenko, Alexey B

    2013-10-21

    We demonstrate that giant Faraday rotation in graphene in the terahertz range due to the cyclotron resonance is further increased by constructive Fabry-Perot interference in the supporting substrate. Simultaneously, an enhanced total transmission is achieved, making this effect doubly advantageous for graphene-based magneto-optical applications. As an example, we present far-infrared spectra of epitaxial multilayer graphene grown on the C-face of 6H-SiC, where the interference fringes are spectrally resolved and a Faraday rotation up to 0.15 radians (9°) is attained. Further, we discuss and compare other ways to increase the Faraday rotation using the principle of an optical cavity.

  13. A Review of Fabry Disease.

    PubMed

    Cinats, A; Heck, E

    2018-05-01

    The class of medications known as Janus kinase inhibitors block cytokine-mediated signaling via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which plays an important role in immunoregulation and normal cell growth. This class includes the drugs tofacitinib, approved for the treatment of rheumatoid arthritis, and ruxolitinib, approved for the treatment of myelofibrosis and polycythemia rubra vera. The most common adverse events (AEs) reported in patients taking tofacitinib are infections, whereas the most common AEs in patients taking ruxolitinib are anemia and thrombocytopenia. Both first and second generation Janus kinase inhibitors have become promising treatment modalities for dermatologic conditions such as psoriasis, atopic dermatitis, alopecia areata, vilitigo, dermatomyositis, and graft-versus-host disease. Future promising areas of investigation include treatment of cutaneous lupus, cutaneous T-cell lymphoma, melanoma, allergic contact dermatitis, and lichen planus.

  14. A novel fiber optic Fabry-Perot structure with a micrometric diameter tip

    NASA Astrophysics Data System (ADS)

    Wang, Xingwei; Xu, Juncheng; Wang, Zhuang; Cooper, Kristie L.; Wang, Anbo

    2006-08-01

    This paper presents a novel fiber optic Fabry-Perot (FP) structure with a micrometric diameter tip. The fabrication of micro scale probes has become essential in intracellular surgery, in cell sensing, manipulation, and injection. It is of great importance in many fields, such as genetics, pathology, criminology, pharmacogenetics, and food safety. With such a tiny protrusion, the sensor can be inserted into micron size cells, say, for DNA analysis. With the FP cavity inside the fiber, the change of optical path difference (OPD) caused by the environment can be demodulated. In addition, the structure is intrinsically capable of temperature compensation. What's more, it is simple, cost-efficient, and compact. Last but not the least, the structure shows promise for nanometric protrusion. Once this goal is achieved, the sensor can be inserted into most cells. The sensor could pave the way for faster, more accurate medical diagnostic tests for countless conditions and may ultimately save lives by allowing earlier disease detection and intervention.

  15. A fiber-Bragg-grating sensor interrogation system using in-fiber Fabry-Pérot interferometer

    NASA Astrophysics Data System (ADS)

    Wang, Ting-ting; Wang, Ming

    2011-11-01

    A fiber-Bragg-grating sensor interrogation system using a in-fiber Fabry-Pérot interferometer (IFFPI) is presented. The IFFPI was formed by splicing together a conventional single-mode fiber and a photonic crystal fiber with simple arcdischarge technique. The ellipsoidal air-cavity between the two fibers forms Fabry-Pérot cavity. The diffraction loss can be very low due to the focusing of reentrant and very short cavity length, thus resulting in high visibility and long period. The IFFPI is used as the filter component of the interrogation system. The resolving wavelength can achieve 2pm by using an Er-doped ring FBG laser in the experimental system. The advantages of this system are an all-fiber design, temperature insensitivity, quasistatic and dynamic operation, potential high speed and large range demodulation.

  16. Effects of Electroacupuncture on Interstitial Cells of Cajal (ICC) Ultrastructure and Connexin 43 Protein Expression in the Gastrointestinal Tract of Functional Dyspepsia (FD) Rats

    PubMed Central

    Zhang, Guoshan; Xie, Shen; Hu, Wei; Liu, Yuer; Liu, Mailan; Liu, Mi; Chang, Xiaorong

    2016-01-01

    Background Gastrointestinal motility disorder is the main clinical manifestation in functional dyspepsia (FD) patients. Electroacupuncture is effective in improving gastrointestinal motility disorder in FD; however, the underlying mechanism remains unclear. It has been demonstrated that interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal tract, and the pacemaker potential is transmitted to nearby cells through gap junctions between ICC or ICC and the smooth muscle. Therefore, this study aimed to assess the effects of electroacupuncture on ICC ultrastructure and expression of the gap junction protein connexin 43 (Cx43) in FD rats. Material/Methods The animals were randomized into 3 groups: control, model, and electroacupuncture. Electroacupuncture was applied at Zusanli (ST36) in the electroacupuncture group daily for 10 days, while no electroacupuncture was applied to model group animals. Results Ultrastructure of ICC recovered normally in gastric antrum and small intestine specimens was improved, with Cx43 expression levels in these tissues significantly increased in the electroacupuncture group compared with the model group. Conclusions These findings indicated that electroacupuncture is effective in alleviating ICC damage and reduces Cx43 levels in FD rats, and suggest that ICC and Cx43 are involved in electroacupuncture treatment in rats with FD to improve gastrointestinal motility disorders. PMID:27297942

  17. Effects of Electroacupuncture on Interstitial Cells of Cajal (ICC) Ultrastructure and Connexin 43 Protein Expression in the Gastrointestinal Tract of Functional Dyspepsia (FD) Rats.

    PubMed

    Zhang, Guoshan; Xie, Shen; Hu, Wei; Liu, Yuer; Liu, Mailan; Liu, Mi; Chang, Xiaorong

    2016-06-14

    BACKGROUND Gastrointestinal motility disorder is the main clinical manifestation in functional dyspepsia (FD) patients. Electroacupuncture is effective in improving gastrointestinal motility disorder in FD; however, the underlying mechanism remains unclear. It has been demonstrated that interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal tract, and the pacemaker potential is transmitted to nearby cells through gap junctions between ICC or ICC and the smooth muscle. Therefore, this study aimed to assess the effects of electroacupuncture on ICC ultrastructure and expression of the gap junction protein connexin 43 (Cx43) in FD rats. MATERIAL AND METHODS The animals were randomized into 3 groups: control, model, and electroacupuncture. Electroacupuncture was applied at Zusanli (ST36) in the electroacupuncture group daily for 10 days, while no electroacupuncture was applied to model group animals. RESULTS Ultrastructure of ICC recovered normally in gastric antrum and small intestine specimens was improved, with Cx43 expression levels in these tissues significantly increased in the electroacupuncture group compared with the model group. CONCLUSIONS These findings indicated that electroacupuncture is effective in alleviating ICC damage and reduces Cx43 levels in FD rats, and suggest that ICC and Cx43 are involved in electroacupuncture treatment in rats with FD to improve gastrointestinal motility disorders.

  18. The low coherence Fabry-Pérot interferometer with diamond and ZnO layers

    NASA Astrophysics Data System (ADS)

    Majchrowicz, D.; Den, W.; Hirsch, M.

    2016-09-01

    The authors present a fiber-optic Fabry-Pérot interferometer built with the application of diamond and zinc oxide (ZnO) thin layers. Thin ZnO films were deposited on the tip of a standard telecommunication single-mode optical fiber (SMF- 28) while the diamond layer was grown on the plate of silicon substrate. Investigated ZnO layers were fabricated by atomic layer deposition (ALD) and the diamond films were deposited using Microwave Plasma Enhanced Chemical Vapor Deposition (μPE CVD) system. Different thickness of layers was examined. The measurements were performed for the fiber-optic Fabry-Pérot interferometer working in the reflective mode. Spectra were registered for various thicknesses of ZnO layer and various length of the air cavity. As a light source, two superluminescent diodes (SLD) with central wavelength of 1300 nm and 1550 nm were used in measurement set-up.

  19. Weakly modulated silicon-dioxide-cladding gratings for silicon waveguide Fabry-Pérot cavities.

    PubMed

    Grote, Richard R; Driscoll, Jeffrey B; Biris, Claudiu G; Panoiu, Nicolae C; Osgood, Richard M

    2011-12-19

    We show by theory and experiment that silicon-dioxide-cladding gratings for Fabry-Pérot cavities on silicon-on-insulator channel ("wire") waveguides provide a low-refractive-index perturbation, which is required for several important integrated photonics components. The underlying refractive index perturbation of these gratings is significantly weaker than that of analogous silicon gratings, leading to finer control of the coupling coefficient κ. Our Fabry-Pérot cavities are designed using the transfer-matrix method (TMM) in conjunction with the finite element method (FEM) for calculating the effective index of each waveguide section. Device parameters such as coupling coefficient, κ, Bragg mirror stop band, Bragg mirror reflectivity, and quality factor Q are examined via TMM modeling. Devices are fabricated with representative values of distributed Bragg reflector lengths, cavity lengths, and propagation losses. The measured transmission spectra show excellent agreement with the FEM/TMM calculations.

  20. Perfect Undetectable Acoustic Device from Fabry-Pérot Resonances

    NASA Astrophysics Data System (ADS)

    Chen, Huanyang; Zhou, Yangyang; Zhou, Mengying; Xu, Lin; Liu, Qing Huo

    2018-02-01

    Transformation acoustics is a method to design novel acoustic devices, while the complexity of the material parameters hinders its progress. In this paper, we analytically present a three-dimensional perfect undetectable acoustic device from Fabry-Pérot resonances and confirm its functionality from Mie theory. Such a mechanism goes beyond the traditional transformation acoustics. In addition, such a reduced version can be realized by holey-structured metamaterials. Our theory paves a way to the implementation of three-dimensional transformation acoustic devices.