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

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.

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.

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

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.
.

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

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.

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

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.

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

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.

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

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

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.

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.

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.

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

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.

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

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.

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

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

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

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.

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/

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

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.

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.

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.

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

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.

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

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.

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.

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

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.

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

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

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

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.

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.

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.

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

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).

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.

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

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.

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.

[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.

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.

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.

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.

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.

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.

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

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.

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.

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

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.

[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.

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

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.

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

Single and tandem Fabry-Perot etalons as solar background filters for lidar.

PubMed

McKay, J A

1999-09-20

Atmospheric lidar is difficult in daylight because of sunlight scattered into the receiver field of view. In this research methods for the design and performance analysis of Fabry-Perot etalons as solar background filters are presented. The factor by which the signal to background ratio is enhanced is defined as a measure of the performance of the etalon as a filter. Equations for evaluating this parameter are presented for single-, double-, and triple-etalon filter systems. The role of reflective coupling between etalons is examined and shown to substantially reduce the contributions of the second and third etalons to the filter performance. Attenuators placed between the etalons can improve the filter performance, at modest cost to the signal transmittance. The principal parameter governing the performance of the etalon filters is the etalon defect finesse. Practical limitations on etalon plate smoothness and parallelism cause the defect finesse to be relatively low, especially in the ultraviolet, and this sets upper limits to the capability of tandem etalon filters to suppress the solar background at tolerable cost to the signal.

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.

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.

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.

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/

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

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.

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.

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.

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.

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.

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

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).

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

[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.

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.

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.

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.

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

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.

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.

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.

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.

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

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.

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.

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

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.

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.

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.

[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.

[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.

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.

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.

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

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.

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.

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

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.

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.

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.

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

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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

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

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.

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.

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

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.

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.

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.

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.

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

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.

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

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.

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

[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.

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.

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

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.

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

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.

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.

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.

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

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

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.

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.

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.

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/.

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.

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.

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).

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.

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.

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.

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.

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

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.

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.

[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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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.

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.

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

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

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.

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.

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

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.

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.

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

Tunable Fabry-Perot etalon-based long-wavelength infrared imaging spectroradiometer.

PubMed

Marinelli, W J; Gittins, C M; Gelb, A H; Green, B D

1999-04-20

Imaging spectrometry enables passive, stand-off detection and analysis of the chemical composition of gas plumes and surfaces over wide geographic areas. We describe the use of a long-wavelength infrared imaging spectroradiometer, comprised of a low-order tunable Fabry-Perot etalon coupled to a HgCdTe detector array, to perform multispectral detection of chemical vapor plumes. The tunable Fabry-Perot etalon used in this research provides coverage of the 9.5-14-microm spectral region with a resolution of 7-9 cm(-1). The etalon-based imaging system provides the opportunity to image a scene at only those wavelengths needed for chemical species identification and quantification and thereby minimize the data volume necessary for selective species detection. We present initial results using a brassboard imaging system for stand-off detection and quantification of chemical vapor plumes against near-ambient-temperature backgrounds. These data show detection limits of 22 parts per million by volume times meter (ppmv x m) and 0.6 ppmv x m for dimethyl methyphosphonate and SF6, respectively, for a gas/background DeltaT of 6 K. The system noise-equivalent spectral radiance is approximately 2 microW cm(-2) sr(-1) microm(-1). Model calculations are presented comparing the measured sensitivity of the sensor to the anticipated signal levels for two chemical release scenarios.

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

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.

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.

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].

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.

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.

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.

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.

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

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.

Application of the CCD Fabry-Perot Annular Summing Technique to Thermospheric O(1)D.

NASA Astrophysics Data System (ADS)

Coakley, Monica Marie

1995-01-01

This work will detail the verification of the advantages of the Fabry-Perot charge coupled device (CCD) annular summing technique, the development of the technique for analysis of daysky spectra, and the implications of the resulting spectra for neutral temperature and wind measurements in the daysky thermosphere. The daysky spectral feature of interest is the bright (1 kilo-Rayleigh) thermospheric (OI) emission at 6300 A which had been observed in the nightsky in order to determine winds and temperatures in the vicinity of the altitude of 250 km. In the daysky, the emission line sits on top of a bright Rayleigh scattered continuum background which significantly complicates the observation. With a triple etalon Fabry-Perot spectrometer, the continuum background can be reduced while maintaining high throughput and high resolution. The inclusion of a CCD camera results in significant savings in integration time over the two more standard scanning photomultiplier systems that have made the same wind and temperature measurements in the past. A comparable CCD system can experience an order of magnitude savings in integration time over a PMT system. Laboratory and field tests which address the advantages and limitations of both the Fabry-Perot CCD annular summing technique and the daysky CCD imaging are included in Chap. 2 and Chap. 3. With a sufficiently large throughput associated with the spectrometer and a CCD detector, rapid observations (~4 minute integrations) can be made. Extraction of the line width and line center from the daysky near-continuum background is complicated compared to the nightsky case, but possible. Methods of fitting the line are included in Chap. 4. The daysky O ^1D temperatures are consistent with a lower average emission height than predicted by models. The data and models are discussed in Chap. 5. Although some discrepancies exist between resulting temperatures and models, the observations indicate the potential for other direct measurements

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

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

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.

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.

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

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.

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;

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

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.

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.

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.

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.

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

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.

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.

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.

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.

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

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.

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

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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...

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)

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.

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.

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.

Reduction of time-resolved space-based CCD photometry developed for MOST Fabry Imaging data*

NASA Astrophysics Data System (ADS)

Reegen, P.; Kallinger, T.; Frast, D.; Gruberbauer, M.; Huber, D.; Matthews, J. M.; Punz, D.; Schraml, S.; Weiss, W. W.; Kuschnig, R.; Moffat, A. F. J.; Walker, G. A. H.; Guenther, D. B.; Rucinski, S. M.; Sasselov, D.

2006-04-01

The MOST (Microvariability and Oscillations of Stars) satellite obtains ultraprecise photometry from space with high sampling rates and duty cycles. Astronomical photometry or imaging missions in low Earth orbits, like MOST, are especially sensitive to scattered light from Earthshine, and all these missions have a common need to extract target information from voluminous data cubes. They consist of upwards of hundreds of thousands of two-dimensional CCD frames (or subrasters) containing from hundreds to millions of pixels each, where the target information, superposed on background and instrumental effects, is contained only in a subset of pixels (Fabry Images, defocused images, mini-spectra). We describe a novel reduction technique for such data cubes: resolving linear correlations of target and background pixel intensities. This step-wise multiple linear regression removes only those target variations which are also detected in the background. The advantage of regression analysis versus background subtraction is the appropriate scaling, taking into account that the amount of contamination may differ from pixel to pixel. The multivariate solution for all pairs of target/background pixels is minimally invasive of the raw photometry while being very effective in reducing contamination due to, e.g. stray light. The technique is tested and demonstrated with both simulated oscillation signals and real MOST photometry.

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.

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.

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

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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/

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.

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).

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.

Enzyme replacement therapy for Anderson-Fabry disease: A complementary overview of a Cochrane publication through a linear regression and a pooled analysis of proportions from cohort studies

PubMed Central

El Dib, Regina; Gomaa, Huda; Ortiz, Alberto; Politei, Juan; Kapoor, Anil; Barreto, Fellype

2017-01-01

Background Anderson-Fabry disease (AFD) is an X-linked recessive inborn error of glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A. Renal failure, heart and cerebrovascular involvement reduce survival. A Cochrane review provided little evidence on the use of enzyme replacement therapy (ERT). We now complement this review through a linear regression and a pooled analysis of proportions from cohort studies. Objectives To evaluate the efficacy and safety of ERT for AFD. Materials and methods For the systematic review, a literature search was performed, from inception to March 2016, using Medline, EMBASE and LILACS. Inclusion criteria were cohort studies, patients with AFD on ERT or natural history, and at least one patient-important outcome (all-cause mortality, renal, cardiovascular or cerebrovascular events, and adverse events) reported. The pooled proportion and the confidence interval (CI) are shown for each outcome. Simple linear regressions for composite endpoints were performed. Results 77 cohort studies involving 15,305 participants proved eligible. The pooled proportions were as follows: a) for renal complications, agalsidase alfa 15.3% [95% CI 0.048, 0.303; I2 = 77.2%, p = 0.0005]; agalsidase beta 6% [95% CI 0.04, 0.07; I2 = not applicable]; and untreated patients 21.4% [95% CI 0.1522, 0.2835; I2 = 89.6%, p<0.0001]. Effect differences favored agalsidase beta compared to untreated patients; b) for cardiovascular complications, agalsidase alfa 28% [95% CI 0.07, 0.55; I2 = 96.7%, p<0.0001]; agalsidase beta 7% [95% CI 0.05, 0.08; I2 = not applicable]; and untreated patients 26.2% [95% CI 0.149, 0.394; I2 = 98.8%, p<0.0001]. Effect differences favored agalsidase beta compared to untreated patients; and c) for cerebrovascular complications, agalsidase alfa 11.1% [95% CI 0.058, 0.179; I2 = 70.5%, p = 0.0024]; agalsidase beta 3.5% [95% CI 0.024, 0.046; I2 = 0%, p = 0.4209]; and untreated patients 18.3% [95% CI 0.129, 0.245; I2 = 95% p < 0

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.

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.

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.

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.

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.

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.

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

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).

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.

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.

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.

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.

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.

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.

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

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%.

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.

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

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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

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

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.

Genetic background of supernumerary teeth

PubMed Central

Subasioglu, Asli; Savas, Selcuk; Kucukyilmaz, Ebru; Kesim, Servet; Yagci, Ahmet; Dundar, Munis

2015-01-01

Supernumerary teeth (ST) are odontostomatologic anomaly characterized by as the existence excessive number of teeth in relation to the normal dental formula. This condition is commonly seen with several congenital genetic disorders such as Gardner's syndrome, cleidocranial dysostosis and cleft lip and palate. Less common syndromes that are associated with ST are; Fabry Disease, Ellis-van Creveld syndrome, Nance-Horan syndrome, Rubinstein-Taybi Syndrome and Trico–Rhino–Phalangeal syndrome. ST can be an important component of a distinctive disorder and an important clue for early diagnosis. Certainly early detecting the abnormalities gives us to make correct management of the patient and also it is important for making well-informed decisions about long-term medical care and treatment. In this review, the genetic syndromes that are related with ST were discussed. PMID:25713500

Genetic background of supernumerary teeth.

PubMed

Subasioglu, Asli; Savas, Selcuk; Kucukyilmaz, Ebru; Kesim, Servet; Yagci, Ahmet; Dundar, Munis

2015-01-01

Supernumerary teeth (ST) are odontostomatologic anomaly characterized by as the existence excessive number of teeth in relation to the normal dental formula. This condition is commonly seen with several congenital genetic disorders such as Gardner's syndrome, cleidocranial dysostosis and cleft lip and palate. Less common syndromes that are associated with ST are; Fabry Disease, Ellis-van Creveld syndrome, Nance-Horan syndrome, Rubinstein-Taybi Syndrome and Trico-Rhino-Phalangeal syndrome. ST can be an important component of a distinctive disorder and an important clue for early diagnosis. Certainly early detecting the abnormalities gives us to make correct management of the patient and also it is important for making well-informed decisions about long-term medical care and treatment. In this review, the genetic syndromes that are related with ST were discussed.

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.

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.

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.

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.

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.

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.

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.

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.

Association of Radon Background and Total Background Ionizing Radiation with Alzheimer's Disease Deaths in U.S. States.

PubMed

Lehrer, Steven; Rheinstein, Peter H; Rosenzweig, Kenneth E

2017-01-01

Exposure of the brain to ionizing radiation might promote the development of Alzheimer's disease (AD). Analysis of AD death rates versus radon background radiation and total background radiation in U.S. states. Total background, radon background, cosmic and terrestrial background radiation measurements are from Assessment of Variations in Radiation Exposure in the United States and Report No. 160 - Ionizing Radiation Exposure of the Population of the United States. 2013 AD death rates by U.S. state are from the Alzheimer's Association. Radon background ionizing radiation was significantly correlated with AD death rate in 50 states and the District of Columbia (r = 0.467, p = 0.001). Total background ionizing radiation was also significantly correlated with AD death rate in 50 states and the District of Columbia (r = 0.452, p = 0.001). Multivariate linear regression weighted by state population demonstrated that AD death rate was significantly correlated with radon background (β= 0.169, p < 0.001), age (β= 0.231, p < 0.001), hypertension (β= 0.155, p < 0.001), and diabetes (β= 0.353, p < 0.001). Our findings, like other studies, suggest that ionizing radiation is a risk factor for AD. Intranasal inhalation of radon gas could subject the rhinencephalon and hippocampus to damaging radiation that initiates AD. The damage would accumulate over time, causing age to be a powerful risk factor.

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.

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.

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.

Gaucher disease and other storage disorders.

PubMed

Grabowski, Gregory A

2012-01-01

In 1882, Philippe Gaucher described a 32-year-old woman with massive splenomegaly and unusually large cells in the spleen, which he called a "primary epithelioma of the spleen." The systemic nature and inheritance of the disease and its variants involving the viscera and CNS were described over the next century. The delineation of the causal enzymatic defects, genetics, molecular pathology, and genomics have provided pathogenic insights into the phenotypic spectrum and the bases for development of specific therapies for what is now known as Gaucher disease. As a prototype, the clinically and economically successful intracellular enzyme therapy provided the impetus for the expansion of similar research and therapeutic developments for other lysosomal storage diseases (LSDs) and orphan diseases, including Fabry, Pompe, and Niemann-Pick diseases, as well as several mucopolysaccharidoses. Continuing studies of such LSDs, which occur as a group in more than 7000 live births, have revealed the complex molecular interdigitation with the autophagy and apoptotic pathways and proteostasis and the impact of disruptions of the lysosomal/autophagy and proteostasis systems on more common diseases has been recognized. Examples include age-related neurodegenerative diseases (eg, Parkinson disease and Gaucher disease), idiopathic hypertrophic myocardiopathies, stroke and renal failure (eg, Fabry disease), and Nonalcoholic Fatty Liver Disease/Nonalcoholic SteatoHepatitis (NAFLD/NASH) and atherosclerosis (eg, lysosomal acid lipase deficiencies). Although perceived as rare, the availability of treatment and the impact of the LSDs on more common diseases require their integration into routine clinical practice.

A Fabry-Pérot electro-optic sensing system using a drive-current-tuned wavelength laser diode.

PubMed

Kuo, Wen-Kai; Wu, Pei-Yu; Lee, Chang-Ching

2010-05-01

A Fabry-Pérot enhanced electro-optic sensing system that utilizes a drive-current-tuned wavelength laser diode is presented. An electro-optic prober made of LiNbO(3) crystal with an asymmetric Fabry-Pérot cavity is used in this system. To lock the wavelength of the laser diode at resonant condition, a closed-loop power control scheme is proposed. Experiment results show that the system can keep the electro-optic prober at high sensitivity for a long working time when the closed-loop control function is on. If this function is off, the sensitivity may be fluctuated and only one-third of the best level in the worst case.

A modified cross-correlation method for white-light optical fiber extrinsic Fabry-Perot interferometric hydrogen sensors

NASA Astrophysics Data System (ADS)

Yang, Zhen; Zhang, Min; Liao, Yanbiao; Lai, Shurong; Tian, Qian; Li, Qisheng; Zhang, Yi; Zhuang, Zhi

2009-11-01

An extrinsic Fabry-Perot interferometric (EFPI) optical fiber hydrogen sensor based on palladium silver (Pd-Ag) film is designed for hydrogen leakage detection. A modified cross correlation signal processing method for an optical fiber EFPI hydrogen sensor is presented. As the applying of a special correlating factor which advises the effect on the fringe visibility of the gap length and wavelength, the cross correlation method has a high accuracy which is insensitive to light source power drift or changes in attenuation in the fiber, and the segment search method is employed to reduce computation and demodulating speed is fast. The Fabry-Perot gap length resolution of better than 0.2nm is achieved in a certain concentration of hydrogen.

Clinical Features, Diagnosis, and Management of Patients With Anderson-Fabry Cardiomyopathy.

PubMed

Yogasundaram, Haran; Kim, Daniel; Oudit, Omar; Thompson, Richard B; Weidemann, Frank; Oudit, Gavin Y

2017-07-01

Anderson-Fabry disease (AFD) is an X-linked recessive, multisystem disease of lysosomal storage. A mutation in the gene encoding the hydrolase enzyme α-galactosidase A results in its deficiency, or complete absence of activity. Subsequent progressive intracellular accumulation of glycosphingolipids, predominantly globotriaosylceramide, in various tissues, results in progressive organ dysfunction and failure, most commonly affecting the kidneys, nervous system, skin, eyes, vascular endothelium, and the heart. Cardiac involvement in AFD represents a leading cause of morbidity and mortality. Globotriaosylceramide accumulation affects cardiomyocytes, smooth muscle cells, vascular endothelial cells, and fibroblasts leading to various pathologies including valvular regurgitation, conduction disease and arrhythmias, coronary microvascular dysfunction, and right and left ventricular hypertrophy (LVH) leading to early diastolic dysfunction and late-stage systolic impairment. Diagnosis is on the basis of decreased plasma α-galactosidase activity in men and positive genetic testing in women. Contemporary large-scale screening studies have revealed a prevalence of 1%-5% in patients with unexplained LVH in multiple cohorts. Cardiac magnetic resonance imaging, with its unique tissue characterization capabilities, is the most important imaging modality to assess for cardiomyopathy in patients with AFD. Enzyme replacement therapy is indicated in AFD patients with significant organ involvement, and has been shown to clear sphingolipids from endothelial cells in other organs, as well as to reduce left ventricular mass as early as 6 months after starting treatment. There is increasing evidence that enzyme replacement therapy might be more effective if given at earlier stages of disease, before the development of LVH and myocardial fibrosis. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Fabry-Pérot Interference in Gapped Bilayer Graphene with Broken Anti-Klein Tunneling

NASA Astrophysics Data System (ADS)

Varlet, Anastasia; Liu, Ming-Hao; Krueckl, Viktor; Bischoff, Dominik; Simonet, Pauline; Watanabe, Kenji; Taniguchi, Takashi; Richter, Klaus; Ensslin, Klaus; Ihn, Thomas

2014-09-01

We report the experimental observation of Fabry-Pérot interference in the conductance of a gate-defined cavity in a dual-gated bilayer graphene device. The high quality of the bilayer graphene flake, combined with the device's electrical robustness provided by the encapsulation between two hexagonal boron nitride layers, allows us to observe ballistic phase-coherent transport through a 1-μm-long cavity. We confirm the origin of the observed interference pattern by comparing to tight-binding calculations accounting for the gate-tunable band gap. The good agreement between experiment and theory, free of tuning parameters, further verifies that a gap opens in our device. The gap is shown to destroy the perfect reflection for electrons traversing the barrier with normal incidence (anti-Klein tunneling). The broken anti-Klein tunneling implies that the Berry phase, which is found to vary with the gate voltages, is always involved in the Fabry-Pérot oscillations regardless of the magnetic field, in sharp contrast with single-layer graphene.

Transfer functions of double- and multiple-cavity Fabry-Perot filters driven by Lorentzian sources.

PubMed

Marti, J; Capmany, J

1996-12-20

We derive expressions for the transfer functions of double- and multiple-cavity Fabry-Perot filters driven by laser sources with Lorentzian spectrum. These are of interest because of their applications in sensing and channel filtering in optical frequency-division multiplexing networks.

Transfer functions of double- and multiple-cavity Fabry Perot filters driven by Lorentzian sources

NASA Astrophysics Data System (ADS)

Marti, Javier; Capmany, Jose

1996-12-01

We derive expressions for the transfer functions of double- and multiple-cavity Fabry Perot filters driven by laser sources with Lorentzian spectrum. These are of interest because of their applications in sensing and channel filtering in optical frequency-division multiplexing networks.

Anti-α-galactosidase A antibody response to agalsidase beta treatment: data from the Fabry Registry.

PubMed

Wilcox, William R; Linthorst, Gabor E; Germain, Dominique P; Feldt-Rasmussen, Ulla; Waldek, Stephen; Richards, Susan M; Beitner-Johnson, Dana; Cizmarik, Marta; Cole, J Alexander; Kingma, Wytske; Warnock, David G

2012-03-01

Agalsidase beta, a form of recombinant human α-galactosidase A (αGAL), is approved for use as enzyme replacement therapy (ERT) for Fabry disease. An immunogenic response against a therapeutic protein could potentially impact its efficacy or safety. The development of anti-αGAL IgG antibodies was evaluated in 571 men and 251 women from the Fabry Registry who were treated with agalsidase beta. Most men developed antibodies (416 of 571, 73%), whereas most women did not (31 of 251, 12%). Women were also significantly more likely to tolerize than men; whereas 18 of 31 women tolerized (58%, 95%CI: 52%-64%), only 47 of 416 men tolerized during the observation period (11%, 95% CI: 8%-15%). Patients who eventually tolerized had lower median peak anti-αGAL IgG antibody titers than patients who remained seropositive at their most recent assessment (400 versus 3200 in men, 200 versus 400 in women, respectively). Patients with nonsense mutations in the GLA gene were more likely to develop anti-αGAL IgG antibodies than patients with missense mutations. Approximately 26% of men (151 of 571) reported infusion-associated reactions (IARs), compared to 11% of women (27 of 251). Men who developed anti-αGAL IgG antibodies were more likely to experience IARs compared to those who remained seronegative. Nine percent of seronegative men and women (34 of 375) reported IARs. The majority of IARs occurred during the first 6 to 12 months of agalsidase beta treatment and decreased over time, in both seroconverted and seronegative patients. Copyright © 2012 Elsevier Inc. All rights reserved.

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.

Micromachined fiber optic Fabry-Perot underwater acoustic probe

NASA Astrophysics Data System (ADS)

Wang, Fuyin; Shao, Zhengzheng; Hu, Zhengliang; Luo, Hong; Xie, Jiehui; Hu, Yongming

2014-08-01

One of the most important branches in the development trend of the traditional fiber optic physical sensor is the miniaturization of sensor structure. Miniature fiber optic sensor can realize point measurement, and then to develop sensor networks to achieve quasi-distributed or distributed sensing as well as line measurement to area monitoring, which will greatly extend the application area of fiber optic sensors. The development of MEMS technology brings a light path to address the problems brought by the procedure of sensor miniaturization. Sensors manufactured by MEMS technology possess the advantages of small volume, light weight, easy fabricated and low cost. In this paper, a fiber optic extrinsic Fabry-Perot interferometric underwater acoustic probe utilizing micromachined diaphragm collaborated with fiber optic technology and MEMS technology has been designed and implemented to actualize underwater acoustic sensing. Diaphragm with central embossment, where the embossment is used to anti-hydrostatic pressure which would largely deflect the diaphragm that induce interferometric fringe fading, has been made by double-sided etching of silicon on insulator. By bonding the acoustic-sensitive diaphragm as well as a cleaved fiber end in ferrule with an outer sleeve, an extrinsic Fabry-Perot interferometer has been constructed. The sensor has been interrogated by quadrature-point control method and tested in field-stable acoustic standing wave tube. Results have been shown that the recovered signal detected by the sensor coincided well with the corresponding transmitted signal and the sensitivity response was flat in frequency range from 10 Hz to 2kHz with the value about -154.6 dB re. 1/μPa. It has been manifest that the designed sensor could be used as an underwater acoustic probe.

Fabry-Perot Based Radiometers for Precise Measurement of Greenhouse Gases

NASA Technical Reports Server (NTRS)

Heaps, William S.; Wilson, Emily L.; Georgieva, Elena

2007-01-01

Differential radiometers based upon the Fabry-Perot interferometer have been developed and demonstrated that exhibit very great sensitivity to changes in the atmospheric column of carbon dioxide, oxygen, and water vapor. These instruments employ a solid Fabry-Perot etalon that is tuned to the proper wavelength by changing the temperature. By choosing the thickness of the etalon its multiple pass bands can be made to align with regularly space absorption features of the molecule under investigation. Use of multiple absorption features improves the optical throughput of the instrument and improves the stability of the instrument response with respect to environmental changes. Efforts are underway at Goddard to extend this technique to the carbon 13 isotope of carbon dioxide and to methane. These instruments are intrinsically rugged and can be made rather small and inexpensively. They therefore hold promise for widespread use in ground based networks for calibration of satellite instruments such as OCO and GOSAT. Results will be presented for ground based and airborne operations for these systems. The effects of atmospheric scattering, pointing errors, pressure broadening and temperature effects will be discussed with regard to achieving precision better than .5% required for validation of carbon dioxide column measured from space. Designs permitting the extension of the technique to an even larger number of atmospheric species will be discussed along with theoretical analysis of potential system performance.

Ultrasonic imaging of seismic physical models using a fringe visibility enhanced fiber-optic Fabry-Perot interferometric sensor.

PubMed

Zhang, Wenlu; Chen, Fengyi; Ma, Wenwen; Rong, Qiangzhou; Qiao, Xueguang; Wang, Ruohui

2018-04-16

A fringe visibility enhanced fiber-optic Fabry-Perot interferometer based ultrasonic sensor is proposed and experimentally demonstrated for seismic physical model imaging. The sensor consists of a graded index multimode fiber collimator and a PTFE (polytetrafluoroethylene) diaphragm to form a Fabry-Perot interferometer. Owing to the increase of the sensor's spectral sideband slope and the smaller Young's modulus of the PTFE diaphragm, a high response to both continuous and pulsed ultrasound with a high SNR of 42.92 dB in 300 kHz is achieved when the spectral sideband filter technique is used to interrogate the sensor. The ultrasonic reconstructed images can clearly differentiate the shape of models with a high resolution.

A Theoretical Study and Numerical Simulation of a Quasi-Distributed Sensor Based on the Low-Finesse Fabry-Perot Interferometer: Frequency-Division Multiplexing

PubMed Central

Guillen Bonilla, José Trinidad; Guillen Bonilla, Alex; Rodríguez Betancourtt, Verónica M.; Guillen Bonilla, Héctor; Casillas Zamora, Antonio

2017-01-01

The application of the sensor optical fibers in the areas of scientific instrumentation and industrial instrumentation is very attractive due to its numerous advantages. In the industry of civil engineering for example, quasi-distributed sensors made with optical fiber are used for reliable strain and temperature measurements. Here, a quasi-distributed sensor in the frequency domain is discussed. The sensor consists of a series of low-finesse Fabry-Perot interferometers where each Fabry-Perot interferometer acts as a local sensor. Fabry-Perot interferometers are formed by pairs of identical low reflective Bragg gratings imprinted in a single mode fiber. All interferometer sensors have different cavity length, provoking frequency-domain multiplexing. The optical signal represents the superposition of all interference patterns which can be decomposed using the Fourier transform. The frequency spectrum was analyzed and sensor’s properties were defined. Following that, a quasi-distributed sensor was numerically simulated. Our sensor simulation considers sensor properties, signal processing, noise system, and instrumentation. The numerical results show the behavior of resolution vs. signal-to-noise ratio. From our results, the Fabry-Perot sensor has high resolution and low resolution. Both resolutions are conceivable because the Fourier Domain Phase Analysis (FDPA) algorithm elaborates two evaluations of Bragg wavelength shift. PMID:28420083

A Theoretical Study and Numerical Simulation of a Quasi-Distributed Sensor Based on the Low-Finesse Fabry-Perot Interferometer: Frequency-Division Multiplexing.

PubMed

Guillen Bonilla, José Trinidad; Guillen Bonilla, Alex; Rodríguez Betancourtt, Verónica M; Guillen Bonilla, Héctor; Casillas Zamora, Antonio

2017-04-14

The application of the sensor optical fibers in the areas of scientific instrumentation and industrial instrumentation is very attractive due to its numerous advantages. In the industry of civil engineering for example, quasi-distributed sensors made with optical fiber are used for reliable strain and temperature measurements. Here, a quasi-distributed sensor in the frequency domain is discussed. The sensor consists of a series of low-finesse Fabry-Perot interferometers where each Fabry-Perot interferometer acts as a local sensor. Fabry-Perot interferometers are formed by pairs of identical low reflective Bragg gratings imprinted in a single mode fiber. All interferometer sensors have different cavity length, provoking frequency-domain multiplexing. The optical signal represents the superposition of all interference patterns which can be decomposed using the Fourier transform. The frequency spectrum was analyzed and sensor's properties were defined. Following that, a quasi-distributed sensor was numerically simulated. Our sensor simulation considers sensor properties, signal processing, noise system, and instrumentation. The numerical results show the behavior of resolution vs. signal-to-noise ratio. From our results, the Fabry-Perot sensor has high resolution and low resolution. Both resolutions are conceivable because the Fourier Domain Phase Analysis (FDPA) algorithm elaborates two evaluations of Bragg wavelength shift.

Watt-level widely tunable single-mode emission by injection-locking of a multimode Fabry-Perot quantum cascade laser

NASA Astrophysics Data System (ADS)

Chevalier, Paul; Piccardo, Marco; Anand, Sajant; Mejia, Enrique A.; Wang, Yongrui; Mansuripur, Tobias S.; Xie, Feng; Lascola, Kevin; Belyanin, Alexey; Capasso, Federico

2018-02-01

Free-running Fabry-Perot lasers normally operate in a single-mode regime until the pumping current is increased beyond the single-mode instability threshold, above which they evolve into a multimode state. As a result of this instability, the single-mode operation of these lasers is typically constrained to few percents of their output power range, this being an undesired limitation in spectroscopy applications. In order to expand the span of single-mode operation, we use an optical injection seed generated by an external-cavity single-mode laser source to force the Fabry-Perot quantum cascade laser into a single-mode state in the high current range, where it would otherwise operate in a multimode regime. Utilizing this approach, we achieve single-mode emission at room temperature with a tuning range of 36 cm-1 and stable continuous-wave output power exceeding 1 W at 4.5 μm. Far-field measurements show that a single transverse mode is emitted up to the highest optical power, indicating that the beam properties of the seeded Fabry-Perot laser remain unchanged as compared to free-running operation.

Molecular dispersion spectroscopy based on Fabry-Perot quantum cascade lasers.

PubMed

Sterczewski, Lukasz A; Westberg, Jonas; Wysocki, Gerard

2017-01-15

Two Fabry-Perot quantum cascade lasers are used in a differential dual comb configuration to perform rapidly swept dispersion spectroscopy of low-pressure nitrous oxide with <1  ms acquisition time. Active feedback control of the laser injection current enables simultaneous wavelength modulation of both lasers at kilohertz rates. The system demonstrates similar performance in both absorption and dispersion spectroscopy modes and achieves a noise-equivalent absorption figure of merit in the low 10^-4/Hz range.

[Cryptogenic stroke in a young patient with heart disease and kidney failure].

PubMed

Oyanguren, B; Segoviano, R; Alegria, E; Besada, E; Gonzalez-Salaices, M; Eimil-Ortiz, M; Lopez de Silanes, C

2017-05-16

Fabry's disease is an infrequent metabolic pathology linked to the X chromosome which causes a wide variety of signs and symptoms. A 39-year-old male who was admitted to our stroke unit with right-side hemiparesis (1 + 0) and dysarthria (1). The score on the National Institute of Health Stroke Scale was 2. The patient presented angiokeratomas in both thighs. A computerised axial tomography scan of the head showed left thalamic acute infarction. The duplex scan of the supra-aortic trunks was normal, and the transcranial Doppler reflected a generalised increase in the pulsatility indices. Transthoracic echocardiography showed left ventricular hypertrophy and left atrial dilatation. He was discharged five days later, with antiaggregating medication but asymptomatic. The prolonged Holter-electrocardiogram recording showed paroxysmal atrial fibrillation. One notable value in the urine analysis was microalbuminuria of 281 mg/L. In view of the multi-organic involvement and the family history, a study for Fabry's disease was performed. Activity of the enzyme alpha-galactosidase A was diminished, and the presence of a mutation in the GLA gene was found. The patient's brother, who suffered from kidney failure and atrial fibrillation, was positive for this mutation. The patient is on treatment with agalsidase beta. Fabry's disease must be suspected in young males with heart disease, stroke or peripheral neuropathy, skin lesions, kidney failure and a history of cases in the family. Hormone replacement therapy must be established at an early stage, as it can improve the prognosis.

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

Cardiovascular magnetic resonance demonstration of the spectrum of morphological phenotypes and patterns of myocardial scarring in Anderson-Fabry disease.

PubMed

Deva, Djeven Parameshvara; Hanneman, Kate; Li, Qin; Ng, Ming Yen; Wasim, Syed; Morel, Chantal; Iwanochko, Robert M; Thavendiranathan, Paaladinesh; Crean, Andrew Michael

2016-03-31

Although it is known that Anderson-Fabry Disease (AFD) can mimic the morphologic manifestations of hypertrophic cardiomyopathy (HCM) on echocardiography, there is a lack of cardiovascular magnetic resonance (CMR) literature on this. There is limited information in the published literature on the distribution of myocardial fibrosis in patients with AFD, with scar reported principally in the basal inferolateral midwall. All patients with confirmed AFD undergoing CMR at our center were included. Left ventricular (LV) volumes, wall thicknesses and scar were analyzed offline. Patients were categorized into 4 groups: (1) no wall thickening; (2) concentric hypertrophy; (3) asymmetric septal hypertrophy (ASH); and (4) apical hypertrophy. Charts were reviewed for clinical information. Thirty-nine patients were included (20 males [51%], median age 45.2 years [range 22.3-64.4]). Almost half (17/39) had concentric wall thickening. Almost half (17/39) had pathologic LV scar; three quarters of these (13/17) had typical inferolateral midwall scar. A quarter (9/39) had both concentric wall thickening and typical inferolateral scar. A subgroup with ASH and apical hypertrophy (n = 5) had greater maximum wall thickness, total LV scar, apical scar and mid-ventricular scar than those with concentric hypertrophy (n = 17, p < 0.05). Patients with elevated LVMI had more overall arrhythmia (p = 0.007) more ventricular arrhythmia (p = 0.007) and sustained ventricular tachycardia (p = 0.008). Concentric thickening and inferolateral mid-myocardial scar are the most common manifestations of AFD, but the spectrum includes cases morphologically identical to apical and ASH subtypes of HCM and these have more apical and mid-ventricular LV scar. Significant LVH is associated with ventricular arrhythmia.

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.

SUNLITE program. Sub-Hertz relative frequency stabilization of two diode laser pumped Nd:YAG lasers locked to a Fabry-Perot interferometer

NASA Technical Reports Server (NTRS)

Byer, R. L.

1990-01-01

Two laser pumped Nd:YAG lasers were frequency stabilized to a commercial 6.327 GHz free spectral range Fabry-Perot interferometer yielding a best case beatnote linewidth of 330 MHz. In addition, a Fabry-Perot interferometer with a free spectral range of 680 MHz, a linewidth of 25 kHz, and a finesse of 27,500 was built, and when it was substituted in place of the commercial interferometer, it produced a robust and easily repeatable beatnote linewidth of 700 MHz.

Development of a Fabry-Perot Interferometer for Ultra-Precise Measurements of Column CO2

NASA Technical Reports Server (NTRS)

Wilson, Emily L.; Georgieva, Elena M.; Heaps, William S.

2005-01-01

A passive Fabry-Perot based instrument is described for detecting column CO2 through absorption measurements at 1.58 microns . In this design, solar flux reaches the instrument platform and is directed through two channels. In the first channel, transmittance fi5nges from a Fabry-Perot interferometer are aligned with CO2 absorption lines so that absorption due to CO2 is primarily detected. The second channel encompasses the same frequency region as the first, but is comparatively more sensitive to changes in the solar flux than absorption due to CO2. The ratio of these channels is sensitive to changes in the total CO2 column, but not to changes in solar flux. This inexpensive instrument will offer high precision measurements (error 4%) in a compact package. Design of this instrument and preliminary ground-based measurements of column CO2 are presented here as well as strategies for deployment on aircraft and satellite platforms.

A Novel, Poly-Etalon, Fabry-Perot for Planetary Research

NASA Technical Reports Server (NTRS)

Kerr, Robert B.; Doe, Richard; Noto, John

1997-01-01

In an effort to develop a mechanically robust, high throughput and solid state spectrometer several liquid crystal Fabry-Perot etalons were constructed. The etalons were tested for spectral response, radiation resistance and optical transmission. The first year of this project was spent developing and understanding the properties of the liquid crystal etalons; in the second year an intensified all-sky imaging system was developed around a pair of LC etalons. The imaging system, developed jointly with SRI International represents a unique brassboard to demonstrate the use of LC etalons as tunable filters. The first set of etalons constructed in year one of this project were tested for spectral response and throughput while etalon surrogates were exposed to proton radiation simulating the exposure of an object in Low Earth Orbit (LEO). The 2" diameter etalons had a measure finesse of approximately 10 and were tunable over five orders. Liquid crystals exposed to proton irradiation showed no signs of damage. In year two two larger diameter (3") etalons were constructed with gaps of 3 and 5 microns. This pair of etalons is for use in a high resolution, all-sky spectral imager. The WATUMI imager system follows the heritage of all sky, narrow band, intensified imagers however it includes two LC Fabry-Perot etalons to provide tunability and the ability to switch wavelengths rapidly, an import consideration in auroral airglow imaging. This work also resulted in two publications and one poster presentation. The instrument will be uniquely capable, with superior throughput and speed, to measure optical airglow of multiple emission lines in harsh conditions.

Hypersonic force measurements using internal balance based on optical micromachined Fabry-Perot interferometry.

PubMed

Qiu, Huacheng; Min, Fu; Zhong, Shaolong; Song, Xin; Yang, Yanguang

2018-03-01

Force measurements using wind tunnel balance are necessary for determining a variety of aerodynamic performance parameters, while the harsh environment in hypersonic flows requires that the measurement instrument should be reliable and robust, in against strong electromagnetic interference, high vacuum, or metal (oxide) dusts. In this paper, we demonstrated a three-component internal balance for hypersonic aerodynamic force measurements, using novel optical micromachined Fabry-Perot interferometric (FPI) strain gauges as sensing elements. The FPI gauges were fabricated using Micro-Opto-Electro-Mechanical Systems (MOEMS) surface and bulk fabrication techniques. High-reflectivity coatings are used to form a high-finesse Fabry-Perot cavity, which benefits a high resolution. Antireflective and passivation coatings are used to reduce unwanted interferences. The FPI strain gauge based balance has been calibrated and evaluated in a Mach 5 hypersonic flow. The results are compared with the traditional technique using the foil resistive strain gauge balance, indicating that the proposed balance based on the MOEMS FPI strain gauge is reliable and robust and is potentially suitable for the hypersonic wind tunnel harsh environment.

Hypersonic force measurements using internal balance based on optical micromachined Fabry-Perot interferometry

NASA Astrophysics Data System (ADS)

Qiu, Huacheng; Min, Fu; Zhong, Shaolong; Song, Xin; Yang, Yanguang

2018-03-01

Force measurements using wind tunnel balance are necessary for determining a variety of aerodynamic performance parameters, while the harsh environment in hypersonic flows requires that the measurement instrument should be reliable and robust, in against strong electromagnetic interference, high vacuum, or metal (oxide) dusts. In this paper, we demonstrated a three-component internal balance for hypersonic aerodynamic force measurements, using novel optical micromachined Fabry-Perot interferometric (FPI) strain gauges as sensing elements. The FPI gauges were fabricated using Micro-Opto-Electro-Mechanical Systems (MOEMS) surface and bulk fabrication techniques. High-reflectivity coatings are used to form a high-finesse Fabry-Perot cavity, which benefits a high resolution. Antireflective and passivation coatings are used to reduce unwanted interferences. The FPI strain gauge based balance has been calibrated and evaluated in a Mach 5 hypersonic flow. The results are compared with the traditional technique using the foil resistive strain gauge balance, indicating that the proposed balance based on the MOEMS FPI strain gauge is reliable and robust and is potentially suitable for the hypersonic wind tunnel harsh environment.

Severe infusion reactions to fabry enzyme replacement therapy: rechallenge after tracheostomy.

PubMed

Nicholls, K; Bleasel, K; Becker, G

2012-01-01

A 34-year-old male patient with Fabry disease (OMIM 301500) commenced enzyme replacement therapy (ERT) with Agalsidase alfa, with positive clinical response. Infusion reactions, initially mild and easily managed, commenced during his 13th infusion, and continued over the next 3 years. Severity of reactions subsequently increased despite very slow infusion, extended prophylactic medication and attempted desensitisation, requiring regular intensive care unit (ICU) admissions. Facial oedema and flushing, throat tightness, headache and joint pain typically occurred 4-36 h after completion of most infusions, responding rapidly to subcutaneous adrenaline. Low titre specific IgG seroconversion was noted at 12 months, with subsequent reversion to negative after 5 years, despite persistence of infusion reactions. Specific IgE and skin testing was negative. Trial of ERT product switch to Agalsidase-beta resulted in no improvement in reactions. At 5 years, ERT was ceased in the face of recurrent ICU readmissions. In the face of progressive clinical deterioration, he underwent tracheostomy to allow recommencement of ERT. Two years later, he has clinically improved on regular attenuated dose Agalsidase-beta, administered by slow infusion in a local hospital setting.

Study of Fabry-Perot Etalon Stability and Tuning for Spectroscopic Rayleigh Scattering

NASA Technical Reports Server (NTRS)

Clem, Michelle M.; Mielke-Fagan, Amy F.; Elam, Kristie A.

2010-01-01

The Fabry-Perot interferometer is a commonly employed instrument for resolving the spectrum of molecular Rayleigh scattered light for the purpose of evaluating flow properties such as gas velocity and temperature. Rayleigh scattered light from a focused laser beam can be directly imaged through a solid Fabry-Perot etalon onto a CCD detector to provide the spectral content of the scattered light. The spatial resolution of the measurements is governed by the locations of interference fringes. The location of the fringes can be changed by altering the etalon?s physical characteristics, such as thickness and index of refraction. For a fused silica solid etalon the physical properties can be adjusted by changing the etalon temperature; hence changing the order of the interference pattern and the physical fringe locations. Controlling the temperature of the etalon can provide for a slow time-response spatial scanning method for this type of etalon system. A custom designed liquid crystal Fabry-Perot (LCFP) can provide for a fast time-response method of scanning the etalon system. Voltage applied to the liquid crystal interface sets the etalon?s properties allowing Rayleigh measurements to be acquired at varying spatial locations across the image of the laser beam over a very short time period. A standard fused silica etalon and a tunable LCFP etalon are characterized to select the system that is best suited for Rayleigh scattering measurements in subsonic and supersonic flow regimes. A frequency-stabilized laser is used to investigate the apparent frequency stability and temperature sensitivity of the etalon systems. Frequency stability and temperature sensitivity data of the fused silica and LCFP etalon systems are presented in this paper, along with measurements of the LCFP etalon?s tuning capabilities. Rayleigh scattering velocity measurements with both etalon systems are presented, in an effort to determine which etalon is better suited to provide optical flow

The background puzzle: how identical mutations in the same gene lead to different disease symptoms.

PubMed

Kammenga, Jan E

2017-10-01

Identical disease-causing mutations can lead to different symptoms in different people. The reason for this has been a puzzling problem for geneticists. Differential penetrance and expressivity of mutations has been observed within individuals with different and similar genetic backgrounds. Attempts have been made to uncover the underlying mechanisms that determine differential phenotypic effects of identical mutations through studies of model organisms. From these studies evidence is accumulating that to understand disease mechanism or predict disease prevalence, an understanding of the influence of genetic background is as important as the putative disease-causing mutations of relatively large effect. This review highlights current insights into phenotypic variation due to gene interactions, epigenetics and stochasticity in model organisms, and discusses their importance for understanding the mutational effect on disease symptoms. © 2017 Federation of European Biochemical Societies.

Observations of comet Levy 1990c in the (OI) 6300-A line with an imaging Fabry-Perot

NASA Technical Reports Server (NTRS)

Prasad, C. Debi; Jockers, Klaus; Rauer, H.; Geyer, E. H.

1992-01-01

We have observed the comet Levy 1990c during 16-25 August 1990 using the MPAE focal reducer system based Fabry-Perot etalon coupled with the 1 meter telescope of the Observatory of Hoher List. The free spectral range and resolution limit of the interferometer was approximately 2.18 A and approximately 0.171 A respectively. Classical Fabry-Perot fringes were recorded on a CCD in the cometary (OI) 6300 A line. They are well resolved from telluric air glow and cometary NH2 emission. Our observations indicate that the (OI) is distributed asymmetrically with respect to the center of the comet. In this paper we report the spatial distribution of (OI) emission and its line width in the coma of comet Levy.

Background sequence characteristics influence the occurrence and severity of disease-causing mtDNA mutations

PubMed Central

Wei, Wei; Hudson, Gavin

2017-01-01

Inherited mitochondrial DNA (mtDNA) mutations have emerged as a common cause of human disease, with mutations occurring multiple times in the world population. The clinical presentation of three pathogenic mtDNA mutations is strongly associated with a background mtDNA haplogroup, but it is not clear whether this is limited to a handful of examples or is a more general phenomenon. To address this, we determined the characteristics of 30,506 mtDNA sequences sampled globally. After performing several quality control steps, we ascribed an established pathogenicity score to the major alleles for each sequence. The mean pathogenicity score for known disease-causing mutations was significantly different between mtDNA macro-haplogroups. Several mutations were observed across all haplogroup backgrounds, whereas others were only observed on specific clades. In some instances this reflected a founder effect, but in others, the mutation recurred but only within the same phylogenetic cluster. Sequence diversity estimates showed that disease-causing mutations were more frequent on young sequences, and genomes with two or more disease-causing mutations were more common than expected by chance. These findings implicate the mtDNA background more generally in recurrent mutation events that have been purified through natural selection in older populations. This provides an explanation for the low frequency of mtDNA disease reported in specific ethnic groups. PMID:29253894

Characteristics of Extrinsic Fabry-Perot Interferometric (EFPI) Fiber-Optic Strain Gages

NASA Technical Reports Server (NTRS)

Hare, David A.; Moore, Thomas C., Sr.

2000-01-01

The focus of this paper is a comparison of the strain-measuring characteristics of one type of commercially available fiber-optic strain sensor with the performance of conventional resistance strain gages. Fabry-Perot type fiber-optic strain sensors were selected for this testing program. Comparative testing is emphasized and includes load testing at room temperature with apparent strain characterization cryogenically and at elevated temperatures. The absolute accuracy of either of these types of strain gages is not addressed.

The Characteristics in the Sensitivity of Microfiber Fabry-Perot Interferometric Transducers

NASA Astrophysics Data System (ADS)

Wang, Xiuxin; Li, Zhangyong; Lin, Jinzhao; Wang, Wei; Tian, Yin; Pang, Yu

2018-01-01

We inscribe a Fabry-Perot (FP) resonator in the microfiber utilizing the 193-nm UV exposure and the phase mask technique. Some new characteristics in contrast to the conventional counterparts are measured, which are attributed to the index change in the grating and the dispersion of the effective grating length, respectively. The FP spectral dependencies on external strain, temperature, and refractive index are investigated. Our fabricated structures can have potential of acting as ultrasonic transducers and photo acoustic imaging.

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.

[The project and simulation of a compositive miniature spectrum instrument based on the array of Fabry-Perot cavity].

PubMed

Wen, Zhi-yu; Chen, Gang; Wang, Jian-guo

2006-10-01

This paper advances a kind of micro-spectrometer based on Fabry-Perot cavity's character of filtering the waves. The basic structure of the micro-spectrometer is the array of Fabry-Perot cavity which contains many different lengths of cavity on the substrate of silicon, consequently the authors can achieve the detection at several wavelengths simultaneously. The unit of probing is a Fabry-Perot cavity made up of the substrate of silicon-metal film-silicon dioxide layer-metal film. The authors carried out the corresponding simulation. In the basic structure of aluminum film(14 nm)-silicon dioxide layer-silver film(39 nm), the resolution can reach 15 nm. When the area of a unit of probing is 0.14 mm x 0.14 mm only, it can reach the luminous flux of miniature grating spectrum instrument (the minimum volume in the order of cm), but the volume of the part of spectrum detection is only of the order of mm. The design size of the micro-spectrometer is a few millimeters. Furthermore it has no movable parts and could detect several wavelengths at the same time. It is possible to fabricate such micro-spectrometer through existing processing methods of IC technology.

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.

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.

Phase-generated carrier demodulation scheme for fiber Fabry-Pérot interferometric sensor with high finesse

NASA Astrophysics Data System (ADS)

Rao, Wei; Niu, Siliang; Zhang, Nan; Cao, Chunyan; Hu, Yongmin

2011-09-01

This paper presents a demodulation scheme using phase-generated carrier (PGC) for a fiber Fabry-Pérot interferometric (FFPI) sensor with high finesse. The FFPI is constructed by a polarization maintaining fiber ring resonator with dual-coupler (PMDC-FRR), which can eliminate the polarization induced fading phenomenon. Compared with the former phase demodulation methods, the PGC scheme in this paper does not assume a two-beam interferometric approximation for the Fabry-Pérot cavity, and can work at arbitrary value of finesse in theory. Two PMDC-FRRs with reflective coefficients of 0.5 and 0.9 are made in experiments for demodulation. Both the single-frequency and the wideband signals are successfully demodulated from the transmission intensities using the PGC demodulation scheme. The experimental results demonstrate that the PGC demodulation scheme is feasible for the FFPI sensor with high finesse. The effects of the reflective coefficient and the intensity loss to the finesse are also discussed.

A double-fibre Fabry-Perot sensor based on modified fringe counting and direct phase demodulation

NASA Astrophysics Data System (ADS)

Li, M.; Tong, B.; Arsad, N.; Guo, J. J.

2013-09-01

A modified double-fibre Fabry-Perot cavity is developed for determination of the fringe moving direction and higher sensitivity in applications of liquid level and displacement sensors. Two fibres are integrated into a silica ferrule where the ends of the two fibres in the ferrule serve as the front surfaces of the Fabry-Perot cavities, and a diaphragm, which is replaced by a moving mirror for measurement of displacement, serves as the rear surface for both cavities in liquid level sensing. Our design has no strict requirements for a specific phase difference between the two optical paths, just a constant difference resulting from the processing error between the two fibre end positions rather than a precise optical path difference of λ/8 to judge the pattern shift direction. Experimental results demonstrate the feasibility of this approach to determining the fringe moving direction, a displacement sensitivity of 3 µm and good linearity for both applications.

Geometric phase and o -mode blueshift in a chiral anisotropic medium inside a Fabry-Pérot cavity

NASA Astrophysics Data System (ADS)

Timofeev, Ivan V.; Gunyakov, Vladimir A.; Sutormin, Vitaly S.; Myslivets, Sergey A.; Arkhipkin, Vasily G.; Vetrov, Stepan Ya.; Lee, Wei; Zyryanov, Victor Ya.

2015-11-01

Anomalous spectral shift of transmission peaks is observed in a Fabry-Pérot cavity filled with a chiral anisotropic medium. The effective refractive index value resides out of the interval between the ordinary and the extraordinary refractive indices. The spectral shift is explained by contribution of a geometric phase. The problem is solved analytically using the approximate Jones matrix method, numerically using the accurate Berreman method, and geometrically using the generalized Mauguin-Poincaré rolling cone method. The o -mode blueshift is measured for a 4-methoxybenzylidene-4 '-n -butylaniline twisted-nematic layer inside the Fabry-Pérot cavity. The twist is electrically induced due to the homeoplanar-twisted configuration transition in an ionic-surfactant-doped liquid crystal layer. Experimental evidence confirms the validity of the theoretical model.

Tuning operating point of extrinsic Fabry-Perot interferometric fiber-optic sensors using microstructured fiber and gas pressure.

PubMed

Tian, Jiajun; Zhang, Qi; Fink, Thomas; Li, Hong; Peng, Wei; Han, Ming

2012-11-15

Intensity-based demodulation of extrinsic Fabry-Perot interferometric (EFPI) fiber-optic sensors requires the light wavelength to be on the quadrature point of the interferometric fringes for maximum sensitivity. In this Letter, we propose a novel and remote operating-point tuning method for EFPI fiber-optic sensors using microstructured fibers (MFs) and gas pressure. We demonstrated the method using a diaphragm-based EFPI sensor with a microstructured lead-in fiber. The holes in the MF were used as gas channels to remotely control the gas pressure inside the Fabry-Perot cavity. Because of the deformation of the diaphragm with gas pressure, the cavity length and consequently the operating point can be remotely tuned for maximum sensitivity. The proposed operating-point tuning method has the advantage of reduced complexity and cost compared to previously reported methods.

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.

Far Infrared Spectrometry of the Cosmic Background Radiation

DOE R&D Accomplishments Database

Mather, J. C.

1974-01-01

I describe two experiments to measure the cosmic background radiation near 1 mm wavelength. The first was a ground-based search for spectral lines, made with a Fabry-Perot interferometer and an InSb detector. The second is a measurement of the spectrum from 3 to 18 cm{sup -1}, made with a balloon-borne Fourier transform spectrometer. It is a polarizing Michelson interferometer, cooled in liquid helium, and operated with a germanium bolometer. I give the theory of operation, construction details, and experimental results. The first experiment was successfully completed but the second suffered equipment malfunction on its first flight. I describe the theory of Fourier transformations and give a new understanding of convolutional phase correction computations. I discuss for infrared bolometer calibration procedures, and tabulate test results on nine detectors. I describe methods of improving bolometer sensitivity with immersion optics and with conductive film blackening.

A miniature electronically tunable Fabry-Perot filter

NASA Astrophysics Data System (ADS)

O'Sullivan, B.; Pietraszewski, K. A. R.

A miniature electronically tunable, servo controlled Fabry-Perot filter for use in fiber optic sensors, spectroscopy, data and telecommunications, and laser tuning has been developed. The servo control system utilizes capacitance micrometry and piezo technology to maintain stable cavity mirror separations with a noise of less than 0.9nm rms while enabling random access tuning to any wavelength in the design range in less than 0.5ms. Free spectral ranges from 75,000GHz to 300GHz (560nm to 1.5nm at 1500nm wavelength) are typical with finesses between 3 and 300. At present the device has been made commercially available in two formats: fiber optically coupled, with single-mode or multimode fiber, or with a 3mm clear aperture. The design and performance of the instrument are presented along with some typical application examples.

Nonlinear regression method for estimating neutral wind and temperature from Fabry-Perot interferometer data.

PubMed

Harding, Brian J; Gehrels, Thomas W; Makela, Jonathan J

2014-02-01

The Earth's thermosphere plays a critical role in driving electrodynamic processes in the ionosphere and in transferring solar energy to the atmosphere, yet measurements of thermospheric state parameters, such as wind and temperature, are sparse. One of the most popular techniques for measuring these parameters is to use a Fabry-Perot interferometer to monitor the Doppler width and breadth of naturally occurring airglow emissions in the thermosphere. In this work, we present a technique for estimating upper-atmospheric winds and temperatures from images of Fabry-Perot fringes captured by a CCD detector. We estimate instrument parameters from fringe patterns of a frequency-stabilized laser, and we use these parameters to estimate winds and temperatures from airglow fringe patterns. A unique feature of this technique is the model used for the laser and airglow fringe patterns, which fits all fringes simultaneously and attempts to model the effects of optical defects. This technique yields accurate estimates for winds, temperatures, and the associated uncertainties in these parameters, as we show with a Monte Carlo simulation.

[Quartz-enhanced photoacoustic spectroscopy trace gas detection system based on the Fabry-Perot demodulation].

PubMed

Lin, Cheng; Zhu, Yong; Wei, Wei; Zhang, Jie; Tian, Li; Xu, Zu-Wen

2013-05-01

An all-optical quartz-enhanced photoacoustic spectroscopy system, based on the F-P demodulation, for trace gas detection in the open environment was proposed. In quartz-enhanced photoacoustic spectroscopy (QEPAS), an optical fiber Fabry-Perot method was used to replace the conventional electronic demodulation method. The photoacoustic signal was obtained by demodulating the variation of the Fabry-Perot cavity between the quartz tuning fork side and the fiber face. An experimental system was setup. The experiment for detection of water vapour in the open environment was carried on. A normalized noise equivalent absorption coefficient of 2.80 x 10(-7) cm(-1) x W x Hz(-1/2) was achieved. The result demonstrated that the sensitivity of the all-optical quartz-enhanced photoacoustic spectroscopy system is about 2.6 times higher than that of the conventional QEPAS system. The all-optical quartz-enhanced photoacoustic spectroscopy system is immune to electromagnetic interference, safe in flammable and explosive gas detection, suitable for high temperature and high humidity environments and realizable for long distance, multi-point and network sensing.

Spectral response of fiber-coupled Fabry-Perot etalons.

PubMed

Ionov, Pavel

2014-03-01

In many remote sensing applications one or multiple Fabry-Perot etalons are used as high-spectral-resolution filter elements. These etalons are often coupled to a receiving telescope with a multimode fiber, leading to subtle effects of the fiber mode order on the overall spectral response of the system. A theoretical model is developed to treat the spectral response of the combined system: fiber, collimator, and etalon. The method is based on a closed-form expression of the diffracted mode in terms of a Hankel transform. In this representation, it is shown how the spectral effect of the fiber and collimator can be separated from the details of the etalon and can be viewed as a mode-dependent spectral broadening and shift.

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

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.

Measurement of the carrier envelope offset frequency of a femtosecond frequency comb using a Fabry-Perot interferometer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Basnak, D V; Bikmukhametov, K A; Dmitrieva, N I

2010-10-15

A method for measuring the carrier envelope offset (CEO) frequency of the femtosecond frequency comb with a bandwidth of less than one octave by using a Fabry-Perot interferometer is proposed and experimentally demonstrated. (laser components)

High-precision thermal expansion measurements using small Fabry-Perot etalons

NASA Astrophysics Data System (ADS)

Davis, Mark J.; Hayden, Joseph S.; Farber, Daniel L.

2007-09-01

Coefficient of thermal expansion (CTE) measurements using small Fabry-Perot etalons were conducted on high and low thermal expansion materials differing in CTE by a factor of nearly 400. The smallest detectable change in length was ~10 -12 m. The sample consisted of a mm-sized Fabry-Perot etalon equipped with spherical mirrors; the material-under-test served as the 2.5 mm-thick spacer between the mirrors. A heterodyne optical setup was used with one laser locked to an ~780 nm hyperfine line of Rb gas and the other locked to a resonance of the sample etalon; changes in the beat frequency between the two lasers as a function of temperature directly provided a CTE value. The measurement system was tested using the high-CTE SCHOTT optical glass N-KF9 (CTE = 9.5 ppm/K at 23 °C). Measurements conducted under reproducibility conditions using five identically-prepared N-KF9 etalons demonstrate a precision of 0.1 ppm/K; absolute values (accuracy) are within 2-sigma errors with those made using mechanical dilatometers with 100-mm long sample rods. Etalon-based CTE measurements were also made on a high-CTE (~10.5 ppm/K), proprietary glass-ceramic used for high peak-pressure electrical feedthroughs and revealed statistically significant differences among parts made under what were assumed to be identical conditions. Finally, CTE measurements were made on etalons constructed from SCHOTT's ultra-low CTE Zerodur (R) glass-ceramic (CTE about -20 ppb/K at 50 °C for the material tested herein).

Simple interrogator for optical fiber-based white light Fabry-Perot interferometers.

PubMed

Yu, Zhihao; Tian, Zhipeng; Wang, Anbo

2017-02-15

In this Letter, we present the design of a simple signal interrogator for optical fiber-based white light Fabry-Perot (F-P) interferometers. With the hardware being composed of only a flat fused silica wafer and a CCD camera, this interrogator translates the spectral interference into a spatial interference pattern, and then demodulates the F-P cavity length with the use of a relatively simple demodulation algorithm. The concept is demonstrated experimentally in a fiber optic sensor with a sapphire wafer as the F-P cavity.

Two-wavelength quadrature multipoint detection of partial discharge in power transformers using fiber Fabry-Perot acoustic sensors

NASA Astrophysics Data System (ADS)

Dong, Bo; Han, Ming; Wang, Anbo

2012-06-01

A reliable and low-cost two-wavelength quadrature interrogating method has been developed to demodulate optical signals from diaphragm-based Fabry-Perot interferometric fiber optic sensors for multipoint partial discharge detection in power transformers. Commercial available fused-silica parts (a wafer, a fiber ferrule, and a mating sleeve) and a cleaved optical single mode fiber were bonded together to form an extrinsic Fabry-Perot acoustic sensor. Two lasers with center wavelengths separated by a quarter of the period of sensor interference fringes were used to probe acousticwave- induced diaphragm vibration. A coarse wavelength-division multiplexing (CWDM) add/drop multiplexer was used to separate the reflected two wavelengths before two photo detectors. Optical couplers were used to distribute mixed laser light to each sensor-detector module for multiplexing purpose. Sensor structure, detection system design and experiment results are presented.

Fiber Optic Fabry-Perot Current Sensor Integrated with Magnetic Fluid Using a Fiber Bragg Grating Demodulation

PubMed Central

Xia, Ji; Wang, Qi; Liu, Xu; Luo, Hong

2015-01-01

An optical fiber current sensor based on Fabry-Perot interferometer using a fiber Bragg grating demodulation is proposed. Magnetic fluid is used as a sensitive medium in fiber optical Fabry-Perot (F-P) cavity for the optical characteristic of magnetic-controlled refractive index. A Fiber Bragg grating (FBG) is connected after the F-P interferometer which is used to reflect the optical power at the Bragg wavelength of the interference transmission spectrum. The corresponding reflective power of the FBG will change with different external current intensity, due to the shift on the interference spectrum of the F-P interferometer. The sensing probe has the advantages of convenient measurement for its demodulation, low cost and high current measurement accuracy on account of its sensing structure. Experimental results show that an optimal sensitivity of 0.8522 nw/A and measurement resolution of 0.001 A is obtained with a FBG at 1550 nm with 99% reflectivity. PMID:26184201

Fiber Optic Fabry-Perot Current Sensor Integrated with Magnetic Fluid Using a Fiber Bragg Grating Demodulation.

PubMed

Xia, Ji; Wang, Qi; Liu, Xu; Luo, Hong

2015-07-09

An optical fiber current sensor based on Fabry-Perot interferometer using a fiber Bragg grating demodulation is proposed. Magnetic fluid is used as a sensitive medium in fiber optical Fabry-Perot (F-P) cavity for the optical characteristic of magnetic-controlled refractive index. A Fiber Bragg grating (FBG) is connected after the F-P interferometer which is used to reflect the optical power at the Bragg wavelength of the interference transmission spectrum. The corresponding reflective power of the FBG will change with different external current intensity, due to the shift on the interference spectrum of the F-P interferometer. The sensing probe has the advantages of convenient measurement for its demodulation, low cost and high current measurement accuracy on account of its sensing structure. Experimental results show that an optimal sensitivity of 0.8522 nw/A and measurement resolution of 0.001 A is obtained with a FBG at 1550 nm with 99% reflectivity.

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.

Hyperspectral Infrared Imaging of Flames Using a Spectrally Scanning Fabry-Perot Filter

NASA Technical Reports Server (NTRS)

Rawlins, W. T.; Lawrence, W. G.; Marinelli, W. J.; Allen, M. G.; Piltch, N. (Technical Monitor)

2001-01-01

The temperatures and compositions of gases in and around flames can be diagnosed using infrared emission spectroscopy to observe molecular band shapes and intensities. We have combined this approach with a low-order scanning Fabry-Perot filter and an infrared camera to obtain spectrally scanned infrared emission images of a laboratory flame and exhaust plume from 3.7 to 5.0 micrometers, at a spectral resolution of 0.043 micrometers, and a spatial resolution of 1 mm. The scanning filter or AIRIS (Adaptive Infrared Imaging Spectroradiometer) is a Fabry-Perot etalon operating in low order (mirror spacing = wavelength) such that the central spot, containing a monochromatic image of the scene, is viewed by the detector array. The detection system is a 128 x 128 liquid-nitrogen-cooled InSb focal plane array. The field of view is controlled by a 50 mm focal length multielement lens and an V4.8 aperture, resulting in an image 6.4 x 6.4 cm in extent at the flame and a depth of field of approximately 4 cm. Hyperspectral images above a laboratory CH4/air flame show primarily the strong emission from CO2 at 4.3 micrometers, and weaker emissions from CO and H2O. We discuss techniques to analyze the spectra, and plans to use this instrument in microgravity flame spread experiments.

Functional analysis of variant lysosomal acid glycosidases of Anderson-Fabry and Pompe disease in a human embryonic kidney epithelial cell line (HEK 293 T).

PubMed

Ebrahim, Hatim Y; Baker, Robert J; Mehta, Atul B; Hughes, Derralynn A

2012-03-01

The functional significance of missense mutations in genes encoding acid glycosidases of lysosomal storage disorders (LSDs) is not always clear. Here we describe a method of investigating functional properties of variant enzymes in vitro using a human embryonic kidney epithelial cell line. Site-directed mutagenesis was performed on the parental plasmids containing cDNA encoding for alpha-galactosidase A (α-Gal A) and acid maltase (α-Glu) to prepare plasmids encoding relevant point mutations. Mutant plasmids were transfected into HEK 293 T cells, and transient over-expression of variant enzymes was measured after 3 days. We have illustrated the method by examining enzymatic activities of four unknown α-Gal A and one α-Glu variants identified in our patients with Anderson-Fabry disease and Pompe diseases respectively. Comparison with control variants known to be either pathogenic or non-pathogenic together with over-expression of wild-type enzyme allowed determination of the pathogenicity of the mutation. One leader sequence novel variant of α-Gal A (p.A15T) was shown not to significantly reduce enzyme activity, whereas three other novel α-Gal A variants (p.D93Y, p.L372P and p.T410I) were shown to be pathogenic as they resulted in significant reduction of enzyme activity. A novel α-Glu variant (p.L72R) was shown to be pathogenic as this significantly reduced enzyme activity. Certain acid glycosidase variants that have been described in association with late-onset LSDs and which are known to have variable residual plasma and leukocyte enzyme activity in patients appear to show intermediate to low enzyme activity (p.N215S and p.Q279E α-Gal A respectively) in the over-expression system.

Refractive index and absorption detector for liquid chromatography based on Fabry-Perot interferometry

DOEpatents

Yeung, E.S.; Woodruff, S.D.

1984-06-19

A refractive index and absorption detector are disclosed for liquid chromatography. It is based in part on a Fabry-Perot interferometer and is used for the improved detection of refractive index and absorption. It includes a Fabry-Perot interferometer having a normally fixed first partially reflecting mirror and a movable second partially reflecting mirror. A chromatographic flow-cell is positioned between the mirrors along the optical axis of a monochromatic laser beam passing through the interferometer. A means for deriving information about the interference fringes coming out of the interferometer is used with a mini-computer to compute the refractive index of the specimen injected into the flow cell. The minicomputer continuously scans the interferometer for continuous refractive index readings and outputs the continuous results of the scans on a chart recorder. The absorption of the specimen can concurrently be scanned by including a second optical path for an excitation laser which will not interfere with the first laser, but will affect the specimen so that absorption properties can be detected. By first scanning for the refractive index of the specimen, and then immediately adding the excitation laser and subsequently scanning for the refractive index again, the absorption of the specimen can be computed and recorded. 10 figs.

Refractive index and absorption detector for liquid chromatography based on Fabry-Perot interferometry

DOEpatents

Yeung, Edward S.; Woodruff, Steven D.

1984-06-19

A refractive index and absorption detector for liquid chromatography. It is based in part on a Fabry-Perot interferometer and is used for the improved detection of refractive index and absorption. It includes a Fabry-Perot interferometer having a normally fixed first partially reflecting mirror and a movable second partially reflecting mirror. A chromatographic flow-cell is positioned between the mirrors along the optical axis of a monochromatic laser beam passing through the interferometer. A means for deriving information about the interference fringes coming out of the interferometer is used with a mini-computer to compute the refractive index of the specimen injected into the flow cell. The minicomputer continuously scans the interferometer for continuous refractive index readings and outputs the continuous results of the scans on a chart recorder. The absorption of the specimen can concurrently be scanned by including a second optical path for an excitation laser which will not interfere with the first laser, but will affect the specimen so that absorption properties can be detected. By first scanning for the refractive index of the specimen, and then immediately adding the excitation laser and subsequently scanning for the refractive index again, the absorption of the specimen can be computed and recorded.

Modeling of low-finesse, extrinsic fiber optic Fabry-Perot white light interferometers

NASA Astrophysics Data System (ADS)

Ma, Cheng; Tian, Zhipeng; Wang, Anbo

2012-06-01

This article introduces an approach for modeling the fiber optic low-finesse extrinsic Fabry-Pérot Interferometers (EFPI), aiming to address signal processing problems in EFPI demodulation algorithms based on white light interferometry. The main goal is to seek physical interpretations to correlate the sensor spectrum with the interferometer geometry (most importantly, the optical path difference). Because the signal demodulation quality and reliability hinge heavily on the understanding of such relationships, the model sheds light on optimizing the sensor performance.

Use of complementary and alternative medicine by patients with lysosomal storage diseases.

PubMed

Balwani, Manisha; Fuerstman, Laura; Desnick, Robert J; Buckley, Brian; McGovern, Margaret M

2009-10-01

To evaluate the extent of complementary and alternative medicine use and perceived effectiveness in patients with lysosomal storage diseases. A 26-item survey was distributed to 495 patients with type 1 Gaucher, Fabry, and type B Niemann-Pick diseases who were seen at the Lysosomal Storage Disease Program at the Mount Sinai School of Medicine. Survey responses were entered into an access database and analyzed using descriptive statistics. Surveys were completed by 167 respondents with an overall response rate of 34%. Complementary and alternative medicines were used by 45% of patients with type 1 Gaucher disease, 41% of patients with Fabry disease, and 47% of patients with type B Niemann-Pick for symptoms related to their disease. Complementary and alternative medicines were used most frequently by adult females (55%), in patients who reported having one or more invasive procedures due to their disease, patients who use one or more conventional medical therapies, or those with depression and/or anxiety. Overall perceived effectiveness of complementary and alternative medicine supplements was low; however, complementary and alternative medicine therapies were perceived as effective. Complementary and alternative medicines are commonly used among patients with lysosomal storage diseases. Assessment of the effectiveness of these approaches in the lysosomal storage diseases is needed, and physicians should be aware of complementary and alternative medicine therapies used by patients to evaluate safety and possible drug interactions.

Fiber Fabry-Perot Interferometric Sensor for the Measurement of Electric Current Flowing through a Fuse

NASA Astrophysics Data System (ADS)

Park, Jaehee

2007-06-01

A fiber Fabry-Perot inteferometric sensor bonded close to a fusing element has been studied for the measurement of electric current flowing through a fuse. The phase shift of the sensor output signal is proportional to the square of the electric current passing through the fuse and the sensitivity is 0.827°/mA2.

A sensitive and stable confocal Fabry-Pérot interferometer for surface ultrasonic vibration detection

NASA Astrophysics Data System (ADS)

Ding, Hong-sheng; Tong, Li-ge; Chen, Geng-hua

2001-08-01

A new confocal Fabry-Pérot interferometer (CFPI) has been constructed. By using both of the conjugate rays, the sensitivity of the system was doubled. Moreover, the negative feedback control loop of a single-chip microcomputer (MCS-51) was applied to stabilize the working point at an optimum position. The system has been used in detecting the piezoelectric ultrasonic vibration on the surface of an aluminium sample.

Enhanced Bulk-Edge Coulomb Coupling in Fractional Fabry-Perot Interferometers.

PubMed

von Keyserlingk, C W; Simon, S H; Rosenow, Bernd

2015-09-18

Recent experiments use Fabry-Perot (FP) interferometry to claim that the ν=5/2 quantum Hall state exhibits non-Abelian topological order. We note that the experiments appear inconsistent with a model neglecting bulk-edge Coulomb coupling and Majorana tunneling, so we reexamine the theory of FP devices. Even a moderate Coulomb coupling may strongly affect some fractional plateaus, but very weakly affect others, allowing us to model the data over a wide range of plateaus. While experiments are consistent with the ν=5/2 state harboring Moore-Read topological order, they may have measured Coulomb effects rather than an "even-odd effect" due to non-Abelian braiding.

Elevated Endomyocardial Biopsy Macrophage-Related Markers in Intractable Myocardial Diseases.

PubMed

Hayashi, Yuka; Hanawa, Haruo; Jiao, Shuang; Hasegawa, Go; Ohno, Yukako; Yoshida, Kaori; Suzuki, Tomoyasu; Kashimura, Takeshi; Obata, Hiroaki; Tanaka, Komei; Watanabe, Tohru; Minamino, Tohru

2015-12-01

Tissue macrophages can be activated by endogenous danger signals released from cells that are stressed or injured, leading to infiltration of inflammatory macrophages and neutrophils. We postulated that macrophage-related markers might be closely associated with the existence of endogenous danger signals, reflecting ongoing tissue injury in the absence of foreign substances. This study was designed to assess the ability of macrophage-related markers in endomyocardial biopsies to predict ongoing cardiac injury in non-inflammatory myocardial diseases. We examined levels of macrophage-related markers (CD68, CD163, CD45) in endomyocardial biopsies from patients (n = 86) with various myocardial diseases by quantitative reverse transcription-polymerase chain reaction (n = 78) and immunohistochemistry (n = 56). Thirty-three patients without inflammatory cardiac disease such as myocarditis and sarcoidosis were classified as "improved" or "non-improved" defined as a 10% increase in left ventricular ejection fraction by echocardiograph and a value greater than 30% at the time of follow-up. All macrophage-related (MacR) markers levels were not higher in non-improved dilated cardiomyopathy (DCM) patients than improved patients. However, patients with cardiac amyloidosis, cardiac Fabry disease, mitochondrial cardiomyopathy, and biventricular arrhythmogenic right ventricular cardiomyopathy (ARVC), which were categorized as "non-improvement diseases," had elevated macrophage-related markers compared to improved patients. Macrophage-related markers levels were increased in endomyocardial biopsy samples of patients with intractable myocardial diseases such as amyloidosis, mitochondrial disease, Fabry disease, and biventricular ARVC.

Faraday-Active Fabry-Perot Resonator: Transmission, Reflection, and Emissivity

NASA Technical Reports Server (NTRS)

Liptuga, Anatoliy; Morozhenko, Vasyl; Pipa, Viktor; Venger, Evgen; Kostiuk, Theodor

2011-01-01

The propagation of light within a semiconductor Faraday-active Fabry-Perot resonator (FAFR) is investigated theoretically and experimentally. It is shown that an external magnetic field radically changes the angular and spectral characteristics of transmission, reflection and emissivity of the resonator not only for polarized, but also for unpolarized light. Suppression of interference patterns and phase inversion of the interference extrema were observed in both monochromatic and polychromatic light. The investigations were carried out for the plane-parallel plates of n-InAs in the spectral range of free charge carrier absorption. The results can be used to create new controllable optical and spectroscopic devices for investigation of Faraday-active material properties and for control of parameters of plane-parallel layers and structures.

A Fabry-Perot interferometric imaging spectrometer in LWIR

NASA Astrophysics Data System (ADS)

Zhang, Fang; Gao, Jiaobo; Wang, Nan; Wu, Jianghui; Meng, Hemin; Zhang, Lei; Gao, Shan

2017-02-01

With applications ranging from the desktop to remote sensing, the long wave infrared (LWIR) interferometric spectral imaging system is always with huge volume and large weight. In order to miniaturize and light the instrument, a new method of LWIR spectral imaging system based on a variable gap Fabry-Perot (FP) interferometer is researched. With the system working principle analyzed, theoretically, it is researched that how to make certain the primary parameter, such as, wedge angle of interferometric cavity, f-number of the imaging lens and the relationship between the wedge angle and the modulation of the interferogram. A prototype is developed and a good experimental result of a uniform radiation source, a monochromatic source, is obtained. The research shows that besides high throughput and high spectral resolution, the advantage of miniaturization is also simultaneously achieved in this method.

HTS Fabry-Perot resonators for the far infrared

NASA Astrophysics Data System (ADS)

Keller, Philipp; Prenninger, Martin; Pechen, Evgeny V.; Renk, Karl F.

1996-06-01

We report on far infrared (FIR) Fabry-Perot resonators (FPR) with high temperature superconductor (HTS) thin films as mirrors. For the fabrication of FPR we use two parallel MgO plates covered with YBa2Cu3O7-delta thin films on adjacent sides. We have measured the far-infrared transmissivity at 10 K with a Fourier transform infrared spectrometer. Very sharp resonances can be observed for frequencies below 6 THz where the MgO is transparent. The finesse (width of the first order resonance) is comparable to the FPR with metallic meshes as reflectors that are applied in the FIR spectroscopy and astronomy. We have also shown that thin films of gold are not adequate substitute to HTS thin films and not suitable for the fabrication of high-quality FPR due to the ohmic losses.

A Fabry-Perot spectrometer for high-resolution observation of the Sun

NASA Astrophysics Data System (ADS)

Kneer, F.; Hirzberger, H.

2001-12-01

Fabry-Perot interferometers (FPIs) are powerful instruments for spectro-polarimetry of the Sun with high spatial resolution. They allow easy image reconstruction of two-dimensional fields of view. Some examples of high quality results obtained with the ``Göttingen'' FPI spectrometer, mounted in the Vacuum Tower Telescope at the Observatorio del Teide/Tenerife, are presented in a poster to this workshop. We thus concentrate on the design of a new instrument for the 1.5 m GREGOR solar telescope. We discuss the pros and cons of telecentric and collimated mounting and describe the expected performance, especially the spectral resolution, of our design.

High precision optical fiber Fabry-Perot sensor for gas pressure detection

NASA Astrophysics Data System (ADS)

Mao, Yan; Tong, Xing-lin

2013-09-01

An optical fiber Fabry-Perot (F-P) sensor with quartz diaphragm for gas pressure testing was designed and fabricated. It consisted of single-mode fiber, hollow glass tube and quartz diaphragm. It uses the double peak demodulation to obtain the initialized cavity length. The variety of cavity length can be calcultated by the single peak demodulation after changing the gas pressure. The results show that the sensor is small in size, whose sensitivity is 19 pm/kPa in the range of the 10 ~ 260 kPa gas pressure. And it has good linearity and repeatability.

Downstream Fabry-Perot interferometer for acoustic wave monitoring in photoacoustic tomography.

PubMed

Nuster, Robert; Gruen, Hubert; Reitinger, Bernhard; Burgholzer, Peter; Gratt, Sibylle; Passler, Klaus; Paltauf, Guenther

2011-03-15

An optical detection setup consisting of a focused laser beam fed into a downstream Fabry-Perot interferometer (FPI) for demodulation of acoustically generated optical phase variations is investigated for its applicability in photoacoustic tomography. The device measures the time derivative of acoustic signals integrated along the beam. Compared to a setup where the detection beam is part of a Mach-Zehnder interferometer, the signal-to-noise ratio of the FPI is lower, but the image quality of the two devices is similar. Using the FPI in a photoacoustic tomograph allows scanning the probe beam around the imaging object without moving the latter.

Fiber Fabry-Perot interferometer sensor for measuring resonances of piezoelectric elements

NASA Astrophysics Data System (ADS)

da Silva, Ricardo E.; Oliveira, Roberson A.; Pohl, Alexandre A. P.

2011-05-01

The development of a fiber extrinsic Fabry-Perot interferometer for measuring vibration amplitude and resonances of piezoelectric elements is reported. The signal demodulation method based on the use of an optical spectrum analyzer allows the measurement of displacements and resonances with high resolution. The technique consists basically in monitoring changes in the intensity or the wavelength of a single interferometric fringe at a point of high sensitivity in the sensor response curve. For sensor calibration, three signal processing techniques were employed. Vibration amplitude measurement with 0.84 nm/V sensitivity and the characterization of the piezo resonance is demonstrated.

Photonic crystal fiber Fabry-Perot interferometers with high-reflectance internal mirrors

NASA Astrophysics Data System (ADS)

Fan, Rong; Hou, Yuanbin; Sun, Wei

2015-06-01

We demonstrated an in-line micro fiber-optic Fabry-Perot interferometer with an air cavity which was created by multi-step fusion splicing a muti-mode photonic crystal fiber (MPCF) to a standard single mode fiber (SMF). The fringe visibility of the interference pattern was up to 20 dB by reshaping the air cavity. Experimental results showed that such a device could be used as a highly sensitive strain sensor with the sensitivity of 4.5 pm/μɛ. Moreover, it offered some other outstanding advantages, such as the extremely compact structure, easy fabrication, low cost, and high accuracy.

Modified Fabry-Perot interferometer for displacement measurement in ultra large measuring range

NASA Astrophysics Data System (ADS)

Chang, Chung-Ping; Tung, Pi-Cheng; Shyu, Lih-Horng; Wang, Yung-Cheng; Manske, Eberhard

2013-05-01

Laser interferometers have demonstrated outstanding measuring performances for high precision positioning or dimensional measurements in the precision industry, especially in the length measurement. Due to the non-common-optical-path structure, appreciable measurement errors can be easily induced under ordinary measurement conditions. That will lead to the limitation and inconvenience for in situ industrial applications. To minimize the environmental and mechanical effects, a new interferometric displacement measuring system with the common-optical-path structure and the resistance to tilt-angle is proposed. With the integration of optomechatronic modules in the novel interferometric system, the resolution up to picometer order, high precision, and ultra large measuring range have been realized. For the signal stabilization of displacement measurement, an automatic gain control module has been proposed. A self-developed interpolation model has been employed for enhancing the resolution. The novel interferometer can hold the advantage of high resolution and large measuring range simultaneously. By the experimental verifications, it has been proven that the actual resolution of 2.5 nm can be achieved in the measuring range of 500 mm. According to the comparison experiments, the maximal standard deviation of the difference between the self-developed Fabry-Perot interferometer and the reference commercial Michelson interferometer is 0.146 μm in the traveling range of 500 mm. With the prominent measuring characteristics, this should be the largest dynamic measurement range of a Fabry-Perot interferometer up till now.

VTT's Fabry-Perot interferometer technologies for hyperspectral imaging and mobile sensing applications

NASA Astrophysics Data System (ADS)

Rissanen, Anna; Guo, Bin; Saari, Heikki; Näsilä, Antti; Mannila, Rami; Akujärvi, Altti; Ojanen, Harri

2017-02-01

VTT's Fabry-Perot interferometers (FPI) technology enables creation of small and cost-efficient microspectrometers and hyperspectral imagers - these robust and light-weight sensors are currently finding their way into a variety of novel applications, including emerging medical products, automotive sensors, space instruments and mobile sensing devices. This presentation gives an overview of our core FPI technologies with current advances in generation of novel sensing applications including recent mobile technology demonstrators of a hyperspectral iPhone and a mobile phone CO2 sensor, which aim to advance mobile spectroscopic sensing.

Fiber Fabry-Perot sensors for detection of partial discharges in power transformers.

PubMed

Yu, Bing; Kim, Dae Woong; Deng, Jiangdong; Xiao, Hai; Wang, Anbo

2003-06-01

A diaphragm-based interferometric fiberoptic sensor that uses a low-coherence light source was designed and tested for on-line detection of the acoustic waves generated by partial discharges inside high-voltage power transformers. The sensor uses a fused-silica diaphragm and a single-mode optical fiber encapsulated in a fused-silica glass tube to form an extrinsic Fabry-Perot interferometer, which is interrogated by low-coherence light. Test results indicate that these fiber optic acoustic sensors are capable of faithfully detecting acoustic signals propagating inside transformer oil with high sensitivity and wide bandwidth.

Single resonance monolithic Fabry-Perot filters formed by volume Bragg gratings and multilayer dielectric mirrors

NASA Astrophysics Data System (ADS)

Lumeau, Julien; Koc, Cihan; Mokhun, Oleksiy; Smirnov, Vadim; Lequime, Michel; Glebov, Leonid B.

2012-02-01

High efficiency reflecting volume Bragg gratings (VBGs) recorded in PTR glass plates have shown un-preceded performances that make them very good candidates for narrowband spectral filtering with sub-nanometer spectral widths. However, decreasing the bandwidth to value below 30-50 pm is very challenging as it requires increasing the thickness of the RBG to more than 15-20 mm. To overcome this limitation, we propose a new approach which is a monolithic Fabry-Perot cavity which consists from a reflecting VBG with a multilayer dielectric mirror (MDM) deposited on its surface. A VBG with a grating vector perpendicular to its surface and a MDM produce a Fabry-Perot resonator with a single transmission band inside of the reflection spectrum of the VBG. We present a theoretical description of this new class of filters that allow achieving a single ultra-narrowband resonance associated with several hundred nanometers rejection band. Then we show the methods for designing and fabricating such filter. Finally, we present the steps that we followed in order to fabricate a first prototype for 852 nm and 1062 nm region that demonstrates a 30 pm bandwidth, 90+% transmission at resonance and a good agreement with theoretical simulation.

High quality factor surface Fabry-Perot cavity of acoustic waves

NASA Astrophysics Data System (ADS)

Xu, Yuntao; Fu, Wei; Zou, Chang-ling; Shen, Zhen; Tang, Hong X.

2018-02-01

Surface acoustic wave (SAW) resonators are critical components in wireless communications and many sensing applications. They have also recently emerged as a subject of study in quantum acoustics at the single phonon level. Acoustic loss reduction and mode confinement are key performance factors in SAW resonators. Here, we report the design and experimental realization of high quality factor Fabry-Perot SAW resonators formed in between the tapered phononic crystal mirrors patterned on a GaN-on-sapphire material platform. The fabricated SAW resonators are characterized by both an electrical network analyzer and an optical heterodyne vibrometer. We observed standing Rayleigh waves inside the cavity, with an intrinsic quality factor exceeding 1.3 × 104 at ambient conditions.

Proton and gamma irradiation of Fabry-Perot quantum cascade lasers for space qualification

DOE PAGES

Myers, Tanya L.; Cannon, Bret D.; Brauer, Carolyn S.; ...

2015-01-20

Fabry-Perot quantum cascade lasers (QCLs) were characterized following irradiation by high energy (64 MeV) protons and Cobalt-60 gamma rays. Seven QCLs were exposed to radiation dosages that are typical for a space mission in which the total accumulated dosages from both radiation sources varied from 20 krad(Si) to 46.3 krad(Si). In conclusion, the QCLs did not show any measurable changes in threshold current or slope efficiency suggesting the suitability of QCLs for use in space-based missions.

Use of Myocardial T1 Mapping at 3.0 T to Differentiate Anderson-Fabry Disease from Hypertrophic Cardiomyopathy.

PubMed

Karur, Gauri R; Robison, Sean; Iwanochko, Robert M; Morel, Chantal F; Crean, Andrew M; Thavendiranathan, Paaladinesh; Nguyen, Elsie T; Mathur, Shobhit; Wasim, Syed; Hanneman, Kate

2018-04-24

Purpose To compare left ventricular (LV) and right ventricular (RV) 3.0-T cardiac magnetic resonance (MR) imaging T1 values in Anderson-Fabry disease (AFD) and hypertrophic cardiomyopathy (HCM) and evaluate the diagnostic value of native T1 values beyond age, sex, and conventional imaging features. Materials and Methods For this prospective study, 30 patients with gene-positive AFD (37% male; mean age ± standard deviation, 45.0 years ± 14.1) and 30 patients with HCM (57% male; mean age, 49.3 years ± 13.5) were prospectively recruited between June 2016 and September 2017 to undergo cardiac MR imaging T1 mapping with a modified Look-Locker inversion recovery (MOLLI) acquisition scheme at 3.0 T (repetition time msec/echo time msec, 280/1.12; section thickness, 8 mm). LV and RV T1 values were evaluated. Statistical analysis included independent samples t test, receiver operating characteristic curve analysis, multivariable logistic regression, and likelihood ratio test. Results Septal LV, global LV, and RV native T1 values were significantly lower in AFD compared with those in HCM (1161 msec ± 47 vs 1296 msec ± 55, respectively [P < .001]; 1192 msec ± 52 vs 1268 msec ± 55 [P < .001]; and 1221 msec ± 54 vs 1271 msec ± 37 [P = .001], respectively). A septal LV native T1 cutoff point of 1220 msec or lower distinguished AFD from HCM with sensitivity of 97%, specificity of 93%, and accuracy of 95%. Septal LV native T1 values differentiated AFD from HCM after adjustment for age, sex, and conventional imaging features (odds ratio, 0.94; 95% confidence interval: 0.91, 0.98; P = < .001). In a nested logistic regression model with age, sex, and conventional imaging features, model fit was significantly improved by the addition of septal LV native T1 values (χ 2 [df = 1] = 33.4; P < .001). Conclusion Cardiac MR imaging native T1 values at 3.0 T are significantly lower in patients with AFD compared with those with HCM and provide independent and incremental diagnostic

Evaluation of a Magneto-optical Filter and a Fabry-perot Interferometer for the Measurement of Solar Velocity Fields from Space

NASA Technical Reports Server (NTRS)

Rhodes, E. J., Jr.; Cacciani, A.; Blamont, J.; Tomczyk, S.; Ulrich, R. K.; Howard, R. F.

1984-01-01

A program was developed to evaluate the performance of three different devices as possible space-borne solar velocity field imagers. Two of these three devices, a magneto-optical filter and a molecular adherence Fabry-Perot interferometer were installed in a newly-constructed observing system located at the 60-foot tower telescope at the Mt. Wilson Observatory. Time series of solar filtergrams and Dopplergrams lasting up to 10 hours per day were obtained with the filter while shorter runs were obtained with the Fabry-Perot. Two-dimensional k (sub h)-omega power spectra which show clearly the well-known p-mode ridges were computed from the time series obtained with the magneto-optical filter. These power spectra were compared with similar power spectra obtained recently with the 13.7-m McMath spectrograph at Kitt Peak.

Transversely coupled Fabry-Perot resonators with Bragg grating reflectors.

PubMed

Saber, Md Ghulam; Wang, Yun; El-Fiky, Eslam; Patel, David; Shahriar, Kh Arif; Alam, Md Samiul; Jacques, Maxime; Xing, Zhenping; Xu, Luhua; Abadía, Nicolás; Plant, David V

2018-01-01

We design and demonstrate Fabry-Perot resonators with transverse coupling using Bragg gratings as reflectors on the silicon-on-insulator (SOI) platform. The effects of tailoring the cavity length and the coupling coefficient of the directional coupler on the spectral characteristics of the device are studied. The fabricated resonators achieved an extinction ratio (ER) of 37.28 dB and a Q-factor of 3356 with an effective cavity length of 110 μm, and an ER of 8.69 dB and a Q-factor of 23642 with a 943 μm effective cavity length. The resonator structure presented here has the highest reported ER on SOI and provides additional degrees of freedom compared to an all-pass ring resonator to tune the spectral characteristics.

GHGSat-D: Greenhouse gas plume imaging and quantification from space using a Fabry-Perot imaging spectrometer

NASA Astrophysics Data System (ADS)

McKeever, J.; Durak, B. O. A.; Gains, D.; Jervis, D.; Varon, D. J.; Germain, S.; Sloan, J. J.

2017-12-01

GHGSat, Inc. has launched the first satellite designed to detect and quantify greenhouse gas emissions from individual industrial sites. Our demonstration satellite GHGSat-D or "CLAIRE" was launched in June 2016. It weighs less than 15 kg and its primary instrument is a miniaturized Fabry-Perot imaging spectrometer with spectral resolution on the order of 0.1 nm. The spectral bandpass is 1635-1670 nm, giving the instrument access to absorption bands of both CO2 and CH4. Our system is based on targeted observations rather than global coverage, and our spatial imaging resolution is a key differentiator. Specifically, with a ground sampling distance of <50 m within a 12 km field of view, we are able to spatially resolve the increased column densities associated with individual emission plumes. For a given emission rate and wind speed the magnitude of the local excess column increases approximately linearly as pixel resolution decreases. Consequently, at GHGSat's resolution the total column can exceed local background by well over 10% for many industrial sites with strong but realistic emission rates. GHGSat uses a novel measurement and retrievals concept where the emitter site of interest is captured in a sequence of 150-200 overlapping two-dimensional images. The combined effect of the Fabry-Perot resonator and the scrolling scene gives a different spectral sampling of each surface location in every image. While our data processing toolchain does not produce a conventional hyperspectral dataset, it does yield a spectral decomposition of the spatially resolved signal that is compared to a model that includes atmospheric radiative transfer and the instrument's pixel-dependent spectral responsivity. Our presentation will describe the instrument design, concept of operations and retrievals approach. We will also present images and results from GHGSat-D at different processing levels, including high-resolution column density retrievals. An observation of the degassing

Fabry-Perot Interferometer for Column CO2

NASA Technical Reports Server (NTRS)

Heaps, William S.; Kawa, Randolph; Bhartia, P. K. (Technical Monitor)

2002-01-01

Global atmospheric CO2 measurements are essential to resolving significant discrepancies in our understanding of the global carbon budget and, hence, humankind's role in global climate change. The science measurement requirements for CO2 are extremely demanding (precision approx. 0.3%). No atmospheric chemical species has ever been measured from space with this precision. We are developing a novel application of a Fabry-Perot interferometer to detect spectral absorption of reflected sunlight by CO2 and O2 in the atmosphere. Preliminary design studies indicate that the method will be able to achieve the sensitivity and signal-to-noise detection required to measure column CO2 at the target specification. The objective of this program is to construct a prototype instrument for deployment on an aircraft to test the instrument performance and our ability to retrieve the data in the real atmosphere. To date we have assembled a laboratory bench system to begin testing the optical and electronic components. We are also measuring signal and noise levels in actual sunlight to evaluate component performance.

A Fabry-Perot Spectrometer for High-Resolution Observation of the Sun

NASA Astrophysics Data System (ADS)

Kneer, F.; Hirzberger, J.

Fabry-Perot interferometers (FPIs) are powerful instruments for spectro-polarimetry of the Sun with high spatial resolution. They allow easy image reconstruction of two-dimensional narrow-band fields of view. Some examples of high quality results obtained with the ``Göttingen'' FPI spectrometer, mounted in the Vacuum Tower Telescope at the Observatorio del Teide/Tenerife, are presented in a poster to this workshop. We thus concentrate on the design of a new instrument for the 1.5 m GREGOR solar telescope. We discuss the pros and cons of telecentric and collimated mounting and describe the expected performance, especially the spectral resolution, of our design.

Multimode fiber tip Fabry-Perot cavity for highly sensitive pressure measurement.

PubMed

Chen, W P; Wang, D N; Xu, Ben; Zhao, C L; Chen, H F

2017-03-23

We demonstrate an optical Fabry-Perot interferometer fiber tip sensor based on an etched end of multimode fiber filled with ultraviolet adhesive. The fiber device is miniature (with diameter of less than 60 μm), robust and low cost, in a convenient reflection mode of operation, and has a very high gas pressure sensitivity of -40.94 nm/MPa, a large temperature sensitivity of 213 pm/°C within the range from 55 to 85 °C, and a relatively low temperature cross-sensitivity of 5.2 kPa/°C. This device has a high potential in monitoring environment of high pressure.

Genetic background in nonalcoholic fatty liver disease: A comprehensive review

PubMed Central

Macaluso, Fabio Salvatore; Maida, Marcello; Petta, Salvatore

2015-01-01

In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease. PMID:26494964

A polymer-based Fabry-Perot filter integrated with 3-D MEMS structures

NASA Astrophysics Data System (ADS)

Zhang, Ping (Cerina); Le, Kevin; Malalur-Nagaraja-Rao, Smitha; Hsu, Lun-Chen; Chiao, J.-C.

2006-01-01

Polymers have been considered as one of the most versatile materials in making optical devices for communication and sensor applications. They provide good optical transparency to form filters, lenses and many optical components with ease of fabrication. They are scalable and compatible in dimensions with requirements in optics and can be fabricated on inorganic substrates, such as silicon and quartz. Recent polymer synthesis also made great progresses on conductive and nonlinear polymers, opening opportunities for new applications. In this paper, we discussed hybrid-material integration of polymers on silicon-based microelectromechanical system (MEMS) devices. The motivation is to combine the advantages of demonstrated silicon-based MEMS actuators and excellent optical performance of polymers. We demonstrated the idea with a polymer-based out-of-plane Fabry-Perot filter that can be self-assembled by scratch drive actuators. We utilized a fabrication foundry service, MUMPS (Multi-User MEMS Process), to demonstrate the feasibility and flexibility of integration. The polysilicon, used as the structural material for construction of 3-D framework and actuators, has high absorption in the visible and near infrared ranges. Therefore, previous efforts using a polysilicon layer as optical interfaces suffer from high losses. We applied the organic compound materials on the silicon-based framework within the optical signal propagation path to form the optical interfaces. In this paper, we have shown low losses in the optical signal processing and feasibility of building a thin-film Fabry-Perot filter. We discussed the optical filter designs, mechanical design, actuation mechanism, fabrication issues, optical measurements, and results.

Displacement and Strain Measurement up to 1000 °C Using a Hollow Coaxial Cable Fabry-Perot Resonator.

PubMed

Zhu, Chen; Chen, Yizheng; Zhuang, Yiyang; Huang, Jie

2018-04-24

We present a hollow coaxial cable Fabry-Perot resonator for displacement and strain measurement up to 1000 °C. By employing a novel homemade hollow coaxial cable made of stainless steel as a sensing platform, the high-temperature tolerance of the sensor is dramatically improved. A Fabry-Perot resonator is implemented on this hollow coaxial cable by introducing two highly-reflective reflectors along the cable. Based on a nested structure design, the external displacement and strain can be directly correlated to the cavity length of the resonator. By tracking the shift of the amplitude reflection spectrum of the microwave resonator, the applied displacement and strain can be determined. The displacement measurement experiment showed that the sensor could function properly up to 1000 °C. The sensor was also employed to measure the thermal strain of a steel plate during the heating process. The stability of the novel sensor was also investigated. The developed sensing platform and sensing configurations are robust, cost-effective, easy to manufacture, and can be flexibly designed for many other measurement applications in harsh high-temperature environments.

Control of resonant wavelength from organic light-emitting materials by use of a Fabry-Perot microcavity structure.

PubMed

Jung, Boo Young; Kim, Nam Young; Lee, Changhee; Hwangbo, Chang Kwon; Seoul, Chang

2002-06-01

We report the fabrication of Fabry-Perot microcavity structures with the organic light-emitting material tris-(8-hydroxyquinoline) aluminum (Alq3) and derive their optical properties by measuring their photoluminescence (PL) and absorption. Silver and a TiO2-SiO2 multilayer were used as metal and dielectric reflectors, respectively, in a Fabry-Perot microcavity structure. Three types of microcavity were prepared: type A consisted of [air[Ag[Alq3]Ag]glass]; type B, of [air[dielectric[Alq3]dielectric]glass]; and type C, of [air[Ag[Alq2]dielectric]glass]. A bare Alq3 film of [air[Alq3]glass] had its PL peak near 514 nm, and its full width at half-maximum (FWHM) was 80 nm. The broad FWHM of a bare Alq3 film was reduced to 15-27.5, 7-10.5, and 16-16.6 nm for microcavity types A, B, and C, respectively. Also, we could control the PL peak of the microcavity structure by changing the spacer thickness, the amount of phase change on reflection, and the angle of incidence.

Displacement and Strain Measurement up to 1000 °C Using a Hollow Coaxial Cable Fabry-Perot Resonator

PubMed Central

Chen, Yizheng; Zhuang, Yiyang

2018-01-01

We present a hollow coaxial cable Fabry-Perot resonator for displacement and strain measurement up to 1000 °C. By employing a novel homemade hollow coaxial cable made of stainless steel as a sensing platform, the high-temperature tolerance of the sensor is dramatically improved. A Fabry-Perot resonator is implemented on this hollow coaxial cable by introducing two highly-reflective reflectors along the cable. Based on a nested structure design, the external displacement and strain can be directly correlated to the cavity length of the resonator. By tracking the shift of the amplitude reflection spectrum of the microwave resonator, the applied displacement and strain can be determined. The displacement measurement experiment showed that the sensor could function properly up to 1000 °C. The sensor was also employed to measure the thermal strain of a steel plate during the heating process. The stability of the novel sensor was also investigated. The developed sensing platform and sensing configurations are robust, cost-effective, easy to manufacture, and can be flexibly designed for many other measurement applications in harsh high-temperature environments. PMID:29695063

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.

FAST: A near-infrared imaging Fabry-Perot spectrometer

NASA Astrophysics Data System (ADS)

Krabbe, A.; Rotaciuc, V.; Storey, J. W. V.; Cameron, M.; Blietz, M.; Drapatz, S.; Hofmann, R.; Saemann, G.; Genzel, R.

1993-12-01

The near-infrared imaging spectrometer Fabry-Perot Array Spectrometer (FAST) provides a spectral resolution of 1000-2700 over a field of view of approximately 30 x 30 sq arcsec with a plate scale of 0.5-1.0 arcsec/pixel. FAST is based on a SBRC InSb 58 x 62 FPA working at 6 K, yielding a sensitivity 5(sigma), tint = 100 s, K band) of 1.1 x 10-4 erg/s (sq cm) (sr) at R = 1000. As a portable, self-contained instrument FAST has already been successfully deployed at several 2- and 4-m class telescopes. The optical and mechanical design, computer hardware and software control, as well as spectral calibration of the FPI, special treatment of the detectors, and the main data reduction steps are described. The necessity for such a dedicated system in the investigation of line-emission mechanisms in various galactic and extragalactic environments is illustrated by recently obtained results.

Fabry-Perot microcavity sensor for H2-breath-test analysis

NASA Astrophysics Data System (ADS)

Vincenti, Maria Antonietta; De Sario, Marco; Petruzzelli, V.; D'Orazio, Antonella; Prudenzano, Francesco; de Ceglia, Domenico; Scalora, Michael

2007-10-01

Leak detection of hydrogen for medical purposes, based on the monitoring of the optical response of a simple Fabry-Perot microcavity, is proposed to investigate either the occurrence of lactose intolerance, or lactose malabsorption condition. Both pathologic conditions result in bacterial overgrowth in the intestine, which causes increased spontaneous emission of H2 in the human breath. Two sensitivity figures of merit are introduced to inspect changes in the sensor response, and to relate the microcavity response to a pathologic condition, which is strictly related to a different level of exhaled hydrogen. Different sensor configurations using a metal-dielectric microcavity are reported and discussed in order to make the most of the well-known ability of palladium to spontaneously absorb hydrogen.

Linear FBG Temperature Sensor Interrogation with Fabry-Perot ITU Multi-wavelength Reference.

PubMed

Park, Hyoung-Jun; Song, Minho

2008-10-29

The equidistantly spaced multi-passbands of a Fabry-Perot ITU filter are used as an efficient multi-wavelength reference for fiber Bragg grating sensor demodulation. To compensate for the nonlinear wavelength tuning effect in the FBG sensor demodulator, a polynomial fitting algorithm was applied to the temporal peaks of the wavelength-scanned ITU filter. The fitted wavelength values are assigned to the peak locations of the FBG sensor reflections, obtaining constant accuracy, regardless of the wavelength scan range and frequency. A linearity error of about 0.18% against a reference thermocouple thermometer was obtained with the suggested method.

Linear FBG Temperature Sensor Interrogation with Fabry-Perot ITU Multi-wavelength Reference

PubMed Central

Park, Hyoung-Jun; Song, Minho

2008-01-01

The equidistantly spaced multi-passbands of a Fabry-Perot ITU filter are used as an efficient multi-wavelength reference for fiber Bragg grating sensor demodulation. To compensate for the nonlinear wavelength tuning effect in the FBG sensor demodulator, a polynomial fitting algorithm was applied to the temporal peaks of the wavelength-scanned ITU filter. The fitted wavelength values are assigned to the peak locations of the FBG sensor reflections, obtaining constant accuracy, regardless of the wavelength scan range and frequency. A linearity error of about 0.18% against a reference thermocouple thermometer was obtained with the suggested method. PMID:27873898

PCF-based Fabry-Perot interferometric sensor for strain measurement under high-temperature

NASA Astrophysics Data System (ADS)

Deng, Ming; Tang, Chang-Ping; Zhu, Tao; Rao, Yun-Jiang

2011-05-01

We report a simple and robust all-fiber in-line Fabry-Perot interferometer (FPI) with bubble cavity, which is fabricated by directly splicing a mutimode photonic crystal fiber to a conventional single mode fiber by using a commercial splicer. The fabrication process only involves fusion splicing and cleaving. The high-temperature strain characteristic of such a device is evaluated and experimental results shows that this FPI can be used as an ideal sensor for precise strain measurement under high temperatures of up to 750°C. Therefore, such a FPI sensor may find important applications in aeronautics or metallurgy areas.

Enzyme replacement therapy for Anderson-Fabry disease: A complementary overview of a Cochrane publication through a linear regression and a pooled analysis of proportions from cohort studies.

PubMed

El Dib, Regina; Gomaa, Huda; Ortiz, Alberto; Politei, Juan; Kapoor, Anil; Barreto, Fellype

2017-01-01

Anderson-Fabry disease (AFD) is an X-linked recessive inborn error of glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A. Renal failure, heart and cerebrovascular involvement reduce survival. A Cochrane review provided little evidence on the use of enzyme replacement therapy (ERT). We now complement this review through a linear regression and a pooled analysis of proportions from cohort studies. To evaluate the efficacy and safety of ERT for AFD. For the systematic review, a literature search was performed, from inception to March 2016, using Medline, EMBASE and LILACS. Inclusion criteria were cohort studies, patients with AFD on ERT or natural history, and at least one patient-important outcome (all-cause mortality, renal, cardiovascular or cerebrovascular events, and adverse events) reported. The pooled proportion and the confidence interval (CI) are shown for each outcome. Simple linear regressions for composite endpoints were performed. 77 cohort studies involving 15,305 participants proved eligible. The pooled proportions were as follows: a) for renal complications, agalsidase alfa 15.3% [95% CI 0.048, 0.303; I2 = 77.2%, p = 0.0005]; agalsidase beta 6% [95% CI 0.04, 0.07; I2 = not applicable]; and untreated patients 21.4% [95% CI 0.1522, 0.2835; I2 = 89.6%, p<0.0001]. Effect differences favored agalsidase beta compared to untreated patients; b) for cardiovascular complications, agalsidase alfa 28% [95% CI 0.07, 0.55; I2 = 96.7%, p<0.0001]; agalsidase beta 7% [95% CI 0.05, 0.08; I2 = not applicable]; and untreated patients 26.2% [95% CI 0.149, 0.394; I2 = 98.8%, p<0.0001]. Effect differences favored agalsidase beta compared to untreated patients; and c) for cerebrovascular complications, agalsidase alfa 11.1% [95% CI 0.058, 0.179; I2 = 70.5%, p = 0.0024]; agalsidase beta 3.5% [95% CI 0.024, 0.046; I2 = 0%, p = 0.4209]; and untreated patients 18.3% [95% CI 0.129, 0.245; I2 = 95% p < 0.0001]. Effect differences favored agalsidase beta

Biomarkers and Imaging Findings of Anderson–Fabry Disease—What We Know Now

PubMed Central

Beirão, Idalina; Cabrita, Ana; Torres, Márcia; Silva, Fernando; Aguiar, Patrício; Laranjeira, Francisco; Gomes, Ana Marta

2017-01-01

Anderson–Fabry disease (AFD) is an X-linked lysosomal storage disorder, caused by deficiency or absence of the alpha-galactosidase A activity, with a consequent glycosphingolipid accumulation. Biomarkers and imaging findings may be useful for diagnosis, identification of an organ involvement, therapy monitoring and prognosis. The aim of this article is to review the current available literature on biomarkers and imaging findings of AFD patients. An extensive bibliographic review from PubMed, Medline and Clinical Key databases was performed by a group of experts from nephrology, neurology, genetics, cardiology and internal medicine, aiming for consensus. Lyso-GB3 is a valuable biomarker to establish the diagnosis. Proteinuria and creatinine are the most valuable to detect renal damage. Troponin I and high-sensitivity assays for cardiac troponin T can identify patients with cardiac lesions, but new techniques of cardiac imaging are essential to detect incipient damage. Specific cerebrovascular imaging findings are present in AFD patients. Techniques as metabolomics and proteomics have been developed in order to find an AFD fingerprint. Lyso-GB3 is important for evaluating the pathogenic mutations and monitoring the response to treatment. Many biomarkers can detect renal, cardiac and cerebrovascular involvement, but none of these have proved to be important to monitoring the response to treatment. Imaging features are preferred in order to find cardiac and cerebrovascular compromise in AFD patients. PMID:28933368

Versatile tissue lasers based on high-Q Fabry-Pérot microcavities.

PubMed