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  1. Fabry Disease

    MedlinePlus

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

  2. [Fabry disease].

    PubMed

    Boggio, Paula; Luna, Paula Carolina; Abad, María Eugenia; Larralde, Margarita

    2009-01-01

    Fabry disease is an uncommon, X-linked lysosomal storage disorder, caused by partial or complete deficiency of the enzyme a-galactosidase A. The defect leads to accumulation of uncleaved globotriaosylceramide on the vascular endothelium and visceral tissues, being the skin, heart, kidneys and central nervous system the most affected organs. We performed review of the literature related to the disease and emphasized that early recognition of angiokeratomas and hypohidrosis are key diagnostic signs of this serious disease. We also addressed the need of multidisciplinary assessment of these patients.

  3. Fabry disease.

    PubMed

    Schiffmann, Raphael

    2015-01-01

    Fabry disease, an X-linked disorder of glycosphingolipids that is caused by mutations of the GLA gene that codes for α-galactosidase A, leads to dysfunction of many cell types and includes a systemic vasculopathy. As a result, patients have a markedly increased risk of developing ischemic stroke, small-fiber peripheral neuropathy, cardiac dysfunction and chronic kidney disease. Virtually all complications of Fabry disease are non-specific in nature and clinically indistinguishable from similar abnormalities that occur in the context of more common disorders in the general population. Recent studies suggested a much higher incidence of mutations of the GLA gene, suggesting that this disorder is under-diagnosed. However, some of the gene variants may be benign. Although the etiology of Fabry disease has been known for many years, the mechanism by which the accumulating α-D-galactosyl moieties cause this multi organ disorder has only recently been studied and is yet to be completely elucidated. Specific therapy for Fabry disease has been developed in the last few years but its role in the management of the disorder is still being investigated. Fortunately, standard 'non-specific' medical and surgical therapy is effective in slowing deterioration or compensating for organ failure in patients with Fabry disease.

  4. Fabry disease.

    PubMed

    Toyooka, Keiko

    2013-01-01

    Fabry disease results from deficient activity of the enzyme α-galactosidase A and progressive lysosomal deposition of globotriaosylceramide (GL-3) in cells throughout the body. The main neurological presentations of Fabry disease patients are painful neuropathy, hypohidrosis, and stroke. Fabry neuropathy is characterized as a length-dependent peripheral neuropathy affecting mainly the small myelinated (Aδ) fibers and unmyelinated (C) fibers. Enzyme replacement therapy (ERT) has been shown to have some positive effects on the reduction of neuropathic pain, the improvement of detection threshold for thermal sensation, and sweat function. On the contrary, the effect of ERT on the central nervous system has not been established. Early initiation of ERT before irreversible organ failure is extremely important, and alternative therapeutic approaches are currently being explored. Heterozygotes suffer from peripheral neuropathy at a higher rate than previously shown, significant multisystemic disease, and severely decreased quality of life. As well as being carriers, heterozygotes also display symptoms of Fabry disease, and should be carefully monitored and given adequate therapy.

  5. [Fabry disease].

    PubMed

    Stephan, F; Haber, R

    2017-02-01

    Fabry disease, also known as Anderson-Fabry disease or angiokeratoma corporis diffusum universale, is an X-linked recessive form of sphingolipidosis caused by total or partial deficiency of the lysosomal hydrolase, alpha-galactosidase A. From the youngest age, it results in a gradual ubiquitous build-up of glycosphingolipids that are not degraded by the missing enzyme. Cutaneous, neurological, nephrologic, cardiac, gastrointestinal, ophthalmological, respiratory, cochleovestibular and haematological involvement are responsible for increased mortality and significant impairment of quality of life in subjects affected by the disease. Angiokeratomas are the most common cutaneous sign of this disease, although they are not specific to it and must be distinguished from angiokeratomas either occurring in isolation or associated with systemic diseases. Other cutaneous signs encountered in this disease include hyperhidrosis, oral lesions, lower limb oedemas, etc. The diagnosis is mainly clinical and should be considered in the presence of a personal and/or familial history; it is confirmed by assay of enzyme activity within leucocytes or by molecular studies. Management is multidisciplinary and involves symptomatic treatment as well as specific treatment, resulting in improved survival and enhanced quality of life for patients presenting the disease. Enzyme replacement therapy with alpha-galactosidase A forms the cornerstone of specific treatment and may be associated with other types of treatments such as galactose and molecular chaperones. Gene therapy is now also used extensively. At present, these marked therapeutic advances, which closely involve dermatologists, could help transform the prognosis for patients presenting Fabry disease.

  6. Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease

    PubMed Central

    Üçeyler, Nurcan; Schröter, Nils; Kafke, Waldemar; Kramer, Daniela; Wanner, Christoph; Weidemann, Frank; Sommer, Claudia

    2016-01-01

    Background The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity. Methods At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data. Results We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy. Conclusions Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients. PMID:27851774

  7. 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

  8. Genetics Home Reference: Fabry disease

    MedlinePlus

    ... Anderson-Fabry disease angiokeratoma corporis diffusum angiokeratoma diffuse ceramide trihexosidase deficiency Fabry's ... Lipid Metabolism Disorders Genetic and Rare Diseases Information Center ( ...

  9. Anderson-Fabry disease: a multiorgan disease.

    PubMed

    Tuttolomondo, Antonino; Pecoraro, Rosaria; Simonetta, Irene; Miceli, Salvatore; Pinto, Antonio; Licata, Giuseppe

    2013-01-01

    Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A. FD causes glycolipids, such as globotriaosylceramide (Gb3), to accumulate in the vascular endothelium of several organs (Fig. 2), including the skin, kidneys, nervous system, and heart, thereby triggering inflammation and fibrosis. These processes generally result in organ dysfunction, which is usually the first clinical evidence of FD. Patients with classic FD have various symptoms, eg, acroparesthesias, hypohidrosis, angiokeratomas, corneal opacities, cerebrovascular lesions, cardiac disorders, andrenal dysfunction.However, evolving knowledge about the natural course of disease suggests that it is more appropriate to describe FD as a disease with a wide spectrum of heterogeneously progressive clinical phenotypes. Indeed, most female heterozygotes develop symptoms due to yet undetermined mechanisms and a high percentage of females develops vital organ involvement including the kidneys, heart and/or brain about a decade later than males. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. The principal clinical manifestations in Fabry disease consist of artery associated complications (such as cerebral disease and nephropathy), but the pathophysiology of this specific vasculopathy is unclear. Several studies

  10. Morphological features of iPS cells generated from Fabry disease skin fibroblasts using Sendai virus vector (SeVdp).

    PubMed

    Kawagoe, Shiho; Higuchi, Takashi; Otaka, Manami; Shimada, Yohta; Kobayashi, Hiroshi; Ida, Hiroyuki; Ohashi, Toya; Okano, Hirotaka J; Nakanishi, Mahito; Eto, Yoshikatsu

    2013-08-01

    We generated iPS cells from human dermal fibroblasts (HDFs) of Fabry disease using a Sendai virus (SeVdp) vector; this method has been established by Nakanishi et al. for pathogenic evaluation. We received SeVdp vector from Nakanishi and loaded it simultaneously with four reprogramming factors (Klf4, Oct4, Sox2, and c-Myc) to HDFs of Fabry disease; subsequently, we observed the presence of human iPS-like cells. The Sendai virus nucleocapsid protein was not detected in the fibroblasts by RT-PCR analysis. Additionally, we confirmed an undifferentiated state, alkaline phosphatase staining, and the presence of SSEA-4, TRA-1-60, and TRA-1-81. Moreover, ultrastructural features of these iPS cells included massive membranous cytoplasmic bodies typical of HDFs of Fabry disease. Thus, we successfully generated human iPS cells from HDFs of Fabry disease that retained the genetic conditions of Fabry disease; also, these abnormal iPS cells could not be easily differentiated into mature cell types such as neuronal cells, cardiomyocytes, etc. because of a massive accumulation of membranous cytoplasmic bodies in lysosomes, possibly the persistent damages of intracellular architecture. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Fabry disease simulating Crohn's ileitis.

    PubMed

    Rubio, Carlos A; Villnow, Elizabeth; Sundelin, Birgitta; Eriksson, Elina; Dolapcsiev, Karoli; Björk, Jan; Befrits, Ragnar; Tengvar, Magnus; Iversen, Henrik

    2014-05-01

    Fabry disease is an inherited (X-linked) lysosomal storage disorder caused by deficiency of α-galactosidase A, leading to accumulation of globotriaosylceramide in various tissues. A 57-year-old male with a family history and laboratory findings of Fabry disease, was consulted for severe abdominal pain, undulating pyrexia, weight loss and diarrhea. The tentative clinical diagnosis of Crohn's ileitis was supported at computed tomographic examination, at laparotomy and at inspection of the resected ileal segment. Histology revealed chronic and acute inflammation, thick-walled occluded vessels, fibrosis and characteristic bi-refringent lamellar deposits of globotriaosylceramide and calcifications. Multi-nucleated giant cells contained phagocytized bi-refringent material. Transmission electron microscopy showed cells with irregular cytoplasmic bodies displaying distinctive zebra-like lamellar structures. It is submitted that the gastrointestinal phenotype of Fabry disease may concur with symptoms resembling abdominal Crohn's disease.

  12. The pathophysiology of Fabry disease.

    PubMed

    Olivera-González, S; Josa-Laorden, C; Torralba-Cabeza, M A

    2017-08-23

    Fabry disease is a lysosomal condition with systemic clinical expression, caused by the tissue deposit of globotriaosylceramide, due to a deficit in its degradation. As with most lysosomal diseases, the presence of a mutation in a gene does not explain the pathophysiological disorders shown by patients. We conducted a comprehensive review of the pathogenic mechanisms that occur in Fabry disease. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

  13. Fabry disease: experience of screening dialysis patients for Fabry disease.

    PubMed

    Kusano, Eiji; Saito, Osamu; Akimoto, Tetsu; Asano, Yasushi

    2014-04-01

    The prevalence rate for Fabry disease is conventionally considered to be 1 case in 40,000; however, due to increased screening accuracy, reports now suggest that prevalence is 1 case in 1,500 among male children, and it is likely that the clinical importance of the condition will increase in the future. In dialysis patients to date, prevalence rates are between 0.16 and 1.2 %. Globotriaosylsphingosine (Lyso-GL-3), which is a substrate of α-galactosidase A (α-Gal A), has surfaced as a new biomarker, and is also effective in the determination and monitoring of the effects of enzyme replacement therapy. In terms of genetic abnormalities, the E66Q mutation has recently become a topic of discussion, and although doubts have been expressed over whether or not it is the gene responsible for Fabry disease, there is still a strong possibility that it is a functional genetic polymorphism. At present, the standard treatment for Fabry disease is enzyme replacement therapy, and in order to overcome the problems involved with this, a method of producing recombinant human α-Gal A using methanol-assimilating yeast, and chemical or medicinal chaperone treatment are of current interest. Migalastat hydrochloride is known as a pharmacological chaperone, but is currently in Phase III global clinical trials. Adding saposin B to modified α-N-acetyl galactosaminidase is also under consideration as a treatment method.

  14. Fabry disease: a review of current management strategies.

    PubMed

    Mehta, A; Beck, M; Eyskens, F; Feliciani, C; Kantola, I; Ramaswami, U; Rolfs, A; Rivera, A; Waldek, S; Germain, D P

    2010-09-01

    Fabry disease is an X-linked inherited condition due to the absence or reduction of alpha-galactosidase activity in lysosomes, that results in accumulation of globotriaosylceramide (Gb3) and related neutral glycosphingolipids. Manifestations of Fabry disease include serious and progressive impairment of renal and cardiac function. In addition, patients experience pain, gastrointestinal disturbance, transient ischaemic attacks and strokes. Additional effects on the skin, eyes, ears, lungs and bones are often seen. The first symptoms of classic Fabry disease usually appear in childhood. Despite being X-linked, females can suffer the same severity of symptoms as males, and life expectancy is reduced in both females and males. Enzyme replacement therapy (ERT) can stabilize the progression of the disease. The rarity of the classic form of Fabry disease, however, means that there is a need to improve the knowledge and understanding that the majority of physicians have concerning Fabry disease, in order to avoid misdiagnosis and/or delayed diagnosis. This review aims to raise awareness of the signs and symptoms of Fabry disease; to provide a general diagnostic algorithm and to give an overview of the effects of ERT and concomitant treatments. We highlight a need to develop comprehensive international guidelines to optimize ERT and adjunctive therapy in patients with Fabry disease, including females and children.

  15. Electroneuromyographic Features in Fabry Disease: A Retrospective Review

    PubMed Central

    AKPINAR, Çetin Kürşad; TÜRKER, Hande; BAYRAK, Oytun; CENGİZ, Nilgün

    2015-01-01

    can be normal at the early stages. Quantitative sensory test, autonomic tests (R-R interval and sympathetic skin response) and skin biopsy should be performed in such cases. In our country, pediatric physicians work on Fabry disease more than physicians dealing with Fabry disease in adults. Therefore, in this retrospective study, we aimed to draw adult and pediatric neurologists’ attention to Fabry disease.

  16. Fabry disease and cardiovascular involvement.

    PubMed

    Anastasakis, Aris; Papatheodorou, Efstathios; Steriotis, Alexandros Klavdios

    2013-01-01

    Fabry disease (FD, OMIM 301500) is a rare X-linked lysosomal storage disorder of the glycosphigolipid metabolism caused by total or partial deficiency of the lysosomal enzyme alpha-galactosidase A (α-gal A). Progressive intralysosomal accumulation of neutral glycosphingolipids in a variety of cell types triggers a cascade of pathophysiological events including cellular death, compromised energy metabolism, small vessel injury, K(Ca)3.1 channel dysfunction in endothelial cells, oxidative stress, impaired autophagosome maturation, tissue ischemia and, importantly, development of irreversible cardiac and renal tissue fibrosis, leading to major multisystemic manifestations. Cardiovascular complications of the disease are very frequent and contribute substantially to disease-related morbidity and mortality in men. Cardiovascular involvement is the leading cause of premature death in heterozygous female patients with FD. Left ventricular hypertrophy is the most prominent cardiac manifestation followed by conduction system disease, valve dysfunction, arrhythmias, vessel disease and coronary microvascular dysfunction. The diagnosis of subclinical forms of the disease, before the development of cardiac hypertrophy, using newer techniques (tissue doppler imaging, strain rate and cardiac magnetic resonance) is crucial to the early initation of the treatment. Greatest benefit of the enzyme replacement treatment is achieved when started at an early stage of the disease before extensive fibrosis or other irreversible tissue damage takes place. Fabry disease should be included in the differential diagnosis algorithm of idiopathic hypertrophy. Determination of Alpha-Gal A activity on plasma and peripheral leukocytes in males and genetic testing in females are the diagnostic gold-standards.

  17. Coexistence of Fabry Disease and Membranous Nephropathy.

    PubMed

    Liu, Ying; Xie, Hua; Lin, Hongli; Chen, Shuni; Wang, Weidong; Zhao, Guangben; Zhang, Xu

    2016-01-01

    A 21-year-old man with no family history or characteristic symptoms of Fabry disease presented with proteinuria. Histological and immunofluorescent analysis of kidney tissue collected revealed stage 1 membranous nephropathy. Electron microscopy of the same tissue revealed a large number of myeloid bodies (zebra bodies) in the glomerular epithelial cytoplasm and a mild irregular thickening of basement membrane. A diagnosis of Fabry disease was supported by the low α-galactosidase A activity detected in the patient's plasma, and confirmed by the detection of a pathogenic homozygous mutation in the α-galactosidase A gene. Therefore, the final diagnosis was of coexistent Fabry disease and stage 1 membranous nephropathy. This is the first case study reporting the coexistence of Fabry disease and membranous nephropathy. Our results emphasize the importance of electron microscopy in Fabry disease diagnosis.

  18. Cognitive and psychological functioning in Fabry disease.

    PubMed

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

    2014-11-01

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

  19. Nailfold capillaroscopy: Specific features in Fabry disease.

    PubMed

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

    2009-01-01

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

  20. Renal complications of Fabry disease in children.

    PubMed

    Najafian, Behzad; Mauer, Michael; Hopkin, Robert J; Svarstad, Einar

    2013-05-01

    Fabry disease is an X-linked α-galactosidase A deficiency, resulting in accumulation of glycosphingolipids, especially globotriaosylceramide, in cells in different organs in the body. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. Recent studies support the value of renal biopsy in providing histological information relevant to kidney function and prognosis, and renal biopsy could potentially be used to guide treatment decisions in young Fabry patients. This review aims to provide an update of the current understanding, challenges, and needs to better approach renal complications of Fabry disease in children.

  1. Renal Complications of Fabry Disease in Children

    PubMed Central

    Najafian, Behzad; Mauer, Michael; Hopkin, Robert J; Svarstad, Einar

    2013-01-01

    Fabry disease is an X-linked α-galactosidase A deficiency, resulting in accumulation of glycosphingolipids, especially globotriaosylceramide, in cells in different organs in the body. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. Recent studies support the value of renal biopsy in providing histological information relevant to kidney function and prognosis and renal biopsy could potentially be used to guide treatment decisions in young Fabry patients. This review aims to provide an update of the current understanding, challenges and needs to better approach renal complications of Fabry disease in children. PMID:22898981

  2. [Hearing loss in patients with Fabry disease].

    PubMed

    Limberger, A; Beck, M; Delgado-Sanchez, S; Keilmann, A

    2007-03-01

    Fabry disease is an X-linked lysosomal storage disease involving deficient activity of alpha-galactosidase A, which leads initially to pain, and later to renal insufficiency, cardiomyopathy and stroke. Until now few details are available on hearing impairment in patients with Fabry disease, and especially few relating to female patients. We examined 43 female and 29 male patients. In this study we looked into the question of whether and to what extent patients of both genders are affected by hearing impairment. Hearing loss is characteristic being more severe at high frequencies frequencies. Overall, 22 female and 15 male patients were found to have suffered a hearing loss. Patients with severe symptoms of Fabry disease usually demonstrate more prominent hearing losses. Both men and women with Fabry disease are affected by hearing impairment. It seems that the hearing loss is less marked in female than in male patients. Children with Fabry disease complain of tinnitus more frequently than other children and quite early in the course of the disease.

  3. Fabry disease, respiratory symptoms, and airway limitation - a systematic review.

    PubMed

    Svensson, Camilla Kara; Feldt-Rasmussen, Ulla; Backer, Vibeke

    2015-01-01

    Fabry disease is an X-linked disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A, resulting in accumulation of glycosphingolipids in multiple organs, primarily heart, kidneys, skin, CNS, and lungs. A systematic literature search was performed using the PubMed database, leading to a total number of 154 hits. Due to language restriction, this number was reduced to 135; 53 papers did not concern Fabry disease, 19 were either animal studies or gene therapy studies, and 36 papers did not have lung involvement in Fabry disease as a topic. The remaining 27 articles were relevant for this review. The current literature concerning lung manifestations describes various respiratory symptoms such as dyspnoea or shortness of breath, wheezing, and dry cough. These symptoms are often related to cardiac involvement in Fabry disease as respiratory examinations are seldom performed. Pulmonary function tests primarily show obstructive airway limitation, but a few articles also report of patients with restrictive limitation and a mixture of both. No significant association has been found between smoking and the development of symptoms or spirometry abnormalities in patients with Fabry disease. Electron microscopy of lung biopsy and induced sputum show lamellar inclusion bodies (Zebra bodies) in the cytoplasm of cells in the airway wall. X-ray and CT scan have shown patchy ground-glass pulmonary infiltrations, fibrosis, and air trapping. Fibrosis diagnosed by high-resolution CT has not been significantly correlated with lung spirometry. Consistent findings have not been shown in the current literature. Pulmonary function tests and registration of symptoms showed various results; however, there is a trend towards obstructive airway limitation in patients with Fabry disease. Further studies are needed to evaluate pathogenesis, progression, and the effects of treatment.

  4. Cutaneous complications of Anderson-Fabry disease.

    PubMed

    Giuseppe, Pistone; Daniele, Rizzo; Rita, Bongiorno Maria

    2013-01-01

    Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by a defect in the α-galactosidase A gene, which leads to the deficiency of the hydrolytic enzyme α-galactosidase A. The consequent inability to catabolize glycosphingolipids causes progressive accumulation of globotriaosylceramide in the vascular endothelium throughout the body. Fatalities in the classical phenotype may usually occur as a consequence of cerebral, cardiac or renal disease. Dermatological manifestations are a relevant feature of Fabry disease and include angiokeratomas, telangiectasiae, lymphedema, anhidrosis or hypohidrosis and pseudo-acromegalic facial appearance. The actual causal treatment for Fabry disease is the enzyme replacement therapy. Dermatologists have a key role, since cutaneous manifestations may lead to the diagnosis. This may help an early therapeutic intervention, reducing both morbidity and mortality.

  5. Cognitive and Psychological Functioning in Fabry Disease

    PubMed Central

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

    2014-01-01

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

  6. [Evaluation of patients with Fabry disease in Argentina].

    PubMed

    2010-01-01

    Fabry disease is an X- linked lysosomal disorder due to deficient activity of the enzyme alpha galactosidase A which leads to multisystemic storage of globotriaosylceramide with neurologic, gastrointestinal, cardiac, renal, skin and ophtalmological involvement. Recent studies indicate that heterozygous females develop symptoms similar to the males, but comparative information regarding the relative frequency of clinical manifestations, age of onset and severity of the disorder between males and females with Fabry disease is not available in Argentina. We identified 59 symptomatic adult patients with Fabry disease: 32 males (mean age 34.8 years) and 27 females (mean age 46.6 years). Diagnosis was made by enzymatic analysis in males and by genetic studies in females. We compared the frequency and severity of the clinical manifestations in females and males with this disease. The most frequent manifestations were: acroparesthesias, angiokeratomas, hypohydrosis (all them were significantly more frequent in males than in females, as well as the severity of symptoms), and cornea verticillata. Proteinuria and ventricular hypertrophy were frequent findings both in males and females. There was a delayed latency between age at onset and age at diagnosis in our group: 14 years for men and 30 years for females. Fabry disease is an underdiagnosed and potentially fatal disorder that affects both sexes. The availability of enzyme replacement therapy should stimulate the identification of signs and symptoms suggestive of this disorder, to allow earlier diagnosis and treatment.

  7. Fabry disease and incidence of cancer.

    PubMed

    Bird, Sarah; Hadjimichael, Efthymios; Mehta, Atul; Ramaswami, Uma; Hughes, Derralynn

    2017-09-06

    Fabry disease is an X-linked lysosomal storage disorder caused by deficient activity of α-galactosidase A and the resulting accumulation of the glycosphingolipid globotriaosylceramide (Gb3) and its derivatives, including globotriaosylsphingosine (Lyso-Gb3). Increased cellular and plasma levels of Gb3 and Lyso-Gb3 affect multiple organs, with specific clinical consequences for the kidneys, heart and brain. There is growing evidence that alterations in glycosphingolipids may have an oncogenic role and this prompted a review of cases of cancer and benign lesions in a large single centre cohort of Fabry patients. We also explored whether there is a difference in the risk of cancer in Fabry patients compared to the general population. Our results suggest that Fabry patients may have a marginally reduced rate of all cancer (incidence rate ratio 0.61, 95% confidence interval 0.37 to 0.99) but possibly increased rates of melanoma, urological malignancies and meningiomas. Greater knowledge and awareness of cancer in patients with Fabry disease may help identify at-risk individuals and elucidate cancer mechanisms in this rare inherited disease, which may potentially be relevant to the wider cancer population.

  8. Kidney transplantation in patients with Fabry disease.

    PubMed

    Cybulla, Markus; Walter, Kerstin Nanette; Schwarting, Andreas; Divito, Raffaelle; Feriozzi, Sandro; Sunder-Plassmann, Gere

    2009-04-01

    Little is known about the effects of enzyme replacement therapy (ERT) in kidney transplant recipients with Fabry disease. Clinical characteristics of transplant recipients in the Fabry Outcome Survey (FOS) were therefore examined in patients with Fabry disease with or without ERT. Of the 837 European patients in FOS (March 2006), 34 male patients and two female patients had received kidney transplants. Mean age at transplantation was 37.6 +/- 10.9 years, mean time since transplantation was 7.7 +/- 6.4 years, median estimated glomerular filtration rate (eGFR) was 44.4 ml/min/1.73 m(2), and median proteinuria was 296 mg/24 h. Of 27 patients with baseline data, 59% had hypertension, 74% had left ventricular hypertrophy, 22% had cardiac valve disease, 30% had arrhythmia, and 22% had transient ischaemic attacks and 15% stroke. Twenty patients (74%; two female patients, 18 male patients) were receiving ERT with agalsidase alfa. At enrollment or at the start of ERT, median eGFRs were 59 and 35 ml/min/1.73 m(2) (P = 0.05) and median proteinuria levels were 240 and 420 mg/24 h (not significant) in treated and untreated patients respectively. Renal function remained stable in patients receiving ERT. In conclusion, agalsidase alfa is well tolerated in patients with Fabry disease who have undergone renal transplantation.

  9. Multiple parapelvic cysts in Fabry disease.

    PubMed

    Azancot, María A; Vila, Josefa; Domínguez, Carmen; Serres, Xavier; Espinel, Eugenia

    2016-01-01

    Fabry disease is an inherited, X-linked lysosomal storage disorder caused by deficiency of the enzyme alpha galactosidase A (alpha-GLA A), which leads to glycosphingolipid accumulation, mainly globotriaosylceramide, in tissues. Disease prevalence and the index of suspicion are both low, which tends to result in delayed diagnosis and treatment. We present the case of a male Fabry disease patient who manifested no angiokeratoma lesions but presented multiple parapelvic cysts and renal failure. The genetic study revealed an alpha-GLA A gene mutation that had not been recorded in the mutations registry. The de novo mutation was not found in his relatives and it was not transmitted to his offspring. The large number and peculiar appearance of the parapelvic cysts led to the diagnosis.

  10. Ear symptoms in children with Fabry disease: data from the Fabry Outcome Survey.

    PubMed

    Keilmann, A; Hajioff, D; Ramaswami, U

    2009-12-01

    Hearing loss and tinnitus are common symptoms in Fabry disease and increase in prevalence with age. This study aimed to provide an epidemiological description of hearing impairment and tinnitus in children with Fabry disease in the Fabry Outcome Survey (FOS), an international database to assess the natural history of Fabry disease and the efficacy of enzyme replacement therapy with agalsidase alpha. Signs and symptoms questionnaires were completed for 543 children with Fabry disease. Pure-tone audiograms were obtained from 101 children (53 girls, 48 boys). On questioning, 33% of the children (n = 179) reported subjective hearing impairment. However, when assessed by age-appropriate audiometry, only 19 of 101 patients (19%) had a persistent hearing loss at least one frequency. Of these, 14 had a high-frequency hearing loss, 4 a pan-frequency hearing loss, and 1 a pattern typical of noise-induced loss. Of the 101 children with audiometry, 44 complained of tinnitus. Only 2 children reported sudden hearing loss, which was not verified by audiometry. Children with tinnitus had greater disease severity scores. Hearing loss is a well-known clinical manifestation in patients with Fabry disease. It was reported in significant numbers of children in the FOS signs and symptoms questionnaire, but confirmed in only 19% by formal audiometry. The subjective hearing impairment may have been due to middle-ear effusions in many cases. Tinnitus is a well-recognized symptom in Fabry disease and can present in childhood. The presence of tinnitus correlated with overall disease severity.

  11. Blood pressure, proteinuria and nephropathy in Fabry disease.

    PubMed

    Jain, Gaurav; Warnock, David G

    2011-01-01

    Fabry disease is an X-linked disorder leading to abnormal accumulation of glycosphingolipids with multisystem involvement, including cardiac, renal, dermatologic and neurologic manifestations. Fabry nephropathy, specifically proteinuria and progressive chronic kidney disease, have taken center stage over the past decade, defining disease outcomes as well as mortality associated with Fabry disease. Systemic blood pressure among patients with Fabry disease is relatively low, compared to other forms of proteinuric chronic kidney disease. This review is based on a systematic survey of recent publications that describe the diagnosis and treatment of Fabry nephropathy in adults. A high percentage of patients with Fabry disease have been shown to have proteinuria, and a small but significant percentage of Fabry patients have overt hypertension. Recent efforts have focused on the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEIs/ARBs) in addition to enzyme replacement therapy (ERT) for treatment of Fabry nephropathy. The proven beneficial effects of ACEI/ARBs for more common forms of proteinuric kidney disease have been extrapolated to the treatment of Fabry nephropathy. The overall treatment goal with ACEIs/ARBs, in combination with ERT, is reduction of urinary protein excretion to less than 500 mg/day, and stabilization of the decline of kidney function to -1 ml/min/1.73 m(2)/year. ERT alone, in the absence of ACEIs/ARBs does not decrease proteinuria in Fabry patients. We present the prevalence of proteinuria, kidney disease and hypertension in Fabry disease and discuss treatment goals for the treatment of this unusual form of proteinuric kidney disease. There are some practical challenges to the use of standard antiproteinuric therapy in Fabry disease that need to be addressed to optimize patient outcome, with the expectation that kidney function can be preserved with the combination of ERT and ACEI/ARB therapy. Copyright © 2010 S

  12. [Fabry disease and cystinosis, two lysosomal diseases: similarities and differences].

    PubMed

    Grünfeld, J-P; Servais, A

    2010-12-01

    Fabry disease and cystinosis are both lysosomal diseases. Some clinical features (such as renal and corneal involvement) are shared by both diseases whereas many other features are different (mode of inheritance, rate of progression, mechanism of lysosomal storage, therapeutic modalities etc.). Intermediary mechanisms that lead from lysosomal overload to lesions and disease are still incompletely understood.

  13. Electrocardiographic Changes and Arrhythmia in Fabry Disease

    PubMed Central

    Namdar, Mehdi

    2016-01-01

    Fabry disease is an X-chromosome-linked lysosomal storage disease characterized by a deficient activity or, in most males, absence of the enzyme α-galactosidase A (a-Gal A) leading to systemic, primary lysosomal accumulation of globotriaosylceramide (Gb3) (1). Recent literature refers to an overall birth prevalence of 1:40,000–170,000; however, such data do not allow an estimation on an actual patient number suffering from Fabry disease (2). Multisystem morbidity commonly develops in childhood and, with progression of the disease, life-threatening complications often occur in adulthood, including renal failure, cardiovascular dysfunction, neuropathy, and stroke (3–6). Life expectancy is reduced by an average of 15 years in female patients and 20 years in male patients (7, 8). The pathognomonic Gb3 accumulation has been repeatedly observed over the past decades by many groups in vascular endothelial and smooth muscle cells, cardiomyocytes, cardiac conduction tissue, and valvular fibroblasts (3). Although incompletely described, it is likely that inflammatory and neurohormonal mechanisms are involved in subsequent cellular and vascular dysfunction, leading to tissue ischemia, hypertrophy, and fibrosis (9). Furthermore, recently published works on cardiomyocyte dysfunction and conduction tissue involvement have suggested that cardiac dysfunction may reflect increased myocardial nitric oxide production with oxidative damage of cardiomyocyte myofilaments and DNA, causing cell dysfunction and death, and accelerated conduction with prolonged refractoriness and electric instability (10, 11). PMID:27047943

  14. Delayed diagnosis of Fabry disease presenting as myocardial ischaemia.

    PubMed

    Marcì, Marcello; Duro, Giovanni; Tuttolomondo, Antonino; Tuttolomondo, Bruno; Pinto, Antonio; Cirrincione, Vincenzo; Sanfilippo, Nicola

    2012-01-01

    Cardiovascular complications due to the accumulation of globotriaosylceramide in cardiac cells occur in almost all patients affected by Anderson-Fabry disease. Cardiac manifestations include left ventricular hypertrophy, mitral regurgitation, conduction disturbances and myocardial ischaemia. We report a case of Fabry's disease diagnosed several years after the onset of early cardiac symptoms.

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

    PubMed

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

    2017-09-04

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

  16. Inner ear function in children with Fabry disease.

    PubMed

    Keilmann, A

    2003-12-01

    The prevalence of hearing loss in patients with Fabry disease is still uncertain. This paper examines hearing loss in a group of young patients with Fabry disease. A clinical ear nose and throat examination, pure-tone air and bone conduction audiometry, speech audiometry and middle ear testing (tympanometry and acoustic reflex testing) were carried out in four girls and two boys with Fabry disease (age, 7-17 years), receiving enzyme replacement therapy (ERT). None of the patients complained of a hearing disorder or suffered from hearing loss. Three female patients reported tinnitus; however, this was not reported as being a problem. One boy reported tinnitus for the first time during 6 months of ERT. Based on this small sample of patients, it appears that the hearing disorders associated with Fabry disease develop mainly in adulthood. Tinnitus may be an earlier symptom than previously thought in Fabry disease.

  17. [Cardiological follow-up in patients with Fabry disease].

    PubMed

    Pieruzzi, Federico; Pieroni, Maurizio; Chimenti, Cristina; Frustaci, Andrea; Sarais, Cristiano; Cecchi, Franco

    2010-01-01

    Fabry disease is a rare tesaurismosis due to a deficit of the lysosomal enzyme activity of alpha-galactosidase, needed for the normal catabolism of globotriaosylceramides (GL3). Fabry cardiac involvement has several clinical manifestations: concentric left ventricular hypertrophy without left ventricular dilation and severe loss of left ventricular systolic function, mitral and aortic valvulopathy, disorders of the atrioventricular conduction or repolarization, and compromised diastolic function. Differentiating Fabry disease from similar conditions is often quite straightforward, e.g., cardiac amyloidosis is often associated with low electrocardiographic voltages, and systemic symptoms are usually associated with hemochromatosis and sarcoidosis. However, sometimes second-level (genetic analysis, alpha-galactosidase levels) or invasive investigations are required, which can include endomyocardial biopsy. Diagnostic imaging techniques have been described, but they lack specificity. Echocardiographic imaging with tissue Doppler analysis and/or strain rate analysis can allow diagnosis of Fabry disease even before left ventricular hypertrophy becomes apparent. This review illustrates the techniques for staging cardiac involvement and damage in Fabry disease and for the long-term follow-up of Fabry patients with or without cardiac involvement. Careful cardiac monitoring is especially important in elderly female carriers, who often develop renal disorders and/or left ventricular hypertrophy as the only manifestations of their late Fabry disease. In some clinical series, Fabry disease was diagnosed in 12% of women with adult-onset hypertrophic cardiomyopathy. Cardiological problems and outcomes of enzyme replacement therapy, associated with or without other cardiological treatments, are also discussed.

  18. Functional and structural nerve fiber findings in heterozygote patients with Fabry disease.

    PubMed

    Torvin Møller, Anette; Winther Bach, Flemming; Feldt-Rasmussen, Ulla; Rasmussen, Ase; Hasholt, Lis; Lan, He; Sommer, Claudia; Kølvraa, Steen; Ballegaard, Martin; Staehelin Jensen, Troels

    2009-09-01

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

  19. Involvement of dorsal root ganglia in Fabry's disease.

    PubMed

    Gadoth, N; Sandbank, U

    1983-08-01

    Bouts of shooting pain along the extremities are common in the early stages of Fabry's disease. No pathological explanation has been advanced to clarify the mechanism of such pain. In the present case neuronal storage of glycolipid was confined to dorsal root ganglia neurones only. It is suggested that this may explain the shooting pain in Fabry's disease. In hereditary sensory radicular neuropathy, familial dysautonomia, and tabes dorsalis, changes in dorsal root ganglia cells cause similar clinical signs and thus it may be concluded that shooting pains in Fabry's disease may be caused by damage to dorsal root ganglia neurones.

  20. Involvement of dorsal root ganglia in Fabry's disease.

    PubMed Central

    Gadoth, N; Sandbank, U

    1983-01-01

    Bouts of shooting pain along the extremities are common in the early stages of Fabry's disease. No pathological explanation has been advanced to clarify the mechanism of such pain. In the present case neuronal storage of glycolipid was confined to dorsal root ganglia neurones only. It is suggested that this may explain the shooting pain in Fabry's disease. In hereditary sensory radicular neuropathy, familial dysautonomia, and tabes dorsalis, changes in dorsal root ganglia cells cause similar clinical signs and thus it may be concluded that shooting pains in Fabry's disease may be caused by damage to dorsal root ganglia neurones. Images PMID:6413695

  1. Urinary Podocyte Loss Is Increased in Patients with Fabry Disease and Correlates with Clinical Severity of Fabry Nephropathy

    PubMed Central

    Fall, Brent; Scott, C. Ronald; Mauer, Michael; Shankland, Stuart; Pippin, Jeffrey; Jefferson, Jonathan A.; Wallace, Eric; Warnock, David; Najafian, Behzad

    2016-01-01

    Chronic kidney disease is a major complication of Fabry disease. Podocytes accumulate globotriaosylceramide inclusions more than other kidney cell types in Fabry patients. Podocyte injury occurs early in age, and is progressive. Since injured podocytes detach into the urine (podocyturia), we hypothesized that podocyturia would increase in Fabry patients and correlate with clinical severity of Fabry nephropathy. Urine specimens from 39 Fabry patients and 24 healthy subjects were evaluated for podocyturia. Most of the Fabry patients and many healthy subjects had podocyturia. The number of podocytes per gram of urine creatinine (UPodo/g Cr) was 3.6 fold greater in Fabry patients (3,741 ± 2796; p = 0.001) than healthy subjects (1,040 ± 972). Fabry patients with normoalbuminuria and normoproteinuria had over 2-fold greater UPodo/g Cr than healthy subjects (p = 0.048). UPodo/gCr was inversely related to eGFR in male patients (r = -0.69, p = 0.003). UPodo/gCr was directly related to urine protein creatinine ratio (r = 0.33; p = 0.04) in all Fabry patients. These studies confirm increased podocyturia in Fabry disease, even when proteinuria and albuminuria are absent. Podocyturia correlates with clinical severity of Fabry nephropathy, and potentially may be of prognostic value. PMID:27992580

  2. Urinary Podocyte Loss Is Increased in Patients with Fabry Disease and Correlates with Clinical Severity of Fabry Nephropathy.

    PubMed

    Fall, Brent; Scott, C Ronald; Mauer, Michael; Shankland, Stuart; Pippin, Jeffrey; Jefferson, Jonathan A; Wallace, Eric; Warnock, David; Najafian, Behzad

    2016-01-01

    Chronic kidney disease is a major complication of Fabry disease. Podocytes accumulate globotriaosylceramide inclusions more than other kidney cell types in Fabry patients. Podocyte injury occurs early in age, and is progressive. Since injured podocytes detach into the urine (podocyturia), we hypothesized that podocyturia would increase in Fabry patients and correlate with clinical severity of Fabry nephropathy. Urine specimens from 39 Fabry patients and 24 healthy subjects were evaluated for podocyturia. Most of the Fabry patients and many healthy subjects had podocyturia. The number of podocytes per gram of urine creatinine (UPodo/g Cr) was 3.6 fold greater in Fabry patients (3,741 ± 2796; p = 0.001) than healthy subjects (1,040 ± 972). Fabry patients with normoalbuminuria and normoproteinuria had over 2-fold greater UPodo/g Cr than healthy subjects (p = 0.048). UPodo/gCr was inversely related to eGFR in male patients (r = -0.69, p = 0.003). UPodo/gCr was directly related to urine protein creatinine ratio (r = 0.33; p = 0.04) in all Fabry patients. These studies confirm increased podocyturia in Fabry disease, even when proteinuria and albuminuria are absent. Podocyturia correlates with clinical severity of Fabry nephropathy, and potentially may be of prognostic value.

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

    PubMed

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

    2016-12-15

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

  4. Cerebral hemodynamics and endothelial function in patients with Fabry disease.

    PubMed

    Segura, Tomás; Ayo-Martín, Oscar; Gómez-Fernandez, Isabel; Andrés, Carolina; Barba, Miguel A; Vivancos, José

    2013-11-11

    Cerebral vasculopathy have been described in Fabry disease, in which altered cerebral blood flow, vascular remodelling or impairment of endothelial function could be involved. Our study aims to evaluate these three possibilities in a group of Fabry patients, and compare it to healthy controls. Cerebral hemodynamics, vascular remodelling and systemic endothelial function were investigated in 10 Fabry patients and compared to data from 17 healthy controls. Transcranial Doppler was used to study blood flow velocity of intracranial arteries and cerebral vasomotor reactivity. For the study of vascular remodelling and endothelial function, intima-media thickness of common carotid arteries, flow-mediated dilation in brachial artery and serum levels of soluble VCAM-1, TNF-α, high-sensitive CRP and IL-6 were measured. Differences between groups were evaluated using appropriate tests. No relevant differences were observed in cerebral hemodynamic parameters, intima-media thickness or flow-mediated dilation. There was a trend for low serum levels of IL-6 and high serum levels of TNF-α and high-sensitive CRP in Fabry patients; plasma concentrations of soluble VCAM-1 were significantly higher in Fabry disease patients than in healthy volunteers (p = 0.02). In our sample, we did not find relevant alterations of cerebral hemodynamics in Fabry disease patients. Increased levels of plasmatic endothelial biomarkers seem to be the most important feature indicative of possible vascular dysfunction in Fabry disease patients.

  5. Cerebral hemodynamics and endothelial function in patients with Fabry disease

    PubMed Central

    2013-01-01

    Background Cerebral vasculopathy have been described in Fabry disease, in which altered cerebral blood flow, vascular remodelling or impairment of endothelial function could be involved. Our study aims to evaluate these three possibilities in a group of Fabry patients, and compare it to healthy controls. Methods Cerebral hemodynamics, vascular remodelling and systemic endothelial function were investigated in 10 Fabry patients and compared to data from 17 healthy controls. Transcranial Doppler was used to study blood flow velocity of intracranial arteries and cerebral vasomotor reactivity. For the study of vascular remodelling and endothelial function, intima-media thickness of common carotid arteries, flow-mediated dilation in brachial artery and serum levels of soluble VCAM-1, TNF-α, high-sensitive CRP and IL-6 were measured. Differences between groups were evaluated using appropriate tests. Results No relevant differences were observed in cerebral hemodynamic parameters, intima-media thickness or flow-mediated dilation. There was a trend for low serum levels of IL-6 and high serum levels of TNF-α and high-sensitive CRP in Fabry patients; plasma concentrations of soluble VCAM-1 were significantly higher in Fabry disease patients than in healthy volunteers (p = 0.02). Conclusions In our sample, we did not find relevant alterations of cerebral hemodynamics in Fabry disease patients. Increased levels of plasmatic endothelial biomarkers seem to be the most important feature indicative of possible vascular dysfunction in Fabry disease patients. PMID:24207059

  6. Gastrointestinal involvement in Fabry disease. So important, yet often neglected.

    PubMed

    Politei, J; Thurberg, B L; Wallace, E; Warnock, D; Serebrinsky, G; Durand, C; Schenone, A B

    2016-01-01

    Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal alpha-galactosidase A which causes accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Gastrointestinal signs and symptoms-abdominal pain, nausea, diarrhea and diverticular disease--are some of the most frequently reported complaints in patients with Fabry disease but are often neglected. Gastrointestinal symptoms are due to intestinal dysmotility as well as impaired autonomic function, vasculopathy and myopathy. Since 2001, enzyme replacement therapy has been a mainstay in treatment of gastrointestinal symptoms of Fabry disease (FD), resulting in reduced gastrointestinal symptoms. Here, we report on four patients with Fabry disease (FD) who manifested early gastrointestinal involvement.

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

    PubMed Central

    2013-01-01

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

  8. Experiences of Being Heterozygous for Fabry Disease: a Qualitative Study.

    PubMed

    von der Lippe, Charlotte; Frich, Jan C; Harris, Anna; Solbrække, Kari Nyheim

    2016-10-01

    Little is known about the experiences of women with Fabry disease. The aim of this study was to explore women's experiences of being heterozygous for Fabry disease. We used an explorative qualitative study design and selected ten Norwegian women who were known heterozygous for Fabry disease to participate. We conducted in-depth semi-structured interviews and analyzed the interviews using inductive thematic analysis. We found that learning about one's heterozygous status may be devastating for some. However, for most of the participants, heterozygous status, as well as doctors' acceptance of symptoms in women heterozygous for Fabry disease, provided an explanation and relief. Although many women did not consider themselves ill, they wished to be acknowledged as more than "just carriers." The participants were grateful for enzyme replacement therapy, although it had its burdens regarding time, planning, and absences from school or work. Women with Fabry disease felt that the lack of knowledge among healthcare professionals about Fabry disease was frustrating and worrisome. These findings suggest that healthcare professionals should acknowledge the different ways women react to their diagnosis, and be aware of the personal costs of receiving treatment.

  9. Pituitary function and morphology in Fabry disease.

    PubMed

    Maione, Luigi; Tortora, Fabio; Modica, Roberta; Ramundo, Valeria; Riccio, Eleonora; Daniele, Aurora; Belfiore, Maria Paola; Colao, Annamaria; Pisani, Antonio; Faggiano, Antongiulio

    2015-11-01

    Endocrine abnormalities are known to affect patients with Fabry disease (FD). Pituitary gland theoretically represents an ideal target for FD because of high vascularization and low proliferation rate. We explored pituitary morphology and function in a cohort of FD patients through a prospectic, monocentric study at an Academic Tertiary Center. The study population included 28 FD patients and 42 sex and age-matched normal subjects. The protocol included a contrast enhancement pituitary MRI, the assessment of pituitary hormones, anti-pituitary, and anti-hypothalamus antibodies. At pituitary MRI, an empty sella was found in 11 (39%) FD patients, and in 2 (5%) controls (p < 0.001). Pituitary volume was significantly smaller in FD than in controls (p < 0.001). Determinants of pituitary volume were age and alpha-galactosidase enzyme activity. Both parameters resulted independently correlated at multivariate analysis. Pituitary function was substantially preserved in FD patients. Empty sella is a common finding in patients with FD. The major prevalence in the elderly supports the hypothesis of a progressive pituitary shrinkage overtime. Pituitary function seems not to be impaired in FD. An endocrine workup with pituitary hormone assessment should be periodically performed in FD patients, who are already at risk of cardiovascular complications.

  10. Anderson-Fabry disease in children.

    PubMed

    Sestito, Simona; Ceravolo, Ferdinando; Concolino, Daniela

    2013-01-01

    Although clinical evidence of major organ damage is typical of adulthood, many of the signs and symptoms of Anderson Fabry Disease (AFD) occur frequently in childhood. The clinical phenotype of AFD in pediatric patients has been described in several studies which show a higher incidence and an earlier onset of symptoms in male patients than in females. These include neurological manifestations (acroparaesthesias, chronic neuropathic pain, hypo-anhidrosis, tinnitus, hearing, loss), gastrointestinal (GI) symptoms (abdominal pain and diarrhea), angiokeratomas, ocular abnormalities (cornea verticillata, tortuous retinal vessels and subcapsular cataracts). Such manifestations may impair quality of life and, because of their unspecific nature, rarely lead to an early diagnosis. In addition, signs of major organ damage (microalbuminuria or proteinuria, urinary hyperfiltration, impaired heart rate variability, left ventricular hypertrophy, stroke) are encountered in children with AFD. Clinical trials of enzyme replacement therapy (ERT) with agalsidase alfa and agalsidase beta have been conducted in children, with clinical and pharmacodinamc effects proved by both enzyme formulations, whereas differences in safety profile and administration were found. Although several studies suggest that ERT should be started before irreversible damage in critical organs have occurred, the issue of when to initiate it has not yet been resolved. More controlled trials must be done in order to demonstrate that an early start of ERT could prevent adult complications and to assess the optimal timing of treatment in children with AFD. This review aims to provide an update of the current understanding for a better approach of pediatric AFD.

  11. [Females with Fabry's disease - an interdisciplinary diagnostic and therapeutic challenge].

    PubMed

    Weidemann, Frank; Niemann, Markus; Sommer, Claudia; Beer, Meinrad; Breunig, Frank; Wanner, Christoph

    2010-09-01

    Fabry's disease is a rare genetic storage disorder leading to an accumulation of globotriaosylceramides in the lysosomes of various organs. Being X-chromosomal-linked, most studies in the past focused on involvement in male patients. However, it has been elucidated recently that female patients can present typical organ involvement and, thus, have to be treated respectively. This synopsis wants to systematically review the typical organ involvement in female Fabry patients. Moreover, therapy recommendations especially for female patients are discussed.

  12. [Fabry disease: clinic and enzymatic diagnosis of homozygous and heterozygous. New therapeutic prospects].

    PubMed

    Peces, R; Olea, T

    2002-01-01

    Fabry disease is an X-linked recessive lysosomal storage disorder caused by a partial or complete deficiency of alpha-galactosidase A. Intracellular accumulation of globotriaosylceramide, the glycolipid substrate of this enzyme, leads to severe painful neuropathy with progressive renal, cardiovascular, and cerebrovascular dysfunction and early death. Men are predominantly affected but many female carriers have similar clinical involvement, including increased risk of stroke. Physical stigmata, such as angiokeratomas in skin and mucous membranes and characteristic benign corneal abnormalities, facilitate identification of Fabry disease. The finding of a marked decreased activity of (alpha-galactosidase A in plasma, white blood cells or cultured skin fibroblasts confirms the diagnosis. Treatment thus far has been symptomatic only. Etiology-based therapies are being developed that include enzyme replacement therapy, gene therapy, and substrate deprivation. The recently completed double-blind, placebo-controlled trials of intravenous infusions of (alpha-galactosidase A in patients with Fabry disease demonstrated the safety and efficacy of this treatment. We report a family with Fabry disease composed of hemicygous and heterocygous. The propositus developed chronic renal failure and received a cadaver renal transplant, which remained with adequate renal function during 15 years.

  13. Fabry disease, respiratory symptoms, and airway limitation – a systematic review

    PubMed Central

    Svensson, Camilla Kara; Feldt-Rasmussen, Ulla; Backer, Vibeke

    2015-01-01

    Background Fabry disease is an X-linked disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A, resulting in accumulation of glycosphingolipids in multiple organs, primarily heart, kidneys, skin, CNS, and lungs. Materials and method A systematic literature search was performed using the PubMed database, leading to a total number of 154 hits. Due to language restriction, this number was reduced to 135; 53 papers did not concern Fabry disease, 19 were either animal studies or gene therapy studies, and 36 papers did not have lung involvement in Fabry disease as a topic. The remaining 27 articles were relevant for this review. Results The current literature concerning lung manifestations describes various respiratory symptoms such as dyspnoea or shortness of breath, wheezing, and dry cough. These symptoms are often related to cardiac involvement in Fabry disease as respiratory examinations are seldom performed. Pulmonary function tests primarily show obstructive airway limitation, but a few articles also report of patients with restrictive limitation and a mixture of both. No significant association has been found between smoking and the development of symptoms or spirometry abnormalities in patients with Fabry disease. Electron microscopy of lung biopsy and induced sputum show lamellar inclusion bodies (Zebra bodies) in the cytoplasm of cells in the airway wall. X-ray and CT scan have shown patchy ground-glass pulmonary infiltrations, fibrosis, and air trapping. Fibrosis diagnosed by high-resolution CT has not been significantly correlated with lung spirometry. Conclusion Consistent findings have not been shown in the current literature. Pulmonary function tests and registration of symptoms showed various results; however, there is a trend towards obstructive airway limitation in patients with Fabry disease. Further studies are needed to evaluate pathogenesis, progression, and the effects of treatment. PMID:26557248

  14. Understanding the gastrointestinal manifestations of Fabry disease: promoting prompt diagnosis

    PubMed Central

    Zar-Kessler, Claire; Karaa, Amel; Sims, Katherine Bustin; Clarke, Virginia; Kuo, Braden

    2016-01-01

    Fabry disease is a rare X-linked lysosomal storage disease characterized by the dysfunction of multiple systems, including significant gastrointestinal involvement such as diarrhea, abdominal pain, early satiety and nausea. The gastrointestinal symptoms of Fabry disease are thought to be due to neuropathic and myopathic changes leading to symptoms of dysmotility that are encountered in many other disorders. The gastrointestinal symptoms can often be one of the presenting signs of the disease in childhood, but can be misdiagnosed by gastroenterologists for many years due to their nonspecific presentation. As the chief treatment for Fabry is enzyme-replacement therapy that has been shown to stabilize and possibly reverse disease course, recognition of these symptoms and early diagnosis in an attempt to prevent progression with treatment, is critical. PMID:27366228

  15. High prevalence of subclinical hypothyroidism in patients with Anderson-Fabry disease.

    PubMed

    Hauser, A C; Gessl, A; Lorenz, M; Voigtländer, T; Födinger, M; Sunder-Plassmann, G

    2005-01-01

    Anderson-Fabry disease is a rare lysosomal storage disorder. It results from a deficiency of the lysosomal alpha-galactosidase A and leads to progressive accumulation of globotriaosylceramide in the endothelium and tissue cells of various organs. Some of the typical clinical findings such as tiredness, dry skin, myalgia and arthralgia as well as vague gastrointestinal complaints are also symptoms of hypothyroidism. Therefore, we studied the thyroid function in patients with Anderson-Fabry disease. Thyroid function was studied in 11 patients (6 female, 5 male) with Anderson-Fabry disease by measuring thyroid-stimulating hormone (TSH) and free thyroxine serum levels. Nine patients had chronic kidney disease with stage 1 and two with stage 5. Subclinical hypothyroidism (normal serum free thyroxine concentrations along with elevated serum TSH levels) was found in 4 of 11 patients (36.4%). Subclinical hypothyroidism was observed in both male and female patients as well as in patients with stage 1 and stage 5 kidney disease. Subclinical hypothyroidism is a common finding in patients with Anderson-Fabry disease, showing an excess prevalence as compared to the normal population. The high frequency seems to be relevant regarding the potential consequences of a hypothyroid state.

  16. 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.

  17. Cardiac device implantation in Fabry disease

    PubMed Central

    Sené, Thomas; Lidove, Olivier; Sebbah, Joel; Darondel, Jean-Marc; Picard, Hervé; Aaron, Laurent; Fain, Olivier; Zenone, Thierry; Joly, Dominique; Charron, Philippe; Ziza, Jean-Marc

    2016-01-01

    Abstract The incidence and predictive factors of arrhythmias and/or conduction abnormalities (ACAs) requiring cardiac device (CD) implantation are poorly characterized in Fabry disease (FD). The aim of our retrospective study was to determine the prevalence, incidence, and factors associated with ACA requiring CD implantation in a monocentric cohort of patients with confirmed FD who were followed up in a department of internal medicine and reference center for FD. Forty-nine patients (20M, 29F) were included. Nine patients (4M, 5F; 18%) had at least one episode of ACA leading to device therapy. Six patients (4M/2F) required a pacemaker (PM) for sinus node dysfunction (n = 4) or atrioventricular disease (n = 2). One female patient required an internal cardioverter-defibrillator (ICD) to prevent sudden cardiac death because of nonsustained ventricular tachycardia (nSVT). One female patient required PM-ICD for sinus node dysfunction and nSVT. One patient underwent CD implantation before the diagnosis of FD. The annual rate of CD implantation was estimated at 1.90 per 100 person years. On univariate analysis at the end of the follow-up period, the factors associated with ACAs requiring CD implantation were as follows: delayed diagnosis of FD, delayed initiation of enzyme replacement therapy, age at the last follow-up visit, and severe multiorgan phenotype (hypertrophic cardiomyopathy, chronic kidney disease, and/or sensorineural hearing loss). On multivariate analysis, age at diagnosis of FD and age at the last follow-up visit were independently associated with an increased risk of ACAs requiring CD (P < 0.05). Considering the high frequency of ACAs requiring CD implantation and the risk of sudden death in patients with FD, regular monitoring is mandatory, especially in patients with a late diagnosis of FD and/or with a severe phenotype. Regular Holter ECGs, therapeutic education of patients, and deliverance of an emergency card including a phenotype

  18. 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

  19. Fabry disease - current treatment and new drug development.

    PubMed

    Motabar, Omid; Sidransky, Ellen; Goldin, Ehud; Zheng, Wei

    2010-07-23

    Fabry disease is a rare inherited lysosomal storage disorder caused by a partial or complete deficiency of α-galactosidase A (GLA), resulting in the storage of excess cellular glycosphingolipids. Enzyme replacement therapy is available for the treatment of Fabry disease, but it is a costly, intravenous treatment. Alternative therapeutic approaches, including small molecule chaperone therapy, are currently being explored. High throughput screening (HTS) technologies can be utilized to discover other small molecule compounds, including non-inhibitory chaperones, enzyme activators, molecules that reduce GLA substrate, and molecules that activate GLA gene promoters. This review outlines the current therapeutic approaches, emerging treatment strategies, and the process of drug discovery and development for Fabry disease.

  20. Skin Diseases: Skin Health and Skin Diseases

    MedlinePlus

    ... and dryness. Sunlight is a major cause of skin aging. ( See "Skin and Sun—Not a Good Mix") . ... person has smoked. Many products claim to revitalize aging skin or reduce wrinkles, but the Food and Drug ...

  1. Fabry disease in Argentina: an evaluation of patients enrolled in the Fabry Registry.

    PubMed

    Politei, J M; Cabrera, G; Amartino, H; Valdez, R; Masllorens, F; Ripeau, D; Antongiovanni, N; Soliani, A; Luna, P; Cedrolla, M; Fernandez, S; Fainboim, A

    2013-01-01

    Fabry disease (FD) is an X-linked inborn error of metabolism caused by alpha-galactosidase A deficiency. The Fabry Registry is an ongoing, global observational database that compiles clinical data from patients with FD. Demographic and baseline clinical characteristics of Fabry Registry patients enrolled in Argentina were analysed and compared with patients enrolled in the rest of the world (ROW). Baseline clinical parameters included chronic kidney disease (CKD) stage, urine protein-to-creatinine ratio and left ventricular posterior wall thickness. Only data from untreated patients were included. As of 1 October 2010, 3752 patients were enrolled in the Registry, 70 patients from Argentina and 3682 from the ROW. Argentinean male subjects were younger than Fabry Registry male subjects enrolled in ROW: mean current age 32.5 years vs. 39.0 years for men (p = 0.0257 by t-test). The current age (mean ± standard deviation) of female subjects enrolled in Argentina was not significantly different from that of female subjects enrolled in the ROW: 40.1 ± 17.28 vs. 43.2 ±17.95 years respectively (p = 0.2967). Overall, a smaller percentage of patients from Argentina received ERT compared with patients in the ROW (54% vs. 58% respectively). When evaluated by gender, more men and fewer women in Argentina received ERT compared with ROW (85% vs. 79% for men and 27% vs. 38% for women). A larger proportion of patients in ROW had severe CKD (stage 4 or 5) compared with Argentina (9.8% vs. 0%), most likely because of the older age of the ROW population. The enrolment of Argentinean patients into the Fabry Registry has steadily increased, as has the inclusion of female and paediatric patients with FD. The medical community in Argentina should be aware of FD in these populations, as awareness will facilitate prompt diagnosis and initiation of treatment, thus leading to improved outcomes. © 2012 Blackwell Publishing Ltd.

  2. Apical left ventricular hypertrophy and mid-ventricular obstruction in fabry disease.

    PubMed

    Cianciulli, Tomás F; Saccheri, María C; Fernández, Segundo P; Fernández, Cinthia C; Rozenfeld, Paula A; Kisinovsky, Isaac

    2015-05-01

    We report the case of a rare cardiac presentation of Fabry disease. Although concentric left ventricular hypertrophy is a major cardiac finding in Fabry disease, there is no case report of dynamic obstruction at mid-left ventricular level. We describe a 59-year-old-woman suffering from a severe form of Fabry disease, mimicking an apical hypertrophic cardiomyopathy with mid-ventricular obstruction. Differentiation of Fabry disease from hypertrophic cardiomyopathy is crucial given the therapeutic and prognostic differences. Fabry disease should always be suspected in an adult, independently of the pattern of left ventricular hypertrophy.

  3. 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.

  4. Early markers of Fabry disease revealed by proteomics.

    PubMed

    Matafora, V; Cuccurullo, M; Beneduci, A; Petrazzuolo, O; Simeone, A; Anastasio, P; Mignani, R; Feriozzi, S; Pisani, A; Comotti, C; Bachi, A; Capasso, G

    2015-06-01

    Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal hydrolase α-galactosidase A (α-GalA) that leads to the intra-lysosomal accumulation of globotriaosylceramide (Gb3) in various organ systems. As a consequence, a multisystems disorder develops, culminating in stroke, progressive renal and cardiac dysfunction. Enzyme replacement therapy (ERT) offers a specific treatment for patients affected by FD, though the monitoring of treatment is hindered by a lack of surrogate markers of response. Remarkably, due to the high heterogeneity of the Fabry phenotype, both diagnostic testing and treatment decisions are more challenging in females than in males; thus, reliable biomarkers for Fabry disease are needed, particularly for female patients. Here, we use a proteomic approach for the identification of disease-associated markers that can be used for the early diagnosis of FD as well as for monitoring the effectiveness of ERT. Our data show that the urinary proteome of Fabry naïve patients is different from that of normal subjects. In addition, biological pathways mainly affected by FD are related to immune response, inflammation, and energetic metabolism. In particular, the up-regulation of uromodulin, prostaglandin H2 d-isomerase and prosaposin in the urine of FD patients was demonstrated; these proteins might be involved in kidney damage at the tubular level, inflammation and immune response. Furthermore, comparing the expression of these proteins in Fabry patients before and after ERT treatment, a decrease of their concentration was observed, thus demonstrating the correlation between the identified markers and the effectiveness of the pharmacological treatment.

  5. [Fabry disease: An overlooked diagnosis in adult cardiac patients].

    PubMed

    Kayıkçıoğlu, Meral; Şimşek, Evrim; Kalkan Uçar, Sema; Bayraktaroğlu, Selen; Onay, Hüseyin; Sözmen, Eser; Çoker, Mahmut

    2017-09-01

    Fabry disease is a rare, X-linked, lysosomal glycosphingolipid storage disorder. A deficiency of the enzyme alpha-galactosidase results in intracellular accumulation of globotriaosylceramide in multiple cell types, such as those of the nerves, kidneys, cardiac, and cutaneous tissues, leading to a multisystem disease. Male patients are more severely affected; however, heterozygous female patients may also be afflicted, though often the symptoms develop later. Cardiac involvement can include left ventricular hypertrophy, conduction abnormalities, arrhythmias, valvular abnormalities, and heart failure. A variant of the disease affects only cardiac tissue and mostly manifests as unexplained ventricular hypertrophy. Presently described are 2 cases of Fabry disease and the signs and symptoms of cardiac involvement, as well as the importance of early diagnosis to start enzyme replacement therapy before the development of irreversible tissue damage.

  6. Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN)

    PubMed Central

    Fogo, Agnes B.; Bostad, Leif; Svarstad, Einar; Cook, William J.; Moll, Solange; Barbey, Federic; Geldenhuys, Laurette; West, Michael; Ferluga, Dusan; Vujkovac, Bojan; Howie, Alexander J.; Burns, Áine; Reeve, Roy; Waldek, Stephen; Noël, Laure-Hélène; Grünfeld, Jean-Pierre; Valbuena, Carmen; Oliveira, João Paulo; Müller, Justus; Breunig, Frank; Zhang, Xiao; Warnock, David G.

    2010-01-01

    Background. In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function. Methods. An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported. Results. We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 μmol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m2 and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1–2 chronic kidney disease with minimal proteinuria. Conclusions. The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for

  7. Genomic analysis of Brazilian patients with Fabry disease.

    PubMed

    Pereira, F S; Jardim, L B; Netto, C B; Burin, M G; Cecchin, C; Giugliani, R; Matte, U S

    2007-12-01

    Fabry disease is an X-linked lysosomal disorder due to a-galactosidase A deficiency that causes storage of globotriaosylceramide. The gene coding for this lysosomal enzyme is located on the long arm of the X chromosome, in region Xq21.33-Xq22. Disease progression leads to vascular disease secondary to involvement of kidney, heart and the central nervous system. Detection of female carriers based solely on enzyme assays is often inconclusive. Therefore, mutation analysis is a valuable tool for diagnosis and genetic counseling. Many mutations of the a-galactosidase A gene have been reported with high genetic heterogeneity, being most mutations private found in only one family. The disease is panethnic, and estimates of incidence range from about 1 in 40,000 to 60,000 males. Our objective was to describe the analysis of 6 male and 7 female individuals belonging to 4 different Fabry disease families by automated sequencing of the seven exons of the alpha-galactosidase gene. Sequencing was performed using PCR fragments for each exon amplified from DNA extracted from peripheral blood. Three known mutations and one previously described in another Brazilian family were detected. Of 7 female relatives studied, 4 were carriers. Although the present study confirms the heterogeneity of mutations in Fabry disease, the finding of the same mutation previously detected in another Fabry family from our region raises the possibility of some founder effect, or genetic drift. Finally, the present study highlights the importance of molecular analysis for carrier detection and genetic counseling.

  8. Selective arterial distribution of cerebral hyperperfusion in Fabry disease.

    PubMed

    Moore, D F; Herscovitch, P; Schiffmann, R

    2001-07-01

    Fabry disease is an X-linked recessive deficiency of lysosomal alpha-galactosidase A associated with an increased risk of early onset cerebrovascular disease. The disorder is reported to affect the posterior circulation predominantly. This hypothesis was investigated directly by the measurement of regional cerebral blood flow with positron emission tomography (PET). Resting regional cerebral blood flow (rCBF) in 26 hemizygous patients with Fabry disease and 10 control participants was examined using H(2)15O and PET. Statistical parametric mapping (SPM(t), SPM99) and PET images of patients and controls were produced. Significantly increased SPM(t) clusters were then color coded and blended with a coregistered T1 magnetic resonance imaging (MRI) template. Cerebral arterial territory maps were digitized and rescaled. Custom OpenGL and ImageVision Library C++ code was written to allow a first-order affine transformation of the blended SPM(t) and MRI template onto the arterial territory map. The affine transformation was constrained by choosing corresponding cerebral landmark "tie points" between the SPM(t) [symbol: see text] MRI template images and the cerebral arterial territory maps. The data demonstrated that the posterior circulation is the predominant arterial territory with a significantly increased rCBF in Fabry disease. No arterial distribution had a decreased rCBF.

  9. Fabry Disease Presenting with Hypertrophic Cardiomyopathy and Tricuspid Regurgitation

    PubMed Central

    Cho, Sang-Cheol; Yoo, Han-Wook; Lee, Jae Won; Jang, Jeong Yoon; Heo, Ran

    2016-01-01

    A 71-year-old female who was diagnosed with nonobstructive hypertrophic cardiomyopathy since 1999 presented with dyspnea and severe edema on both legs. For the management of her symptom, cardiac surgery including tricuspid annuloplasty, Maze operation and right atrial reduction plasty was performed. During follow-up after cardiac surgery, a plasma α-galactosidase activity was checked for the screening of Fabry disease and the result was around lower normal limit. DNA analysis was implemented for confirmation and it revealed a heterozygote α-galactosidase mutation at exon 6 [c.901C>T (p.Arg301Ter)]. This case suggests that Fabry disease might be easily undetected, and clinical suspicion is critical. PMID:28090261

  10. Enzyme replacement therapy for Fabry disease: a systematic review of available evidence.

    PubMed

    Schaefer, Roland M; Tylki-Szymańska, Anna; Hilz, Max J

    2009-11-12

    majority of which were subclinical parameters rather than clinical outcomes. Plasma levels of GL-3 together with accumulation in the kidney, heart and skin were the most commonly studied endpoints, followed by renal endpoints of proteinuria and glomerular filtration rate, whereas cardiac and neurological endpoints were not commonly studied. To date, only one RCT with ERT defined hard clinical outcomes in the form of cardiac, renal or cerebrovascular events, or death as its primary endpoint. The currently available data from prospective RCTs and open-label studies in patients with Fabry disease are more robust for ERT at a dose of 1 mg/kg EOW than a dose of 0.2 mg/kg EOW, although the beneficial effects of ERT with either dose or preparation are variable.

  11. Dialysis and transplantation in Fabry disease: indications for enzyme replacement therapy.

    PubMed

    Mignani, Renzo; Feriozzi, Sandro; Schaefer, Roland M; Breunig, Frank; Oliveira, João Paulo; Ruggenenti, Piero; Sunder-Plassmann, Gere

    2010-02-01

    ESRD is a major cause of morbidity and premature mortality in Fabry disease, particularly in classically affected males. The decline of renal function in Fabry nephropathy is adversely affected by male gender, advanced chronic kidney disease (CKD), and severe proteinuria. The diagnosis of Fabry nephropathy may be missed if not specifically addressed in progressive CKD and patients have been first identified in screening programs of dialysis patients. Fabry patients have worse 3-year survival rates on dialysis as compared with nondiabetic controls. The 5-year survival rate of transplanted Fabry patients is also lower than that of controls. However, because Fabry nephropathy does not recur in the allograft and transplanted Fabry patients appear to have better overall outcomes than those maintained on dialysis, kidney transplantation should be recommended as a first choice in renal replacement therapy (RRT) for Fabry disease. Appropriately designed and powered studies are not available to answer the question whether enzyme replacement therapy (ERT) influences outcomes, the course of cardiomyopathy, events, or survival in Fabry patients on RRT. The authors are not aware of compelling indications for ERT in RRT patients because progression of cardiomyopathy was documented during ERT. Whether the excess mortality risk of Fabry patients on RRT can be prevented by ERT is unknown. Despite observational reports of symptomatic improvement, the available evidence supporting ERT for such patients is not compelling enough. To clarify this issue, studies are needed to test the effectiveness of agalsidases in preventing cardiac and cerebrovascular complications in Fabry patients with ESRD.

  12. Fabry disease in children and the effects of enzyme replacement treatment.

    PubMed

    Pintos-Morell, Guillem; Beck, Michael

    2009-11-01

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

  13. Age at First Cardiac Symptoms in Fabry Disease: Association with a Chinese Hotspot Fabry Mutation (IVS4+919G>A), Classical Fabry Mutations, and Sex in a Taiwanese Population from the Fabry Outcome Survey (FOS).

    PubMed

    Liu, Hao-Chuan; Perrin, Amandine; Hsu, Ting-Rong; Yang, Chia-Feng; Lin, Hsiang-Yu; Yu, Wen-Chung; Niu, Dau-Ming

    2015-01-01

    This is a descriptive analysis of a cohort of 59 Taiwanese patients with Fabry disease and either classical Fabry or cardiac variant IVS4+919G>A (IVS4) mutations from a disease registry, the Fabry Outcome Survey (FOS; sponsored by Shire). Most of our classical Fabry patients were symptomatic and were identified upon seeking medical advice at our clinics, whereas most of our IVS4 patients attended our clinics after newborn screening identified this mutation in their grandsons. The objective was to determine differences in cardiac manifestations between patients with classical Fabry or IVS4 mutations by comparing age at onset of selected cardiac symptoms. Data were extracted in August 2013 and analyzed retrospectively. Fifty-nine Taiwanese patients (median age at extract 60.7 years [range 15.0-86.9]; n = 36 [61%] male) with proven IVS4 (n = 41 [69%]) or classical Fabry mutations (n = 18 [31%]) had available data on cardiac symptoms. Of 55 (93%) patients with reported left ventricular hypertrophy (LVH), mean [SD] age (years) at first symptom was lower in classical Fabry males (30.0 [15.1]; n = 4) than classical Fabry females (49.6 [8.9]; n = 11; p < 0.05), but not in IVS4 females (57.4 [13.7]; n = 10) compared with IVS4 males (55.9 [11.3]; n = 30). Mean age at first LVH diagnosis was significantly lower in classical Fabry males versus IVS4 males (p < 0.05). No significant difference in age at onset of arrhythmia or conductive abnormality, chest pain, or palpitations or cardiac syncope was found between the groups. The most noteworthy finding of this study is the lack of a significant gender sex difference in age at onset of cardiac symptoms in IVS4 patients.

  14. The Mutation p.D313Y is Associated with Organ Manifestation in Fabry Disease.

    PubMed

    du Moulin, M; Koehn, A F; Golsari, A; Dulz, S; Atiskova, Y; Patten, M; Münch, J; Avanesov, M; Ullrich, K; Muschol, N

    2017-03-09

    Fabry disease is a multisystem lysosomal storage disorder caused by mutations in the GLA gene. The clinical significance of the mutation p.D313Y is still under debate. Retrospective chart analysis of clinical (neurological, cardiac, renal, ophthalmological), genetic, and biochemical (lyso-globotriaosylsphingosine, lyso-Gb3; enzyme activity) data was done in all our patients carrying the p.D313Y mutation. Fourteen patients from 5 families (10 female, 4 male; age range 10-51) were included. Symptoms and organ manifestations compatible with Fabry disease could be identified in 10 patients. Cerebrovascular events occurred in 4 females. Seven patients reported pain or acroparaesthesia. Cornea verticillata was found in one patient, mild retinal vascular tortuosity in 5 patients. Lyso-Gb3 was elevated in 2 females with cerebrovascular involvement. Classical cardiac, renal or skin manifestations could not be identified. The mutation p.D313Y in the GLA gene may lead to organ manifestations and elevation of the Fabry-specific biomarker lyso-Gb3. Neurological symptoms (stroke and pain) and ocular manifestations seem to be the leading findings. Annual routine visits are recommended for patients carrying the p.D313Y mutation. Enzyme replacement therapy might be considered in symptomatic patients.

  15. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry.

    PubMed

    Wilcox, William R; Oliveira, João Paulo; Hopkin, Robert J; Ortiz, Alberto; Banikazemi, Maryam; Feldt-Rasmussen, Ulla; Sims, Katherine; Waldek, Stephen; Pastores, Gregory M; Lee, Philip; Eng, Christine M; Marodi, Laszlo; Stanford, Kevin E; Breunig, Frank; Wanner, Christoph; Warnock, David G; Lemay, Roberta M; Germain, Dominique P

    2008-02-01

    Fabry disease (FD) is an X-linked lysosomal storage disease caused by alpha-galactosidase A deficiency. The Fabry Registry is a global clinical effort to collect longitudinal data on FD. In the past, most "carrier" females were usually thought to be clinically unaffected. A systematic effort has been made to enroll all FD females, regardless of symptomology. Of the 1077 enrolled females in the Registry, 69.4% had symptoms and signs of FD. The median age at symptom onset among females was 13 years, and even though 84.1% had a positive family history, the diagnosis was not made until a median age of 31 years. Twenty percent experienced major cerebrovascular, cardiac, or renal events, at a median age of 46 years. Among adult females with estimated glomerular filtration rate (eGFR) data (N=638), 62.5% had an eGFR <90 ml/min/1.73 m2 and 19.0% had eGFR <60 ml/min/1.73 m2. Proteinuria 300 mg/day was present in 39.0% of females, and 22.2% had >1 gram/day. Quality of life (QoL), as measured by the SF-36((R)) survey, was impaired at a later age than in males, but both genders experience significantly impaired QoL from the third decade of life onward. Thus, females with FD have a significant risk for major organ involvement and decreased QoL. Females should be regularly monitored for signs and symptoms of FD, and considered for enzyme replacement therapy.

  16. Ocular signs correlate well with disease severity and genotype in Fabry disease.

    PubMed

    Pitz, Susanne; Kalkum, Gisela; Arash, Laila; Karabul, Nesrin; Sodi, Andrea; Larroque, Sylvain; Beck, Michael; Gal, Andreas

    2015-01-01

    Ocular signs in Fabry disease have generally been regarded to be primarily of diagnostic value. We explored whether ocular findings, alone or in particular in combination with the α-galactosidase A gene mutation, have predictive value for disease severity. Data from the Fabry Outcome Survey (FOS), a large, global database sponsored by Shire, were selected for adult patients who had undergone ophthalmological examination. Three ocular signs were assessed: cornea verticillata, tortuous conjunctival and/or retinal vessels, and cataract. Fabry disease severity was measured using FOS Mainz Severity Score Index and modifications thereof. Ophthalmological data were available for 1203 (699 female, 504 male) adult patients with eye findings characteristic of Fabry disease in 55.1%. Cornea verticillata had a similar distribution in women (51.1%) and men (50.8%), whereas tortuous vessels and Fabry cataract were somewhat more frequent in men than in women. Patients with cornea verticillata, selected as the principal ocular sign for this study, had more severe disease (median score, 20.0) versus those without ocular signs (11.0; P<0.001). This finding could be confirmed by applying age adjusted severity scores. Moreover, the prevalence of cornea verticillata was significantly higher in patients with null (male, 76.9%; female, 64.5%) and missense (male, 79.2%; female, 67.4%) mutations versus mild missense (male, 17.1%; female, 23.1%) and the p.N215S (male, 15.0%; female, 15.6%) mutations (P<0.01). Our analyses show a correlation between the prevalence of ocular changes in Fabry disease and disease severity. Consequently, information on ocular findings and α-galactosidase A gene mutation may help assess the risk for more severe Fabry disease. These observed findings are of notable clinical importance, as Fabry disease is characterized by high clinical course variability and only weak genotype-phenotype correlation at the individual patient level. Further confirmatory studies

  17. Fabry's Disease: Case Series and Review of Literature

    PubMed Central

    Wani, Muzaffar Maqsood; Khan, Imran; Bhat, Riyaz Ahmad; Ahmad, Muzaffar

    2016-01-01

    Fabry's disease is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A enzyme with the progressive accumulation of globotriaosylceramide in vascular endothelial cells leading to cardiovascular, renal, gastrointestinal, neuropathic, lenticular, and dermatological manifestations. It is a rare cause of end-stage renal disease. It classically affects males whereas 10–15% of female heterozygote carriers are affected depending on localization. Both the FD and its association with ESRD is rare. With this background, this case series of five patient's along with the review of literature is presented here. PMID:27398254

  18. Viral Skin Diseases.

    PubMed

    Ramdass, Priya; Mullick, Sahil; Farber, Harold F

    2015-12-01

    In the vast world of skin diseases, viral skin disorders account for a significant percentage. Most viral skin diseases present with an exanthem (skin rash) and, oftentimes, an accompanying enanthem (lesions involving the mucosal membrane). In this article, the various viral skin diseases are explored, including viral childhood exanthems (measles, rubella, erythema infectiosum, and roseola), herpes viruses (herpes simplex virus, varicella zoster virus, Kaposi sarcoma herpes virus, viral zoonotic infections [orf, monkeypox, ebola, smallpox]), and several other viral skin diseases, such as human papilloma virus, hand, foot, and mouth disease, molluscum contagiosum, and Gianotti-Crosti syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Contribution of inflammatory pathways to Fabry disease pathogenesis.

    PubMed

    Rozenfeld, Paula; Feriozzi, Sandro

    2017-09-13

    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

  20. Cardiovascular manifestations of Fabry disease and the novel therapeutic strategies.

    PubMed

    Seino, Yoshihiko; Takahashi, Hiroshi; Fukumoto, Hiroko; Utsumi, Kouichi; Hirai, Yukihiko

    2005-10-01

    Fabry disease is an inherited lysosomal storage disorder characterized by a pathological intracellular glycosphingolipid deposition. The disease is caused by a deficit in the lysosomal enzyme alpha-galatosidase A, the gene for which is located in the X chrosomal region Xq 22. Globotriaosylceramide (Gb3) accumulate progressively in multi-organ vulnerable cells throughout the body, including cardiovascular, renal, and cerebrovascular systems. The present manuscript is to review cardiovascular and renal manifestations of Fabry disease and the new diagnostic procedures for earlier detection and the therapeutic assessments of this disease. We are applying noninvasive cardiovascular and microcirculation analysis methods and novel cardiac biomarkers. Novel therapeutic strategies for this disease have been developing in recent years, which include the clinically introduced enzyme infusion replacement therapy and experimentally developing gene-transfer therapy. We have reported that AAV-mediated muscule-directed gene transfer is very effective for long-term systemic delivery of alpha-gal A (25% of normal mice enzyme activity), resulting in complete clearance of multi-organs Gb3 accumulation. Echocardiographic and immunohistochemical examination demonstrated structural improvement of cardiac hypertrophy. When and to whom the novel therapeutic strategies should be applied to obtain the maximum efficacy and safety remain to be established.

  1. [The Fabry's Disease Cardiomyopathy as Differential Diagnosis of Acute Coronary Syndrome].

    PubMed

    Oder, Daniel; Störk, Stefan; Wanner, Christoph; Ertl, Georg; Weidemann, Frank; Nordbeck, Peter

    2017-03-01

    The progressive cardiomyopathy in patients with Fabry disease is often accompanied by angina pectoris and elevated levels of high-sensitive troponin T (hs-TnT), potentially mimicking acute coronary syndrome. Here, we present to representative cases with focus on clinical, diagnostic and therapeutic settings. An overview on the cardiomyopathy associated with Fabry disease and its role as differential diagnosis of acute coronary syndrome is provided. Fabry cardiomyopathy might exhibit similar clinical and biochemical constellations as seen in acute coronary syndrome. Thus, Fabry cardiomyopathy should be considered a differential diagnosis in acute coronary syndrome, particularly in patients demonstrating left ventricular hypertrophy of unknown origin.

  2. FAbry STabilization indEX (FASTEX): an innovative tool for the assessment of clinical stabilization in Fabry disease.

    PubMed

    Mignani, Renzo; Pieruzzi, Federico; Berri, Francesco; Burlina, Alessandro; Chinea, Benito; Gallieni, Maurizio; Pieroni, Maurizio; Salviati, Alessandro; Spada, Marco

    2016-10-01

    Two disease severity scoring systems, the Mainz Severity Score Index (MSSI) and Fabry Disease Severity Scoring System (DS3), have been validated for quantifying the disease burden of Fabry disease. We aimed to develop a dynamic mathematical model [the FASTEX (FAbry STabilization indEX)] to assess the clinical stability. A multidisciplinary panel of experts in Fabry disease first defined a novel score of severity [raw score (RS)] based on three domains with a small number items in each domain (nervous system domain: pain, cerebrovascular events; renal domain: proteinuria, glomerular filtration rate; cardiac domain: echocardiography parameters, electrocardiograph parameters and New York Heart Association class) and evaluated the clinical stability over time. The RS was tested in 28 patients (15 males, 13 females) with the classic form of Fabry disease. There was good statistical correlation between the newly established RS and a weighted score (WS), with DS3 and MSSI (R (2) = 0.914, 0.949, 0.910 and 0.938, respectively). In order to refine the RS further, a WS, which was expressed as a percentage value, was calculated. This was based on the relative clinical significance of each item within the domain with the panel agreeing on the attribution of a different weight of clinical damage to a specific organ system. To test the variation of the clinical burden over time, the RS was repeated after 1 year. The panel agreed on a cut-off of a 20% change from baseline as the clinical WS to define clinical stability. The FASTEX model showed good correlation with the clinical assessment and with clinical variation over time in all patients.

  3. FAbry STabilization indEX (FASTEX): an innovative tool for the assessment of clinical stabilization in Fabry disease

    PubMed Central

    Mignani, Renzo; Pieruzzi, Federico; Berri, Francesco; Burlina, Alessandro; Chinea, Benito; Gallieni, Maurizio; Pieroni, Maurizio; Salviati, Alessandro; Spada, Marco

    2016-01-01

    Two disease severity scoring systems, the Mainz Severity Score Index (MSSI) and Fabry Disease Severity Scoring System (DS3), have been validated for quantifying the disease burden of Fabry disease. We aimed to develop a dynamic mathematical model [the FASTEX (FAbry STabilization indEX)] to assess the clinical stability. A multidisciplinary panel of experts in Fabry disease first defined a novel score of severity [raw score (RS)] based on three domains with a small number items in each domain (nervous system domain: pain, cerebrovascular events; renal domain: proteinuria, glomerular filtration rate; cardiac domain: echocardiography parameters, electrocardiograph parameters and New York Heart Association class) and evaluated the clinical stability over time. The RS was tested in 28 patients (15 males, 13 females) with the classic form of Fabry disease. There was good statistical correlation between the newly established RS and a weighted score (WS), with DS3 and MSSI (R2 = 0.914, 0.949, 0.910 and 0.938, respectively). In order to refine the RS further, a WS, which was expressed as a percentage value, was calculated. This was based on the relative clinical significance of each item within the domain with the panel agreeing on the attribution of a different weight of clinical damage to a specific organ system. To test the variation of the clinical burden over time, the RS was repeated after 1 year. The panel agreed on a cut-off of a 20% change from baseline as the clinical WS to define clinical stability. The FASTEX model showed good correlation with the clinical assessment and with clinical variation over time in all patients. PMID:27679722

  4. 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.

  5. Absence of α-galactosidase cross-correction in Fabry heterozygote cultured skin fibroblasts.

    PubMed

    Fuller, Maria; Mellett, Natalie; Hein, Leanne K; Brooks, Doug A; Meikle, Peter J

    2015-02-01

    Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from deficiency of α-galactosidase A (GLA). Traditionally, heterozygotes were considered asymptomatic carriers of FD, but it is now apparent that the asymptomatic female carrier is the exception and most heterozygotes suffer significant multisystemic disease. To determine why the process of cross-correction does not occur effectively in FD heterozygotes, we investigated GLA production and secretion in cultured skin fibroblasts as well as GLA levels in plasma. The maturation of GLA was similar in FD heterozygotes and control fibroblasts, confirming that both produce the 46kDa mature form; the same as that present in control plasma. However, the proportion of GLA secreted into the culture media was substantially less than eight other lysosomal proteins. Artificial generation of FD heterozygotes in cellulo, along with another lysosomal storage disorder, mucopolysaccharidosis type II, revealed no cross-correction in the FD system, whereas MPS II fibroblasts were able to cross-correct. In plasma, GLA was present as the 46kDa mature form, which lacks the mannose 6-phosphorylated moiety and is not able to be efficiently endocytosed by affected cells. Our evidence shows that fibroblasts secrete minimal amounts of GLA and consequently normal fibroblasts are unable to cross-correct FD fibroblasts. We suggest that symptomatic FD heterozygotes arise due to the secretion of primarily the mature form, with only small amounts of the mannose 6-phosphorylated form of GLA from unaffected cells. This limits capacity for enzyme cross correction of affected cells, despite uptake of exogenous recombinant GLA. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Identification of a novel GLA mutation (F69 L) in a Japanese patient with late-onset Fabry disease.

    PubMed

    Umeda, Toshiko; Hashimoto, Seiji; Noriyasu, Kazuyuki; Takamura, Ayumi; Fujisaki, Miwa; Eto, Yoshikatsu

    2015-01-01

    Fabry disease is an X-linked recessive inborn error of glycosphingolipid catabolism caused by a mutation in the GLA gene. We sequenced the α-galactosidase A gene (GLA) of a patient who had been clinically diagnosed with late-onset Fabry disease. Abundant globotriaosylceramide was present in his urine, which indicated typical Fabry disease. Here, we report a novel hemizygous mutation, c.207C>A (Phe69 Leu), which caused a mild/late-onset form of Fabry disease.

  7. Agalsidase alfa and kidney dysfunction in Fabry disease.

    PubMed

    West, Michael; Nicholls, Kathy; Mehta, Atul; Clarke, Joe T R; Steiner, Robert; Beck, Michael; Barshop, Bruce A; Rhead, William; Mensah, Robert; Ries, Markus; Schiffmann, Raphael

    2009-05-01

    In male patients with Fabry disease, an X-linked disorder of glycosphingolipid metabolism caused by deficient activity of the lysosomal enzyme alpha-galactosidase A, kidney dysfunction becomes apparent by the third decade of life and invariably progresses to ESRD without treatment. Here, we summarize the effects of agalsidase alfa on kidney function from three prospective, randomized, placebo-controlled trials and their open-label extension studies involving 108 adult male patients. The mean baseline GFR among 54 nonhyperfiltrating patients (measured GFR <135 ml/min per 1.73 m(2)) treated with placebo was 85.4 +/- 29.6 ml/min per 1.73 m(2); during 6 mo of placebo, the mean annualized rate of change in GFR was -7.0 +/- 32.9 ml/min per 1.73 m(2). Among 85 nonhyperfiltrating patients treated with agalsidase alfa, the annualized rate of change was -2.9 +/- 8.7 ml/min per 1.73 m(2). Treatment with agalsidase alfa did not affect proteinuria. Multivariate analysis revealed that GFR and proteinuria category (< 1 or > or = 1 g/d) at baseline significantly predicted the rate of decline of GFR during treatment. This summary represents the largest group of male patients who had Fabry disease and for whom the effects of enzyme replacement therapy on kidney function have been studied. These data suggest that agalsidase alfa may stabilize kidney function in these patients.

  8. Microbiome and skin diseases.

    PubMed

    Zeeuwen, Patrick L J M; Kleerebezem, Michiel; Timmerman, Harro M; Schalkwijk, Joost

    2013-10-01

    This article reviews recent findings on the skin microbiome. It provides an update on the current understanding of the role of microbiota in healthy skin and in inflammatory and allergic skin diseases. Advances in computing and high-throughput sequencing technology have enabled in-depth analysis of microbiota composition and functionality of human skin. Most data generated to date are related to the skin microbiome of healthy volunteers, but recent studies have also addressed the dynamics of the microbiome in diseased and injured skin. Currently, reports are emerging that evaluate the strategies to manipulate the skin microbiome, intending to modulate diseases and/or their symptoms. The microbiome of normal human skin was found to have a high diversity and high interpersonal variation. Microbiota compositions of diseased lesional skin (in atopic dermatitis and psoriasis) showed distinct differences compared with healthy skin. The function of microbial colonization in establishing immune system homeostasis has been reported, whereas host-microbe interactions and genetically determined variation of stratum corneum properties might be linked to skin dysbiosis. Both are relevant for cutaneous disorders with aberrant immune responses and/or disturbed skin barrier function. Modulation of skin microbiota composition to restore host-microbiota homeostasis could be future strategies to treat or prevent disease.

  9. Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice

    PubMed Central

    Ohshima, Toshio; Schiffmann, Raphael; Murray, Gary J.; Kopp, Jeffrey; Quirk, Jane M.; Stahl, Stefanie; Chan, Chi-Chao; Zerfas, Patricia; Tao-Cheng, Jung-Hwa; Ward, J. M.; Brady, Roscoe O.; Kulkarni, Ashok B.

    1999-01-01

    Fabry disease is an X-linked metabolic disorder caused by a deficiency of α-galactosidase A (α-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with α-galactosyl moieties consisting predominantly of globotriaosylceramide (Gb3). In patients with this disorder, glycolipid deposition in endothelial cells leads to renal failure and cardiac and cerebrovascular disease. Recently, we generated α-Gal A gene knockout mouse lines and described the phenotype of 10-week-old mice. In the present study, we characterize the progression of the disease with aging and explore the effects of bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of α-Gal A −/0 mice revealed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Gb3 accumulation and pathological lesions in the affected organs increased with age. Treatment with BMT from the wild-type mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of α-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease. PMID:10339603

  10. 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.

  11. [Skin diseases of swine].

    PubMed

    von Altrock, A; Höltig, D

    2013-01-01

    Skin alterations can be caused by both environmental conditions and diseases of the organism. Some diseases may only manifest in the skin while others represent signs of a generalized infection. Regarding their origin, skin diseases can be divided into congenital, infectious, and nutritional disorders, and those resulting from housing scarcities. Additionally, there are skin diseases with unknown causes. Skin diseases in a swine herd can result in economic losses through decreased feed efficiency and growth rate and increased mortality. The knowledge of causes and symptoms as well as the selection of appropriate further laboratory investigations provide a valid diagnosis and enable a quick and effective therapy. This description of several skin diseases should provide a background.

  12. [Skin diseases and obesity].

    PubMed

    Guerra-Segovia, Carolina; Ocampo-Candiani, Jorge

    2015-01-01

    Obesity is a public health problem worldwide. It predominates in industrialized countries; however, it is prevalent in all nations. It is defined as a condition of excess adipose tissue and is the result of changes in lifestyle, excessive consumption of energy-dense foods with poor nutritional value, physical inactivity and the reduction of open space where one can practice a sport. Although obesity is associated with multiple diseases, it is important to stress that the metabolic changes caused by it affect skin physiology and play a predisposing factor for the development of skin diseases. Very little has been studied on the impact of obesity on the skin. The purpose of this article is to review the most frequently skin diseases in obesity. Some skin pathologies in obesity are caused by changes in skin physiology, others are related to insulin resistance or constitute an exacerbating factor for dermatitis. This article covers the clinical features of obesity related skin disease and its management.

  13. Occupational skin diseases.

    PubMed

    Diepgen, Thomas L

    2012-05-01

    Occupational skin diseases are the most commonly reported notifiable occupational diseases. In Germany, 23 596 out of a total of 71 263 reported occupational diseases in 2010 were classified as occupational skin diseases (BK No. 5101: "severe or recurrent skin diseases which have forced the person to discontinue all occupational activities that caused or could cause the development, worsening, or recurrence of the disease"). Contact dermatitis (allergic, irritant) of the hands is the most common skin disease and atopic skin diathesis is often an important co-factor. The number of work-related skin diseases is many times higher than the number of notified occupational dermatoses. This CME article explains the legal framework of occupational diseases, the tasks and obligations of the legal statutory work insurance. Typical allergens and irritants of high risk professions are also presented as are the important steps from diagnosis to compensation. Early prevention of occupational skin diseases is very important to avoid severe chronic hand eczema. Therefore the "dermatologist's report" is crucial. Other occupational dermatoses (outside of BK 5101) are briefly mentioned. In recent years the number of notifications of occupational skin cancer due to occupational UV-irradiation has increased. According to recent epidemiological findings, there is a significant and consistent positive association between occupational UV-irradiation and squamous cell carcinoma. Therefore, an important criterion for a new occupational disease is fulfilled. © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.

  14. A male Fabry disease patient treated with intravenous thrombolysis for acute ischemic stroke.

    PubMed

    Saarinen, Jukka T; Sillanpää, Niko; Kantola, Ilkka

    2015-02-01

    The use of intravenous thrombolytic therapy for acute ischemic stroke is associated with improved outcomes. Fabry disease is an X-linked glycosphingolipid storage disease with vascular endothelial deposits. Affected males with the classic phenotype develop renal, cardiac, and cerebrovascular disease and die prematurely. However, Fabry disease is rare in young men with first ischemic stroke of undetermined cause. We report a 38-year-old man with acute aphasia and a left M2 segment of the middle cerebral artery thrombus with no recanalization who was finally diagnosed with Fabry disease after left ventricular hypertrophy of undetermined cause had been identified. A gene test revealed a R227X mutation typical of Fabry disease with the classical phenotype. To our knowledge our patient is the first reported male Fabry patient who was given intravenous thrombolytic therapy and the first reported Fabry patient who received intravenous thrombolytic therapy between 3 and 4.5 hours of the symptom onset. Despite favorable prognostic indicators on admission imaging, our patient suffered a significant stroke and had an unfavorable clinical outcome. Fortunately, the episode was not complicated by intracranial hemorrhage. Further studies are needed to evaluate the efficacy and safety of intravenous thrombolytic therapy in treating patients with Fabry disease and acute ischemic stroke.

  15. Histopathological evidence of Fabry disease in a female patient with left ventricular noncompaction.

    PubMed

    Martins, Elisabete; Pinho, Teresa; Carpenter, Stirling; Leite, Sérgio; Garcia, Raquel; Madureira, António; Oliveira, João Paulo

    2014-09-01

    Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase gene. The most frequent cardiac presentation of Fabry disease is cardiomyopathy characterized by left ventricular (LV) hypertrophy, usually concentric. Heart disease in affected females tends to be clinically recognized later than in males and cardiac complications are the most frequently reported cause of death in females with Fabry disease. There are few data regarding the association between Fabry disease and LV noncompaction. We report a case of a 30-year-old asymptomatic woman, heterozygous for a nonsense alpha-galactosidase gene mutation (p.R220X), who presented LV noncompaction on cardiac magnetic resonance imaging, without LV wall hypertrophy. Histopathological examination of myocardial fragments showed marked deposition of glycosphingolipids in cardiomyocytes, confirming the diagnosis of Fabry cardiomyopathy. Based on this finding, the patient was proposed for enzyme replacement therapy. This case illustrates the role of endomyocardial biopsy in the clarification of doubtful or atypical findings related to cardiac Fabry disease, even in heterozygous women, and corroborates the contention that Fabry disease should be included in the differential diagnosis of LV hypertrabeculation/noncompaction.

  16. Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic Counselors.

    PubMed

    Bennett, Robin L; Hart, Kimberly A; O'Rourke, Erin; Barranger, John A; Johnson, Jack; MacDermot, Kay D; Pastores, Gregory M; Steiner, Robert D; Thadhani, Ravi

    2002-04-01

    The objective of this document is to provide health care professionals with recommendations for genetic counseling and testing of individuals with a suspected or confirmed diagnosis of Fabry disease, with a family history of Fabry disease, and those identified as female carriers of Fabry disease. These recommendations are the opinions of a multicenter working group of genetic counselors, medical geneticists, and other health professionals with expertise in Fabry disease counseling, as well as an individual with Fabry disease who is a founder of a Fabry disease patient advocacy group in the United States. The recommendations are U.S. Preventive Task Force Class III, and they are based on clinical experience, a review of pertinent English-language articles, and reports of expert committees. This document reviews the genetics of Fabry disease, the indications for genetic testing and interpretation of results, psychosocial considerations, and references for professional and patient resources. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a healthcare provider, familiar with the facts and circumstances of a specific case, will always supersede these recommendations.

  17. Increased arterial diameters in the posterior cerebral circulation in men with Fabry disease.

    PubMed

    Uçeyler, 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.

  18. 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

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

    PubMed

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

    2017-11-01

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

  20. [Atypical symptoms of Fabry's disease: sudden bilateral deafness, lymphoedema and Lown-Ganong-Levine syndrome].

    PubMed

    Undas, Anetta; Ryś, Donata; Wegrzyn, Wojciech; Musiał, Jacek

    2002-11-01

    A 40-year-old man with Fabry disease, confirmed by decreased leukocyte alpha-galactosidase A activity in 2001, complained of sudden bilateral deafness, as evidenced by clinical history and audiometry. Magnetic resonance of the brain revealed features typical of Fabry disease. Other clinical manifestations of the disease included: angiokeratoma, mild proteinuria with normal renal function, lymphoedema of the lower limbs, pre-excitation syndrome, myocardial hypertrophy.

  1. Reduced glucosylceramide in the mouse model of Fabry disease: correction by successful enzyme replacement therapy.

    PubMed

    Quinta, Rui; Rodrigues, Daniel; Assunção, Marisa; Macedo, Maria Fatima; Azevedo, Olga; Cunha, Damião; Oliveira, Pedro; Sá Miranda, Maria Clara

    2014-02-15

    Fabry disease is an X-linked lysosomal storage disease (LSD) caused by deficient activity of α-Galactosidase A (α-Gal A). As a result, glycosphingolipids, mainly globotriaosylceramide (Gb3), progressively accumulate in body fluids and tissues. Studies aiming at the identification of secondary lipid alterations in Fabry disease may be potentially useful for the monitorization of the response to enzyme replacement therapy (ERT) and development of future therapies. The focus of this study was to evaluate if α-Gal A deficiency has an effect on two key groups of molecules of sphingolipids metabolism: glucosylceramides (GlucCers) and ceramides (Cers). Studies performed in a mouse model of Fabry disease showed reduced level of GlucCer and normal level of Cer in plasma, liver, spleen, kidney and heart. Moreover, analysis of GlucCer isoforms in Fabry knockout mice showed that GlucCer isoforms are unequally reduced in different tissues of these animals. ERT had a specific effect on the liver's GlucCer levels of Fabry knockout mice, increasing hepatic GlucCer to the levels observed in wild type mice. In contrast to Fabry knockout mice, plasma of Fabry patients had normal GlucCer and Cer but an increased GlucCer/Cer ratio. This alteration showed a positive correlation with plasma globotriaosylsphingosine (lyso-Gb3) concentration. In conclusion, this work reveals novel secondary lipid imbalances caused by α-Gal A deficiency.

  2. A renal variant of Fabry disease: A case with a novel Gal A hemizygote mutation

    PubMed Central

    H. Mukdsi, Jorge; Gutiérrez, Silvina; Barrón, Belén; Novoa, Pablo; Fernández, Segundo; de Diller, Ana B; I. Torres, Alicia; Formica Jr., Richard N; Orías, Marcelo

    2012-01-01

    Background Fabry disease is caused by an X-linked recessive inborn error of glycosphingolipid metabolism with deficient activity of a lysosomal enzyme, alpha-galactosidase A (α-GalA). Case Presentation A 46 year-old man with progressive kidney disease showed on kidney biopsy electron microscopic evidence of Fabry disease. The patient had no systemic manifestations of Fabry disease, despite residual α-GalA activity, therefore genetic testing was done by direct DNA sequencing, demonstrating a new GAL A gene mutation (C174G-exon 3). After three years of enzyme replacement therapy (agalsidase beta) treatment, a second biopsy was done. Although there was demonstrable clearance of intracellular inclusions, remarkable podocyte activation was evident. Conclusions This report represents an unusual renal variant of Fabry disease and provides histologic data on long-term follow up after enzyme replacement therapy. PMID:24475416

  3. A Renal Variant of Fabry Disease Diagnosed by the Presence of Urinary Mulberry Cells

    PubMed Central

    Shimohata, Homare; Ogawa, Yujiro; Maruyama, Hiroshi; Hirayama, Kouichi; Kobayashi, Masaki

    2016-01-01

    Fabry disease is a lysosomal storage disorder caused by a deficiency of α-galactosidase A. This disease is classified into two types, namely a classical and variant type. We herein present the case of a 36-year-old man who showed a renal variant of Fabry disease and was diagnosed at an early stage by the presence of mulberry cells. He had no history of general symptoms except for proteinuria. The presence of mulberry cells caused us to suspect Fabry disease and he was thereafter diagnosed to have a renal variant of Fabry disease based on the findings of a renal biopsy, a mutation analysis and a low level of α-galactosidase A activity. PMID:27904112

  4. Characterization of a chemically modified plant cell culture expressed human α-Galactosidase-A enzyme for treatment of Fabry disease.

    PubMed

    Kizhner, Tali; Azulay, Yaniv; Hainrichson, Mariana; Tekoah, Yoram; Arvatz, Gil; Shulman, Avidor; Ruderfer, Ilya; Aviezer, David; Shaaltiel, Yoseph

    2015-02-01

    Fabry disease is an X-linked recessive disorder caused by the loss of function of the lysosomal enzyme α-Galactosidase-A. Although two enzyme replacement therapies (ERTs) are commercially available, they may not effectively reverse some of the Fabry pathology. PRX-102 is a novel enzyme for the therapy of Fabry disease expressed in a BY2 Tobacco cell culture. PRX-102 is chemically modified, resulting in a cross-linked homo-dimer. We have characterized the in-vitro and in-vivo properties of PRX-102 and compared the results with the two commercially produced α-Galactosidase-A enzymes. Results show that PRX-102 has prolonged in-vitro stability in plasma, after 1h incubation it retains 30% activity compared with complete inactivation of the commercial enzymes. Under lysosomal-like conditions PRX-102 maintains over 80% activity following 10 days of incubation, while commercial enzymes become inactive after 2days. Pharmacokinetic profile of PRX-102 measured in male Fabry mice shows a 10 fold increase in t1/2 in mice (581min) compared to approved drugs. The enzyme has significantly different kinetic parameters to the alternative ERTs available (p-value<0.05, one way ANOVA), although these differences do not indicate any significant biochemical variations. PRX-102 is uptaken to primary human Fabry fibroblasts. The repeat administration of the enzyme to Fabry mice caused significant reduction (p-value<0.05) of Gb3 in various tissues (the measured residual content was 64% in kidney, liver was cleaned, 23% in heart, 5.7% in skin and 16.2% in spleen). PRX-102 has a relatively simple glycosylation pattern, characteristic to plants, having mainly tri-mannose structures with the addition of either α(1-3)-linked fucose or β(1-2)-linked xylose, or both, in addition to various high mannose structures, while agalsidase beta has a mixture of sialylated glycans in addition to high mannose structures. This study concludes that PRX-102 is equivalent in functionality to the current

  5. Rheumatologic Skin Disease.

    PubMed

    Kalus, Andrea

    2015-11-01

    In common rheumatologic diseases skin findings are an important diagnostic clue for astute clinicians. Skin manifestations can help identify systemic disease or may require therapy uniquely targeted at the cutaneous problem. This article discusses 3 common rheumatologic conditions seen in adults by dermatologists: cutaneous lupus, dermatomyositis, and morphea. The focus is on the cutaneous findings and clinical presentation. Some approaches to treatment are explored. Clues to help identify systemic disease are also highlighted.

  6. [Fabry's disease: an example of cardiorenal syndrome type 5].

    PubMed

    Villa, Gianluca; Romagnoli, Stefano; Sharma, Aashish; Ronco, Claudio

    2017-03-01

    Fabry's disease (FD) is a severe congenital metabolic disorder characterized by the deficient activity of lysosomal exoglycohydrolase alpha-galactosidase, characterized by glycosphingolipid deposition in several cells, such as capillary endothelial cells, renal, cardiac, and nerve cells. As a systemic disease leading to a contemporaneous myocardial and renal dysfunction, FD might be an example of cardiorenal syndrome type 5 (CRS-5). Kidney damage is commonly characterized by proteinuria, isosthenuria and altered tubular function when occurs at the second-third decade, azotemia and end-stage renal disease in third-fifth decade. Beyond the irreversible glomerular, tubular and vascular damages, the podocytes foot process effacement is the major cause of kidney dysfunction. Myocardial damage is usually observed with right and left ventricular hypertrophy, arrhythmias (due to sinus node and conduction system impairment), diastolic dysfunction, congestive heart failure, myocardial ischemia, fibrosis and cardiac death. The enzymatic replacement therapy is essential for the management of FD, as well as the control of renal (with anti-proteinuric agents such as angiotensin-converting enzyme inhibitors- and/or angiotensin II receptor blockers), brain (coated aspirin, clopidogrel and statins to prevent strokes) and heart complications (calcium channel blockers for ischemic cardiomyopathy, warfarin and amiodarone or cardioverter device for arrhythmias). Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.

  7. Clinical prodromes of neurodegeneration in Anderson-Fabry disease

    PubMed Central

    Hughes, Derralynn; Milligan, Alan; Richfield, Linda; Reichmann, Heinz; Mehta, Atul; Schapira, Anthony H.V.

    2015-01-01

    Objective: To estimate the prevalence of prodromal clinical features of neurodegeneration in patients with Anderson-Fabry disease (AFD) in comparison to age-matched controls. Methods: This is a single-center, prospective, cross-sectional study in 167 participants (60 heterozygous females and 50 hemizygous males with genetically confirmed AFD, 57 age-matched controls) using a clinical screening program consisting of structured interview, quantitative tests of motor function, and assessments of cognition, depression, olfaction, orthostatic intolerance, pain, REM sleep behavior disorder, and daytime sleepiness. Results: In comparison to age-matched controls (mean age 48.3 years), patients with AFD (mean age 49.0 years) showed slower gait and transfer speed, poorer fine manual dexterity, and lower hand speed, which was independent of focal symptoms due to cerebrovascular disease. Patients with AFD were more severely affected by depression, pain, and daytime sleepiness and had a lower quality of life. These motor and nonmotor manifestations significantly correlated with clinical disease severity. However, patients with AFD did not reveal extrapyramidal motor features or signs of significant cognitive impairment, hyposmia, orthostatic intolerance, or REM sleep behavior disorder, which commonly precede later neurodegenerative disease. In our cohort, there were no differences in neurologic manifestations of AFD between heterozygous females and hemizygous males. Conclusions: Aside from cerebrovascular manifestations and small fiber neuropathy, AFD results in a distinct neurologic phenotype comprising poorer motor performance and specific nonmotor features. In contrast to functional loss of glucocerebrosidase in Gaucher disease, α-galactosidase deficiency in AFD is not associated with a typical cluster of clinical features prodromal for neurodegenerative diseases, such as Parkinson disease. PMID:25762709

  8. The management and treatment of children with Fabry disease: A United States-based perspective.

    PubMed

    Hopkin, Robert J; Jefferies, John L; Laney, Dawn A; Lawson, Victoria H; Mauer, Michael; Taylor, Matthew R; Wilcox, William R

    2016-02-01

    Fabry disease is an inherited X-linked disorder that presents during childhood in male and female patients. Young patients may initially experience pain, hypohidrosis, and gastrointestinal symptoms. Other manifestations of Fabry disease, such as renal and cardiac disease, manifest later in adolescence or adulthood. In the pediatric population, renal damage is typically subclinical and identifiable only through biopsy. Specialists from the United States with expertise in Fabry disease convened during 2013-2014 in order to develop these consensus guidelines about the management and treatment of children with Fabry disease. The presence of symptoms in boys and girls of any age is an indication to begin therapy. Early treatment before the onset of potentially irreversible vital organ pathology is ideal. Asymptomatic children with Fabry mutations should be followed closely for the development of renal, cardiac, neurological, or gastrointestinal signs, symptoms, or laboratory changes, which would warrant treatment initiation. A comprehensive care plan should be implemented by the treating physicians to guide the management of children with Fabry disease.

  9. Hormonal profile and fertility in patients with Anderson-Fabry disease.

    PubMed

    Hauser, A C; Gessl, A; Harm, F; Wiesholzer, M; Kleinert, J; Wallner, M; Voigtländer, T; Bieglmayer, C; Sunder-Plassmann, G

    2005-09-01

    Anderson-Fabry disease is a glycosphingolipid storage disorder with an X-linked recessive inheritance. The alpha-galactosidase A deficiency leads to a progressive accumulation of globotriaosylceramide in the endothelium and tissue cells of various organs. The kidney, heart and brain are predominantly affected. Reports on endocrine function and fertility rates in patients with Anderson-Fabry disease are sparse. In the present study, we assessed ovarian, testicular and adrenal function in a cohort of patients with Anderson-Fabry disease. Plasma follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, testosterone, sex hormone-binding globulin, somatotropin, insulin-like growth factor-I and serum cortisol were measured in 13 patients (six female and seven male), currently observed in an outpatient clinic. The profile revealed an undisturbed hormonal function and a normal fertility rate in both male and female Anderson-Fabry patients when compared with the corresponding Austrian population.

  10. Fabry's disease: an example of cardiorenal syndrome type 5.

    PubMed

    Sharma, Aashish; Sartori, Marco; Zaragoza, Jose J; Villa, Gianluca; Lu, Renhua; Faggiana, Elena; Brocca, Alessandra; Di Lullo, Luca; Feriozzi, Sandro; Ronco, Claudio

    2015-11-01

    Cardiorenal syndrome type 5 (CRS-5) includes conditions where there is a simultaneous involvement of the heart and kidney from a systemic disorder. This is a bilateral organ cross talk. Fabry's disease (FD) is a devastating progressive inborn error of metabolism with lysosomal glycosphingolipid deposition in variety of cell types, capillary endothelial cells, renal, cardiac and nerve cells. Basic effect is absent or deficient activity of lysosomal exoglycohydrolase a-galactosidase A. Renal involvement consists of proteinuria, isosthenuria, altered tubular function, presenting in second or third decade leading to azotemia and end-stage renal disease in third to fifth decade mainly due to irreversible changes to glomerular, tubular and vascular structures, especially highlighted by podocytes foot process effacement. Cardiac involvement consists of left ventricular hypertrophy, right ventricular hypertrophy, arrhythmias (sinus node and conduction system impairment), diastolic dysfunction, myocardial ischemia, infarction, transmural replacement fibrosis, congestive heart failure and cardiac death. Management of FD is based on enzymatic replacement therapy and control of renal (with anti-proteinuric agents such as angiotensin-converting enzyme inhibitors-and/or angiotensin II receptor blockers), brain (coated aspirin, clopidogrel and statin to prevent strokes) and heart complications (calcium channel blockers for ischemic cardiomyopathy, warfarin and amiodarone or cardioverter device for arrhythmias).

  11. Light- and electron-microscopic histochemistry of Fabry's disease.

    PubMed Central

    Faraggiana, T.; Churg, J.; Grishman, E.; Strauss, L.; Prado, A.; Bishop, D. F.; Schuchman, E.; Desnick, R. J.

    1981-01-01

    A histochemical study was performed on light- and electron-microscopic level in a case of Fabry's disease. The patient underwent kidney transplantation for renal failure and died of heart failure 6 months later. Patient's tissues were studied at the light- and electron-microscopic levels with various embedding and staining techniques for lipids and carbohydrates. Two peroxidase-labeled lectins (from Ricinus communis and from Bandeiraea simplicifolia) known to have affinity for alpha- and beta-D-galactose, were strongly reactive with the storage material on frozen sections. The ultrahistochemical and extraction tests showed that the typical granules had a variable reactivity and morphologic characteristics in different cells, probably reflecting different composition. A small number of typical deposits were also observed in the transplanted kidney. This is the first reported case of recurrence of the storage disease in the allograft. Of interest was also the fact that the patient's blood inhibited normal alpha-galactosidase activity, suggesting a possible inhibitor-related mechanism in the pathogenesis of the recurrence. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 Figure 19 Figure 20 PMID:6786101

  12. Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease.

    PubMed

    Najafian, Behzad; Svarstad, Einar; Bostad, Leif; Gubler, Marie-Claire; Tøndel, Camilla; Whitley, Chester; Mauer, Michael

    2011-03-01

    Progressive renal failure often complicates Fabry disease, the pathogenesis of which is not well understood. To further explore this we applied unbiased stereological quantitative methods to electron microscopic changes of Fabry nephropathy and the relationship between parameters of glomerular structure and renal function in 14 young Fabry patients (median age 12 years). Renal biopsies were obtained shortly before enzyme replacement therapy from these patients and from nine normal living kidney donors as controls. Podocyte globotriaosylceramide (GL-3) inclusion volume density increased progressively with age; however, there were no significant relationships between age and endothelial or mesangial inclusion volume densities. Foot process width, greater in male Fabry patients, also progressively increased with age compared with the controls, and correlated directly with proteinuria. In comparison to the biopsies of the controls, endothelial fenestration was reduced in Fabry patients. Thus, our study found relationships between quantitative parameters of glomerular structure in Fabry nephropathy and age, as well as urinary protein excretion. Hence, podocyte injury may play a pivotal role in the development and progression of Fabry nephropathy.

  13. X-chromosome inactivation in female patients with Fabry disease.

    PubMed

    Echevarria, L; Benistan, K; Toussaint, A; Dubourg, O; Hagege, A A; Eladari, D; Jabbour, F; Beldjord, C; De Mazancourt, P; Germain, D P

    2016-01-01

    Fabry disease (FD) is an X-linked genetic disorder caused by the deficient activity of lysosomal α-galactosidase (α-Gal). While males are usually severely affected, clinical presentation in female patients may be more variable ranging from asymptomatic to, occasionally, as severely affected as male patients. The aim of this study was to evaluate the existence of skewed X-chromosome inactivation (XCI) in females with FD, its concordance between tissues, and its contribution to the phenotype. Fifty-six females with FD were enrolled. Clinical and biological work-up included two global scores [Mainz Severity Score Index (MSSI) and DS3], cardiac magnetic resonance imaging, measured glomerular filtration rate, and measurement of α-Gal activity. XCI was analyzed in four tissues using DNA methylation studies. Skewed XCI was found in 29% of the study population. A correlation was found in XCI patterns between blood and the other analyzed tissues although some punctual variability was detected. Significant differences in residual α-Gal levels, severity scores, progression of cardiomyopathy and deterioration of kidney function, depending on the direction and degree of skewing of XCI were evidenced. XCI significantly impacts the phenotype and natural history of FD in females.

  14. Genetic variants associated with gastrointestinal symptoms in Fabry disease

    PubMed Central

    Sestito, Simona; Nicoletti, Angela; Arbitrio, Mariamena; Guzzi, Pietro Hiram; Talarico, Valentina; Altomare, Federica; Sanseviero, Maria Teresa; Agapito, Giuseppe; Pisani, Antonio; Riccio, Eleonora; Borrelli, Osvaldo; Concolino, Daniela; Pensabene, Licia

    2016-01-01

    Gastrointestinal symptoms (GIS) are often among the earliest presenting events in Fabry disease (FD), an X-linked lysosomal disorder caused by the deficiency of α-galactosidase A. Despite recent advances in clinical and molecular characterization of FD, the pathophysiology of the GIS is still poorly understood. To shed light either on differential clinical presentation or on intervariability of GIS in FD, we genotyped 1936 genetic markers across 231 genes that encode for drug-metabolizing enzymes and drug transport proteins in 49 FD patients, using the DMET Plus platform. All nine single nucleotide polymorphisms (SNPs) mapped within four genes showed statistically significant differences in genotype frequencies between FD patients who experienced GIS and patients without GIS: ABCB11 (odd ratio (OR) = 18.07, P = 0,0019; OR = 8.21, P = 0,0083; OR=8.21, P = 0,0083; OR = 8.21, P = 0,0083),SLCO1B1 (OR = 9.23, P = 0,0065; OR = 5.08, P = 0,0289; OR = 8.21, P = 0,0083), NR1I3 (OR = 5.40, P = 0,0191) and ABCC5 (OR = 14.44, P = 0,0060). This is the first study that investigates the relationships between genetic heterogeneity in drug absorption, distribution, metabolism and excretion (ADME) related genes and GIS in FD. Our findings provide a novel genetic variant framework which warrants further investigation for precision medicine in FD. PMID:27825144

  15. Urinary total globotriaosylceramide and isoforms to identify women with Fabry disease: a diagnostic test study.

    PubMed

    Paschke, Eduard; Fauler, Guenter; Winkler, Heimo; Schlagenhauf, Axel; Plecko, Barbara; Erwa, Wolfgang; Breunig, Frank; Urban, Wolfgang; Vujkovac, Bojan; Sunder-Plassmann, Gere; Kotanko, Peter

    2011-05-01

    Fabry disease is a treatable X-linked lysosomal storage disorder caused by alterations in the structural gene (GLA) of α-galactosidase A (AGAL), manifesting with cardiovascular and/or kidney disease and decreased life span. Although males as well as females can be affected, females cannot be identified using AGAL activity. We evaluated urinary total globotriaosylceramide (Gb3) and single N-acyl isoforms for the detection of Fabry disease in female patients with and without chronic kidney disease (CKD). Diagnostic accuracy study. 28 untreated women with Fabry disease and 335 female outpatients without Fabry disease with (n = 213) and without CKD (n = 122). Assessment of urinary Gb3 using electrospray ionization tandem mass spectrometry, including 6 N-acyl isoforms, total Gb3 related to urinary creatinine, and ratios of Gb3-24 to Gb3-18 and Gb3-24 to urinary AGAL. Fabry disease, diagnosed by identification of known pathogenic GLA mutations in patients or their male relatives. 6 parameters (ratio of Gb3-24 to urinary AGAL activity; Gb3-24; ratio of Gb3-24 to Gb3-18; Gb3-22; Gb3-16; and total Gb3) were highly informative for the diagnosis of Fabry disease independent of the presence or absence of CKD (area under the receiver operating characteristic curve, 0.876-0.927; all P < 0.001). Because of low signal-to-noise ratios, 15.8% of samples had to be excluded. Total urinary Gb3 and Gb3 isoforms can be used for the diagnosis of Fabry disease in women. Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  16. 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

  17. Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis.

    PubMed

    Beck, Michael; Hughes, Derralynn; Kampmann, Christoph; Larroque, Sylvain; Mehta, Atul; Pintos-Morell, Guillem; Ramaswami, Uma; West, Michael; Wijatyk, Anna; Giugliani, Roberto

    2015-06-01

    Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were the annualized rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of ~ 5 years. Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Treated male patients with baseline eGFR < 60 mL/min/1.73 m(2) had a mean (standard error of the mean [SEM]) annualized change in eGFR of - 2.86 (0.53) mL/min/1.73 m(2)/y compared with - 6.8 (1.5) in the published untreated cohort. The mean (SEM) rate of LVMI increase with treatment was 0.33 (0.10) g/m(2.7)/y in males and 0.48 (0.09) in females, compared with 4.07 (1.03) in untreated males and 2.31 (0.81) in untreated females. Morbidity occurred later in treated patients, with ~ 16% risk of a composite morbidity event (26% in males) after 24 months with ERT versus ~ 45% without treatment, with first events and deaths also occurring at older ages in patients administered ERT (e.g., estimated median survival in treated males was 77.5 years versus 60 years in untreated males). Findings from these retrospective comparisons of observational data and published literature support the long-term benefits of ERT with agalsidase alfa for Fabry disease in slowing the progression of renal impairment and cardiomyopathy. Treatment also appeared to delay the onset of morbidity and mortality. Interpretation of these findings should take

  18. Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis

    PubMed Central

    Beck, Michael; Hughes, Derralynn; Kampmann, Christoph; Larroque, Sylvain; Mehta, Atul; Pintos-Morell, Guillem; Ramaswami, Uma; West, Michael; Wijatyk, Anna; Giugliani, Roberto

    2015-01-01

    Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were the annualized rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of ~ 5 years. Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Treated male patients with baseline eGFR < 60 mL/min/1.73 m2 had a mean (standard error of the mean [SEM]) annualized change in eGFR of − 2.86 (0.53) mL/min/1.73 m2/y compared with − 6.8 (1.5) in the published untreated cohort. The mean (SEM) rate of LVMI increase with treatment was 0.33 (0.10) g/m2.7/y in males and 0.48 (0.09) in females, compared with 4.07 (1.03) in untreated males and 2.31 (0.81) in untreated females. Morbidity occurred later in treated patients, with ~ 16% risk of a composite morbidity event (26% in males) after 24 months with ERT versus ~ 45% without treatment, with first events and deaths also occurring at older ages in patients administered ERT (e.g., estimated median survival in treated males was 77.5 years versus 60 years in untreated males). Findings from these retrospective comparisons of observational data and published literature support the long-term benefits of ERT with agalsidase alfa for Fabry disease in slowing the progression of renal impairment and cardiomyopathy. Treatment also appeared to delay the onset of morbidity and mortality. Interpretation of these findings should take into

  19. Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease.

    PubMed

    Rombach, S M; Dekker, N; Bouwman, M G; Linthorst, G E; Zwinderman, A H; Wijburg, F A; Kuiper, S; Vd Bergh Weerman, M A; Groener, J E M; Poorthuis, B J; Hollak, C E M; Aerts, J M F G

    2010-09-01

    Fabry disease is an X-linked lysosomal storage disorder due to deficiency of alpha-Galactosidase A, causing accumulation of globotriaosylceramide and elevated plasma globotriaosylsphingosine (lysoGb3). The diagnostic value and clinical relevance of plasma lysoGb3 concentration was investigated. All male and adult female patients with classical Fabry disease could be discerned by an elevated plasma lysoGb3. In young pre-symptomatic Fabry heterozygotes, lysoGb3 levels can be normal. Individuals carrying the R112H and P60L mutations, without classical Fabry symptoms, showed no elevated plasma lysoGb3. Multiple regression analysis showed that there is no correlation of plasma lysoGb3 concentration with total disease severity score in Fabry males. However, plasma lysoGb3 concentration did correlate with white matter lesions (odds ratio: 6.1 per 100 nM lysoGb3 increase (95% CI: 1.4-25.9, p=0.015). In females, plasma lysoGb3 concentration correlated with overall disease severity. Furthermore, plasma lysoGb3 level was related to left ventricular mass (19.5+/-5.5 g increase per 10 nM lysoGb3 increase; p=0.001). In addition, it was assessed whether lifetime exposure to lysoGb3 correlates with disease manifestations. Male Fabry patients with a high lysoGb3 exposure (>10,000 U), were moderately or severely affected, only one mildly. Female patients with a low exposure (<1000 U) were asymptomatic or mildly affected. A large proportion of the females with an exposure >1000 U showed disease complications. Plasma lysoGb3 is useful for the diagnosis of Fabry disease. LysoGb3 is an independent risk factor for development of cerebrovascular white matter lesions in male patients and left ventricular hypertrophy in females. Disease severity correlates with exposure to plasma lysoGb3.

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

    PubMed

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

    2017-09-24

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

  1. Smoking and skin disease.

    PubMed

    Thomsen, S F; Sørensen, L T

    2010-06-01

    Tobacco smoking is a serious and preventable health hazard that can cause or exacerbate a number of diseases and shorten life expectancy, but the role of smoking as an etiologic factor in the development of skin disease is largely unknown. Although epidemiological evidence is sparse, findings suggest that tobacco smoking is a contributing factor in systemic lupus erythematosus, psoriasis, palmoplantar pustulosis, cutaneous squamous cell carcinoma, hidradenitis suppurativa, and genital warts. In contrast, smoking may confer some protective effects and mitigate other skin diseases, notably pemphigus vulgaris, pyoderma gangrenosum, aphthous ulcers, and Behçet's disease. Various degenerative dermatologic conditions are also impacted by smoking, such as skin wrinkling and dysregulated wound healing, which can result in post-surgical complications and delayed or even arrested healing of chronic wounds. Most likely, alteration of inflammatory cell function and extracellular matrix turnover caused by smoking-induced oxidative stress are involved in the pathophysiologic mechanisms.

  2. Neuro-Otological and Peripheral Nerve Involvement in Fabry Disease

    PubMed Central

    Carmona, Sergio; Weinschelbaum, Romina; Pardal, Ana; Marchesoni, Cintia; Zuberbuhler, Paz; Acosta, Patricia; Cáceres, Guillermo; Kisinovsky, Isaac; Bayón, Luciana; Reisin, Ricardo

    2017-01-01

    Fabry disease (FD) is an X-linked lysosomal storage disease, with multisystemic glycosphingolipids deposits. Neuro-otological involvement leading to hearing loss and vestibular dysfunctions has been described, but there is limited information about the frequency, site of lesion, or the relationship with peripheral neuropathy. The aim was to evaluate the presence of auditory and vestibular symptoms, and assess neurophysiological involvement of the VIII cranial nerve, correlating these findings with clinical and neurophysiological features of peripheral neuropathy. We studied 36 patients with FD with a complete neurological and neuro-otological evaluation including nerve conduction studies, quantitative sensory testing (to evaluate small fiber by warm and cold threshold detection and cold and heat pain), vestibular evoked myogenic potentials, videonistagmography, audiometry and brainstem auditory evoked potentials. Neuro-otologic symptoms included hearing loss (22.2%), vertigo (27.8%) or both (25%). An involvement of either cochlear or vestibular function was identified in most patients (75%). In 70% of our patients the involvement of both cochlear and vestibular function could not be explained by a neural or vascular mechanism. Small fiber neuropathy was identified in 77.7%. There were no significant associations between neuro-otological and QST abnormalities. Neuro-otologic involvement is frequent and most likely under-recognized in patients with FD. It lacks a specific neural or vascular pattern, suggesting multi-systemic, end organ damage. Small fiber neuropathy is an earlier manifestation of FD, but there is no correlation between the development of neuropathy and neuro-otological abnormalities. PMID:28794847

  3. 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

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

    PubMed

    Weidemann, Frank; Sanchez-Niño, Maria D; Politei, Juan; Oliveira, João-Paulo; Wanner, Christoph; Warnock, David G; Ortiz, Alberto

    2013-08-06

    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.

  5. Anderson-Fabry disease: a case-finding study among male kidney transplant recipients in Austria.

    PubMed

    Kleinert, Julia; Kotanko, Peter; Spada, Marco; Pagliardini, Severo; Paschke, Eduard; Paul, Karl; Voigtländer, Till; Wallner, Manfred; Kramar, Reinhard; Stummvoll, Hans-Krister; Schwarz, Christoph; Horn, Sabine; Holzer, Herwig; Födinger, Manuela; Sunder-Plassmann, Gere

    2009-03-01

    The diagnosis of Anderson-Fabry disease is often delayed or even missed. As severe renal manifestations are a hallmark of alfa-galactosidase A (AGAL) deficiency, we tested the hypothesis that Anderson-Fabry disease is under-recognized among male kidney transplant recipients. This nation-wide study in Austria enrolled 1306 patients (ca 65% of all kidney transplanted males) from 30 kidney centers. AGAL activity was determined from filter paper dried blood spots by a fluorescence assay. A positive screening test was defined by an AGAL activity below 1.5 nmol/h/ml. In patients with a positive blood spot-screening test, AGAL activity was re-examined in peripheral blood leukocytes. Genetic testing for mutations in the GLA gene was performed by sequencing to confirm the diagnosis of Anderson-Fabry disease. Two previously not recognized cases with Anderson-Fabry disease were identified. Our study is the first showing that a diagnosis of Anderson-Fabry disease can be missed even in patients who undergo kidney transplantation. Case-finding strategies may be considered a useful tool for diagnosis of this rare disease that may be somewhat more prevalent among kidney transplant recipients compared with dialysis populations.

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

    PubMed Central

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

    2006-01-01

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

  7. The Impact of Fabry Disease on Reproductive Fitness.

    PubMed

    Laney, Dawn A; Clarke, Virginia; Foley, Allison; Hall, Eric W; Gillespie, Scott E; Holida, Myrl; Simmons, Morgan; Wadley, Alexandrea

    2017-03-22

    Fabry disease (FD) is a pan-ethnic, X-linked, progressive lysosomal storage disorder caused by pathogenic mutations in the GLA gene. Published case reports and abstracts suggest that decreased reproductive fitness may occur in males with FD. In order to understand the impact of FD on reproductive fitness and increase the accuracy of reproductive genetic counseling, this study examines a large, multi-centered population of individuals with FD to determine if males have reduced reproductive fitness. Study data were collected on 376 patients through two, gender-specific surveys distributed across the United States and Canada. The number of biological live-born children among individuals with FD was compared to statistics from the general population. Information was also collected on reduced sperm count, depression, pain, use of assisted reproductive technology, and reproductive choice. On average, females affected by FD had more biological live-born children (1.8) than males affected by FD (1.1). However, males affected by FD had an increased mean number of biological children (1.1) compared to the mean number of biological children fathered by men in the United States (0.9). Sixteen of the 134 males with FD reported oligospermia, which suggests that an infertility work up may be indicated for males having difficulty impregnating their partners. In our large multicenter sample, males and females with FD do not exhibit reduced reproductive fitness; on average they have more biological children than the general population in the United States. This information should assist clinicians in providing accurate reproductive genetic counseling and treatment for individuals with FD.

  8. The neurocognitive impact of Fabry disease on pediatric patients.

    PubMed

    Bugescu, Nicolle; Alioto, Andrea; Segal, Summer; Cordova, Matthew; Packman, Wendy

    2015-04-01

    Fabry disease (FD) is an X-linked lysosomal storage disorder that results in progressive multisystemic organ complications. Several studies have examined neurocognitive impairments in adults; however, there is a paucity of research examining neurocognitive functioning in children with FD. This is the first exploratory study to examine the neurocognitive functioning of pediatric patients with FD and to evaluate the effects of enzyme replacement therapy (ERT) on neurocognitive functioning within this population. Families attending a national conference with at least one child with FD and one parent affected by FD comprised the sample (n = 48; 24 pediatric patients, 24 parents). Pediatric participants (10 males, 14 females) between the ages of 6 and 18 years and their parent(s) were involved in the study. Data from a demographic questionnaire and two neurocognitive self-report and parent-report measures were analyzed. Parent reports of neurocognitive functioning were also compared to a sample of children with and without head injury and to a sample of children who had undergone liver transplant (LT). Children with FD had poorer cognitive and executive functioning than healthy peers, and were comparable to children with head injury and LT. In addition, children using ERT had higher scores on measures of overall cognitive functioning, as well as fewer problems with attention/working memory and executive functioning. Results of this study suggest that children with FD may exhibit poorer cognitive and executive functioning relative to healthy peers. The use of ERT may mitigate the negative impact of FD on neurocognitive functioning in pediatric patients. © 2015 Wiley Periodicals, Inc.

  9. Prevalence of Raynaud Phenomenon and Nailfold Capillaroscopic Abnormalities in Fabry Disease

    PubMed Central

    Deshayes, Samuel; Auboire, Laurent; Jaussaud, Roland; Lidove, Olivier; Parienti, Jean-Jacques; Triclin, Nathalie; Imbert, Bernard; Bienvenu, Boris; Aouba, Achille

    2015-01-01

    Abstract Fabry disease (FD) is a lysosomal disorder leading to progressive systemic involvement, including microvascular damage that leads to neurological and cardiovascular disorders. We hypothesize that the latter could be documented at an early stage by performing a microcirculation study with nailfold capillaroscopy and evaluation of Raynaud phenomenon. The objective was to measure the prevalence of Raynaud phenomenon and nailfold capillaroscopic abnormalities in FD. This cross-sectional study included a standardized questionnaire and a nailfold capillaroscopy that assessed previously reported patterns in FD (dystrophic and giant capillaries, avascular fields, irregular architecture, dilatation and density of capillaries, hemorrhage), and was conducted on 32 Fabry patients and 39 controls. Capillaroscopic photographs were reviewed by 2 independent blinded investigators. Twelve Fabry patients (38%) suffered from Raynaud phenomenon, 5 were males (ie, 50% of male Fabry patients), compared with 2 controls (13%) (P < 0.001), of whom none were males (P < 0.001). Raynaud phenomenon was concomitant or before the occurrence of pain in the extremities in 42% of Fabry patients. More ramified capillaries were significantly observed in Fabry patients (12/32, 38%) than in controls (5/39, 13%, P = 0.016). Secondary Raynaud phenomenon should lead to screening for FD, especially in men. By extension, in high-risk populations for FD, the presence of Raynaud phenomenon and ramified capillaries should be assessed. PMID:25997047

  10. Prevalence of Raynaud phenomenon and nailfold capillaroscopic abnormalities in Fabry disease: a cross-sectional study.

    PubMed

    Deshayes, Samuel; Auboire, Laurent; Jaussaud, Roland; Lidove, Olivier; Parienti, Jean-Jacques; Triclin, Nathalie; Imbert, Bernard; Bienvenu, Boris; Aouba, Achille

    2015-05-01

    Fabry disease (FD) is a lysosomal disorder leading to progressive systemic involvement, including microvascular damage that leads to neurological and cardiovascular disorders. We hypothesize that the latter could be documented at an early stage by performing a microcirculation study with nailfold capillaroscopy and evaluation of Raynaud phenomenon.The objective was to measure the prevalence of Raynaud phenomenon and nailfold capillaroscopic abnormalities in FD.This cross-sectional study included a standardized questionnaire and a nailfold capillaroscopy that assessed previously reported patterns in FD (dystrophic and giant capillaries, avascular fields, irregular architecture, dilatation and density of capillaries, hemorrhage), and was conducted on 32 Fabry patients and 39 controls. Capillaroscopic photographs were reviewed by 2 independent blinded investigators.Twelve Fabry patients (38%) suffered from Raynaud phenomenon, 5 were males (ie, 50% of male Fabry patients), compared with 2 controls (13%) (P < 0.001), of whom none were males (P < 0.001). Raynaud phenomenon was concomitant or before the occurrence of pain in the extremities in 42% of Fabry patients.More ramified capillaries were significantly observed in Fabry patients (12/32, 38%) than in controls (5/39, 13%, P = 0.016).Secondary Raynaud phenomenon should lead to screening for FD, especially in men. By extension, in high-risk populations for FD, the presence of Raynaud phenomenon and ramified capillaries should be assessed.

  11. 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

  12. Cardiac device implantation in Fabry disease: A retrospective monocentric study.

    PubMed

    Sené, Thomas; Lidove, Olivier; Sebbah, Joel; Darondel, Jean-Marc; Picard, Hervé; Aaron, Laurent; Fain, Olivier; Zenone, Thierry; Joly, Dominique; Charron, Philippe; Ziza, Jean-Marc

    2016-10-01

    The incidence and predictive factors of arrhythmias and/or conduction abnormalities (ACAs) requiring cardiac device (CD) implantation are poorly characterized in Fabry disease (FD). The aim of our retrospective study was to determine the prevalence, incidence, and factors associated with ACA requiring CD implantation in a monocentric cohort of patients with confirmed FD who were followed up in a department of internal medicine and reference center for FD.Forty-nine patients (20M, 29F) were included. Nine patients (4M, 5F; 18%) had at least one episode of ACA leading to device therapy. Six patients (4M/2F) required a pacemaker (PM) for sinus node dysfunction (n = 4) or atrioventricular disease (n = 2). One female patient required an internal cardioverter-defibrillator (ICD) to prevent sudden cardiac death because of nonsustained ventricular tachycardia (nSVT). One female patient required PM-ICD for sinus node dysfunction and nSVT. One patient underwent CD implantation before the diagnosis of FD. The annual rate of CD implantation was estimated at 1.90 per 100 person years. On univariate analysis at the end of the follow-up period, the factors associated with ACAs requiring CD implantation were as follows: delayed diagnosis of FD, delayed initiation of enzyme replacement therapy, age at the last follow-up visit, and severe multiorgan phenotype (hypertrophic cardiomyopathy, chronic kidney disease, and/or sensorineural hearing loss). On multivariate analysis, age at diagnosis of FD and age at the last follow-up visit were independently associated with an increased risk of ACAs requiring CD (P < 0.05).Considering the high frequency of ACAs requiring CD implantation and the risk of sudden death in patients with FD, regular monitoring is mandatory, especially in patients with a late diagnosis of FD and/or with a severe phenotype. Regular Holter ECGs, therapeutic education of patients, and deliverance of an emergency card including a phenotype summary are

  13. Results of a nationwide screening for Anderson-Fabry disease among dialysis patients.

    PubMed

    Kotanko, Peter; Kramar, Reinhard; Devrnja, Danijela; Paschke, Eduard; Voigtländer, Till; Auinger, Martin; Pagliardini, Severo; Spada, Marco; Demmelbauer, Klaus; Lorenz, Matthias; Hauser, Anna-Christine; Kofler, Hans-Jörg; Lhotta, Karl; Neyer, Ulrich; Pronai, Wolfgang; Wallner, Manfred; Wieser, Clemens; Wiesholzer, Martin; Zodl, Herbert; Födinger, Manuela; Sunder-Plassmann, Gere

    2004-05-01

    Anderson-Fabry disease is possibly underdiagnosed in patients with end-stage renal disease. Nationwide screening was therefore undertaken for Anderson-Fabry disease among dialysis patients in Austria. Screening for alpha-galactosidase A (AGAL) deficiency was performed by a blood spot test. In patients with a positive screening test, AGAL activity in leukocytes was determined. Individuals with decreased leukocyte AGAL activity were subjected to mutation testing in the GLA gene. Fifty (90.9%) of 55 Austrian hemodialysis centers participated in this study; 2480 dialysis patients (80.1% of the Austrian dialysis population) were screened. In 85 patients, the screening test was positive (85 of 2480, 3.42%; women, 3.32%; men, 3.50%). Among these 85 patients, 4 men (in 3 of whom Anderson-Fabry disease was already known before screening) had a severely decreased and 11 subjects had a borderline low AGAL activity. Genetic testing revealed mutations associated with Fabry disease in all four men with severely decreased AGAL activity resulting in a prevalence of 0.161% for the entire study population. A nationwide screening of dialysis patients permitted detection of a hitherto unknown man with Anderson-Fabry disease. The overall prevalence among dialysis patients was at least ten times higher as compared with recent registry data. Screening programs among patients with end-stage renal disease, especially men, should be put in place to identify families with Anderson-Fabry disease who probably may benefit from specific clinical care, and perhaps from enzyme replacement therapy. In dialysis patients, however, there is no evidence to support enzyme replacement therapy at present.

  14. Identification of Fabry Disease in a Tertiary Referral Cohort of Patients with Hypertrophic Cardiomyopathy.

    PubMed

    Maron, Martin S; Xin, Winnie; Sims, Katherine B; Butler, Rita; Haas, Tammy S; Rowin, Ethan J; Desnick, Robert J; Maron, Barry J

    2017-09-21

    Fabry Disease is a X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness, and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these two diseases diverge, with Fabry disease-specific treatment utilizing recombinant α-galactosidase A enzyme replacement therapy. We studied a prospectively assembled consecutive cohort of 585 patients (71% male) from two hypertrophic cardiomyopathy tertiary referral centers by screening for low α-galactosidase A activity in dried blood spots. Male patients with low α -Gal A activity levels and all females were tested for mutations in the GLA gene. In 585 patients previously diagnosed with hypertrophic cardiomyopathy, we identified two unrelated patients (0.34%), both with the GLA mutation encoding P.N215S the most common mutation causing later-onset Fabry disease phenotype. These patients were both asymptomatic, a male age 53 years and a female aged 69 yearsand demonstrated a mild cardiac phenotype with symmetric distribution of left ventricular hypertrophy..Following family screening, a total of 27 new Fabry disease patients ages 2-81 years were identified in the two families, including 12individuals who are now receiving enzyme replacement therapy. These observations support consideration for routine prospective screening for Fabry disease in all patients without a definitive etiology for left ventriclar hypertrophy. This strategy would likely result, through cascade family testing, in the earlier identification of new Fabry disease-affected males and female heterozygotes who may benefit from monitoring and/or enzyme replacement therapy. Copyright © 2017. Published by Elsevier Inc.

  15. Prevalence of Fabry disease and GLA c.196G>C variant in Japanese stroke patients.

    PubMed

    Nagamatsu, Kiyoshiro; Sekijima, Yoshiki; Nakamura, Katsuya; Nakamura, Kimitoshi; Hattori, Kiyoko; Ota, Masao; Shimizu, Yusaku; Endo, Fumio; Ikeda, Shu-Ichi

    2017-03-09

    Fabry disease is an important underlying disease in young cryptogenic stroke patients. However, little is known regarding the frequency of Fabry disease in the general stroke population, especially in elderly patients. A total of 588 stroke patients (61.7% men; average age 74.1±12.5 years) were enrolled in this prospective study. Blood samples were obtained to produce blood spots to determine α-galactosidase A (α-GalA) activity and for GLA gene analysis. One 65-year-old female patient had a known GLA gene mutation, c.2T>C (p.M1T), causing Fabry disease. Five male patients and two female patients had GLA c.196G>C (p.E66Q) variant, which is not associated with the full clinical manifestations of Fabry disease. The allele frequency of GLA c.196G>C was significantly higher in male patients with small-vessel occlusion (odds ratio 3.95, P=0.048) and non-cardioembolism (odds ratio 4.08, P=0.012) than that in the general Japanese population. Fabry disease is rare in the general Japanese stroke population. However, screening identified one elderly female patient with Fabry disease. GLA c.196G>C variant is a genetic risk factor for cerebral small-vessel occlusion and non-cardioembolism in Japanese males but not in females.Journal of Human Genetics advance online publication, 9 March 2017; doi:10.1038/jhg.2017.31.

  16. Chemokines and skin diseases.

    PubMed

    Sugaya, Makoto

    2015-04-01

    Chemokines are small molecules that induce chemotaxis and activation of certain subsets of leukocytes. The expression patterns of chemokines and chemokine receptors are specific to certain organs and cells. Therefore, chemokines are important to elucidate the mechanism of organ-specific human diseases. CCL17 expressed by Langerhans cells, blood endothelial cells, and fibroblasts plays a key role in attracting Th2 cells and tumor cells of adult T-cell leukemia/lymphoma and mycosis fungoides/Sézary syndrome into the skin, developing various Th2-type inflammatory skin diseases as well as cutaneous lymphoma. CCL11 and CCL26 expressed by skin-resident cells, such as fibroblasts, blood endothelial cells, and keratinocytes, induce infiltration of CCR3-expressing cells such as Th2 cells and eosinophils. CCL11 may also serve as an autocrine as well as a paracrine in anaplastic large cell lymphoma. CX3CL1 expressed on blood endothelial cells leads to infiltration of CX3CR1(+) immune cells, such as mast cells, neutrophils, and macrophages, playing important roles in wound healing, tumor immunity, and vasculitis. Biologics targeting chemokines and their receptors are promising strategies for various skin diseases that are resistant to the current therapy.

  17. Eight-Year Follow-Up of Neuropsychiatric Symptoms and Brain Structural Changes in Fabry Disease.

    PubMed

    Lelieveld, Irene M; Böttcher, Anna; Hennermann, Julia B; Beck, Michael; Fellgiebel, Andreas

    2015-01-01

    Brain structural alterations and neuropsychiatric symptoms have been described repeatedly in Fabry disease, yet cognitive deficits have been shown to be only mild. Here, we aimed to investigate neuropsychiatric symptoms and brain structure longitudinally. We expected no clinically relevant increase of neuropsychiatric symptoms in parallel to increased brain structural alterations. We assessed 14 Fabry patients (46.1 ± 10.8 years) who had participated in our investigation eight years ago. Patients engaged in neuropsychiatric testing, as well as structural magnetic resonance imaging and angiography to determine white matter lesions, hippocampal volume, and the diameter of the larger intracranial arteries. While Fabry patients did not differ on cognitive performance, they showed progressive and significant hippocampal volume loss over the 8-year observation period. White matter lesions were associated with older age and higher white matter lesion load at baseline, but did not reach statistical significance when comparing baseline to follow-up. Likewise, intracranial artery diameters did not increase significantly. None of the imaging parameters were associated with the neuropsychiatric parameters. Depression frequency reduced from 50% at baseline to 21% at follow-up, but it did not reach significance. This investigation demonstrates clinical stability in cognitive function, while pronounced hippocampal atrophy is apparent throughout the 8 years. Our middle-aged Fabry patients appeared to compensate successfully for progressive hippocampal volume loss. The hippocampal volume decline indicates brain regional neuronal involvement in Fabry disease.

  18. 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.

  19. 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

  20. Does geographical location influence the phenotype of Fabry disease in women in Europe?

    PubMed

    Barba-Romero, M-A; Deegan, P; Giugliani, R; Hughes, D

    2010-02-01

    This study examines the relationship between phenotype and geographical location of patients with Fabry disease in Europe. Data were taken from patients enrolled in the Fabry Outcome Survey (FOS), as of October 2007. A modified version of the Mainz Severity Score Index (FOS-MSSI) was used to classify patients according to the severity of disease. European patients were grouped depending on country of residence (northern or southern European countries). Results are presented from 762 patients enrolled in FOS in Europe (357 men and 405 women); 66% lived in northern and 34% in southern countries. Median age at onset of symptoms of Fabry disease was similar in both sexes. No differences in disease severity were seen among men, according to place of residence; however, women living in northern countries had higher severity scores (p < 0.001) than those in southern countries. In men and women, FOS-MSSI scores increased with age, irrespective of place of residence. The results suggest that expression of different phenotypic features in Fabry disease in women living in Europe may be influenced by extra-genetic or epigenetic factors. These factors might be related to dietary or environmental influences that differ according to the patient's country of residence.

  1. Screening for Fabry's disease in young patients with ischemic stroke in a Chinese population.

    PubMed

    Song, Xiaowei; Xue, Sufang; Zhao, Jingyan; Wu, Jian

    2017-04-01

    Fabry disease is an X-linked lysosomal storage disorder frequently associated with cerebrovascular disease. Data regarding Fabry disease and ischemic stroke has been lacking in China. In this study, we investigated the prevalence of Fabry disease and the distribution of the alpha-galactosidase A (α-GalA) gene - GLA mutations in young stroke patients in the Chinese population and its association with stroke subtypes. A total of 357 ischemic stroke patients admitted to Xuanwu Hospital of Capital Medical University, aged 18-55 years old, including 293 patients with cerebral infarction and 64 patients with transient ischemic attack, were enrolled in this study. Mutations in the GLA gene were screened by Sanger sequencing. Enzyme levels were measured to further confirm the disease in patients with the gene mutation. The mutation frequency was compared among different stroke subtypes and further compared with the control group individually. No pathogenic mutations in the coding regions of the GLA gene were identified in this group of patients and thus no Fabry disease was found in our study. However, the frequency of an intronic polymorphism c.-10C>T was significantly different among different Trial of Org 10172 in Acute Stroke Treatment subtypes (p < 0.01). The frequency of the c.-10C>T polymorphism in patients with stroke due to other causes and undetermined causes was much higher than that in the control group (OR = 3.18, 95% CI: 1.29-7.83, p < 0.01). Fabry disease is a rare disease, and it will not benefit to screen all stroke patients. In addition, our results suggested that the c.-10C>T polymorphism may be a risk factor for ischemic stroke of other and undetermined causes. Further study is required to confirm our findings.

  2. Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics.

    PubMed

    Favalli, Valentina; Disabella, Eliana; Molinaro, Mariadelfina; Tagliani, Marilena; Scarabotto, Anna; Serio, Alessandra; Grasso, Maurizia; Narula, Nupoor; Giorgianni, Carmela; Caspani, Clelia; Concardi, Monica; Agozzino, Manuela; Giordano, Calogero; Smirnova, Alexandra; Kodama, Takahide; Giuliani, Lorenzo; Antoniazzi, Elena; Borroni, Riccardo G; Vassallo, Camilla; Mangione, Filippo; Scelsi, Laura; Ghio, Stefano; Pellegrini, Carlo; Zedde, Marialuisa; Fancellu, Laura; Sechi, GianPietro; Ganau, Antonello; Piga, Stefania; Colucci, Annarita; Concolino, Daniela; Di Mascio, Maria Teresa; Toni, Danilo; Diomedi, Marina; Rapezzi, Claudio; Biagini, Elena; Marini, Massimiliano; Rasura, Maurizia; Melis, Maurizio; Nucera, Antonia; Guidetti, Donata; Mancuso, Michelangelo; Scoditti, Umberto; Cassini, Pamela; Narula, Jagat; Tavazzi, Luigi; Arbustini, Eloisa

    2016-09-06

    Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%. This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients. In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations. Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively. Screening probands with clinically

  3. Research on Skin Diseases - USSR -

    DTIC Science & Technology

    1960-09-28

    0T3: 60-31,799 M K\\& £^§ JPRS: 3995 28 September I960 RESEARCH ON SKIN DISEASES USSR - by G. Ya. Travin and D. N. Plishkin L \\s i- £ is...departments» JPRS: 3995 CSO: Ii22k-D RESEARCH ON SKIN DISEASES - USSR - Table of Contents ÜäS£ Ths Incidence of Skin Diseases in Leningrad, USSR...1 The Characteristics of Skin Disease Morbidity in 19$7 at Sverdlovsk, USSR 7 - a - TIE INCIDENCE OF SKIN DISEASES IN LENINGRAD, USSR /Following

  4. Establishing 3-nitrotyrosine as a biomarker for the vasculopathy of Fabry disease

    PubMed Central

    Shu, Liming; Vivekanandan-Giri, Anuradha; Pennathur, Subramaniam; Smid, Bouwien E; Aerts, Johannes M FG; Hollak, Carla E M; Shayman, James A

    2014-01-01

    The endothelial dysfunction of Fabry disease results from α-galactosidase A deficiency leading to the accumulation of globotriaosylceramide. Vasculopathy in the α-galactosidase A null mouse is manifested as oxidant-induced thrombosis, accelerated atherogenesis, and impaired arterial reactivity. To better understand the pathogenesis of Fabry disease in humans, we generated a human cell model by using RNA interference. Hybrid endothelial cells were transiently transfected with small interfering RNA (siRNA) specifically directed against α-galactosidase A. Knockdown of α-galactosidase A was confirmed using immunoblotting and globotriaosylceramide accumulation. Endothelial nitric oxide synthase (eNOS) activity was correspondingly decreased by >60%. Levels of 3-nitrotyrosine (3NT), a specific marker for reactive nitrogen species and quantified using mass spectrometry, increased by 40- to 120-fold without corresponding changes in other oxidized amino acids, consistent with eNOS-derived reactive nitrogen species as the source of the reactive oxygen species. eNOS uncoupling was confirmed by the observed increase in free plasma and protein-bound aortic 3NT levels in the α-galactosidase A knockout mice. Finally, 3NT levels, assayed in biobanked plasma samples from patients with classical Fabry disease, were over sixfold elevated compared with age- and gender-matched controls. Thus, 3NT may serve as a biomarker for the vascular involvement in Fabry disease. PMID:24402087

  5. Substrate Reduction Augments the Efficacy of Enzyme Therapy in a Mouse Model of Fabry Disease

    PubMed Central

    Marshall, John; Ashe, Karen M.; Bangari, Dinesh; McEachern, KerryAnne; Chuang, Wei-Lien; Pacheco, Joshua; Copeland, Diane P.; Desnick, Robert J.; Shayman, James A.; Scheule, Ronald K.; Cheng, Seng H.

    2010-01-01

    Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency in the activity of the lysosomal hydrolase α-galactosidase A (α-gal). This deficiency results in accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in lysosomes. Endothelial cell storage of GL-3 frequently leads to kidney dysfunction, cardiac and cerebrovascular disease. The current treatment for Fabry disease is through infusions of recombinant α-gal (enzyme-replacement therapy; ERT). Although ERT can markedly reduce the lysosomal burden of GL-3 in endothelial cells, variability is seen in the clearance from several other cell types. This suggests that alternative and adjuvant therapies may be desirable. Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease. Here, we show that such an inhibitor (eliglustat tartrate, Genz-112638) was effective at lowering GL-3 accumulation in a mouse model of Fabry disease. Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver. Combination therapy with ERT and SRT provided the most complete clearance of GL-3 from all the tissues. Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response. The differential efficacies of SRT and ERT in the different tissues indicate that the combination approach is both additive and complementary suggesting the possibility of an improved therapeutic paradigm in the management of Fabry disease. PMID:21124789

  6. Compensation for occupational skin diseases.

    PubMed

    Song, Han-Soo; Ryou, Hyun-chul

    2014-06-01

    The Korean list of occupational skin diseases was amended in July 2013. The past list was constructed according to the causative agent and the target organ, and the items of that list had not been reviewed for a long period. The revised list was reconstructed to include diseases classified by the International Classification of Diseases (10th version). Therefore, the items of compensable occupational skin diseases in the amended list in Korea comprise contact dermatitis; chemical burns; Stevens-Johnson syndrome; tar-related skin diseases; infectious skin diseases; skin injury-induced cellulitis; and skin conditions resulting from physical factors such as heat, cold, sun exposure, and ionized radiation. This list will be more practical and convenient for physicians and workers because it follows a disease-based approach. The revised list is in accordance with the International Labor Organization list and is refined according to Korean worker's compensation and the actual occurrence of occupational skin diseases. However, this revised list does not perfectly reflect the actual status of skin diseases because of the few cases of occupational skin diseases, incomplete statistics of skin diseases, and insufficient scientific evidence. Thus, the list of occupational diseases should be modified periodically on the basis of recent evidence and statistics.

  7. Fabry disease: characterisation of the plasma proteome pre- and post-enzyme replacement therapy.

    PubMed

    Heo, Sun Hee; Kang, Eungu; Kim, Yoon-Myung; Go, Heounjeong; Kim, Kyung Yong; Jung, Jae Yong; Kang, Minji; Kim, Gu-Hwan; Kim, Jae-Min; Choi, In-Hee; Choi, Jin-Ho; Jung, Sung-Chul; Desnick, Robert J; Yoo, Han-Wook; Lee, Beom Hee

    2017-08-23

    Fabry disease is characterised by the progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in vascular endothelial cells. Enzyme replacement therapy (ERT) clears this accumulation. We analysed plasma proteome profiles before and after ERT to characterise its molecular pathology. Two-dimensional electrophoresis and matrix-assisted laser desorption/ionisation-time of flight tandem mass spectrometry (MALDI-TOF MS) and tandem mass spectrometry (MS/MS) were done using plasma samples before and after ERT in eight patients with classical Fabry disease RESULTS: After short-term ERT (4-12 months), the levels of 15 plasma proteins involved in inflammation, oxidative and ischaemic injury, or complement activation were reduced significantly. Among them, β-actin (ACTB), inactivated complement C3b (iC3b), and C4B were elevated significantly in pre-ERT Fabry disease plasma compared with control plasma. After longer-term ERT (46-96 months), iC3b levels gradually decreased, whereas the levels of other proteins varied. The gradual reduction of iC3b was comparable to that of Gb3 levels. In addition, iC3b increased significantly in pre-ERT Fabry disease mouse plasma, and C3 deposits were notable in renal tissues of pre-enzyme replacement therapy patients. These results indicated that C3-mediated complement activation might be altered in Fabry disease and ERT might promote its stabilisation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  8. Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease.

    PubMed Central

    Topaloglu, A. K.; Ashley, G. A.; Tong, B.; Shabbeer, J.; Astrin, K. H.; Eng, C. M.; Desnick, R. J.

    1999-01-01

    BACKGROUND: Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal exoglycohydrolase alpha-galactosidase A (EC 3.2.1.22; alpha-Gal A). The nature of the molecular lesions in the alpha-Gal A gene in 30 unrelated families was determined to provide precise heterozygote detection, prenatal diagnosis, and define genotype-phenotype correlations. MATERIALS AND METHODS: Genomic DNA was isolated from affected males and/or carrier females from 30 unrelated families with Fabry disease. The entire alpha-Gal A coding region and flanking intronic sequences were analyzed by PCR amplification and automated sequencing. RESULTS: Twenty new mutations were identified, each in a single family: C142R, G183D, S235C, W236L, D244H, P259L, M267I, I289F, Q321E, C378Y, C52X, W277X, IVS4(+4), IVS6(+2), IVS6(-1), 35del13, 256del1, 892ins1, 1176del4, and 1188del1. In the remaining 10 unrelated Fabry families, 9 previously reported mutations were detected: M42V, R112C, S148R, D165V, N215S (in 2 families), Q99X, C142X, R227X, and 1072del3. Haplotype analysis using markers closely flanking the alpha-Gal A gene indicated that the two patients with the N215S lesion were unrelated. The IVS4(+4) mutation was a rare intronic splice site mutation that causes Fabry disease. CONCLUSIONS: These studies further define the heterogeneity of mutations in the alpha-Gal A gene causing Fabry disease, permit precise heterozygote detection and prenatal diagnosis, and help delineate phenotype-genotype correlations in this disease.

  9. Acute cerebrovascular disease in the young: the Stroke in Young Fabry Patients study.

    PubMed

    Rolfs, Arndt; Fazekas, Franz; Grittner, Ulrike; Dichgans, Martin; Martus, Peter; Holzhausen, Martin; Böttcher, Tobias; Heuschmann, Peter U; Tatlisumak, Turgut; Tanislav, Christian; Jungehulsing, Gerhard J; Giese, Anne-Katrin; Putaala, Jukaa; Huber, Roman; Bodechtel, Ulf; Lichy, Christoph; Enzinger, Christian; Schmidt, Reinhold; Hennerici, Michael G; Kaps, Manfred; Kessler, Christof; Lackner, Karl; Paschke, Eduard; Meyer, Wolfgang; Mascher, Hermann; Riess, Olaf; Kolodny, Edwin; Norrving, Bo

    2013-02-01

    Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients. Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396), hemorrhagic stroke (271), transient ischemic attack (1071) were enrolled in 15 European countries and 47 centers between April 2007 and January 2010 undergoing a detailed, standardized, clinical, laboratory, and radiological protocol. Median age in the overall cohort was 46 years. Definite Fabry disease was diagnosed in 0.5% (95% confidence interval, 0.4%-0.8%; n=27) of all patients; and probable Fabry disease in additional 18 patients. Males dominated the study population (2962/59%) whereas females outnumbered men (65.3%) among the youngest patients (18-24 years). About 80.5% of the patients had a first stroke. Silent infarcts on magnetic resonance imaging were seen in 20% of patients with a first-ever stroke, and in 11.4% of patients with transient ischemic attack and no history of a previous cerebrovascular event. The most common causes of ischemic stroke were large artery atherosclerosis (18.6%) and dissection (9.9%). Definite Fabry disease occurs in 0.5% and probable Fabry disease in further 0.4% of young stroke patients. Silent infarcts, white matter intensities, and classical risk factors were highly prevalent, emphasizing the need for new early preventive strategies. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov.Unique identifier: NCT00414583.

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

    PubMed Central

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

    2017-01-01

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

  11. 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.

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

    PubMed

    Hofmann, Lukas; 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.

  13. 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

  14. Plasma mutant α-galactosidase A protein and globotriaosylsphingosine level in Fabry disease.

    PubMed

    Tsukimura, Takahiro; Nakano, Sachie; Togawa, Tadayasu; Tanaka, Toshie; Saito, Seiji; Ohno, Kazuki; Shibasaki, Futoshi; Sakuraba, Hitoshi

    2014-01-01

    Fabry disease is an X-linked genetic disorder characterized by deficient activity of α-galactosidase A (GLA) and accumulation of glycolipids, and various GLA gene mutations lead to a wide range of clinical phenotypes from the classic form to the later-onset one. To investigate the biochemical heterogeneity and elucidate the basis of the disease using available clinical samples, we measured GLA activity, GLA protein and accumulated globotriaosylsphingosine (Lyso-Gb3), a biomarker of this disease, in plasma samples from Fabry patients. The analysis revealed that both the enzyme activity and the protein level were apparently decreased, and the enzyme activity was well correlated with the protein level in many Fabry patients. In these cases, a defect of biosynthesis or excessive degradation of mutant GLAs should be involved in the pathogenesis, and the residual protein level would determine the accumulation of Lyso-Gb3 and the severity of the disease. However, there are some exceptional cases, i.e., ones harboring p.C142Y, p.R112H and p.M296I, who exhibit a considerable amount of GLA protein. Especially, a subset of Fabry patients with p.R112H or p.M296I has been attracted interest because the patients exhibit almost normal plasma Lyso-Gb3 concentration. Structural analysis revealed that C142Y causes a structural change at the entrance of the active site. It will lead to a complete enzyme activity deficiency, resulting in a high level of plasma Lyso-Gb3 and the classic Fabry disease. On the other hand, it is thought that R112H causes a relatively large structural change on the molecular surface, and M296I a small one in a restricted region from the core to the surface, both the structural changes being far from the active site. These changes will cause not only partial degradation but also degeneration of the mutant GLA proteins, and the degenerated enzymes exhibiting small and residual activity remain and probably facilitate degradation of Lyso-Gb3 in plasma, leading

  15. Keratins and skin disease.

    PubMed

    Knöbel, Maria; O'Toole, Edel A; Smith, Frances J D

    2015-06-01

    Mutations in keratin genes cause a diverse spectrum of skin, hair and mucosal disorders. Cutaneous disorders include epidermolysis bullosa simplex, palmoplantar keratoderma, epidermolytic ichthyosis and pachyonychia congenita. Both clinical and laboratory observations confirm a major role for keratins in maintaining epidermal cell-cell adhesion. When normal tissue homeostasis is disturbed, for example, during wound healing and cancer, keratins play an important non-mechanical role. Post-translational modifications including glycosylation and phosphorylation of keratins play an important role in protection of epithelial cells from injury. Keratins also play a role in modulation of the immune response. A current focus in the area of keratins and disease is the development of new treatments including small inhibitory RNA (siRNA) to mutant keratins and small molecules to modulate keratin expression.

  16. Ventricular Tachycardia in Fabry Disease Detected in a 50-Year-Old Woman during 14-Day Continuous Cardiac Monitoring

    PubMed Central

    Silva-Gburek, Jaime; Rochford, Laura; Hopkin, Robert

    2016-01-01

    Fabry disease is an X-linked lysosomal storage disorder. Female carriers were long thought to be asymptomatic; however, research has revealed the opposite. Cardiac conditions are the chief causes of death in women with Fabry disease. Although ventricular tachycardia has been reported in male patients with Fabry disease, it is not thought to be a frequent finding in females. We describe the case of a 50-year-old woman in whom we used 14-day continuous electrocardiographic monitoring to identify nonsustained ventricular tachycardia, after electrocardiograms and 24-hour Holter monitoring failed to detect the arrhythmia. A permanent implantable cardioverter-defibrillator relieved the patient's symptoms. We discuss why this case supports the need for more extensive electrophysiologic evaluation in women who have Fabry disease. PMID:28100976

  17. 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

  18. Occupational Skin Diseases in Korea

    PubMed Central

    Kim, Min-Gi

    2010-01-01

    Skin disease is the most common occupational disease, but the reported number is small in Korea due to a difficulty of detection and diagnosis in time. We described various official statistics and data from occupational skin disease surveillance system, epidemiological surveys and cases published in scientific journals. Until 1981, 2,222 cases of occupational skin disease were reported by Korean employee's regular medical check-up, accounting for 4.9% of the total occupational diseases. There was no subsequent official statistics to figure out occupational skin diseases till 1998. From 1999, the Korea Occupational Safety and Health Agency (KOSHA) published the number of occupational skin diseases through the statistics of Cause Investigation for Industrial Accidents. A total of 301 cases were reported from 1999 to 2007. Recent one study showed the figures of compensated occupational skin diseases. Many of them belonged to daily-paid workers in the public service, especially forestry workers. Also, it described the interesting cases such as vitiligo and trichloroethylene-induced Stevens-Johnson Syndrome. Skin diseases are still important though the number of cases has decreased, and therefore it is recommended to grasp the status of occupational skin diseases through continuous surveillance system and to make policy protecting high-risk group. PMID:21258591

  19. Substrate-specific gene expression profiles in different kidney cell types are associated with Fabry disease.

    PubMed

    Shin, Youn-Jeong; Jeon, Yeo Jin; Jung, Namhee; Park, Joo-Won; Park, Hae-Young; Jung, Sung-Chul

    2015-10-01

    Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene encoding the α-galactosidase A (α-Gal A) lysosomal enzyme, which results in globotriaosylceramide (Gb3) storage in vascular endothelial cells and different cell types throughout the body. Involvement of the kidney and heart is life threatening, and fibrosis of these organs is considered to be involved in the pathogenesis of Fabry disease. An increased concentration of deacylated Gb3 (lyso‑Gb3) in the plasma of symptomatic patients has also been suggested as a causative molecular event. To elucidate the molecular mechanisms involved in renal fibrosis in Fabry disease, the present analyzed the changes in global gene expression prior to and following Gb3 or lyso‑Gb3 treatment in two types of kidney cell lines, human proximal renal tubular epithelial (HK‑2) and mouse renal glomerular mesangial (SV40 MES 13) cells. Gb3 and lyso‑Gb3 treatment regulated the expression of 199 and 328 genes in each cell type, demonstrating a >2.0‑fold change. The majority of the biological functions of the regulated genes were associated with fibrogenesis or epithelial‑mesenchymal transition (EMT). The gene expression patterns of sphingolipid‑treated HK‑2 cells were distinguishable from the patterns in the SV40 MES 13 cells. Several genes associated with the EMT were selected and evaluated further in kidney cells and in Fabry mouse kidney tissues. In the SV40 MES 13 cells, the DLL1, F8, and HOXA11 genes were downregulated, and FOXP2 was upregulated by treatment with Gb3 or lyso‑Gb3. In the HK‑2 cells, the ADAMTS6, BEST1, IL4, and MYH11 genes were upregulated. Upregulation of the FOXP2, COL15A1, IL4, and MYH11 genes was also observed in the Fabry mouse kidney tissues. The gene expression profiles in kidney cells following the addition of Gb3 or lyso‑Gb3 revealed substrate‑specific and cell‑specific patterns. These findings suggested that Gb3 and lyso‑Gb3 lead to renal

  20. Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model

    PubMed Central

    Lakomá, Jarmila; Rimondini, Roberto; Ferrer Montiel, Antonio; Donadio, Vincenzo; Liguori, Rocco

    2016-01-01

    Fabry disease is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3) in the endothelium and vascular smooth muscles. A hallmark symptom of Fabry disease patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. The α-GalA gene null mouse model (α-GalA(−/0)) has provided molecular evidence for the molecular alterations in small type-C nociceptors in Fabry disease that may underlie their hyperexcitability, although the specific mechanism remains elusive. Here, we have addressed this question and report that small type-C nociceptors from α-GalA(−/0) mice exhibit a significant increase in the expression and function of the TRPV1 channel, a thermoTRP channel implicated in painful heat sensation. Notably, male α-GalA(−/0) mice displayed a ≈2-fold higher heat sensitivity than wild-type animals, consistent with the augmented expression levels and activity of TRPV1 in α-GalA(−/0) nociceptors. Intriguingly, blockade of neuronal exocytosis with peptide DD04107, a process that inhibits among others the algesic membrane recruitment of TRPV1 channels in peptidergic nociceptors, virtually eliminated the enhanced heat nociception of α-GalA(−/0) mice. Together, these findings suggest that the augmented expression of TRPV1 in α-GalA(−/0) nociceptors may underly at least in part their increased heat sensitivity, and imply that blockade of peripheral neuronal exocytosis may be a valuable pharmacological strategy to reduce pain in Fabry disease patients, increasing their quality of life. PMID:27531673

  1. Altered dynamics of a lipid raft associated protein in a kidney model of Fabry disease.

    PubMed

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

    2014-02-01

    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. © 2013 Elsevier Inc. All rights reserved.

  2. Hemizygous Fabry disease associated with IgA nephropathy: a case report.

    PubMed

    Shimohata, Homare; Yoh, Keigyou; Takada, Kenji; Tanaka, Hiroaki; Usui, Joichi; Hirayama, Kouichi; Kobayashi, Masaki; Yamagata, Kunihiro

    2009-01-01

    We present a 22-year-old male patient who showed both classical Fabry disease and IgA nephropathy. He had proteinuria (1.5 g/day), hypohidrosis and neuralgia with fever. Serum creatinine and blood urea nitrogen were 0.9 mg/dL and 11.4 mg/dL, respectively. Renal biopsy showed strikingly vacuolated podocytes and tubular epithelium cells. Myelin-like bodies were detected in podocytes, mesangial cells, endothelial cells and tubular epithelium cells by electron microscopy. On immunofluorescence microscopy, IgA and C3 deposits were detected in mesangial areas. From these results and a markedly low level of alpha-galactosidase A activity, this patient was diagnosed as having classical Fabry disease and IgA nephropathy.

  3. Skin Diseases in the Tropics.

    ERIC Educational Resources Information Center

    Mahe, Antoine; And Others

    1994-01-01

    Common skin diseases are prevalent in tropical countries because of extreme weather conditions, mediocre hygiene, and lack of adequate treatment of infectious dermatoses. This guide describes the major endemic skin diseases and their signs for the purpose of helping unspecialized health agents train themselves and determine when a patient should…

  4. Home infusion program for Fabry disease: experience with agalsidase alfa in Argentina.

    PubMed

    Kisinovsky, Isaac; Cáceres, Guillermo; Coronel, Cristina; Reisin, Ricardo

    2013-01-01

    Fabry disease is an X-linked lysosomal storage disorder caused by inherited deficiency of the enzyme a-galactosidase A. Enzyme replacement treatment using agalsidase alfa significantly reduces pain, improves cardiac function and quality of life, and slows renal deterioration. Nevertheless, it is a life-long treatment which requires regular intravenous infusions and entails a great burden for patients. Our objective was to evaluate retrospectively the safety and tolerability of the home infusion of agalsidase alfa in patients with Fabry disease in Argentina. We evaluated all the patients with Fabry disease who received home infusion with agalsidase alfa 0.2 mg/kg between January 2005 and June 2011. The program included 87 patients; 51 males (mean age: 30 years) and 36 females (mean age: 34 years). A total of 5229 infusions (mean: 59 per patient; range: 1-150) were administered. A total of 5 adverse reactions were seen in 5 patients (5.7% of patients and 0.9% of the total number of infusions). All were mild in severity and resolved by reducing the rate of infusion and by using antihistaminics. All these 5 patients were positive for IgG antibodies, but none of them presented IgE antibodies and none suffered an anaphylactic shock. In our group 18 patients were switched from agalsidase beta to agalsidase alfa without complications. Home infusion with agalsidase alfa is safe, well tolerated and is associated to high compliance.

  5. 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.

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

    PubMed Central

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

    2017-01-01

    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. PMID:28382085

  7. Use of a Modified α-N-Acetylgalactosaminidase in the Development of Enzyme Replacement Therapy for Fabry Disease

    PubMed Central

    Tajima, Youichi; Kawashima, Ikuo; Tsukimura, Takahiro; Sugawara, Kanako; Kuroda, Mayuko; Suzuki, Toshihiro; Togawa, Tadayasu; Chiba, Yasunori; Jigami, Yoshifumi; Ohno, Kazuki; Fukushige, Tomoko; Kanekura, Takuro; Itoh, Kohji; Ohashi, Toya; Sakuraba, Hitoshi

    2009-01-01

    A modified α-N-acetylgalactosaminidase (NAGA) with α-galactosidase A (GLA)-like substrate specificity was designed on the basis of structural studies and was produced in Chinese hamster ovary cells. The enzyme acquired the ability to catalyze the degradation of 4-methylumbelliferyl-α-D-galactopyranoside. It retained the original NAGA's stability in plasma and N-glycans containing many mannose 6-phosphate (M6P) residues, which are advantageous for uptake by cells via M6P receptors. There was no immunological cross-reactivity between the modified NAGA and GLA, and the modified NAGA did not react to serum from a patient with Fabry disease recurrently treated with a recombinant GLA. The enzyme cleaved globotriaosylceramide (Gb3) accumulated in cultured fibroblasts from a patient with Fabry disease. Furthermore, like recombinant GLA proteins presently used for enzyme replacement therapy (ERT) for Fabry disease, the enzyme intravenously injected into Fabry model mice prevented Gb3 storage in the liver, kidneys, and heart and improved the pathological changes in these organs. Because this modified NAGA is hardly expected to cause an allergic reaction in Fabry disease patients, it is highly promising as a new and safe enzyme for ERT for Fabry disease. PMID:19853240

  8. Travel-associated skin disease.

    PubMed

    Morris-Jones, Rachael; Morris-Jones, Stephen

    2012-09-01

    Travel associated skin disease is extremely common and a frequent cause of the returning traveller seeking medical attention. Widespread cutaneous eruptions usually represent reactive rashes, indicating an underlying systemic infection or allergic reaction. Patients with disseminated or spreading rashes following travel often present with fever and malaise. In contrast, those presenting with localised skin disease such as a blister, nodule, plaque, ulcer etc are usually well in themselves but have sustained a bite/sting/penetrating injury or introduction of infection directly into the skin at the affected site. As a general rule widespread rashes are investigated with blood tests/serology and localised lesions with a skin biopsy for culture and histology.

  9. Sun exposed skin disease.

    PubMed

    Lehmann, Percy

    2011-01-01

    A wide variety of dermatoses may arise in exposed areas and are at the same time induced or exacerbated by irradiation from the sun. The spectrum may range from acute sunburn to chronic effects of sun damage, including elastosis and ultraviolet-induced skin cancer. Inflammatory ultraviolet-induced dermatoses have a confusing nomenclature and classification that often leads to difficulties in the differential diagnosis. Modern nosology differentiates primary from secondary photodermatoses. Primary photodermatoses are believed to be mainly irradiation-induced and immunologically mediated. If the pathophysiology is not clearly defined, they are also called idiopathic. In cases of a known photosensitizer, local and systemic phototoxic or photoallergic reactions can be differentiated. Secondary photodermatoses have an established pathophysiology; for example, an enzyme defect such as occurs in the porphyrias or xeroderma pigmentosum, which leads to the abnormal sun sensitivity. Finally, preexisting dermatoses may be exacerbated by irradiation from the sun, as in systemic lupus erythematosus or Darier disease. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Sudoscan as a noninvasive tool to assess sudomotor dysfunction in patients with Fabry disease: results from a case–control study

    PubMed Central

    Sahuc, Pauline; Chiche, Laurent; Dussol, Bertrand; Pouget, Jean; Franques, Jérôme

    2016-01-01

    Hypohidrosis is a frequent and early symptom in patients with Fabry disease. Studies have reported improved sweating in patients treated with enzyme-replacement therapy. A new method, Sudoscan, has been developed that is noninvasive, is quantitative, and can quickly evaluate sweat gland function. It is based on the electrochemical reaction between sweat chlorides and stainless-steel electrodes in contact with the palms and soles. The aim of our study was to evaluate the Sudoscan as a tool to assess sudomotor dysfunction in patients with Fabry disease. Consecutive patients were prospectively recruited who had a diagnosis of Fabry disease, which had been confirmed genetically and/or by measurement of α-galactosidase activity in leukocytes. Healthy controls, matched (1:1) for age and sex, were also enrolled. Test results were expressed immediately as electrochemical skin conductance (ESC, µS) for hands and feet. Sudomotor dysfunction was considered absent, moderate, or severe if the ESC measured on the feet was >60 µS, between 60 and 40 µS, or <40 µS, respectively. Among the 18 patients, 11 had hypohidrosis or anhidrosis. Hand and feet ESCs were significantly lower in patients compared to their controls (P=0.0015 and P=0.0047, respectively). Among patients, 8/18 (44.5%) had a sudomotor dysfunction, moderate in three and severe in five cases. Hand and feet ESCs were significantly lower in those with hypohidrosis/anhidrosis compared to those without (P=0.0014 and P=0.0056, respectively). This study showed that Sudoscan provided a quick, noninvasive, and quantitative measurement of sudomotor function in Fabry disease patients. PMID:26893567

  11. COMPUTER ASSISTED RETINAL VESSEL TORTUOSITY EVALUATION IN NOVEL MUTATION FABRY DISEASE: Towards New Prognostic Markers.

    PubMed

    San Román, Irene; Rodríguez, María-Elena; Caporossi, Orsola; Zoppetti, Claudia; Sodi, Andrea; Mecocci, Alessandro; López, David; Rodríguez, Beatriz; Gimeno, Juan-Ramón

    2017-03-01

    Fabry disease is a rare lysosomal storage disorder with systemic involvement. The authors report on a large Fabry family with GLA p.M187R mutation and exhaustive ophthalmologic assessment. Comprehensive systemic evaluation and genetic diagnosis were performed. Ophthalmologic evaluation included intraocular pressure/visual acuity measurement, refractometry, slit lamp examination, retinography, and optical coherence tomography. Three parameters quantified retinal vessel tortuosity: sum of angle metrics, product of angle distance, and triangular index. Calculations were semiautomatized using dedicated software. Ten individuals (2 males and 8 females) were described. Seventy-five percent had retinal vessel tortuosity. One hundred percent had cornea verticillata. Perimacular vessels were predominantly involved. The correlation between the right and left eye tortuosity measurements was very tight. A significant correlation between retinal vessel tortuosity and systemic severity measured by general Mainz Severity Score Index (MSSI), renal MSSI, and neurological MSSI but no cardiac MSSI was observed. Right sum of angle metrics value was an independent statistical predictor of the general-MSSI score in presence of age. p.M187R mutation causes a severe systemic and ophthalmologic phenotype, in both male and female patients. Semiautomatic assessment of retinal vessel tortuosity is an objective and reproducible tool. All three parameters of tortuosity are closely associated with Fabry severity scores. Studies of larger series are being awaited to establish the role of retinal vessel tortuosity as a noninvasive marker of disease progression.

  12. 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.

  13. 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

  14. Assessment of renal pathology and dysfunction in children with Fabry disease.

    PubMed

    Ramaswami, Uma; Najafian, Behzad; Schieppati, Arrigo; Mauer, Michael; Bichet, Daniel G

    2010-02-01

    Overt renal disease often first presents in male individuals with Fabry disease in early to middle adulthood, but proteinuria and reduced GFR may occur in adolescents and in young children. More recently, kidney biopsy data have shown early renal histologic changes in pediatric patients, and kidney dysfunction, primarily proteinuria, seems to be more common in girls. Renal investigations and their timing in children remain poorly defined. A consensus on renal investigations is necessary to understand the natural progression of the disease and to evaluate the efficacy of treatments such as enzyme replacement therapies. This article addresses three main categories: Use of GFRs, measuring albuminuria, and renal biopsies in children.

  15. 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

  16. Skin Diseases: Cross-section of human skin

    MedlinePlus

    Skip Navigation Bar Home Current Issue Past Issues Skin Diseases Cross-section of human skin Past Issues / Fall 2008 Table of Contents For ... Logical Images, Inc. I n the areas of skin health and skin diseases, the NIH's National Institute ...

  17. Skin Diseases and the Adolescent

    ERIC Educational Resources Information Center

    Bauer, Marjorie

    1970-01-01

    Discusses such concerns as acne, syphilis, drug abuse, and tatoos. Indicates need for physician not only to treat skin diseases but to help adolescents to accept themselves and find constructive directions. (CJ)

  18. Skin Diseases and the Adolescent

    ERIC Educational Resources Information Center

    Bauer, Marjorie

    1970-01-01

    Discusses such concerns as acne, syphilis, drug abuse, and tatoos. Indicates need for physician not only to treat skin diseases but to help adolescents to accept themselves and find constructive directions. (CJ)

  19. Small fiber dysfunction predominates in Fabry neuropathy.

    PubMed

    Dütsch, M; Marthol, H; Stemper, B; Brys, M; Haendl, T; Hilz, M J

    2002-12-01

    Fabry disease is an X-linked recessive disease with a reduction of lysosomal alpha galactosidase A and consecutive storage of glycolipids e.g., in the brain, kidney, skin, and nerve fibers. Cardinal neurologic findings are hypohidrosis, painful episodes, and peripheral neuropathy. So far, the neurophysiological findings regarding the extent of large and small fiber dysfunction are contradictory. This study evaluated large and small nerve fiber function in a homogeneous group of Fabry patients. In 24 of 30 Fabry patients with creatinine below 194.7 mmol/L the authors assessed median, ulnar, and peroneal motor conduction velocity (MCV) and median, ulnar, and sural sensory conduction velocity (SCV) nerve conduction to study the function of thickly myelinated nerve fibers. In addition, the authors studied sympathetic skin responses (SSR) at both hands and feet in 24 patients. To evaluate A beta nerve fiber function, the authors determined vibratory detection thresholds (VDT) at the first toe in 30 patients. Function of A delta and C fibers was assessed by quantitative sensory testing of cold detection threshold (CDT) and heat-pain detection thresholds (HPDT). Nerve conduction studies showed significantly decreased amplitudes of MCVs and SCVs in Fabry patients as compared to controls. However, individual results of MCV and SCV studies were only mildly impaired. SSRs were present in all tested patients but SSR amplitudes were significantly decreased in Fabry patients in comparison to controls. VDT, CDT, and HPDT were significantly elevated in Fabry patients as compared to controls. However, only six patients had pathologic VDT, 19 had increased CDT, and 25 had elevated HPDT at a high level of stimulation. In Fabry patients, small fiber dysfunction is more prominent than large fiber dysfunction, confirming previous findings of sural nerve biopsies. The results suggest a higher vulnerability of small-diameter nerve fibers than of the thickly myelinated fibers.

  20. The ratio of alpha-galactosidase to beta-glucuronidase activities in dried blood for the identification of female Fabry disease patients.

    PubMed

    Lukacs, Z; Keil, A; Kohlschütter, A; Beck, M; Mengel, E

    2005-01-01

    Female heterozygous patients with Fabry disease are difficult to identify because of the relatively high residual activity of alpha-galactosidase. We systematically evaluated the activities of various lysosomal enzymes in dried blood samples from Fabry patients and found that the beta-glucuronidase activity was frequently elevated. The ratio of alpha-galactosidase to beta-glucuronidase proved to be a helpful tool for the diagnosis of female Fabry disease patients.

  1. Depletion of globosides and isoglobosides fully reverts the morphologic phenotype of Fabry disease.

    PubMed

    Porubsky, Stefan; Jennemann, Richard; Lehmann, Lorenz; Gröne, Hermann-Josef

    2014-10-01

    Fabry disease is a monogenic X-linked lysosomal storage disease caused by α-galactosidase A (αGalA) deficiency. Enzyme replacement therapy through administration of the missing αGalA is currently the only accepted therapeutic option. However, this treatment is connected to high costs, has ill-defined indication criteria and its efficacy is controversially discussed. Our aim was to explore the possibility of a novel targeted substrate reduction therapy for Fabry disease. Owing to the fact that αGalA-deficient humans and mice accumulate the same glycosphingolipids (i.e. globosides, galabiosylceramide and isoglobosides), αGalA-deficient mice were crossed with mice deficient in enzymes synthesizing these classes of glycosphingolipids (i.e. globotrihexosylceramide and isoglobotrihexosylceramide synthase, respectively). Functional heart and kidney tests were performed together with an extensive biochemical analysis of urine and serum in aged mice. Lysosomal storage was assessed by thin layer chromatography and electron microscopy. We showed that depletion of globosides was sufficient to fully abolish the storage of glycosphingolipids in heart, kidney and liver and was paralleled by a complete restoration of lysosomal morphology in these organs. In contrast, in dorsal root ganglia, a depletion of both globosides and isoglobosides was necessary to fully counteract the lysosomal storage. The deficiency in globosides and/or isoglobosides did not cause any adverse effects. We conclude that substrate reduction therapy through inhibition of the synthesis of globosides and isoglobosides represents a valuable therapeutic option for Fabry disease, all the more as globosides and isoglobosides seem to be dispensable.

  2. 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.

  3. 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

  4. Characterization of Early Disease Status in Treatment-Naive Male Paediatric Patients with Fabry Disease Enrolled in a Randomized Clinical Trial

    PubMed Central

    Wijburg, Frits A.; Bénichou, Bernard; Bichet, Daniel G.; Clarke, Lorne A.; Dostalova, Gabriela; Fainboim, Alejandro; Fellgiebel, Andreas; Forcelini, Cassiano; An Haack, Kristina; Hopkin, Robert J.; Mauer, Michael; Najafian, Behzad; Scott, C. Ronald; Shankar, Suma P.; Thurberg, Beth L.; Tøndel, Camilla; Tylki-Szymańska, Anna; Ramaswami, Uma

    2015-01-01

    Trial Design This analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial. Methods Males aged 5–18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13–17 years), renal function, and glycolipid levels (plasma, urine). Results Plasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m2 (range 90.4–161.0 mL/min/1.73 m2) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0–27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients. Conclusions These data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of

  5. Molecular damage in Fabry disease: characterization and prediction of alpha-galactosidase A pathological mutations.

    PubMed

    Riera, Casandra; Lois, Sergio; Domínguez, Carmen; Fernandez-Cadenas, Israel; Montaner, Joan; Rodríguez-Sureda, Victor; de la Cruz, Xavier

    2015-01-01

    Loss-of-function mutations of the enzyme alpha-galactosidase A (GLA) causes Fabry disease (FD), that is a rare and potentially fatal disease. Identification of these pathological mutations by sequencing is important because it allows an early treatment of the disease. However, before taking any treatment decision, if the mutation identified is unknown, we first need to establish if it is pathological or not. General bioinformatic tools (PolyPhen-2, SIFT, Condel, etc.) can be used for this purpose, but their performance is still limited. Here we present a new tool, specifically derived for the assessment of GLA mutations. We first compared mutations of this enzyme known to cause FD with neutral sequence variants, using several structure and sequence properties. Then, we used these properties to develop a family of prediction methods adapted to different quality requirements. Trained and tested on a set of known Fabry mutations, our methods have a performance (Matthews correlation: 0.56-0.72) comparable or better than that of the more complex method, Polyphen-2 (Matthews correlation: 0.61), and better than those of SIFT (Matthews correl.: 0.54) and Condel (Matthews correl.: 0.51). This result is validated in an independent set of 65 pathological mutations, for which our method displayed the best success rate (91.0%, 87.7%, and 73.8%, for our method, PolyPhen-2 and SIFT, respectively). These data confirmed that our specific approach can effectively contribute to the identification of pathological mutations in GLA, and therefore enhance the use of sequence information in the identification of undiagnosed Fabry patients.

  6. Relation of burden of myocardial fibrosis to malignant ventricular arrhythmias and outcomes in Fabry disease.

    PubMed

    Krämer, Johannes; Niemann, Markus; Störk, Stefan; Frantz, Stefan; Beer, Meinrad; Ertl, Georg; Wanner, Christoph; Weidemann, Frank

    2014-09-15

    The aim of this study was to investigate the impact of myocardial fibrosis in Fabry disease. Seventy-three patients with genetically confirmed Fabry disease were followed for 4.8 ± 2.4 years. In accordance with current guidelines, 57 patients received enzyme replacement therapy (ERT) after study inclusion, whereas 16 did not. At baseline and latest possible follow-up, myocardial fibrosis was assessed noninvasively by cardiac magnetic resonance, and biomarkers of collagen metabolism were determined. Holter electrocardiography and clinical follow-up at yearly intervals were used to monitor malignant ventricular arrhythmias (MVAs; nonsustained and sustained ventricular tachycardia and sudden cardiac death). In total, 48 patients (66%) showed fibrosis assessed by late enhancement (LE) at baseline, and 4 patients developed new LE during follow-up, 2 of them despite ERT. The 2 patients receiving ERT (1.4 ± 1.9% vs 2.5 ± 2.6%, p <0.001) and the patients not receiving ERT (0.5 ± 0.8% vs 0.7 ± 1.0%, p = 0.035) showed a progression of LE during follow-up. None of the patients displayed reductions of LE during follow-up. Collagen biomarkers were elevated in patients with and without LE but did not correlate with LE amount. Thirteen LE-positive patients at the baseline examination had documented MVAs (including 5 sudden cardiac deaths), whereas none of the patients without LE had MVAs. The yearly increase in fibrosis was 0.9 ± 0.6% in patients with MVAs and 0.2 ± 0.3% in patients without MVAs (p <0.001). Logistic multivariate regression analysis revealed that the annual increase in fibrosis during follow-up was the only independent predictor of MVAs. In conclusion, myocardial fibrosis in Fabry disease is progressive, apparently not modified by ERT, and a crucial outcome determinant.

  7. 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-term agalsidase on

  8. A new mutation found in newborn screening for Fabry disease evaluated by plasma globotriaosylsphingosine levels

    PubMed Central

    Chinen, Yasutsugu; Nakamura, Sadao; Yoshida, Tomohide; Maruyama, Hiroki; Nakamura, Kimitoshi

    2017-01-01

    A pilot study of newborn screening for Fabry disease was performed in Okinawa, Japan. A total of 2,443 neonates were screened using dried blood spot samples over 7 years starting in 2007. Of 13 neonates determined to have low α-galactosidase A (GLA) activity, one boy had a new missense mutation, p.G144D of the GLA gene. This mutation was considered to be a late-onset type, as evaluated based on plasma globotriaosylsphingosine levels and family history. PMID:28224042

  9. A new mutation found in newborn screening for Fabry disease evaluated by plasma globotriaosylsphingosine levels.

    PubMed

    Chinen, Yasutsugu; Nakamura, Sadao; Yoshida, Tomohide; Maruyama, Hiroki; Nakamura, Kimitoshi

    2017-01-01

    A pilot study of newborn screening for Fabry disease was performed in Okinawa, Japan. A total of 2,443 neonates were screened using dried blood spot samples over 7 years starting in 2007. Of 13 neonates determined to have low α-galactosidase A (GLA) activity, one boy had a new missense mutation, p.G144D of the GLA gene. This mutation was considered to be a late-onset type, as evaluated based on plasma globotriaosylsphingosine levels and family history.

  10. Prevalence of chronic kidney disease in fabry disease patients: Multicenter cross sectional study in Argentina.

    PubMed

    Jaurretche, Sebastián; Antogiovanni, Norberto; Perreta, Fernando

    2017-09-01

    Nephropathy is one of the major complications of Fabry Disease (FD) and mainly includes reduced glomerular filtration rate (GFR) and proteinuria. Despite the frequency, scarce information exists regarding the frequency of CKD as well as other related complications in FD patients in Argentina. The aim of the study was to measure the prevalence of CKD at diagnosis of FD as well as to describe other related conditions in a large cohort of patients with FD. Methods: a cross-sectional study performed in three FD centers of Argentina during January 2014 and January 2016. Information at diagnosis regarding patient demographics, disease characteristics, key laboratory values, and renal, cardiac, cerebrovascular diseases and other related complications were collected. Results: A total of 60 patients were included. The mean age at diagnosis was 25.5 ± 16 years. 42% of included patients presented CKD in which the disease was mild (GFR ≥ 60 and < 90) in 60% (n = 15), moderate (GFR ≥ 30 and < 60) in 16% (n = 4), severe (GFR ≥ 15 and < 30) in 4% (n = 1) and failure (GFR < 15) in 20% (n = 5). Arrhythmias were reported for 13.3% of patients. In 33.3% the echocardiographic evaluation demonstrated left ventricular hypertrophy and peripheral neuropathy in 63.3%. Conclusion: This study presents information regarding the prevalence of CKD in a large cohort of FD patients at the moment of diagnosis in Argentina. Future studies will help us to confirm these initial findings.

  11. Insulin resistance and skin diseases.

    PubMed

    Napolitano, Maddalena; Megna, Matteo; Monfrecola, Giuseppe

    2015-01-01

    In medical practice, almost every clinician may encounter patients with skin disease. However, it is not always easy for physicians of all specialties to face the daily task of determining the nature and clinical implication of dermatologic manifestations. Are they confined to the skin, representing a pure dermatologic event? Or are they also markers of internal conditions relating to the patient's overall health? In this review, we will discuss the principal cutaneous conditions which have been linked to metabolic alterations. Particularly, since insulin has an important role in homeostasis and physiology of the skin, we will focus on the relationships between insulin resistance (IR) and skin diseases, analyzing strongly IR-associated conditions such as acanthosis nigricans, acne, and psoriasis, without neglecting emerging and potential scenarios as the ones represented by hidradenitis suppurativa, androgenetic alopecia, and hirsutism.

  12. Insulin Resistance and Skin Diseases

    PubMed Central

    Napolitano, Maddalena; Megna, Matteo; Monfrecola, Giuseppe

    2015-01-01

    In medical practice, almost every clinician may encounter patients with skin disease. However, it is not always easy for physicians of all specialties to face the daily task of determining the nature and clinical implication of dermatologic manifestations. Are they confined to the skin, representing a pure dermatologic event? Or are they also markers of internal conditions relating to the patient's overall health? In this review, we will discuss the principal cutaneous conditions which have been linked to metabolic alterations. Particularly, since insulin has an important role in homeostasis and physiology of the skin, we will focus on the relationships between insulin resistance (IR) and skin diseases, analyzing strongly IR-associated conditions such as acanthosis nigricans, acne, and psoriasis, without neglecting emerging and potential scenarios as the ones represented by hidradenitis suppurativa, androgenetic alopecia, and hirsutism. PMID:25977937

  13. Targeting autophagy in skin diseases.

    PubMed

    Yu, Teng; Zuber, Joshua; Li, Jinchao

    2015-01-01

    Autophagy is a major intracellular degradative process by which cytoplasmic materials are sequestered in double-membraned vesicles and degraded upon fusion with lysosomes. Under normal circumstances, basal autophagy is necessary to maintain cellular homeostasis by scavenging dysfunctional or damaged organelles or proteins. In addition to its vital homeostatic role, this degradation pathway has been implicated in many different cellular processes such as cell apoptosis, inflammation, pathogen clearance, and antigen presentation and thereby has been linked to a variety of human disorders, including metabolic conditions, neurodegenerative diseases, cancers, and infectious diseases. The skin, the largest organ of the body, serves as the first line of defense against many different environmental insults; however, only a few studies have examined the effect of autophagy on the pathogenesis of skin diseases. This review provides an overview of the mechanisms of autophagy and highlights recent findings relevant to the role of autophagy in skin diseases and strategies for therapeutic modulation.

  14. Uric Acid as a Marker of Mortality and Morbidity in Fabry Disease.

    PubMed

    Rob, Daniel; Marek, Josef; Dostálová, Gabriela; Goláň, Lubor; Linhart, Aleš

    2016-01-01

    Serum uric acid (UA) elevation is common in patients with cardiovascular, renal and metabolic diseases. However, no study to date has analysed the role of UA in Fabry disease (FD). To evaluate the association between serum UA levels and mortality and morbidity in FD. We conducted a post-hoc analysis of a prospectively followed-up cohort of 124 patients with genetically proven FD. Serum UA levels were acquired at baseline; clinical events and mortality were assessed during regular visits every 6 to 12 months. The primary endpoint was a composite of multiple secondary outcomes: all-cause mortality, adverse cardiovascular events, progression of renal dysfunction and stroke or transient ischaemic attack (TIA). Predictive value was assessed using the Cox proportional hazards model and the Kaplan Meyer estimator. During follow-up of 7.4 ± 3.7 years, 64 (52%) patients reached the primary combined endpoint. Overall, UA levels were significantly associated with combined outcome (p < 0.001) and remained independently associated after correcting for age, sex and estimated glomerular filtration rate (hazard ratio [HR] per 20 μmol/l increase 1.09, 95% confidence interval [95%CI] (1.00-1.19), p = 0.04). UA was associated with overall mortality in univariate analysis (p = 0.021); however, the association did not reach statistical significance after multivariate correction (HR per 20 μmol/l increase 1.07 95%CI 0.93-1.25, p = 0.32). Higher UA levels were also associated with cardiac adverse outcomes, progression of left ventricular hypertrophy and progression of renal dysfunction (ps < 0.001). No association was observed between UA levels and stroke or TIA (p = 0.323). Increased serum UA levels may represent an independent risk factor for adverse clinical outcomes in Fabry patients and are associated with all-cause mortality. UA is a widely available and cheap biomarker that may improve risk stratification of Fabry patients in clinical practice.

  15. The right ventricle in Fabry disease: natural history and impact of enzyme replacement therapy.

    PubMed

    Niemann, Markus; Breunig, Frank; Beer, Meinrad; Herrmann, Sebastian; Strotmann, Jörg; Hu, Kai; Emmert, Andrea; Voelker, Wolfram; Ertl, Georg; Wanner, Christoph; Weidemann, Frank

    2010-12-01

    Storage of globotriaosylceramides is present in the left and right ventricles of patients with Fabry disease. Improvement of left ventricular morphology and function during enzyme replacement therapy (ERT) has previously been reported. To analyse the effects of long term ERT on right ventricular morphology and function. This was a prospective follow-up of 75 genetically confirmed consecutive Fabry patients for 3.1±1.8 years. According to treatment guidelines the natural history was followed in 18 patients, whereas 57 patients received ERT. Standard echocardiography, strain rate imaging for regional deformation of the right and left ventricle, and magnetic resonance tomography with late enhancement (LE) imaging for the detection of fibrosis were all performed at yearly intervals. Right ventricular hypertrophy was evident in 53 patients (71%) at baseline. A significant positive correlation was found between left and right ventricular wall thickness (r=0.76; p<0.0001). LE was detected in half of the patients (n=38) in the left ventricle at baseline while no patient ever had LE of the right ventricle. Patients with LE in the left ventricle presented with the lowest right ventricular deformation properties. In contrast to the left ventricle, there was no change in right ventricular wall thickness (baseline 6.9±1.6 mm vs follow-up 6.7±1.5 mm; p=0.44) or systolic strain rate (2.2±0.7/s vs 2.1±0.8/s; p=0.31) during follow-up with ERT. The degree of right ventricular involvement in Fabry disease is related to the left ventricular cardiomyopathy stage. ERT seems to have no direct impact on right ventricular morphology and function.

  16. Prevalence of Fabry disease in a predominantly hypertensive population with left ventricular hypertrophy.

    PubMed

    Terryn, Wim; Deschoenmakere, Gert; De Keyser, Jan; Meersseman, Wouter; Van Biesen, Wim; Wuyts, Brigitte; Hemelsoet, Dimitri; Pascale, Hilbert; De Backer, Julie; De Paepe, An; Poppe, Bruce; Vanholder, Raymond

    2013-09-10

    Patients with Fabry disease (FD) develop progressive left ventricular hypertrophy (LVH). In screening studies in patients with LVH, the prevalence of FD ranges from 0 to 12%. This variability is attributable to different factors like diverging inclusion and exclusion criteria, the evaluation of selected populations and suboptimal screening methods. In this study, we aimed to determine the prevalence of FD in an unselected population of everyday clinical practice presenting LVH, defined as a maximal end-diastolic septal or posterior wall thickness ≥ 13 mm, without exclusion of patients with arterial hypertension or valvular pathology, and using optimal screening methods. In adult males, a two-tier approach was used; α-Galactosidase A (aGAL A) activity was measured using a dried bloodspot test (DBS) and diagnosis was confirmed by mutation analysis of the GLA gene. In females, mutation analysis was the primary screening tool. 362 men and 178 women were screened. Six patients were diagnosed with a genetic sequence alteration of the GLA gene. One man had a novel mutation, GLA p.Ala5Glu (c.44C>A), presenting as classical FD. Another man and three women had the previously described GLA p.Ala143Thr (c.427G>A) mutation, which generally presents as an attenuated phenotype. One woman had a novel sequence alteration c.639+6A>C, which appeared to be a polymorphism. All true Fabry patients had arterial hypertension (AHT), and one had hypertrophic obstructive cardiomyopathy (HOCM). In a group of unselected patients with LVH, we found a prevalence of Fabry disease of 0.9%. AHT or type of hypertrophy should not be an exclusion criterion for screening for FD. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  17. Prevalence and Risk Factors of Sleep Disordered Breathing in Fabry disease

    PubMed Central

    Franzen, Daniel; Gerard, Nicolas; Bratton, Daniel J.; Wons, Annette; Gaisl, Thomas; Sievi, Noriane A.; Clarenbach, Christian F.; Kohler, Malcolm; Krayenbühl, Pierre A.

    2015-01-01

    Abstract Excessive daytime sleepiness (EDS) is a frequently reported and not well-understood symptom in patients with Fabry disease (FD). Sleep-disordered breathing (SDB) is a possible factor. As deposition of glycosphingolipids in the upper airway muscles is likely, we hypothesized that obstructive sleep apnoea (OSA) is highly prevalent in FD and positively associated with its severity. All patients with FD who are followed in the Fabry cohort of the University Hospital Zurich (n = 62) were asked to participate in this prospective cohort study. Eligible patients were prospectively investigated by assessing their daytime sleepiness using the Epworth Sleepiness Scale (ESS), the severity of FD using the Mainz Severity Score Index (MSSI), and by an ambulatory overnight respiratory polygraphy between November 1, 2013, and January 31, 2015. SDB was defined as an apnea/hypopnea index (AHI) of > 5/h. Fifty-two patients (mean ± SD age 42.8 ± 14.7 years, 33% men, mean ± SD BMI 23.4 ± 3.6 kg/m2) with a median (IQR) MSSI of 12 (5–19) were included. Median (IQR) ESS was 6 (2–10) and 7 patients (14%) had an ESS > 10. Thirteen patients (25%) had SDB (78% obstructive sleep apnea, 22% central sleep apnea). In the multivariable analysis, the age was the only statistically significant predictor of SDB (OR 1.11, 95% CI 1.04–1.18, P = 0.001). ESS was associated with depression (P < 0.001) but not AHI nor age. This study shows that SDB, especially obstructive sleep apnea is highly prevalent in patients with Fabry disease. However, EDS in FD seems to be related with depression rather than SDB. ClinicalTrials.gov (identifier: NCT01947634). PMID:26717401

  18. The Renal Lesion in Angiokeratoma Corporis Diffusum (Fabry's Disease)

    PubMed Central

    Henry, E. W.; Rally, C. R.

    1963-01-01

    Electron microscopic details of the glomerular and tubular lesions in a 26-year-old man with angiokeratoma corporis diffusum are presented. Though unable to concentrate urine above a specific gravity of 1.012, this patient showed preservation of the ability to acidify and alkalinize the urine following oral loads of ammonium chloride (150 mEq./day) and sodium bicarbonate (158 mEq./day) for several days. This observation is in contrast to previously reported findings and suggests that the regularly observed hyposthenuria in this disease does not depend on defects in ion transfer in the distal tubule system. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10 PMID:13953819

  19. Cannabis and skin diseases.

    PubMed

    Tennstedt, Dominique; Saint-Remy, Anaïs

    2011-01-01

    From time out of mind, man has grown hemp for both "industrial" and "recreational" use (it is then referred to as cannabis). Of course, cannabis has strong psychoactive properties and is one of the most commonly used "soft drugs" in the world. Clinicians should know the adverse effects on mucous membranes and on skin, which may sometimes entail an absolutely necessary stopping of consumption. Raynaud's phenomenon, as well as arteritis due to cannabis consumption may be extremely severe and result in worrying situations for both clinicians and patients.

  20. High Variability of Fabry Disease Manifestations in an Extended Italian Family

    PubMed Central

    Cammarata, Giuseppe; Fatuzzo, Pasquale; Rodolico, Margherita Stefania; Colomba, Paolo; Sicurella, Luigi; Iemolo, Francesco; Zizzo, Carmela; Bartolotta, Caterina; Duro, Giovanni

    2015-01-01

    Fabry disease (FD) is an inherited metabolic disorder caused by partial or full inactivation of the lysosomal hydrolase α-galactosidase A (α-GAL). The impairment of α-GAL results in the accumulation of undegraded glycosphingolipids in lysosomes and subsequent cell and microvascular dysfunctions. This study reports the clinical, biochemical, and molecular characterization of 15 members of the same family. Eight members showed the exonic mutation M51I in the GLA gene, a disease-causing mutation associated with the atypical phenotype. The clinical history of this family highlights a wide phenotypic variability, in terms of involved organs and severity. The phenotypic variability of two male patients is not related to differences in α-GAL enzymatic activity: though both have no enzymatic activity, the youngest shows severe symptoms, while the eldest is asymptomatic. It is noticeable that for two female patients with the M51I mutation the initial clinical diagnosis was different from FD. One of them was diagnosed with Familial Mediterranean Fever, the other with Multiple Sclerosis. Overall, this study confirms that the extreme variability of the clinical manifestations of FD is not entirely attributable to different mutations in the GLA gene and emphasizes the need to consider other factors or mechanisms involved in the pathogenesis of Fabry Disease. PMID:25977923

  1. Novel α-galactosidase A mutation in patients with severe cardiac manifestations of Fabry disease.

    PubMed

    Duro, Giovanni; Musumeci, M Beatrice; Colomba, Paolo; Zizzo, Carmela; Albeggiani, Giuseppe; Mastromarino, Vittoria; Volpe, Massimo; Autore, Camillo

    2014-02-10

    Fabry disease (FD) is a hereditary metabolic disorder caused by the partial or total inactivation of α-galactosidase A (α-gal A), a lysosomal hydrolase. This inactivation is responsible for the accumulation of undegraded glycosphingolipids in the lysosomes with subsequent cellular and microvascular dysfunction. Fabry is considered a rare disease, with an incidence of 1:40,000; however, there are good reasons to believe that it is often seen but rarely diagnosed. To date, more than 600 mutations have been identified in human GLA gene that are responsible for FD. We describe the case of a 54-year-old male patient, who presented with left ventricular hypertrophy, chronic renal failure and acroparaesthesias, which are considered to be specific features of FD. Clinical and instrumental investigations showed several cardiovascular manifestations. The molecular analysis of GLA gene revealed a novel mutation in the fifth exon, called N249K, and the enzymatic analysis showed no α-galactosidase A activity. Family screening detected the same mutation in some relatives and also the enzymatic analysis confirmed the diagnosis of FD. In conclusion, these data suggest that the N249K mutation may be associated with cardiac manifestations of FD combined with other classical features of the disease.

  2. [Skin cancer as occupational disease].

    PubMed

    Bauer, A

    2016-11-01

    The incidence of epithelial skin neoplasms, such as squamous cell carcinoma and basal cell carcinoma is significantly increasing worldwide. Leisure time solar UV exposure is causative in the overwhelming majority of cases in the general population; however, occupational exposure is responsible for a certain percentage of cases. Employees with a relevant exposure to polycyclic aromatic hydrocarbons in soot, raw paraffin, coal tar, anthracene, pitch or similar substances, to sunlight in outdoor occupations as well as to arsenic and ionizing radiation have a significantly increased risk to develop occupational skin cancer compared to the general population. In the official occupational disease list in the appendix of the German by-law on occupational diseases, the following occupational diseases concerning skin cancer are listed: BK 5102 "skin cancer and carcinoma in situ caused by soot, raw paraffin, coal tar, anthracene, pitch or similar substances" (e.g. various solid paraffins, asphalt and mazut as well as mineral oils, grease, cylinder and drilling oils), BK 5103 "squamous cell carcinoma or multiple actinic keratosis caused by natural UV radiation", BK 1108 "diseases caused by arsenic and its compounds" and BK 2402 "diseases caused by ionizing radiation". For further occupational exposure to carcinogenic substances and potential occupationally acquired skin tumors, no official lists are currently available. These cancers might be considered under a special opt out paragraph in the German Social Law (§ 9 para 2 SGB VII). Tumors in scars after occupational skin trauma or occupational burns are compensated as consequences of work accidents. The current official list of occupational skin cancers and new developments for expert opinions are described in this article.

  3. Case study on the pathophysiology of Fabry Disease: Abnormalities of cellular membranes can be reversed by substrate reduction in vitro.

    PubMed

    Brogden, Graham; Shammas, Hadeel; Maalouf, Katia; Naim, Samara L; Wetzel, Gabi; Amiri, Mahdi; von Köckritz-Blickwede, Maren; Das, Anibh M; Naim, Hassan Y

    2017-03-28

    It is still not entirely clear how a-galactosidase (GAA) deficiency translates into clinical symptoms of Fabry disease (FD). The current communication investigates the effects of the mutation N215S in FD on the trafficking and processing of lysosomal GAA and their potential association with alterations in the membrane lipid composition. Abnormalities in lipid rafts were observed in fibroblasts isolated from a male patient with Fabry disease bearing the mutation N215S. Interestingly, lipid raft analysis revealed that the distribution of cholesterol and flotillin-2 are distinctly altered in the Fabry fibroblasts when compared to that of wild type cells. Furthermore, increased levels of glycolipid Gb3 (globotriaosylceramide 3) and sphingomyelin were observed in non-raft membrane fractions of Fabry cells. Substrate reduction with N-butyldeoxynojirimycin in vitro was capable of reversing these abnormalities in this patient. These data lead to the hypothesis that alterations of lipid rafts may contribute to the pathophysiology of Morbus Fabry. Furthermore, it may be suggested that substrate reduction therapy with N-butyldeoxynojirimycin might be a promising approach for the treatment of GAA-deficiency at least for selected patients.

  4. Screening, diagnosis, and management of patients with Fabry disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.

    PubMed

    Schiffmann, Raphael; Hughes, Derralynn A; Linthorst, Gabor E; Ortiz, Alberto; Svarstad, Einar; Warnock, David G; West, Michael L; Wanner, Christoph

    2017-02-01

    Patients with Fabry disease (FD) are at a high risk for developing chronic kidney disease and cardiovascular disease. The availability of specific but costly therapy has elevated the profile of this rare condition. This KDIGO conference addressed controversial areas in the diagnosis, screening, and management of FD, and included enzyme replacement therapy and nonspecific standard-of-care therapy for the various manifestations of FD. Despite marked advances in patient care and improved overall outlook, there is a need to better understand the pathogenesis of this glycosphingolipidosis and to determine the appropriate age to initiate therapy in all types of patients. The need to develop more effective specific therapies was also emphasized.

  5. High Incidence of Later-Onset Fabry Disease Revealed by Newborn Screening*

    PubMed Central

    Spada, Marco; Pagliardini, Severo; Yasuda, Makiko; Tukel, Turgut; Thiagarajan, Geetha; Sakuraba, Hitoshi; Ponzone, Alberto; Desnick, Robert J.

    2006-01-01

    The classic phenotype of Fabry disease, X-linked α-galactosidase A (α-Gal A) deficiency, has an estimated incidence of ∼1 in 50,000 males. The recent recognition of later-onset variants suggested that this treatable lysosomal disease is more frequent. To determine the disease incidence, we undertook newborn screening by assaying the α-Gal A activity in blood spots from 37,104 consecutive Italian male neonates. Enzyme-deficient infants were retested, and “doubly screened-positive” infants and their relatives were diagnostically confirmed by enzyme and mutation analyses. Twelve (0.03%) neonates had deficient α-Gal A activities and specific mutations, including four novel missense mutations (M51I, E66G, A73V, and R118C), three missense mutations (F113L, A143T, and N215S) identified previously in later-onset patients, and one splicing defect (IVS5+1G→T) reported in a patient with the classic phenotype. Molecular modeling and in vitro overexpression of the missense mutations demonstrated structures and residual activities, which were rescued/enhanced by an α-Gal A–specific pharmacologic chaperone, consistent with mutations that cause the later-onset phenotype. Family studies revealed undiagnosed Fabry disease in affected individuals. In this population, the incidence of α-Gal A deficiency was 1 in ∼3,100, with an 11:1 ratio of patients with the later-onset:classic phenotypes. If only known disease-causing mutations were included, the incidence would be 1 in ∼4,600, with a 7:1 ratio of patients with the later-onset:classic phenotypes. These results suggest that the later-onset phenotype of Fabry disease is underdiagnosed among males with cardiac, cerebrovascular, and/or renal disease. Recognition of these patients would permit family screening and earlier therapeutic intervention. However, the higher incidence of the later-onset phenotype in patients raises ethical issues related to when screening should be performed—in the neonatal period or at

  6. Intrafamilial phenotypic variability in four families with Anderson-Fabry disease.

    PubMed

    Rigoldi, M; Concolino, D; Morrone, A; Pieruzzi, F; Ravaglia, R; Furlan, F; Santus, F; Strisciuglio, P; Torti, G; Parini, R

    2014-09-01

    We analysed the clinical history of 16 hemizygous males affected by Anderson-Fabry Disease, from four families, to verify their intrafamilial phenotypic variability. Seven male patients, ranging from 26 to 61 years of age, died, whereas nine (age range 23-55) are alive. Eleven patients have undergone enzyme replacement therapy (ERT) for a period of 5-10 years. We have found a wide range of intrafamilial phenotypic variability in these families, both in terms of target-organs and severity of the disease. Overall, our findings confirm previous data from the literature showing a high degree of intrafamilial phenotypic variability in patients carrying the same mutation. Furthermore, our results underscore the difficulty in giving accurate prognostic information to patients during genetic counselling, both in terms of rate of disease progression and involvement of different organs, when such prognosis is solely based on the patient's family history.

  7. Sometimes when you hear hoof beats, it could be a zebra: consider the diagnosis of Fabry disease

    PubMed Central

    2012-01-01

    Background Fabry disease is an X-linked lysosomal storage disorder that results from a deficiency of the enzyme α-galactosidase A. Fabry disease is present in 4–5% of men with unexplained left ventricular hypertrophy or cryptogenic stroke. As enzyme replacement therapy is now more widely available, it is important to recognise the signs and symptoms of the disease and establish the diagnosis so that early treatment can be started before irreversible organ damage occurs. Case Presentation A previously fit and well 32-year-old Caucasian male presented with multisystem dysfunction including renal impairment. Although he had no suggestive symptoms, a diagnosis of Fabry disease was first established on a native renal biopsy. This was confirmed by enzymatic testing and subsequent genetic analysis that revealed a potentially new pathogenic variant. Conclusions This case highlights the importance both of Fabry disease as a differential diagnosis in patients with renal impairment in the context of multi-system disease and also of adequate tissue sampling for electron microscopy when performing native renal biopsies. PMID:22849389

  8. Gender Differences in the Application of Spanish Criteria for Initiation of Enzyme Replacement Therapy for Fabry Disease in the Fabry Outcome Survey.

    PubMed

    Barba-Romero, Miguel-Ángel; Pintos-Morell, Guillem

    2016-11-24

    Both male/female patients with Fabry disease (FD) may receive enzyme replacement therapy (ERT). Previously published analyses of the Fabry Outcome Survey (FOS; Shire-sponsored) database suggested gender differences in timing of ERT initiation. We assessed alignment of criteria for ERT initiation in the Spanish adult population included in FOS with recommendations of a Spanish national consensus. This retrospective analysis examined baseline clinical data of 88 adults (49 females) enrolled in the FOS database up to August 2014. Thirty-five (39.8%) patients were not receiving ERT: five (12.8%) males and 30 (61.2%) females. Baseline disease severity on the FOS-derived Mainz Severity Score Index was lower in untreated males (median (interquartile range), 0.0 (0.0-1.0)) than treated males (TM; 15.0 (7.5-26.5)), and was similar in untreated and treated females. The percentage of untreated females with at least one criterion for treatment initiation was 76.7% versus 100.0% of treated females (p = 0.0340) and 97.1% (p = 0.0210) of TM. In discordance with Spanish consensus recommendations, a substantial number of females with evidence of FD who might benefit from ERT have not yet initiated treatment. These results suggest unequal gender perceptions with respect to ERT initiation in Spain.

  9. Gender Differences in the Application of Spanish Criteria for Initiation of Enzyme Replacement Therapy for Fabry Disease in the Fabry Outcome Survey

    PubMed Central

    Barba-Romero, Miguel-Ángel; Pintos-Morell, Guillem

    2016-01-01

    Both male/female patients with Fabry disease (FD) may receive enzyme replacement therapy (ERT). Previously published analyses of the Fabry Outcome Survey (FOS; Shire-sponsored) database suggested gender differences in timing of ERT initiation. We assessed alignment of criteria for ERT initiation in the Spanish adult population included in FOS with recommendations of a Spanish national consensus. This retrospective analysis examined baseline clinical data of 88 adults (49 females) enrolled in the FOS database up to August 2014. Thirty-five (39.8%) patients were not receiving ERT: five (12.8%) males and 30 (61.2%) females. Baseline disease severity on the FOS-derived Mainz Severity Score Index was lower in untreated males (median (interquartile range), 0.0 (0.0–1.0)) than treated males (TM; 15.0 (7.5–26.5)), and was similar in untreated and treated females. The percentage of untreated females with at least one criterion for treatment initiation was 76.7% versus 100.0% of treated females (p = 0.0340) and 97.1% (p = 0.0210) of TM. In discordance with Spanish consensus recommendations, a substantial number of females with evidence of FD who might benefit from ERT have not yet initiated treatment. These results suggest unequal gender perceptions with respect to ERT initiation in Spain. PMID:27886142

  10. Skin diseases of the nose.

    PubMed

    Yigider, Ayse Pelin; Kayhan, Fatma Tulin; Yigit, Ozgur; Kavak, Ayse; Cingi, Cemal

    2016-05-01

    The goal of this study was to review the main lesion types of the nasal skin and appropriate treatment strategies rather than to present a comprehensive list of all diseases that affect the skin that can involve the nose. We reviewed the main nasal skin lesion types and available treatment strategies. Nasal skin lesions were classified as benign, premalignant, or malignant. Benign lesions of the nose include nonmalignant tumoral lesions (i.e., freckles, comedo, adenoma sebaceum [Pringle disease], hydrocystoma, fibrous papules, sebaceous hyperplasia, and rhinophyma), autoimmune and inflammatory conditions (i.e., pemphigus, sarcoidosis, systemic lupus erythematosus, facial eosinophilic granuloma, rosacea, herpes zoster infection, leishmaniasis, and leprosy), and vascular lesions (i.e., telangiectasis, hemangioma, and spider nevus). Premalignant lesions are actinic keratosis and keratoacanthoma; and malignant tumors are melanoma, basal cell carcinoma, and squamous cell carcinoma. Regardless of whether or not they are malignant, all facial lesions can yield significant cosmetic discomfort that should be evaluated carefully before commencing any curative or corrective intervention. In general, benign lesions are treated with dermabrasive modalities, such as trichloroacetic acid, phenol, salicylate, and laser ablation. Electrocautery, cryosurgery, and surgical excision are also used, although these methods may result in scar formation, which can sometimes be more problematic than the original lesion itself. Any disease that affects the skin, especially those diseases that are triggered by ultraviolet exposure, can involve the face and nose. Cosmetic defects due both to the lesion itself and the intervention must be discussed with the patient, preferably in the presence of a first-degree relative, before commencement of treatment. As a result of heterogeneity of skin lesions of the nose, appropriate education of general practitioners as well as otorhinolaryngologists is

  11. The skin in Parkinson's disease.

    PubMed

    Flint, A

    1977-09-01

    The characteristic oily skin in individuals with parkinsonism has long been observed by clinicians. The oiliness seems to be associated with periods when the disease is most active. This seborrhea has been observed particularly in post-encephalitic parkinsonism, as well as in idiopathic paralysis agitans. It also occurs in phenothiazine-induced parkinsonism.

  12. Cystatin C and NT-proBNP as prognostic biomarkers in Fabry disease.

    PubMed

    Torralba-Cabeza, Miguel-Ángel; Olivera, Susana; Hughes, Derralynn A; Pastores, Gregory M; Mateo, Ramón Nuviala; Pérez-Calvo, Juan-Ignacio

    2011-11-01

    Fabry disease (FD) is a lysosomal storage disorder caused by mutations in the α-galactosidase A gene. It is characterized by the deposition of the incompletely metabolized substrate globotriaosylceramide in several cell types and multisystem involvement. Major morbidity results from renal, cardiac and cerebrovascular pathology, mediated by endothelial dysfunction. We examined the potential utility of Cystatin C and natriuretic peptides as biomarkers in FD, and evaluated serum levels in 89 FD patients with varying degrees of disease severity. The results revealed that as a prognostic marker, Cystatin C is a good and cost effective indicator of early renal dysfunction and/or heart failure in FD. It is also more useful than serum creatinine in detecting mild renal damage and small decreases in glomerular filtration. In addition, the natriuretic peptide NT-proBNP, was elevated in patients with FD and cardiac involvement, and found to be an adequate detection marker, not only of cardiac involvement, but also of diastolic dysfunction.

  13. Severe hypertrophic cardiomyopathy in a patient with atypical Anderson-Fabry disease.

    PubMed

    Masarone, Daniele; Duro, Giovanni; Dellegrottaglie, Santo; Colomba, Paolo; Rubino, Marta; Cirillo, Annapaola; Pisani, Antonio; Caiazza, Martina; Elliott, Perry Mark; Calabrò, Paolo; Pacileo, Giuseppe; Limongelli, Giuseppe

    2017-09-22

    Anderson-Fabry disease (AFD) is a hereditary disorder caused by a deficiency in the lysosomal enzyme α-galactosidase A which causes dysfunctions in multiple organ systems. Cardiac manifestation includes left ventricular hypertrophy, thickening of the valves, conduction disturbances and in the late phase, extensive areas of myocardial fibrosis with increased risk of sudden cardiac death. Case example: A case of AFD with exclusive cardiac involvement is described. During follow-up, due to the high risk of life-threatening arrhythmic events, implantation of an implantable cardioverter defibrillator is performed. AFD patients with advanced cardiac disease might represent a subgroup of patients who may require an implantable cardioverter defibrillator for primary prevention of sudden cardiac death.

  14. 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

  15. Psychoneuroimmunologic aspects of skin diseases.

    PubMed

    Lugović-Mihić, Liborija; Ljubesić, Luka; Mihić, Josip; Vuković-Cvetković, Vlasta; Troskot, Nina; Situm, Mirna

    2013-09-01

    As mental and psychological issues are important in the development of many dermatologic diseases, these factors are of special interest in research. Psychoneuroimmunology is the study of interaction between psychological processes and the nervous and immune systems of the human body, and it was comprehensively described for the first time about 30 years ago. Communication between the mind and the skin involves the psycho-immuno-endocrine-cutaneous system, encompassing the activities of the brain, the immune system and the skin, with participation of different neuropeptides, interleukins, and immune system messengers. Many common dermatologic diseases have some form of psychomediated pathogenesis that partially accounts for the development of skin lesions. There is a link between emotional stressors (acute or chronic), psychiatric diseases, and dermatoses (e.g., psoriasis, atopic dermatitis, urticaria, viral warts, herpes simplex, vitiligo, acnes, alopecia, prurigo, etc.) and different cytokines and mediators produced in the skin and involved in their pathogenesis. A prominent role is played by those agents that belong to the hypothalamic-pituitary-adrenal axis.

  16. The Role of the Skin Barrier in Occupational Skin Diseases.

    PubMed

    Kasemsarn, Pranee; Bosco, Joanna; Nixon, Rosemary L

    2016-01-01

    Occupational skin diseases (OSDs) are the second most common occupational diseases worldwide. Occupational contact dermatitis (OCD) is the most frequent OSD, and comprises irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), contact urticaria and protein contact dermatitis. There are many endogenous and exogenous factors which affect the development of OCD, including age, sex, ethnicity, atopic skin diathesis, certain occupations and environmental factors. One of the most important contributing causes is skin barrier dysfunction. The skin provides a first-line defense from environmental assaults and incorporates physical, chemical and biological protection. Skin barrier disturbance plays a crucial role in various skin diseases such as atopic dermatitis (AD), ichthyosis, ICD and ACD. Genetic factors, such as filaggrin gene (FLG) mutations, and external factors, such as skin irritants interfering with stratum corneum structure and composition, may lead to abnormalities in skin barrier function and increased vulnerability to skin diseases. FLG encodes the cornified envelope protein, filaggrin, which is involved in skin barrier function. FLG mutation is associated with the development of OCD. High-risk occupations for OCD include health care workers, hairdressers and construction workers. There are often multiple contributing causes to OCD, as workers are exposed to both irritants and allergens. AD is also associated with skin barrier disruption and plays an important role in OCD. ICD often precedes and facilitates the development of ACD, with impairment of the skin barrier contributing to the concurrence of ICD and ACD in many workers with OCD.

  17. 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

    2017-07-19

    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.

  18. 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

  19. One Year of Enzyme Replacement Therapy Reduces Globotriaosylceramide Inclusions in Podocytes in Male Adult Patients with Fabry Disease.

    PubMed

    Najafian, Behzad; Tøndel, Camilla; Svarstad, Einar; Sokolovkiy, Alexey; Smith, Kelly; Mauer, Michael

    2016-01-01

    Fabry nephropathy is associated with progressive accumulation of globotriaosylceramide (GL3) in podocytes. Reducing this GL3 burden may reduce podocyte injury. Sensitive methods to quantify podocyte GL3 content may determine whether a given strategy can benefit podocytes in Fabry disease. We developed an unbiased electron microscopic stereological method to estimate the average volume of podocytes and their GL3 inclusions in 6 paired pre- and post-enzyme replacement therapy (ERT) biopsies from 5 men with Fabry disease. Podocyte GL3 content was regularly reduced (average 73%) after 11-12 months of ERT. This was not detectable using a semi-quantitative approach. Parallel to GL3 reduction, podocytes became remarkably smaller (average 63%). These reductions in podocyte GL3 content or size were not significantly correlated with changes in foot process width (FPW). However, FPW after ERT was significantly correlated with the magnitude of the decrease in podocyte GL3 content from baseline to 11-12 months of ERT. Also podocytes exocytosed GL3 inclusions, a phenomenon correlated with their reduction in their GL3 content. Demonstrable after11-12 months, reduction in podocyte GL3 content allows for early assessment of treatment efficacy and shorter clinical trials in Fabry disease.

  20. Enzyme replacement therapy in two Japanese siblings with Fabry disease, and its effectiveness on angiokeratoma and neuropathic pain.

    PubMed

    Furujo, Mahoko; Kubo, Toshihide; Kobayashi, Masahisa; Ohashi, Toya

    2013-11-01

    Enzyme replacement therapy (ERT) for Fabry disease does not show a clear benefit in angiokeratoma. We describe two Japanese siblings with Fabry disease, who were diagnosed when angiokeratomas were found on the older sibling at the age of 13 years. Neither of the boys complained of pain, while both suffered from hypohidrosis. We evaluated the safety and efficacy of ERT with recombinant human agalsidase alfa (Replagal®, Dainippon-Sumitomo Pharma. Co., Osaka, Japan) in these siblings over a 5-year period. In both siblings, sweating was observed 3 months after the initiation of ERT, which motivated them to adhere to ERT. Pain sensation was regained after 12 to 36 months of ERT, followed by a decrease after 48 to 60 months. Angiokeratomas on the lateral side of the knee of the older sibling partially disappeared after 48 months of ERT. Although the height of both siblings at baseline was lower than the corresponding average age-related heights in the normal Japanese population, during ERT they were within, or close to, the average +1 standard deviation in the non-Fabry population. Their growth rate seemed to indicate catch-up growth. Other clinical symptoms were maintained at baseline levels. Immunoglobulin G anti-agalsidase alfa antibodies were not detected in both sibling during ERT, and no infusion-associated reaction was observed. The treatment was generally well tolerated. ERT was a safe and effective treatment for angiokeratoma and neuropathic pain for these two siblings with Fabry disease.

  1. One Year of Enzyme Replacement Therapy Reduces Globotriaosylceramide Inclusions in Podocytes in Male Adult Patients with Fabry Disease

    PubMed Central

    Najafian, Behzad; Tøndel, Camilla; Svarstad, Einar; Sokolovkiy, Alexey; Smith, Kelly; Mauer, Michael

    2016-01-01

    Fabry nephropathy is associated with progressive accumulation of globotriaosylceramide (GL3) in podocytes. Reducing this GL3 burden may reduce podocyte injury. Sensitive methods to quantify podocyte GL3 content may determine whether a given strategy can benefit podocytes in Fabry disease. We developed an unbiased electron microscopic stereological method to estimate the average volume of podocytes and their GL3 inclusions in 6 paired pre- and post-enzyme replacement therapy (ERT) biopsies from 5 men with Fabry disease. Podocyte GL3 content was regularly reduced (average 73%) after 11–12 months of ERT. This was not detectable using a semi-quantitative approach. Parallel to GL3 reduction, podocytes became remarkably smaller (average 63%). These reductions in podocyte GL3 content or size were not significantly correlated with changes in foot process width (FPW). However, FPW after ERT was significantly correlated with the magnitude of the decrease in podocyte GL3 content from baseline to 11–12 months of ERT. Also podocytes exocytosed GL3 inclusions, a phenomenon correlated with their reduction in their GL3 content. Demonstrable after11–12 months, reduction in podocyte GL3 content allows for early assessment of treatment efficacy and shorter clinical trials in Fabry disease. PMID:27081853

  2. Uric Acid as a Marker of Mortality and Morbidity in Fabry Disease

    PubMed Central

    Rob, Daniel; Marek, Josef; Dostálová, Gabriela; Goláň, Lubor; Linhart, Aleš

    2016-01-01

    Background Serum uric acid (UA) elevation is common in patients with cardiovascular, renal and metabolic diseases. However, no study to date has analysed the role of UA in Fabry disease (FD). Objectives To evaluate the association between serum UA levels and mortality and morbidity in FD. Materials and Methods We conducted a post-hoc analysis of a prospectively followed-up cohort of 124 patients with genetically proven FD. Serum UA levels were acquired at baseline; clinical events and mortality were assessed during regular visits every 6 to 12 months. The primary endpoint was a composite of multiple secondary outcomes: all-cause mortality, adverse cardiovascular events, progression of renal dysfunction and stroke or transient ischaemic attack (TIA). Predictive value was assessed using the Cox proportional hazards model and the Kaplan Meyer estimator. Results During follow-up of 7.4 ± 3.7 years, 64 (52%) patients reached the primary combined endpoint. Overall, UA levels were significantly associated with combined outcome (p < 0.001) and remained independently associated after correcting for age, sex and estimated glomerular filtration rate (hazard ratio [HR] per 20 μmol/l increase 1.09, 95% confidence interval [95%CI] (1.00–1.19), p = 0.04). UA was associated with overall mortality in univariate analysis (p = 0.021); however, the association did not reach statistical significance after multivariate correction (HR per 20 μmol/l increase 1.07 95%CI 0.93–1.25, p = 0.32). Higher UA levels were also associated with cardiac adverse outcomes, progression of left ventricular hypertrophy and progression of renal dysfunction (ps < 0.001). No association was observed between UA levels and stroke or TIA (p = 0.323). Conclusion and Implications Increased serum UA levels may represent an independent risk factor for adverse clinical outcomes in Fabry patients and are associated with all-cause mortality. UA is a widely available and cheap biomarker that may improve risk

  3. [Skin changes in rheumatic diseases].

    PubMed

    Dobrić, Ivan

    2005-01-01

    The Intruduction includes those eflorescences that might be useful for diagnostics in rheumatology. Further in the text we have described four groups of rheumatic disorders. The first group: rheumatic diseases (lupus erythematosus, dermatomyositis, systemic scleroderma, the mixed connective tissue disease, allergic vasculitis, polyarteritis) which are the most common from the dermatological point of view. The second group: rheumatic diseases (Wegener's granulomatosis, rheumatoid arthritis, Sjögren, Reiter and Behçet syndrome and Kawasaki's disease) which are rarely of interest to our dermatologists. In this group there is also psoriatic arthritis, which is not rare in dermatology but its diagnostics and treatment belong to rheumatologists' field of expertise. The third group: infections (rheumatic fever, diseminated gonococcal infection, subacute bacterial endocarditis, Lyme disesease). The fourth group: metabolic disorders (gout). The diseases of the first group are described completely. In the second, third and fourth group of the diseases we have included only skin changes.

  4. Cardiac Anderson-Fabry disease: lessons from a 25-year-follow up.

    PubMed

    Brito, Dulce; Miltenberger-Miltenyi, Gabriel; Moldovan, Oana; Navarro, Carmen; Madeira, Hugo Costa

    2014-04-01

    Sarcomeric hypertrophic cardiomyopathy (HCM) is the most common genetic cause of unexplained left ventricular hypertrophy and has no specific treatment. Anderson-Fabry disease (AFD) is rare and usually multisystemic, but occasionally expresses clinically as a predominantly cardiac phenotype mimicking HCM. We describe an illustrative case of a patient followed regularly for 25 years with a diagnosis of familial HCM and no identified sarcomeric mutations. Next-generation sequencing analysis identified a novel pathogenic mutation in the GLA gene, leading to a diagnosis of previously unknown multisystemic AFD, with consequent implications for the patient's treatment and prognosis and familial screening. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  5. 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.

  6. Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene.

    PubMed

    Ferri, L; Guido, C; la Marca, G; Malvagia, S; Cavicchi, C; Fiumara, A; Barone, R; Parini, R; Antuzzi, D; Feliciani, C; Zampetti, A; Manna, R; Giglio, S; Della Valle, C M; Wu, X; Valenzano, K J; Benjamin, R; Donati, M A; Guerrini, R; Genuardi, M; Morrone, A

    2012-03-01

    Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. Fabry disease (FD) is an X-linked lysosomal storage disorder with a heterogeneous spectrum of clinical manifestations that are caused by the deficiency of α-galactosidase A (α-Gal-A) activity. Although useful for diagnosis in males, enzyme activity is not a reliable biochemical marker in heterozygous females due to random X-chromosome inactivation, thus rendering DNA sequencing of the α-Gal-A gene, alpha-galactosidase gene (GLA), the most reliable test for the confirmation of diagnosis in females. The spectrum of GLA mutations is highly heterogeneous. Many polymorphic GLA variants have been described, but it is unclear if haplotypes formed by combinations of such variants correlate with FD, thus complicating molecular diagnosis in females with normal α-Gal-A activity. We tested 67 female probands with clinical manifestations that may be associated with FD and 110 control males with normal α-Gal-A activity. Five different combinations of GLA polymorphic variants were identified in 14 of the 67 females, whereas clearcut pathogenetic alterations, p.Met51Ile and p.Met290Leu, were identified in two cases. The latter has not been reported so far, and both mutant forms were found to be responsive to the pharmacological chaperone deoxygalactonojirimycin (DGJ; migalastat hydrochloride). Analysis of the male control population, as well as male relatives of a suspected FD female proband, permitted the identification of seven different GLA gene haplotypes in strong linkage disequilibrium. The identification of haplotypes in control males provides evidence against their involvement in the development of FD phenotypic manifestations.

  7. Gene Therapy for Skin Diseases

    PubMed Central

    Gorell, Emily; Nguyen, Ngon; Lane, Alfred; Siprashvili, Zurab

    2014-01-01

    The skin possesses qualities that make it desirable for gene therapy, and studies have focused on gene therapy for multiple cutaneous diseases. Gene therapy uses a vector to introduce genetic material into cells to alter gene expression, negating a pathological process. This can be accomplished with a variety of viral vectors or nonviral administrations. Although results are promising, there are several potential pitfalls that must be addressed to improve the safety profile to make gene therapy widely available clinically. PMID:24692191

  8. α-Galactosidase A Genotype N215S Induces a Specific Cardiac Variant of Fabry Disease.

    PubMed

    Oder, Daniel; Liu, Dan; Hu, Kai; Üçeyler, Nurcan; Salinger, Tim; Müntze, Jonas; Lorenz, Kristina; Kandolf, Reinhard; Gröne, Hermann-Josef; Sommer, Claudia; Ertl, Georg; Wanner, Christoph; Nordbeck, Peter

    2017-10-01

    Hypertrophic cardiomyopathy is the most common type of cardiomyopathy, but many patients lack sarcomeric/myofilament mutations. We studied whether cardio-specific α-galactosidase A gene variants are misinterpreted as hypertrophic cardiomyopathy because of the lack of extracardiac organ involvement. All subjects who tested positive for the N215S genotype (n=26, 13 females, mean age 49±17 [range, 14-74] years) were characterized in this prospective monocentric longitudinal cohort study to determine genotype-specific clinical characteristics of the N215S (c.644A>G [p.Asn215Ser]) α-galactosidase A gene variant. All subjects were initially referred with suspicion of genetically determined hypertrophic cardiomyopathy. Cardiac hypertrophy (interventricular septum, 12±4 [7-23] mm; left ventricular posterior wall, 11±4 [7-21] mm; left ventricular mass, 86±41 [46-195] g/m(2)) was progressive, systolic function mainly preserved (cardiac index 2.8±0.6 [1.9-3.9] L/min per m(2)), and diastolic function mildly abnormal. Cardiac magnetic resonance imaging revealed replacement fibrosis in loco typico (18/26, 69%), particularly in subjects >50 years. Elderly subjects had advanced heart failure, and 6 (23%) were suggested for implantable cardioverter-defibrillator therapy. Leukocyte α-galactosidase A enzyme activity was mildly reduced in 19 subjects and lyso-globotriaosylceramide slightly elevated (median, 4.9; interquartile range, 1.3-9.1 ng/mL). Neurological and renal impairments (serum creatinine, 0.87±0.20; median, 0.80; interquartile range, 0.70-1.01 mg/dL; glomerular filtration rate, 102±23; median, 106; interquartile range, 84-113 mL/min) were discreet. Only 2 subjects developed clinically relevant proteinuria. α-Galactosidase A genotype N215S does not lead to the development of a classical Fabry phenotype but induces a specific cardiac variant of Fabry disease mimicking nonobstructive hypertrophic cardiomyopathy. The lack of prominent noncardiac impairment leads to

  9. Hippocampal atrophy as a surrogate of neuronal involvement in Fabry disease.

    PubMed

    Fellgiebel, Andreas; Wolf, Dominik O; Kolodny, Edwin; Müller, Matthias J

    2012-03-01

    Cerebral micro- and macro-vasculopathy have been described in Fabry disease (FD). Neuronal globotriaosylceramide accumulation in selective cortical and brain stem areas including the hippocampus has been reported by autopsy studies in FD, but clinical surrogates as well as the clinical relevance of these findings have not been investigated so far. We measured the hippocampus volumes in a group of clinically affected patients with FD and correlated the findings with the cognitive performance of the patients. Hippocampal volumes were determined manually on T1-weighted MR-images of 25 FD patients (age 36.5 ± 11.0 years) and 20 age-matched controls. Additionally, individual white matter (WM) and gray matter (GM) volumes were measured using brain segmentation analyses. After controlling for age, white matter lesion (WML) volume, and WM/GM-volumes hippocampal volumes were significantly decreased in FD. These findings were substantially more pronounced in a subgroup of men with FD. WM and WM/GM volumes, and memory function did not significantly differ between patients and controls. In patients with FD hippocampal volumes were neither significantly correlated to WML volume nor to WM or WM/GM volumes. Hippocampus atrophy was not driven by the WML or other brain tissue atrophy and seems to correlate with the neuronal involvement in FD. In this young to middle-aged Fabry cohort the hippocampus degeneration was functionally compensated without memory impairment. Longitudinal studies are needed to determine whether this degenerative component in FD will progress and, in concert with the individual WML-load, predict subsequent cognitive decline.

  10. Impaired Left Atrial Function in Fabry Disease: A Longitudinal Speckle-Tracking Echocardiography Study.

    PubMed

    Pichette, Maxime; Serri, Karim; Pagé, Maude; Di, Lu Zhao; Bichet, Daniel G; Poulin, Frédéric

    2017-02-01

    Fabry disease (FD) is characterized by the accumulation of sphingolipids in multiple organs, including the left atrium. It is uncertain if the left atrial (LA) reservoir, conduit, and contractile functions evaluated by speckle-tracking echocardiography are affected in Fabry cardiomyopathy and whether enzyme replacement therapy can improve LA function. In this retrospective cohort study, LA strain, strain rates, and phasic LA volumes were studied in 50 patients with FD and compared with values in 50 healthy control subjects. All three LA phasic functions were altered. Peak positive strain (reservoir function) was 38.9 ± 14.9% versus 46.5 ± 10.9% (P = .004), and late diastolic strain (contractile function) was 12.6 ± 5.9% versus 15.6 ± 5.3% (P = .010). In 15 patients who started enzyme replacement therapy during the study, most of the LA parameters improved at 1-year follow-up (peak positive strain from 32.0 ± 13.5% to 38.0 ± 13.5%, P = .006), whereas there was a trend toward deterioration in 15 patients who never received treatment (peak positive strain from 47.3 ± 10.8% to 41.3 ± 9.3%, P = .058). Nine patients with FD (21%) experienced new-onset atrial fibrillation or stroke during 4-year follow-up. By univariate analysis, peak positive strain and early diastolic strain demonstrated significant associations with clinical events, surpassing conventional echocardiographic parameters and clinical characteristics. LA reservoir, conduit, and contractile functions by speckle-tracking echocardiography were all affected in FD. Enzyme replacement therapy improved LA function. LA strain parameters were associated with atrial fibrillation and stroke. Copyright © 2016 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

  11. Novel α-Galactosidase A Mutation (K391E) in a Young Woman With Severe Cardiac and Renal Manifestations of Fabry Disease.

    PubMed

    Wakakuri, Hiroaki; Nakamura, Shunichi; Utsumi, Kouichi; Shimizu, Wataru; Yasutake, Masahiro

    2016-09-28

    Fabry disease, an X-linked lysosomal storage disorder due to α-galactosidase A deficiency, is associated with dysfunction of various cell types and results in a systemic vasculopathy. We describe a 29-year-old woman with Fabry disease presenting with severe cardiac and renal manifestations. Gene analysis demonstrated a novel mutation (K391E) in the GLA gene. Enzyme replacement therapy (ERT) was started with agalsidase-β after confirming the diagnosis of Fabry disease, resulting in normalization of LV systolic function and improvement of renal function. As early therapy is crucial for preventing life-threatening sequelae, clinicians should consider Fabry disease in young patients presenting with cardiac and renal disease without any likely causes.

  12. 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

  13. Mild Left Ventricular Hypertrophy Unravels a Novel Nonsense Mutation of the GLA Gene Associated with the Classical Phenotype of Fabry Disease.

    PubMed

    Azevedo, Olga; Gago, Miguel; Miltenberger-Miltenyi, Gabriel; Gaspar, Paulo; Sousa, Nuno; Cunha, Damião

    2017-02-03

    We report on the clinical, biochemical, and genetic findings of a large family with the classical phenotype of Fabry disease due to the novel nonsense mutation c.607G>T (p.E203X) of the GLA gene, which occurs in the active site of the α-galactosidase A enzyme. This report highlights that (i) Fabry disease diagnosis should be considered in all cases of unexplained left ventricular hypertrophy (LVH), even in its milder forms; (ii) a complete evaluation of patients with unexplained LVH is important to find diagnostic red flags of treatable causes of LVH, such as Fabry disease; (iii) cascade family screening is paramount to the earlier diagnosis and treatment of other affected family members; and (iv) the Fabry disease phenotype is highly variable in heterozygote females, even within the same family.

  14. [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.

  15. [Globosides as key players in the pathophysiology of Shiga toxin-associated acute kidney failure and Fabry disease].

    PubMed

    Porubsky, S

    2014-11-01

    Globosides and their isomeric counterparts isoglobosides belong to the class of neutral glycosphingolipids with an as yet undefined physiological function. In the pathogenesis of human diseases, globosides play an important role as cellular receptors for Shiga toxins which are produced by certain strains of S. dysenteriae and E. coli. In order to elucidate the pathogenesis of Shiga toxin-associated kidney failure, we studied human kidney biopsies and animal models. Our work showed that in patients suffering from Shiga toxin-elicited kidney failure, no complement activation could be demonstrated by immunohistochemical analysis of kidney biopsies. Therefore, complement activation is unlikely to play a major role in mediating thrombotic microangiopathy on exposure to Shiga toxin. Moreover, analysis of the human biopsies and of a murine model of Shiga toxin-associated disease pinpointed acute tubular damage as an important and previously neglected contributor to acute kidney failure in patients infected with Shiga toxin-producing E. coli. Furthermore, globosides play a decisive role in the pathogenesis of Fabry disease which results from a decreased or absent activity of the lysosomal enzyme α-galactosidase A. The results on transgenic mice showed that in vital organs, such as the heart, kidneys and liver, it was possible to revert the phenotype of Fabry disease by eliminating the synthesis of globosides. This implicates that substrate reduction therapy through inhibition of globosides might represent a new therapeutic option for Fabry disease, all the more so as globosides seem to be dispensable.

  16. Inter-familial and intra-familial phenotypic variability in three Sicilian families with Anderson-Fabry disease.

    PubMed

    Tuttolomondo, Antonino; Simonetta, Irene; Duro, Giovanni; Pecoraro, Rosaria; Miceli, Salvatore; Colomba, Paolo; Zizzo, Carmela; Nucera, Antonia; Daidone, Mario; Di Chiara, Tiziana; Scaglione, Rosario; Della Corte, Vittoriano; Corpora, Francesca; Vogiatzis, Danai; Pinto, Antonio

    2017-09-22

    Anderson-Fabry disease (AFD) is an inborn lysosomal enzymopathy resulting from the deficient or absent activity of the lysosomal exogalactohydrolase, α-galactosidase A. This deficiency, results in the altered metabolism of glycosphingolipids which leads to their accumulation in lysosomes, thus to cellular and vascular dysfunction. To date, numerous mutations (according to recent data more than 1000 mutations) have been reported in the GLA intronic and exonic mutations. Traditionally, clinical manifestations are more severe in affected hemizygous males than in females. Nevertheless, recent studies have described severe organ dysfunction in women. This study reports clinical, biochemical, and molecular findings of the members of three Sicilian families. The clinical history of these patients highlights a remarkable interfamilial and intrafamilial phenotypic variability which characterizes Fabry disease relative to target organs and severity of clinical manifestations. Our findings, in agreement with previous data, report a little genotype-phenotype correlation for the disease, suggesting that the wide phenotypic variability of Anderson-Fabry disease is not completely ascribable to different gene mutations but other factors and mechanisms seem to be involved in the pathogenesis and clinical expression of the disease. Moreover, this study emphasies the importance of pedigree analysis in the family of each proband for identifying other possibly affected relatives.

  17. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males

    PubMed Central

    MacDermot, K; Holmes, A; Miners, A

    2001-01-01

    OBJECTIVES—To determine the natural history of Anderson-Fabry disease (AFD) as a baseline for efficacy assessment of potentially therapeutic drugs.
DESIGN—The first large cross sectional study of a patient cohort from the AFD clinical and genetic register (UK), maintained for the last 15 years.
MEASURES—Prevalence, mortality, frequency of AFD manifestations, and impact of disease on patient lives, assessed from the AFD register and the disease specific questionnaire.
RESULTS—The median cumulative survival was 50 years (n=51), which represents an approximately 20 year reduction of life span. Neuropathic pain was present in 77% (n=93) with mean pain score of 5 (scale 0-10) despite treatment with anticonvulsants and opiates. Pain stopped in only 11%. Cerebrovascular complications developed in 24.2% and renal failure in 30%. The onset and progression of serious AFD manifestations was highly variable. The relationship of gastrointestinal manifestations on weight, using body mass index (BMI), was significant (p=0.01). High frequency sensorineural deafness was confirmed in 78% of audiograms. Neuropathic pain and angiokeratoma were absent in five adult males (~5%). Median age at diagnosis of AFD was 21.9 years (n=64).
IMPACT OF DISEASE—Attendance at school, sports, and social activity were significantly affected by AFD. Only 56.6% (n=46) of patients were employed. Psychosexual effects of genital angiokeratoma, genital pain, and impotence were not previously recognised.
CONCLUSION—The majority of males experience multiple disease manifestations and the duration of neuropathic pain was lifelong. The AFD register proved useful for the determination of baseline disease parameters in this cohort.


Keywords: Anderson-Fabry disease; natural history; mortality; prevalence PMID:11694547

  18. 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

  19. Dermatitis Herpetiformis: Skin Manifestation of Celiac Disease

    MedlinePlus

    ... a chronic, intensely itchy, blistering skin manifestation of gluten-sensitive enteropathy, commonly known as celiac disease. DH ... external manifestation of an abnormal immune response to gluten, in which IgA antibodies form against the skin ...

  20. Fabry lens.

    NASA Technical Reports Server (NTRS)

    Michlovic, J.

    1972-01-01

    Discussion of the properties, operation, and applications of the Fabry lens. As used in stellar photometry, a Fabry lens is nothing more than a simple converging lens inserted into the optical train of a photometer to construct an image of the objective on the photomultiplier cathode. The thereby derived advantages are reviewed, and some techniques designed to maximize these advantages are outlined.

  1. α-Galactosidase delivery using 30Kc19-human serum albumin nanoparticles for effective treatment of Fabry disease.

    PubMed

    Lee, Hong Jai; Park, Hee Ho; Sohn, Youngsoo; Ryu, Jina; Park, Ju Hyun; Rhee, Won Jong; Park, Tai Hyun

    2016-12-01

    Fabry disease is a genetic lysosomal storage disease caused by deficiency of α-galactosidase, the enzyme-degrading neutral glycosphingolipid that is transported to lysosome. Glycosphingolipid accumulation by this disease causes multi-organ dysfunction and premature death of the patient. Currently, enzyme replacement therapy (ERT) using recombinant α-galactosidase is the only treatment available for Fabry disease. To maximize the efficacy of treatment, enhancement of cellular delivery and enzyme stability is a challenge in ERT using α-galactosidase. In this study, protein nanoparticles using human serum albumin (HSA) and 30Kc19 protein, originating from silkworm, were used to enhance the delivery and intracellular α-galactosidase stability. 30Kc19-HSA nanoparticles loaded with the α-galactosidase were formed by desolvation method. 30Kc19-HSA nanoparticles had a uniform spherical shape and were well dispersed in cell culture media. 30Kc19-HSA nanoparticles had negligible toxicity to human cells. The nanoparticles exhibited enhanced cellular uptake and intracellular stability of delivered α-galactosidase in human foreskin fibroblast. Additionally, they showed enhanced globotriaosylceramide degradation in Fabry patients' fibroblasts. It is expected that 30Kc19-HSA protein nanoparticles could be used as an effective tool for efficient delivery and enhanced stability of drugs.

  2. Gluten intolerance and skin diseases.

    PubMed

    Humbert, Philippe; Pelletier, Fabien; Dreno, Brigitte; Puzenat, Eve; Aubin, François

    2006-01-01

    Gluten sensitivity with or without coeliac disease (CD) symptoms and intestinal pathology has been suggested as a potentially treatable cause of various diseases. CD is a chronic disease which improves on withdrawal of wheat gliadins and barley, rye and oat prolamins from the diet. There have been numerous reports linking CD with several skin conditions. A body of evidence shows that dermatitis herpetiformis is actually a cutaneous manifestation of CD. Autoimmune diseases, allergic diseases, psoriasis and miscellaneous diseases have also been described with gluten intolerance. Dermatologists should be familiar with the appraisal of gluten sensitive enteropathy and should be able to search for an underlying gluten intolerance (GI). Serological screening by means of antigliadin, antiendomysial and transglutaminase antibodies should be performed. HLA typing is often useful in association with serologic tests. Intestinal biopsy is usually needed to establish the diagnosis of CD or GI. Thus, gluten intolerance gives rise to a variety of dermatological manifestations which may benefit from a gluten-free diet.

  3. A novel 6 bp insertion in exon 7 associated with an unusual phenotype in a family with Fabry disease.

    PubMed

    Kroepfl, Th; Paul, K; Kotanko, P; Plecko, B; Paschke, E

    2002-12-01

    A male patient presented with oligosymptomatic Fabry disease (end stage renal failure and non-obstructive cardiomyopathy) at around 30 years of age. His leukocyte alpha-galactosidase activity (alpha-gal) was 2.6% of controls. A 50-year-old sister had similar cardiac symptoms and her asymptomatic heterozygous daughter (33 years) had normal enzyme activity. All three patients carried a novel, 6bp insertion on exon 7 of the AGAL gene. The majority of male Fabry patients carrying mutations in exon 7 have residual alpha-gal below 1% and suffer from neuropathic pain. Comparable oligosymptomatic phenotypes in Caucasian patients carry a common mutation on exon 6 (R301Q) and have a significantly later onset. The course of the disease is likely to be altered by recombinant enzyme therapy in the future. Therefore, a thorough documentation of phenotypes, residual activities and underlying genotypes is of current interest.

  4. Diseases of the Earth's skin

    NASA Astrophysics Data System (ADS)

    The German Government's Scientific Advisory Council on Global Climate Change recently diagnosed a score of ailments of the “Earth's skin,” according to the German Research Service. Like numerous viral and bacterial diseases, many of the earthidermal diseases are named for the regions where scientists first discovered them. For some symptoms, the German Council has also recommended therapeutic treatments, such as terracing of slopes near rivers. It remains to be seen whether universities worldwide will start cranking out specialists in Earth dermatology. But judging by the condition of many regions of the world, it appears this field may offer great growth potential for the Earth sciences, which is welcome news in the current tight job market.

  5. 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.

  6. Late-onset Fabry disease associated with angiokeratoma of Fordyce and multiple cherry angiomas.

    PubMed

    Hogarth, V; Dhoat, S; Mehta, A B; Orteu, C H

    2011-07-01

    Fabry disease (FD) is a lysosomal storage disorder. The prevalence and clinical spectrum is higher than previously thought. The average time between onset of symptoms and diagnosis is 10 years. Early identification of patients is essential to institute enzyme therapy and reduce morbidity. We report the case of a 76-year-old man, who presented with loss of consciousness following exertional chest pain. He was found to have tortuous corneal vessels, > 100 cherry angiomas on his trunk, and angiokeratomas on his scrotum. The latter were indistinguishable from angiokeratoma of Fordyce, a diagnosis reported in 15% of men over the age of 50 years, and generally ignored by them. The patient's α-galactosidase levels were low, and a mutation in exon 5 of the GLA gene was identified on DNA analysis, confirming the diagnosis of FD. This case highlights the importance of considering a diagnosis of FD in all male patients with angiokeratoma. It also raises the question of whether the presence of multiple cherry angiomas in patients with cardiac disease should raise the possible diagnosis of FD.

  7. Agalsidase alfa (Replagal) in the treatment of Anderson-Fabry disease.

    PubMed

    Pastores, Gregory M

    2007-09-01

    Anderson-Fabry disease (AFD) is an X-linked storage disorder caused by a deficiency of the lysosomal hydrolase a-galactosidase A (AGAL) and the resultant accumulation of its glycosphingolipid substrate (Gb3) in several tissue types. Major morbidity and reduced life expectancy among affected individuals are a consequence of renal, cardiac and cerebrovascular involvement. Symptomatic males and females with AFD have been described, although the onset of clinical manifestations may be delayed and more variable among the latter patient group, partly attributed to lyonization. Agalsidase alfa (Replagal()) is a recombinant formulation of human AGAL which has been demonstrated to modify the course of AFD in treated patients. Factors that may influence clinical outcomes include disease stage at the point of treatment initiation and antibody formation. There is incomplete understanding of AFD pathophysiology. Early diagnosis and timely intervention may be essential. The use of adjunctive therapies, directed at risk reduction (eg, aspirin for stroke prophylaxis), require careful scrutiny, but such agents are likely to be vital components of a comprehensive approach to patient care. Long-term studies may clarify the optimal dose and frequency of enzyme administration. Meanwhile, budding strategies such as chaperone-mediated enzyme enhancement may offer the potential for an alternative or multimodality approach to the management of AFD.

  8. Morgellons Disease: Managing a Mysterious Skin Condition

    MedlinePlus

    Morgellons disease: Managing a mysterious skin condition Morgellons disease is mysterious and controversial. Here you'll find answers to common questions about Morgellons disease — and suggestions for coping with it. By ...

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

    PubMed

    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

  10. 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

  11. Interconversion of the Specificities of Human Lysosomal Enzymes Associated with Fabry and Schindler Diseases

    SciTech Connect

    Tomasic, Ivan B.; Metcalf, Matthew C.; Guce, Abigail I.; Clark, Nathaniel E.; Garman, Scott C.

    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 the 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.

  12. Increased oxidative stress contributes to cardiomyocyte dysfunction and death in patients with Fabry disease cardiomyopathy.

    PubMed

    Chimenti, Cristina; Scopelliti, Fernanda; Vulpis, Elisabetta; Tafani, Marco; Villanova, Lidia; Verardo, Romina; De Paulis, Ruggero; Russo, Matteo A; Frustaci, Andrea

    2015-11-01

    Cardiac dysfunction of Fabry disease (FD) has been associated with myofilament damage and cell death as result of α-galactosidase A deficiency and globotriaosylceramide accumulation. We sought to evaluate the role of oxidative stress in FD cardiomyocyte dysfunction. Myocardial tissue from 18 patients with FD was investigated for the expression of inducible nitric oxide synthase (iNOS) and nitrotyrosine by immunohistochemistry. Western blot analysis for nitrotyrosine was also performed. Oxidative damage to DNA was investigated by immunostaining for 8-hydroxydeoxyguanosine (8-OHdG), whereas apoptosis was evaluated by in situ ligation with hairpin probes. iNOS and nitrotyrosine expression was increased in FD hearts compared with hypertrophic cardiomyopathy and normal controls. Remarkably, immunostaining was homogeneously expressed in FD male cardiomyocytes, whereas it was only detected in the affected cardiomyocytes of FD females. Western blot analysis confirmed an increase in FD cardiomyocyte protein nitration compared with controls. 8-OHdG was expressed in 25% of cardiomyocyte nuclei from FD patients, whereas it was absent in controls. The intensity of immunostaining for iNOS/nitrotyrosine correlated with 8-OHdG expression in cardiomyocyte nuclei. Apoptosis of FD cardiomyocytes was 187-fold higher than in controls, and apoptotic nuclei were positive for 8-OHdG. Cardiac dysfunction of FD reflects increased myocardial nitric oxide production with oxidative damage of cardiomyocyte myofilaments and DNA, causing cell dysfunction and death.

  13. Multicomponent nanoparticles as nonviral vectors for the treatment of Fabry disease by gene therapy

    PubMed Central

    Ruiz de Garibay, Aritz Pérez; Delgado, Diego; del Pozo-Rodríguez, Ana; Solinís, María Ángeles; Gascón, Alicia Rodríguez

    2012-01-01

    Purpose: Gene-mediated enzyme replacement is a reasonable and highly promising approach for the treatment of Fabry disease (FD). The objective of the present study was to demonstrate the potential applications of solid lipid nanoparticle (SLN)-based nonviral vectors for the treatment of FD. Methods: SLNs containing the pR-M10-αGal A plasmid that encodes the α-Galactosidase A (α-Gal A) enzyme were prepared and their in vitro transfection efficacy was studied in Hep G2 cells. We also studied the cellular uptake of the vectors and the intracellular disposition of the plasmid. Results: The enzymatic activity of the cells treated with the vectors increased significantly relative to the untreated cells, regardless of the formulation assayed. When the SLNs were prepared with protamine or dextran and protamine, the activity of the α-Gal A enzyme by the transfected Hep G2 cells increased up to 12-fold compared to that of untreated cells. Conclusion: With this work we have revealed in Hep G2 cells the ability of a multicomponent system based on SLNs to act as efficient nonviral vectors to potentially correct low α-Gal A activity levels in FD with gene therapy. PMID:23118528

  14. Biomarkers and Imaging Findings of Anderson-Fabry Disease-What We Know Now.

    PubMed

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

    2017-06-11

    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.

  15. Mutational analysis of the GLA gene in Mexican families with Fabry disease.

    PubMed

    Gutiérrez-Amavizca, Bianca Ethel; Gal, Andreas; Ortíz-Orozco, Rocío; Orth, Ulrich; Prado Montes De Oca, Ernesto; Gutiérrez-Amavizca, Jaime Paul; Figuera, Luis E

    2017-03-01

    Fabry disease (FD) is a lysosomal storage disorder, which develops due to a deficiency in the hydrolytic enzyme, α-galactosidase A (α-Gal A). Alpha-Gal A hydrolyzes glycosphingolipid globotriaosylceramide (Gb3), and an α-Gal A deficiency leads to Gb3 accumulation in tissues and cells in the body. This pathology is likely to involve multiple systems, but it is generally considered to affect primarily vascular endothelium. In this study, we investigated mutations in the GLA gene, which encodes α-Gal A, in Mexican families with FD. We included seven probands with FD that carried known mutations. We analysed pedigrees of the probands, and performed molecular screening in 65 relatives with the potential of carrying a GLA mutation. Five mutations (P40S, IVS4(+4), G328V, R363H, R404del) were detected in seven unrelated Mexican families with the classic FD phenotype. Of the 65 relatives examined, 42 (64.6%) had a GLA gene mutation. In summary, among seven Mexican probands with FD, 65 relatives were at risk of carrying a known GLA mutation, and molecular screening identified 42 individuals with the mutation. Thus, our findings showed that it is important to perform molecular analysis in families with FD to detect mutations and to provide accurate diagnoses for individuals that could be affected.

  16. Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes.

    PubMed Central

    Eng, C. M.; Ashley, G. A.; Burgert, T. S.; Enriquez, A. L.; D'Souza, M.; Desnick, R. J.

    1997-01-01

    BACKGROUND: Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A (alpha-Gal A) gene located at Xq22.1. To determine the nature and frequency of the molecular lesions causing the classical and milder variant Fabry phenotypes and for precise carrier detection, the alpha-Gal A lesions in 42 unrelated Fabry hemizygotes were determined. MATERIALS AND METHODS: Genomic DNA was isolated from affected probands and their family members. The seven alpha-galactosidase A exons and flanking intronic sequences were PCR amplified and the nucleotide sequence was determined by solid-phase direct sequencing. RESULTS: Two patients with the mild cardiac phenotype had missense mutations, I9IT and F113L, respectively. In 38 classically affected patients, 33 new mutations were identified including 20 missense (MIT, A31V, H46R, Y86C, L89P, D92Y, C94Y, A97V, R100T, Y134S, G138R, A143T, S148R, G163V, D170V, C202Y, Y216D, N263S, W287C, and N298S), two nonsense (Q386X, W399X), one splice site mutation (IVS4 + 2T-->C), and eight small exonic insertions or deletions (304del1, 613del9, 777del1, 1057del2, 1074del2, 1077del1, 1212del3, and 1094ins1), which identified exon 7 as a region prone to gene rearrangements. In addition, two unique complex rearrangements consisting of contiguous small insertions and deletions were found in exons 1 and 2 causing L45R/H46S and L120X, respectively. CONCLUSIONS: These studies further define the heterogeneity of mutations causing Fabry disease, permit precise carrier identification and prenatal diagnosis in these families, and facilitate the identification of candidates for enzyme replacement therapy. Images FIG. 2 PMID:9100224

  17. Skin protection in the prevention of skin diseases.

    PubMed

    Elsner, Peter

    2007-01-01

    Occupational skin diseases comprise a wide spectrum of conditions. Under epidemiological aspects, occupational contact dermatitis that is usually manifested on the hands is the most frequent occupational skin disease with an estimated average incidence rate of 0.7-1.5 cases per 1,000 workers per year. Irritant dermatitis is due to individual susceptibility and the exposure to irritants such as wet work combined with detergents or other hydrophilic irritants or solvents at the workplace. Chronic irritant dermatitis is a risk factor for delayed-type sensitization and subsequently allergic contact dermatitis. It is therefore the prevention of chronic or cumulative irritant dermatitis that is the decisive factor in the prevention of occupational skin disease. Within prevention programs at the workplace, skin protection plays an important, but limited role. Others are technical and organizational means to avoid or reduce skin exposure to irritants and allergens. Educational measures to increase the awareness of workers for workplace hazards and to motivate them to use skin protection measures appropriately are just as important as the careful selection of skin protection materials.

  18. Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease.

    PubMed

    Lenders, Malte; Stypmann, Jörg; Duning, Thomas; Schmitz, Boris; Brand, Stefan-Martin; Brand, Eva

    2016-01-01

    Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-α or -β). Agalsidase inhibition was associated with higher lyso-globotriaosylceramide levels and worse disease severity scores in patients. Compared with agalsidase inhibition-negative men, agalsidase inhibition-positive men showed greater left ventricular mass (P=0.02) and substantially lower renal function (difference in eGFR of about -30 ml/min per 1.73 m(2); P=0.04), which was confirmed by a longitudinal 5-year retrospective analysis. Additionally, affected patients presented more often with FD-typical symptoms, such as diarrhea, fatigue, and neuropathic pain, among others. Therefore, patients with poor clinical outcome on agalsidase should be tested for agalsidase inhibition. Future studies are warranted to determine if affected patients with FD benefit from acute reduction of anti-agalsidase antibodies or long-term immune modulation therapies to suppress agalsidase inhibition and to identify mechanisms that minimize antibody generation against agalsidase.

  19. Effectiveness of enzyme replacement therapy in Fabry disease: Long term experience in Argentina.

    PubMed

    Cabrera, Gustavo; Politei, Juan; Antongiovani, Norberto; Amartino, Hernán

    2017-06-01

    Evidence regarding long term effectiveness of enzyme replacement therapy (ERT) in Fabry disease (FD) is needed. The aim of this study was to analyze in a cohort of FD patients in Argentina, the long term effectiveness of ERT on renal, cardiac and cerebrovascular parameters. Patients with genetically proven FD were included from GADYTEF (Argentinean group for the treatment of FD) between 2001 and 2014. Renal, cardiac, and cerebral outcomes were prospectively studied in patients treated with ERT. Additionally, the occurrence of major cardiac complications, stroke, end-stage renal disease and death was analyzed during follow up. During the follow-up 8 major complications occurred in 5 patients (n = 2 deaths, n = 4 cases of end stage renal disease and n = 1 atrial fibrillation), 4 of them males and only 1 female who suffered an atrial fibrillation. Sudden death or stroke did not occur. Four (40%) of 10 males with baseline left ventricular hypertrophy (LVH) reduced left ventricular mass index (LVMI) from 163.1 ± 64.7 to 123.4 ± 49.8 g/m(2), 2 stabilized LVMI and 4 increased LVMI from157.9 ± 32.3 to 261.6 ± 48.6 g/m(2). Estimated glomerular filtration was stable in 30 patients (17 males and 13 females). We observed a few major complications during the follow up. Future studies are necessary to show the effectiveness of ERT in affected patients.

  20. Fabry disease due to D313Y and novel GLA mutations.

    PubMed

    Koulousios, Konstantinos; Stylianou, Konstantinos; Pateinakis, Panagiotis; Zamanakou, Maria; Loules, Gedeon; Manou, Eleni; Kyriklidou, Parthena; Katsinas, Christos; Ouzouni, Alexandra; Kyriazis, John; Speletas, Matthaios; Germenis, Anastasios E

    2017-10-06

    Our aim is to report four novel α-gal A gene (GLA) mutations resulting in Fabry disease (FD) and provide evidence of pathogenicity of the D313Y mutation regarding which contradictory data have been presented in the literature. Twenty-five family members of nine unrelated patients with definite FD diagnosis, 10 clinically suspected cases and 18 members of their families were included in this polycentric cohort study. Genotyping and measurement of lyso-Gb3 was performed in all individuals. The α-Gal A activity was measured in all men as well as plasma and urine Gb3 concentration in selected cases. Optical and electron microscopy was performed in kidney biopsies of selected patients. All the above were evaluated in parallel with the clinical data of the patients. Fourteen new cases of FD were recognised, four of which were carrying already described GLA mutations. Four novel GLA mutations, namely c.835C>T, c.280T>A, c.924A>C and c.511G>A, resulting in a classic FD phenotype were identified. Moreover, FD was definitely diagnosed in five patients carrying the D313Y mutation. Eight D313Y carriers were presenting signs of FD despite not fulfilling the criteria of the disease, two had no FD signs and two others were apparently healthy. Four novel GLA pathogenic mutations are reported and evidence of pathogenicity of the D313Y mutation is provided. It seems that the D313Y mutation is related to a later-onset milder phenotype than the typical phenotype with normal lysoGb3 concentration. Our study underlines the significance of family member genotyping and newborn screening to avoid misdiagnoses and crucial delays in diagnosis and treatment of the disease. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  1. A simple method for quantification of plasma globotriaosylsphingosine: Utility for Fabry disease.

    PubMed

    Talbot, Andrew; Nicholls, Kathy; Fletcher, Janice M; Fuller, Maria

    2017-09-01

    Fabry disease (FD) results from impaired globotriaosylceramide (Gb3) catabolism, due to a deficiency of the lysosomal hydrolase, α-galactosidase A (α-GalA). As a direct consequence, the deacetylated derivative, globotriaosylsphingosine (lyso-Gb3), is produced and contemporary evidence exemplifies its use as a biomarker. Here we developed a simple method to enable quantification of lyso-Gb3 in just 0.01mL of plasma and explored its concentration in a cohort of 73 Australian FD patients, as well as in individuals with other sphingolipidoses. In 2000 patients without FD, but with related metabolic conditions, lyso-Gb3 returned concentrations of <5pmol/mL. In the FD cohort, 53/60 patients with classical mutations returned lyso-Gb3 concentrations≥5pmol/mL whereas only 4/13 patients with "late-onset" mutations had lyso-Gb3≥5pmol/mL. Five females with normal α-GalA activity and genetically confirmed FD returned lyso-Gb3≥5pmol/mL. The prevalence of clinically significant disease including cardiomyopathy, nephropathy and cerebrovascular disease was congruent with higher lyso-Gb3 concentrations. Repeat testing was available for 51 patients-26 undergoing enzyme replacement therapy-and concentrations of lyso-Gb3 remained unaltered throughout 6-18 months independent of sex, mutation or treatment status. Our data suggest that the optimum use of lyso-Gb3 resides in laboratory confirmation of classical FD and for monitoring at least the initial response to therapeutic intervention. There is no evidence that lyso-Gb3 can inform on clinical events. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Impact of immunosuppressive therapy on therapy-neutralizing antibodies in transplanted patients with Fabry disease.

    PubMed

    Lenders, M; Oder, D; Nowak, A; Canaan-Kühl, S; Arash-Kaps, L; Drechsler, C; Schmitz, B; Nordbeck, P; Hennermann, J B; Kampmann, C; Reuter, S; Brand, S-M; Wanner, C; Brand, E

    2017-09-01

    Inhibitory antibodies towards enzyme replacement therapy (ERT) are associated with disease progression and poor outcome in affected male patients with lysosomal disorders such as Fabry disease (FD). However, little is known about the impact of immunosuppressive therapy on ERT inhibition in these patients with FD. In this retrospective study, we investigated the effect of long-term immunosuppression on ERT inhibition in male patients with FD (n = 26) receiving immunosuppressive therapy due to kidney (n = 24) or heart (n = 2) transplantation. No ERT-naïve transplanted patient (n = 8) developed antibodies within follow-up (80 ±72 months) after ERT initiation. Seven (26.9%) patients were tested ERT inhibition positive prior to transplantation. No de novo ERT inhibition was observed after transplantation (n = 18). In patients treated with high dosages of immunosuppressive medication such as prednisolone, tacrolimus and mycophenolate-mofetil/mycophenolate acid, ERT inhibition decreased after transplantation (n = 12; P = 0.0160). Tapering of immunosuppression (especially prednisolone) seemed to re-increase ERT inhibition (n = 4, median [range]: 16.6 [6.9; 36.9] %; P = 0.0972) over time. One ERT inhibition-positive patient required interventions with steroid therapy and increased doses of tacrolimus, which also lowered ERT inhibition. We conclude that the immunosuppressive maintenance therapy after transplantations seems to be sufficient to prevent de novo ERT inhibition in ERT-naïve patients. Intensified high dosages of immunosuppressive drugs are associated with decreased antibody titres and decreased ERT inhibition in affected patients, but did not result in long-term protection. Future studies are needed to establish ERT inhibition-specific immunosuppressive protocols with long-term modulating properties to warrant an improved disease course in ERT inhibition-positive males. © 2017 The Association for the Publication of the Journal of Internal Medicine.

  3. Frequency of Fabry disease in male and female haemodialysis patients in Spain

    PubMed Central

    2010-01-01

    Background Fabry disease (FD), an X-linked lysosomal storage disorder, is caused by a reduced activity of the lysosomal enzyme α-galactosidase A. The disorder ultimately leads to organ damage (including renal failure) in males and females. However, heterozygous females usually present a milder phenotype with a later onset and a slower progression. Methods A combined enzymatic and genetic strategy was used, measuring the activity of α-galactosidase A and genotyping the α-galactosidase A gene (GLA) in dried blood samples (DBS) of 911 patients undergoing haemodialysis in centers across Spain. Results GLA alterations were found in seven unrelated patients (4 males and 3 females). Two novel mutations (p.Gly346AlafsX347 and p.Val199GlyfsX203) were identified as well as a previously described mutation, R118C. The R118C mutation was present in 60% of unrelated patients with GLA causal mutations. The D313Y alteration, considered by some authors as a pseudo-deficiency allele, was also found in two out of seven patients. Conclusions Excluding the controversial D313Y alteration, FD presents a frequency of one in 182 individuals (0.55%) within this population of males and females undergoing haemodialysis. Moreover, our findings suggest that a number of patients with unexplained and atypical symptoms of renal disease may have FD. Screening programmes for FD in populations of individuals presenting severe kidney dysfunction, cardiac alterations or cerebrovascular disease may lead to the diagnosis of FD in those patients, the study of their families and eventually the implementation of a specific therapy. PMID:20122163

  4. Angiotensinogen promoter and angiotensinogen II receptor type 1 gene polymorphisms and incidence of ischemic stroke and neurologic phenotype in Fabry disease.

    PubMed

    Altarescu, Gheona; Haim, Shimon; Elstein, Deborah

    2013-11-01

    Stroke and/or white matter lesions (WMLs) are significant in Fabry disease. Polymorphisms of angiotensinogen (AGT), AGT Promoter and angiotensinogen II receptor type 1 (AGTR1) are correlated with WMLs. We compared AGT. AGT Promoter and AGTR1 genotypes to stroke incidence, Fabry-specific [Mainz Severity Score Index (MSSI)] severity score, and neurologic sub-score (n-MSSI). Sixty-three Fabry patients and 49 matched controls plus historic controls were genotyped. Institutional Review Board approval was received. Results. C and/or CC alleles of AGT Promoter and AGTR1 were significantly correlated with stroke and n-MSSI. Findings are suggestive of role of AGT Promoter and AGTR1 genotypes in Fabry phenotypes.

  5. 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

  6. Preliminary Screening Results of Fabry Disease in Kidney Transplantation Patients: A Single-Center Study.

    PubMed

    Yılmaz, M; Uçar, S K; Aşçı, G; Canda, E; Tan, F A; Hoşcoşkun, C; Çoker, M; Töz, H

    2017-04-01

    Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by the deficiency of alfa-galactosidase A (AGALA) and leads to progressive impairment of renal function in almost all male patients and in a significant proportion of female patients. FD is underdiagnosed or even misdiagnosed in patients undergoing kidney transplantation. We initiated a selective screening study for FD among kidney transplant patients in our center. In this study, 1095 male and female patients were included. Dried blood samples on Guthrie papers were used to analyze galactosidase A enzyme for male patients. Genetic analyses were performed in all female and male patients with low enzyme activity. In total, 648 female and 447 male patients with functioning grafts were evaluated. Among 1095 patients, 5 male patients had AGALA activity below threshold and 3 female patients had galactosidase alpha gene DNA variations. One male patient had a disease-causing mutation. The other 4 patients had polymorphisms causing low enzyme activity. All the 3 female patients had mutations that were associated with FD according to Human Gene Mutation Database (ID: CM025441). In contrast, these mutations were reported as unknown clinical significance in Clinvar (rs149391489). The patients with clinical findings suggesting FD were planned to be analyzed for Lyso Gb3. In our selective screening study, 8 variations were found among 1095 kidney transplantation patients, which needs further investigation to determine causes of FD. Clinical findings, physical examination, and family history are also necessary to evaluate the genetic changes as a mutation in this selected population.

  7. 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

  8. The Genetics of Human Skin Disease

    PubMed Central

    DeStefano, Gina M.; Christiano, Angela M.

    2014-01-01

    The skin is composed of a variety of cell types expressing specific molecules and possessing different properties that facilitate the complex interactions and intercellular communication essential for maintaining the structural integrity of the skin. Importantly, a single mutation in one of these molecules can disrupt the entire organization and function of these essential networks, leading to cell separation, blistering, and other striking phenotypes observed in inherited skin diseases. Over the past several decades, the genetic basis of many monogenic skin diseases has been elucidated using classical genetic techniques. Importantly, the findings from these studies has shed light onto the many classes of molecules and essential genetic as well as molecular interactions that lend the skin its rigid, yet flexible properties. With the advent of the human genome project, next-generation sequencing techniques, as well as several other recently developed methods, tremendous progress has been made in dissecting the genetic architecture of complex, non-Mendelian skin diseases. PMID:25274756

  9. 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

  10. Genotype: A Crucial but Not Unique Factor Affecting the Clinical Phenotypes in Fabry Disease

    PubMed Central

    Wang, Zhaohui; Ren, Hong; Shen, Pingyan; Wang, Weiming; Xu, Yaowen; Ni, Liyan; Yu, Xialian; Chen, Xiaonong; Zhang, Wen; Yang, Li; Li, Xiao; Xu, Jing; Chen, Nan

    2016-01-01

    Numerous α-galactosidase A (α-gal A) gene (GLA) mutations have been identified in Fabry disease (FD), but studies on genotype-phenotype correlation are limited. This study evaluated the features of GLA gene mutations and genotype-phenotype relationship in Chinese FD patients. Gene sequencing results, demographic information, clinical history, and laboratory findings were collected from 73 Chinese FD patients. Totally 47 mutations were identified, including 23 novel mutations which might be pathogenic. For male patients, those with frameshift and nonsense mutations presented the classical FD, whereas those with missense mutations presented both of classical and atypical phenotypes. Interestingly, two male patients with missense mutation p.R356G from two unrelated families, and two with p.R301Q from one family presented different phenotypes. A statistically significant association was found between the levels of α-gal A enzyme activity and ocular changes in males, though no significant association was found between residual enzyme activity level and genotype or clinical phenotypes. For female patients, six out of seven with frameshift mutations and one out of nine with missense mutation presented the classical FD, and α-gal A activity in those patients was found to be significantly lower than that of patients with atypical phenotypes (13.73 vs. 46.32 nmol/ml/h/mg). Our findings suggest that the α-gal A activity might be associated with the clinical severity in female patients with FD. But no obvious associations between activity level of α-gal A and genotype or clinical phenotypes were found for male patients. PMID:27560961

  11. Diagnostic dilemmas in Fabry disease: a case series study on GLA mutations of unknown clinical significance.

    PubMed

    Smid, B E; Hollak, C E M; Poorthuis, B J H M; van den Bergh Weerman, M A; Florquin, S; Kok, W E M; Lekanne Deprez, R H; Timmermans, J; Linthorst, G E

    2015-08-01

    Fabry disease' (FD) phenotype is heterogeneous: alpha-galactosidase A gene mutations (GLA) can lead to classical or non-classical FD, or no FD. The aim of this study is to describe pitfalls in diagnosing non-classical FD and assess the diagnostic value of plasma globotriaosylsphingosine. This is a case series study. Family 1 (p.A143T) presented with hypertrophic cardiomyopathy (HCM), absent classical FD signs, high residual alpha-galactosidase A activity (AGAL-A) and normal plasma globotriaosylsphingosine. Co-segregating sarcomeric mutations were found. Cardiac biopsy excluded FD. In family 2 (p.P60L), FD was suspected after kidney biopsy in a female with chloroquine use. Males had residual AGAL-A, no classical FD signs and minimally increased plasma globotriaosylsphingosine, indicating that p.P60L is most likely non-pathogenic. Non-specific complications and histology can be explained by chloroquine and alternative causes. Males of two unrelated families (p.R112H) show AGAL-A <5%, but slightly elevated plasma globotriaosylsphingosine (1.2-2.0 classical males >50 nmol/l). Histological evidence suggests a variable penetrance of this mutation. Patients with GLA mutations and non-specific findings such as HCM may have non-classical FD or no FD. Other (genetic) causes of FD-like findings should be excluded, including medication inducing FD-like storage. Plasma globotriaosylsphingosine may serve as a diagnostic tool, but histology of an affected organ is often mandatory. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Exploratory screening for Fabry's disease in young adults with cerebrovascular disorders in northern Sardinia.

    PubMed

    Fancellu, Laura; Borsini, Walter; Romani, Ilaria; Pirisi, Angelo; Deiana, Giovanni Andrea; Sechi, Elia; Doneddu, Pietro Emiliano; Rassu, Anna Laura; Demurtas, Rita; Scarabotto, Anna; Cassini, Pamela; Arbustini, Eloisa; Sechi, GianPietro

    2015-12-12

    The etiologic determinants of stroke in young adults remain a diagnostic challenge in up to one-fourth of cases. Increasing evidences led to consider Fabry's disease (FD) as a possible cause to check up. We aimed at evaluating the prevalence of unrecognized FD in a cohort of patients with juvenile stroke in northern Sardinia. For this study, we enrolled 178 patients consecutively admitted to our Neurological Ward for ischemic stroke, transient ischemic attack, intracerebral haemorrhage, neuroradiological evidence of silent infarcts, or white matter lesions possibly related to cerebral vasculopathy at brain MRI, and cerebral venous thrombosis. The qualifying events have to occur between 18 and 55 years of age. We identified two patients with an α-galactosidase A gene variant, with a prevalence of 0.9 %. According to recent diagnostic criteria, one patient, included for the occurrence of multiple white matter lesions at brain MRI, had a diagnosis of definite FD, the other, included for ischemic stroke, had a diagnosis of uncertain FD. Our study places in a middle position among studies that found a prevalence of FD up to 4 % and others that did not find any FD patients. Our findings confirm that FD should be considered in the differential diagnosis of patients with juvenile stroke, particularly those with a personal or familial history positive for cerebrovascular events, or evidence of combined cardiologic and/or renal impairment. All types of cerebrovascular disorders should be screened for FD, including patients with white matter lesions possibly related to cerebral vasculopathy at brain MRI.

  13. 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.

  14. 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

  15. Skin microbiome and skin disease: the example of rosacea.

    PubMed

    Picardo, Mauro; Ottaviani, Monica

    2014-01-01

    The imbalance and/or the perturbation of the microbial populations that colonize the skin and that contribute to its defense may represent one of the causes of the development of noninfectious skin diseases. Atopic dermatitis, psoriasis, acne, and rosacea can be listed among these kinds of pathologies. In particular, considering that microbes have been long addressed as having a role in rosacea, this common dermatosis can be an interesting model to evaluate the correlation between microbiome alterations and the occurrence of clinical manifestations. Different microorganisms have been suggested to have a role in rosacea, but no direct correlation with the incidence of the pathology has been clearly defined. Skin microbiome composition is crucial for the correct skin immune functions and recent findings indicate an abnormal activation of innate immune system associated with the rosacea. The enhanced expression of toll-like receptor 2 in the epidermis of rosacea patients can represent a possible explanation for the amplified inflammatory response to external stimuli observed during the disease. In addition, significantly higher small intestinal bacterial overgrowth prevalence in rosacea subjects has been found and its eradication has been associated with a regression of the skin lesions. In conclusion, both skin and gut microbiome seem to have a role, even if synergistic with other factors, in the pathogenesis of rosacea. A deeper knowledge of human microbiome composition and microbe-host interactions will contribute to clarify the mechanism of development of rosacea and possibly will provide innovative therapeutic approaches.

  16. Plants used to treat skin diseases

    PubMed Central

    Tabassum, Nahida; Hamdani, Mariya

    2014-01-01

    Skin diseases are numerous and a frequently occurring health problem affecting all ages from the neonates to the elderly and cause harm in number of ways. Maintaining healthy skin is important for a healthy body. Many people may develop skin diseases that affect the skin, including cancer, herpes and cellulitis. Some wild plants and their parts are frequently used to treat these diseases. The use of plants is as old as the mankind. Natural treatment is cheap and claimed to be safe. It is also suitable raw material for production of new synthetic agents. A review of some plants for the treatment of skin diseases is provided that summarizes the recent technical advancements that have taken place in this area during the past 17 years. PMID:24600196

  17. Crohn’s disease and skin

    PubMed Central

    Gravina, AG; Federico, A; Ruocco, E; Lo Schiavo, A; Romano, F; Miranda, A; Sgambato, D; Dallio, M; Ruocco, V; Loguercio, C

    2015-01-01

    Crohn’s disease is a chronic inflammatory bowel disease potentially involving any segment of the gastrointestinal tract. Extra-intestinal manifestations may occur in 6%–40% of patients, and disorders of the skin are among the most common. This manuscript will review skin manifestations associated to Crohn’s disease, with a particular focus on lesions associated to anti-tumour necrosis factor therapy. PMID:27087942

  18. 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

  19. Control of proteinuria with increased doses of agalsidase alfa in a patient with Fabry disease with atypical genotype-phenotype expression.

    PubMed

    Paliouras, Christos; Aperis, Georgios; Lamprianou, Foteini; Ntetskas, Giorgos; Roufas, Konstantinos; Alivanis, Polichronis

    2015-01-01

    Fabry disease is a rare X-linked lysosomal storage disorder of glycosphingolipids, caused by the partial or complete deficiency of the lysosomal enzyme alpha-galactosidase A (a-Gal A). The missense mutation pN215S usually causes a milder form of the disease with isolated cardiac involvement. We report a case of a male Fabry patient with the pN215S mutation and a generalized disease. He suffered a relapse in proteinuria which responded to increased doses of the administered recombinant enzyme. Individualization of enzyme replacement therapy must be considered in selected cases characterized by clinical deterioration.

  20. 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.

  1. 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.

  2. α-Galactosidase A knockout mice: progressive organ pathology resembles the type 2 later-onset phenotype of Fabry disease.

    PubMed

    Bangari, Dinesh S; Ashe, Karen M; Desnick, Robert J; Maloney, Colleen; Lydon, John; Piepenhagen, Peter; Budman, Eva; Leonard, John P; Cheng, Seng H; Marshall, John; Thurberg, Beth L

    2015-03-01

    Fabry disease is an X-linked lysosomal storage disease caused by deficient activity of α-galactosidase A and the resultant systemic accumulation of globotrioasylceramide (GL-3) and related glycolipids. α-Galactosidase A gene knockout (Gla KO) mice have no α-galactosidase A activity and progressively accumulate GL-3 in tissues and fluids, similarly to FD patients. The nature and temporal effects of the progressive substrate accumulation on tissue histology in these mice have not previously been characterized. Here, we report the pathology of young to old (3 to 17 months old) Gla KO mice and compare these changes with those in strain-matched control animals. Gla KO mice accumulated GL-3 in various tissues and fluids with age. Lysosomal GL-3 inclusions increased with age in multiple cell types, including renal epithelial, intestinal, and vascular smooth muscle cells, and neurons in trigeminal and dorsal root ganglia, as detected by light and electron microscopy. However, unlike the case for male FD patients with the type 1 classic phenotype, GL-3 inclusions were not detected in vascular endothelial cells or cardiomyocytes. The histological changes in Gla KO mice better resemble the type 2 later-onset phenotype observed in patients with residual α-galactosidase A activity. GL-3 accumulation in the small intestine and sensory ganglia of Gla KO mice provides a model for study of enteropathy and neuropathy in Fabry disease. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  3. Enhanced Endothelial Delivery and Biochemical Effects of α-Galactosidase by ICAM-1-Targeted Nanocarriers for Fabry Disease

    PubMed Central

    Hsu, Janet; Serrano, Daniel; Bhowmick, Tridib; Kumar, Kishan; Shen, Yang; Kuo, Yuan Chia; Garnacho, Carmen; Muro, Silvia

    2010-01-01

    Fabry disease due to deficiency of α-galactosidase A (α-Gal) causes lysosomal accumulation of globotriaosylceramide (Gb3) in multiple tissues and prominently in the vascular endothelium. Although enzyme replacement therapy (ERT) by injection of recombinant α-Gal improves the disease outcome, effects on the vasculopathy associated to life-threatening cerebrovascular, cardiac and renal complications are still limited. We designed a strategy to enhance delivery of α-Gal to organs and endothelial cells (ECs). We targeted α-Gal to intercellular adhesion molecule 1 (ICAM-1), a protein expressed on ECs throughout the vasculature, by loading this enzyme on nanocarriers coated with anti-ICAM (anti-ICAM/α-Gal NCs). In vitro radioisotope tracing showed efficient loading of α-Gal on anti-ICAM NCs, stability of this formulation under storage and in model physiological fluids, and enzyme release in response to lysosome environmental conditions. In mice, delivery of 125I-α-Gal was markedly enhanced by anti-ICAM/125I-α-Gal NCs in brain, kidney, heart, liver, lung, and spleen, and transmission electron microscopy showed anti-ICAM/α-Gal NCs attached to and internalized into the vascular endothelium. Fluorescence microscopy proved targeting, endocytosis and lysosomal transport of anti-ICAM/α-Gal NCs in macro- and micro-vascular ECs, and a marked enhancement of Gb3 degradation. Therefore, ICAM-1-targeting strategy may help improve the efficacy of therapeutic enzymes for Fabry disease. PMID:21047542

  4. 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

    2017-05-03

    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.

  5. Risk assessment of skin in rheumatic disease.

    PubMed

    Firth, Jill

    Patients with a rheumatic disease are considered to be at high risk of developing skin problems because of their restricted mobility, vascular complications and the type of medication they are taking.

  6. Reflectance Confocal Microscopy for Inflammatory Skin Diseases.

    PubMed

    Agozzino, M; Gonzalez, S; Ardigò, M

    2016-10-01

    In vivo reflectance confocal microscopy (RCM) is a relatively novel non-invasive tool for microscopic evaluation of the skin used prevalently for diagnosis and management of skin tumour. Its axial resolution, its non-invasive and easy clinical application represents the goals for a large diffusion of this technique. During the last 15 years, RCM has been demonstrated to be able to increase the sensibility and sensitivity of dermoscopy in the diagnosis of skin tumours integrating in real time clinic, dermoscopic and microscopic information useful for the definition of malignancy. Despite to date, no large comparative studies on inflammatory skin diseases has been published in the literature, several papers already showed that RCM has a potential for the evaluation of the descriptive features of the most common inflammatory skin diseases as psoriasis, lupus erythematosus, contact dermatitis and others. The aim of the application of this technique in non-neoplastic skin diseases has been prevalently focused on the possibility of clinical diagnosis confirmation, as well as therapeutic management. Moreover, the use of RCM as driver for an optimised skin biopsy has been also followed in order to reduce the number of unsuccessful histopathological examination. In this review article we describe the confocal features of the major groups of inflammatory skin disorders focusing on psoriasiform dermatitis, interface dermatitis and spongiotic dermatitis.

  7. Cardiac Troponin I: A Valuable Biomarker Indicating the Cardiac Involvement in Fabry Disease

    PubMed Central

    Giese, Anne Kathrin; Eichler, Sabrina; Sieweke, Nicole; Speth, Maria; Bauer, Timm; Hamm, Christian

    2016-01-01

    Objectives Assessment of the clinical severity of Fabry disease (FD), an X-linked, rare, progressive disorder based on a genetic defect in alpha-galactosidase is challenging, especially regarding cardiac involvement. The aim of the study was to evaluate the diagnostic value of cardiac troponin I (cTnI) in discriminating FD patients with cardiac involvement in a large FD patient cohort. Methods cTnI levels were measured with a contemporary sensitive assay in plasma samples taken routinely from FD patients. The assay was calibrated to measure cTnI levels ≥0.01 ng/ml. Elevated cTnI values (cut-off ≥0.04 ng/ml) were correlated with clinical data. Results cTnI was assessed in 62 FD patients (median age: 47 years, males: 36%). Elevated cTnI levels were detected in 23 (37%) patients. Patients with a cTnI elevation were older (median 55 years versus 36 years, p<0.001). Elevated cTnI levels were associated with the presence of a LVH (16/23 versus 1/39; OR 65.81, CI: 6.747–641.859; p<0.001). In almost all patients with a left ventricular hypertrophy (LVH) elevated cTnI levels were detected (16/17, 94%). Absolute cTnI levels in patients with LVH were higher than in those without (median 0.23 ng/ml versus 0.02 ng/ml; p<0.001). A cTnI level <0.04ng/ml had a high negative predictive value regarding the presence of a LVH (38/39, 97%). In a control group of non-FD patients (n = 17) with LVH (due to hypertension) none showed cTnI levels ≥0.01 ng/ml. Conclusions Elevated cTnI levels are common in FD patients, reflecting cardiac involvement. FD patients might benefit from a continuous cTnI monitoring. PMID:27322070

  8. Enzymatic diagnosis of Fabry disease using a fluorometric assay on dried blood spots: An alternative methodology.

    PubMed

    Caudron, Eric; Prognon, Patrice; Germain, Dominique P

    2015-12-01

    Fabry disease (FD, OMIM#301500) is an X-linked lysosomal storage disorder caused by the functional deficiency of α-galactosidase A, a lysosomal enzyme. A method to screen for FD in large populations has been developed using a fluorometric assay of α-galactosidase A activity in dried blood spots (DBS) on filter paper. However, results can be influenced by quenching of fluorescence by haemoglobin which, together with small sample size, may result in a low light emission signal. An alternative, simple and sensitive fluorometric assay was developed for the determination of α-galactosidase A activity in DBS. The assay uses 4-methylumbelliferyl-α-d-galactose as an artificial substrate. To minimize the risk of false-positives, zinc sulfate was used for protein precipitation to stop the enzymatic reaction and eliminate interfering species (hemoglobin). Samples from 209 individuals (60 hemizygotes, 68 heterozygotes, and 81 controls) were tested to establish reference values for the assay. The mean α-galactosidase A activity of the 81 controls was 9.1 ± 3.3 μmol h(-1) L(-1) (mean ± SD). All 60 hemizygotes affected with FD had AGAL activities below 1.7 μmol h(-1) L(-1) (0.2 ± 0.3 μmol h(-1) L(-1)). For the 68 heterozygous females, AGAL activity ranged from 0 to 12.6 μmol h(-1) L(-1) (3.5 ± 2.7 μmol h(-1) L(-1)). Two-thirds of the female patients could be identified using the enzymatic assay and a cut-off level of 40% of the median control value (<3.4 μmol h(-1) L(-1)). Our fluorometric assay using zinc sulfate protein precipitation was shown to have similar sensitivity and robustness while reducing the risk of false positive results due to quenching of 4-MU fluorescence by haemoglobin. Copyright © 2015. Published by Elsevier Masson SAS.

  9. 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

    2017-08-09

    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

  10. Psychosocial effect of common skin diseases.

    PubMed Central

    Barankin, Benjamin; DeKoven, Joel

    2002-01-01

    OBJECTIVE: To increase awareness of the psychosocial effect of acne, atopic dermatitis, and psoriasis. QUALITY OF EVIDENCE: A literature review was based on a MEDLINE search (1966 to 2000). Selected articles from the dermatologic and psychiatric literature, as well as other relevant medical journals, were reviewed and used as the basis for discussion of how skin disease affects patients' lives and of appropriate management. Studies in the medical literature provide mainly level III evidence predominantly based on descriptive studies and expert opinion. MAIN MESSAGE: Dermatologic problems can result in psychosocial effects that seriously affect patients' lives. More than a cosmetic nuisance, skin disease can produce anxiety, depression, and other psychological problems that affect patients' lives in ways comparable to arthritis or other disabling illnesses. An appreciation for the effects of sex, age, and location of lesions is important, as well as the bidirectional relationship between skin disease and psychological distress. This review focuses on the effects of three common skin diseases seen by family physicians: acne, atopic dermatitis, and psoriasis. CONCLUSION: How skin disease affects psychosocial well-being is underappreciated. Increased understanding of the psychiatric comorbidity associated with skin disease and a biopsychosocial approach to management will ultimately improve patients' lives. PMID:12046366

  11. Characterization and phosphoproteomic analysis of a human immortalized podocyte model of Fabry disease generated using CRISPR/Cas9 technology.

    PubMed

    Pereira, Ester M; Labilloy, Anatália; Eshbach, Megan L; Roy, Ankita; Subramanya, Arohan R; Monte, Semiramis; Labilloy, Guillaume; Weisz, Ora A

    2016-11-01

    Fabry nephropathy is a major cause of morbidity and premature death in patients with Fabry disease (FD), a rare X-linked lysosomal storage disorder. Gb3, the main substrate of α-galactosidase A (α-Gal A), progressively accumulates within cells in a variety of tissues. Establishment of cell models has been useful as a tool for testing hypotheses of disease pathogenesis. We applied CRISPR/Cas9 genome editing technology to the GLA gene to develop human kidney cell models of FD in human immortalized podocytes, which are the main affected renal cell type. Our podocytes lack detectable α-Gal A activity and have increased levels of Gb3. To explore different pathways that could have distinct patterns of activation under conditions of α-gal A deficiency, we used a high-throughput antibody array to perform phosphorylation profiling of CRISPR/Cas9-edited and control podocytes. Changes in both total protein levels and in phosphorylation status per site were observed. Analysis of our candidate proteins suggests that multiple signaling pathways are impaired in FD. Copyright © 2016 the American Physiological Society.

  12. Skin diseases in internationally adopted children.

    PubMed

    Rigal, Émilie; Nourrisson, Céline; Sciauvaud, Julie; Pascal, Julie; Texier, Charlotte; Corbin, Violaine; Poirier, Véronique; Beytout, Jean; Labbe, André; Lesens, Olivier

    2016-08-01

    Internationally adopted children often present diseases contracted in the country of origin. Skin diseases are common in new arrivals, and diagnosis may prove challenging for GPs or even dermatologists if they are inexperienced in the extensive geographic and ethnic diversity of international adoptees. To analyse the frequency and characteristics of skin diseases in international adoptees. In total, 142 adoptees were evaluated for a cross-sectional cohort study. The most frequent diseases observed at arrival were dermatological conditions. Of the adoptees, 70% presented at least one skin disease, of which 57.5% were infectious; Tinea capitis being the most frequent (n = 42). The recovery rate of Tinea capitis was 89% (n = 32/36). Ten cases of scabies were diagnosed. Other diseases included viral skin infection (n = 22), with 16 cases of Molluscum contagiosum and bacterial infection. Skin diseases are very common in internationally adopted children. There is a need for close collaboration between dermatologists and paediatricians to diagnose such infections, as well as clear guidelines to treat them.

  13. A disproportionate contribution of papillary muscles and trabeculations to total left ventricular mass makes choice of cardiovascular magnetic resonance analysis technique critical in Fabry disease.

    PubMed

    Kozor, Rebecca; Callaghan, Fraser; Tchan, Michel; Hamilton-Craig, Christian; Figtree, Gemma A; Grieve, Stuart M

    2015-02-21

    Sphingolipid deposition in Fabry disease causes left ventricular (LV) hypertrophy, of which the accurate assessment is essential. Cardiovascular magnetic resonance (CMR) has been proposed as the gold standard. However, there is debate in the literature as to whether papillary muscles and trabeculations (P&T) should be included in LV mass (LVM). We examined the accuracy of 2 CMR methods of assessing LVM and LV volumes, including (M inc P&T) or excluding (M ex P&T) P&T, in a cohort of Fabry disease subjects (n = 20) compared to a matched control group (n = 20). Significant differences between the two measurement methods were observed for LV end-diastolic volume, LV end-systolic volume, LVM, and LV ejection fraction (LVEF) in both groups. These differences were significantly greater in the Fabry group compared to controls, except for LVEF. P&T contributed to a greater percentage of LVM in Fabry subjects than controls (20 ± 1% vs 13 ± 2%, p = 0.01). In the control group, both volume-derived methods (M inc P&T or MexP&T) provided accurate SV measurements compared with the internal reference of velocity-encoded aortic flow. In the Fabry group, inclusion of P&T (M inc P&T) resulted in good concordance with phase contrast flow imaging (difference between flow and volume techniques: 1 ± 3 ml, p = 0.7). The volumetric contribution of P&T in Fabry disease is markedly increased relative to healthy controls. Failure to account for this results in significant underestimation of LVM and results in misclassification of a proportion of subjects.

  14. Questioning the Pathogenic Role of the GLA p.Ala143Thr "Mutation" in Fabry Disease: Implications for Screening Studies and ERT.

    PubMed

    Terryn, W; Vanholder, R; Hemelsoet, D; Leroy, B P; Van Biesen, W; De Schoenmakere, G; Wuyts, B; Claes, K; De Backer, J; De Paepe, G; Fogo, A; Praet, M; Poppe, B

    2013-01-01

    Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by quantitative or qualitative defects in the lysosomal enzyme alfa-Galactosidase A (aGAL A), ultimately resulting in vital organ dysfunction. Mainly the kidneys, the heart, and the central nervous system are involved. While the classical phenotype of Fabry disease is readily recognizable, screening studies have identified clinical variants. Here, we report the phenotype associated with the GLA p.Ala143Thr (c.427G>A) mutation in 12 patients aged 42-83 years. None of the patients had classical Fabry signs or symptoms as angiokeratoma, hypohidrosis, acroparesthesia, or cornea verticillata. Possible Fabry manifestations were renal failure (5/12), stroke (7/12), and left ventricular hypertrophy (5/12), but these were not necessarily attributable to the p.Ala143Thr mutation, as a cardiac biopsy in one female and left ventricular hypertrophy and kidney biopsies in two males with renal failure and microalbuminuria lacked Gb-3 deposits. The literature data on this mutation as well as data collected in the Fabry Outcome Survey (FOS) database confirm these findings. The association of renal failure, stroke, and left ventricular hypertrophy with this mutation could be the result of selection bias, as most patients were detected in screening studies.We conclude that care should be taken with attribution of vital organ dysfunction to GLA sequence alterations. In case of the p.Ala143Thr mutation, and possibly also other mutations associated with an attenuated phenotype, diagnostic tools such as biopsy and imaging should critically evaluate the relation of end-organ failure with Fabry disease, as this has important consequences for enzyme replacement therapy.

  15. An insight into the global burden of skin diseases.

    PubMed

    Hollestein, Loes M; Nijsten, Tamar

    2014-06-01

    The skin conditions expert group of the Global Burden of Disease 2010 study estimated the global burden of skin conditions worldwide. Health loss due to 15 skin diseases between 1990 and 2010 for 187 countries was quantified. All skin conditions combined were the fourth leading cause of non-fatal disease burden at the global level. The burden of skin conditions was high in both high- and low-income countries, indicating that prevention of skin diseases should be prioritized.

  16. Skin diseases in rural Yucatan, Mexico.

    PubMed

    Paek, So Yeon; Koriakos, Angie; Saxton-Daniels, Stephanie; Pandya, Amit G

    2012-07-01

    There are no known reports of the frequency of skin diseases endemic to rural Yucatan, Mexico. The aim of this study was to report the prevalence of dermatologic conditions in rural villages in that region. We conducted a retrospective descriptive study of all cases of skin disease diagnosed by a team of American board-certified dermatologists during consultations in January 2009, August 2009, and June 2010, in the state of Yucatan, Mexico. Traveling clinics were held in eight different rural locations. Age, sex, and diagnosis, according to history and physical examination, were recorded for each patient. A total of 1071 cases of skin disease were seen in 858 patients. The frequency of parasitic, viral, and fungal infections was 34.5%. Dermatitis and eczema (24.6%) were the next most prevalent conditions, followed by disorders of skin appendages (12.2%), photosensitivity disorders (5.4%), papulosquamous disorders (3.2%), urticaria and erythema (1.5%), bacterial infections of the skin and subcutaneous tissue (1.2%), and neoplastic disorders (2.1%). The most frequently seen single diagnoses were viral warts (12.2%), scabies (8.7%), acne (7.4%), dermatophytosis (6.8%), contact dermatitis (3.5%), and nummular eczema (3.5%). Infectious diseases, acne, and eczemas are the most common skin disorders seen in dermatology clinics in rural Yucatan, Mexico. Our findings may be useful in the development of public health initiatives targeting rural communities in this region. © 2012 The International Society of Dermatology.

  17. Pathophysiological Mechanisms in Sclerosing Skin Diseases

    PubMed Central

    Eckes, Beate; Wang, Fang; Moinzadeh, Pia; Hunzelmann, Nicolas; Krieg, Thomas

    2017-01-01

    Sclerosing skin diseases represent a large number of distinct disease entities, which include systemic sclerosis, localized scleroderma, and scleredema adultorum. These pathologies have a common clinical appearance and share histological features. However, the specific interplay between cytokines and growth factors, which activate different mesenchymal cell populations and production of different extracellular matrix components, determines the biomechanical properties of the skin and the clinical features of each disease. A better understanding of the mechanisms underlying these events is prerequisite for developing novel targeted therapeutic approaches. PMID:28868289

  18. Laser treatment for skin disease

    NASA Astrophysics Data System (ADS)

    Bloznelyte-Plesniene, Laima; Cepulis, Vytautas; Ponomarev, Igor V.

    1996-12-01

    The correct selection of patients is the most difficult part of the laser treatment. Since 1985 the total number of patients treated by us using different laser systems was 1544. High power lasers: Nd:YAG and CO2 lasers were used by us for surgical treatment. Low power lasers: Helium-Neon, Copper vapor, gold vapor and dye lasers were applied by us to PDT or to treatment of port wine hemangiomas. this paper reports our efforts in selecting the patients with different skin lesions for the treatment with different laser systems.

  19. The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain.

    PubMed

    Choi, L; Vernon, J; Kopach, O; Minett, M S; Mills, K; Clayton, P T; Meert, T; Wood, J N

    2015-05-06

    Fabry disease is an X-linked lysosomal storage disorder characterised by accumulation of glycosphingolipids, and accompanied by clinical manifestations, such as cardiac disorders, renal failure, pain and peripheral neuropathy. Globotriaosylsphingosine (lyso-Gb3), a deacylated form of globotriaosylceramide (Gb3), has emerged as a marker of Fabry disease. We investigated the link between Gb3, lyso-Gb3 and pain. Plantar administration of lyso-Gb3 or Gb3 caused mechanical allodynia in healthy mice. In vitro application of 100nM lyso-Gb3 caused uptake of extracellular calcium in 10% of sensory neurons expressing nociceptor markers, rising to 40% of neurons at 1μM, a concentration that may occur in Fabry disease patients. Peak current densities of voltage-dependent Ca(2+) channels were substantially enhanced by application of 1μM lyso-Gb3. These studies suggest a direct role for lyso-Gb3 in the sensitisation of peripheral nociceptive neurons that may provide an opportunity for therapeutic intervention in the treatment of Fabry disease-associated pain.

  20. Skin equivalents: skin from reconstructions as models to study skin development and diseases.

    PubMed

    Ali, N; Hosseini, M; Vainio, S; Taïeb, A; Cario-André, M; Rezvani, H R

    2015-08-01

    While skin is readily available for sampling and direct studies of its constituents, an important intermediate step is to design in vitro and/or in vivo models to address scientific or medical questions in dermatology and skin biology. Pioneered more than 30 years ago, human skin equivalents (HSEs) have been refined with better cell culture techniques and media, together with sophisticated cell biology tools including genetic engineering and cell reprogramming. HSEs mimic key elements of human skin biology and have been instrumental in demonstrating the importance of cell-cell interactions in skin homeostasis and the role of a complex cellular microenvironment to coordinate epidermal proliferation, differentiation and pigmentation. HSEs have a wide field of applications from cell biology to dermocosmetics, modelling diseases, drug development, skin ageing, pathophysiology and regenerative medicine. In this article we critically review the major current approaches used to reconstruct organotypic skin models and their application with a particular emphasis on skin biology and pathophysiology of skin disorders. © 2015 British Association of Dermatologists.

  1. Eosinophilic Skin Diseases: A Comprehensive Review.

    PubMed

    Long, Hai; Zhang, Guiying; Wang, Ling; Lu, Qianjin

    2016-04-01

    Eosinophilic skin diseases, commonly termed as eosinophilic dermatoses, refer to a broad spectrum of skin diseases characterized by eosinophil infiltration and/or degranulation in skin lesions, with or without blood eosinophilia. The majority of eosinophilic dermatoses lie in the allergy-related group, including allergic drug eruption, urticaria, allergic contact dermatitis, atopic dermatitis, and eczema. Parasitic infestations, arthropod bites, and autoimmune blistering skin diseases such as bullous pemphigoid, are also common. Besides these, there are several rare types of eosinophilic dermatoses with unknown origin, in which eosinophil infiltration is a central component and affects specific tissue layers or adnexal structures of the skin, such as the dermis, subcutaneous fat, fascia, follicles, and cutaneous vessels. Some typical examples are eosinophilic cellulitis, granuloma faciale, eosinophilic pustular folliculitis, recurrent cutaneous eosinophilic vasculitis, and eosinophilic fasciitis. Although tissue eosinophilia is a common feature shared by these disorders, their clinical and pathological properties differ dramatically. Among these rare entities, eosinophilic pustular folliculitis may be associated with human immunodeficiency virus (HIV) infection or malignancies, and some other diseases, like eosinophilic fasciitis and eosinophilic cellulitis, may be associated with an underlying hematological disorder, while others are considered idiopathic. However, for most of these rare eosinophilic dermatoses, the causes and the pathogenic mechanisms remain largely unknown, and systemic, high-quality clinical investigations are needed for advances in better strategies for clinical diagnosis and treatment. Here, we present a comprehensive review on the etiology, pathogenesis, clinical features, and management of these rare entities, with an emphasis on recent advances and current consensus.

  2. Correction in trans for Fabry disease: expression, secretion and uptake of alpha-galactosidase A in patient-derived cells driven by a high-titer recombinant retroviral vector.

    PubMed Central

    Medin, J A; Tudor, M; Simovitch, R; Quirk, J M; Jacobson, S; Murray, G J; Brady, R O

    1996-01-01

    Fabry disease is an X-linked metabolic disorder due to a deficiency of alpha-galactosidase A (alpha-gal A; EC 3.2.1.22). Patients accumulate glycosphingolipids with terminal alpha-galactosyl residues that come from intracellular synthesis, circulating metabolites, or from the biodegradation Of senescent cells. Patients eventually succumb to renal, cardio-, or cerebrovascular disease. No specific therapy exists. One possible approach to ameliorating this disorder is to target corrective gene transfer therapy to circulating hematopoietic cells. Toward this end, an amphotropic virus-producer cell line has been developed that produces a high titer (>10(6) i.p. per ml) recombinant retrovirus constructed to transduce and correct target cells. Virus-producer cells also demonstrate expression of large amounts of both intracellular and secreted alpha-gal A. To examine the utility of this therapeutic vector, skin fibroblasts from Fabry patients were corrected for the metabolic defect by infection with this recombinant virus and secreted enzyme was observed. Furthermore, the secreted enzyme was found to be taken up by uncorrected cells in a mannose-6-phosphate receptor-dependent manner. In related experiments, immortalized B cell lines from Fabry patients, created as a hematologic delivery test system, were transduced. As with the fibroblasts, transduced patient B cell lines demonstrated both endogenous enzyme correction and a small amount of secretion together with uptake by uncorrected cells. These studies demonstrate that endogenous metabolic correction in transduced cells, combined with secretion, may provide a continuous source of corrective material in trans to unmodified patient bystander cells (metabolic cooperativity). Images Fig. 2 Fig. 3 Fig. 4 Fig. 6 PMID:8755577

  3. Early diastolic mitral annular velocity and color M-mode flow propagation velocity in the evaluation of left ventricular diastolic function in patients with Fabry disease.

    PubMed

    Palecek, Tomas; Linhart, Ales; Lubanda, Jean Claude; Magage, Sudheera; Karetova, Debora; Bultas, Jan; Aschermann, Michael

    2006-01-01

    Fabry disease is an X-linked genetic disorder characterized by progressive intracellular accumulation of neutral glycosphingolipids. Cardiac involvement is frequent and left ventricular (LV) diastolic dysfunction is present in most of the affected subjects. Pulsed-wave tissue Doppler echocardiography (PW-TDE) and color M-mode are new Doppler methods for LV diastolic function evaluation. Their role in the assessment of Fabry disease-related cardiomyopathy remains to be established. In this study we aimed to determine the utility of PW-TDE and color M-mode-derived parameters in the assessment of LV diastolic function in patients with Fabry disease. Eighty-one echocardiographic examinations performed in 35 patients affected by Fabry disease were retrospectively analyzed. Early diastolic lateral mitral annular velocity (E(m)) determined by PW-TDE and color M-mode flow propagation velocity (V(p)) were measured and compared to LV filling patterns obtained using standard Doppler indexes. The receiver operating characteristics (ROC) curves method was used to determine the summary measure of relative accuracy for E(m) and V(p). A comparison of ROC curves showed a significant difference for areas under the curve in favor of E(m) (P < 0.001). Pseudonormal filling pattern, higher LV mass index, higher relative wall thickness, larger left atrial diameter, and older age were more frequent (all P < 0.001) in patients with incorrect diagnosis of normal LV diastolic function based on the measurement of V(p). E(m) appears to be superior to V(p) in the assessment of LV diastolic function in patients with Fabry disease. V(p) fails to detect abnormal LV diastolic function in subjects with pronounced concentric LV remodeling and pseudonormal filling pattern.

  4. Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns.

    PubMed

    Lee, Beom Hee; Heo, Sun Hee; Kim, Gu-Hwan; Park, Jung-Young; Kim, Woo-Shik; Kang, Duk-Hee; Choe, Kyung Hoon; Kim, Won-Ho; Yang, Song Hyun; Yoo, Han-Wook

    2010-08-01

    Fabry disease is caused by an alpha-galactosidase A (GLA) deficiency. In this study, we identified 28 unrelated Korean families with Fabry disease with 25 distinct mutations in the GLA gene including six novel mutations (p.W47X, p.C90X, p.D61EfsX32, IVS4(-11)T>A, p.D322E and p.W349). Notably, five subjects from four unrelated families carried the p.E66Q variant, previously known as a pathogenic mutation in atypical Fabry disease. Among these patients, only one had proteinuria and two had hypertrophic cardiomyopathy without any other systemic manifestation of Fabry disease. Substantial residual GLA activity was shown both in the leukocytes of p.E66Q patients (19.0-30.3% of normal activity) and in transiently overexpressed COS-7 cells (43.8 + or - 3.03% of normal activity). Although GLA harboring p.E66Q is unstable at neutral pH, the enzyme is efficiently expressed in the lysosomes of COS-7 cells. The location of p.E66 is distant from both the active site and the dimer interface, and has a more accessible surface area than have other mutations of atypical Fabry disease. In addition, the allele frequency of p.E66Q determined in 833 unrelated Korean individuals was remarkably high at 1.046% (95% confidence interval, 0.458-1.634%). These results indicate that p.E66Q is a functional polymorphism rather than a pathogenic mutation.

  5. Two-dimensional speckle tracking as a non-invasive tool for identification of myocardial fibrosis in Fabry disease.

    PubMed

    Krämer, Johannes; Niemann, Markus; Liu, Dan; Hu, Kai; Machann, Wolfram; Beer, Meinrad; Wanner, Christoph; Ertl, Georg; Weidemann, Frank

    2013-06-01

    This cross-sectional study aimed to analyse myocardial deformation in patients with Fabry disease (FD) in order to evaluate speckle tracking as a method for non-invasive determination of myocardial fibrosis. Myocardial fibrosis is common in Fabry cardiomyopathy and is associated with disease progression and severe prognosis. In 101 consecutive Fabry patients (39.8 ± 12.9 years; 42 males), the quantitative measurement of myocardial fibrosis with magnetic resonance imaging was compared with regional myocardial deformation assessed by speckle-tracking imaging. Patients were analysed in relation to per cent of late-enhancement (LE)-positive areas of left-ventricular (LV) mass. Fifty-two patients (51%) displayed LE with a mean volume of 1.2 ± 1.8% of total LV mass. Predominantly basal lateral and posterior segments were affected. Patients with LE had lower global systolic longitudinal strain than those without (LE -14.8 ± 3.5% and -18.9 ± 2.1%, respectively; P < 0.001). Loss of global deformation, quantified by speckle tracking, was predominantly caused by basal posterior (P = 0.049) and lateral (P = 0.005) segments and global systolic strain correlated with the amount of LE (r = 0.543; P < 0.001). Patients with severe LE (>2%, n = 22) showed the lowest deformation values (-5.9 ± 8.4%) in basal postero-lateral segments when compared with those with mild (<2%; n = 30, -7.1 ± 7.5%) or no LE (n = 49, -16.3 ± 3.3%). These changes were accompanied by thinning of the posterior wall and a decrease in diastolic function, whereas ejection fraction and LV end-diastolic diameter were not different. Receiver operating characteristic analysis revealed that the systolic strain of basal postero-lateral segments was the most powerful predictor to distinguish between patients with and without LE (sensitivity = 90%; specificity = 97%, area under the curve = 0.913; P < 0.001). Late enhancement is associated with lower longitudinal strain in the fibrotic wall segments. Speckle

  6. The Coexistence of Multiple Myeloma-associated Amyloid Light-chain Amyloidosis and Fabry Disease in a Hemodialysis Patient.

    PubMed

    Taguchi, Kensei; Moriyama, Atsuo; Kodama, Goh; Nakayama, Yosuke; Fukami, Kei

    2017-01-01

    Fabry disease (FD) is an inherited lysosomal disorder caused by an X-linked α-galactosidase A deficiency. We report the case of a 50-year-old male FD patient on hemodialysis who presented with macroglossia-related speaking difficulty and gastrointestinal symptoms. An endoscopic analysis revealed multiple gastric ulcers, and a histological examination led to a diagnosis of amyloid light-chain amyloidosis. Serum free light-chain and bone marrow analyses detected multiple myeloma (MM). Treatment with bortezomib and dexamethasone significantly improved the patient's symptoms. This is the first case to demonstrate a potential pathogenic relationship between FD and MM. The similar gastrointestinal manifestations might have contributed to the diagnostic difficulty.

  7. Influence of skin diseases on fingerprint recognition.

    PubMed

    Drahansky, Martin; Dolezel, Michal; Urbanek, Jaroslav; Brezinova, Eva; Kim, Tai-hoon

    2012-01-01

    There are many people who suffer from some of the skin diseases. These diseases have a strong influence on the process of fingerprint recognition. People with fingerprint diseases are unable to use fingerprint scanners, which is discriminating for them, since they are not allowed to use their fingerprints for the authentication purposes. First in this paper the various diseases, which might influence functionality of the fingerprint-based systems, are introduced, mainly from the medical point of view. This overview is followed by some examples of diseased finger fingerprints, acquired both from dactyloscopic card and electronic sensors. At the end of this paper the proposed fingerprint image enhancement algorithm is described.

  8. Influence of Skin Diseases on Fingerprint Recognition

    PubMed Central

    Drahansky, Martin; Dolezel, Michal; Urbanek, Jaroslav; Brezinova, Eva; Kim, Tai-hoon

    2012-01-01

    There are many people who suffer from some of the skin diseases. These diseases have a strong influence on the process of fingerprint recognition. People with fingerprint diseases are unable to use fingerprint scanners, which is discriminating for them, since they are not allowed to use their fingerprints for the authentication purposes. First in this paper the various diseases, which might influence functionality of the fingerprint-based systems, are introduced, mainly from the medical point of view. This overview is followed by some examples of diseased finger fingerprints, acquired both from dactyloscopic card and electronic sensors. At the end of this paper the proposed fingerprint image enhancement algorithm is described. PMID:22654483

  9. Effects of climate changes on skin diseases.

    PubMed

    Balato, Nicola; Megna, Matteo; Ayala, Fabio; Balato, Anna; Napolitano, Maddalena; Patruno, Cataldo

    2014-02-01

    Global climate is changing at an extraordinary rate. Climate change (CC) can be caused by several factors including variations in solar radiation, oceanic processes, and also human activities. The degree of this change and its impact on ecological, social, and economical systems have become important matters of debate worldwide, representing CC as one of the greatest challenges of the modern age. Moreover, studies based on observations and predictive models show how CC could affect human health. On the other hand, only a few studies focus on how this change may affect human skin. However, the skin is the most exposed organ to environment; therefore, it is not surprising that cutaneous diseases are inclined to have a high sensitivity to climate. The current review focuses on the effects of CC on skin diseases showing the numerous factors that are contributing to modify the incidence, clinical pattern and natural course of some dermatoses.

  10. A modified lipid composition in Fabry disease leads to an intracellular block of the detergent-resistant membrane-associated dipeptidyl peptidase IV.

    PubMed

    Maalouf, Katia; Jia, Jia; Rizk, Sandra; Brogden, Graham; Keiser, Markus; Das, Anibh; Naim, Hassan Y

    2010-08-01

    Fabry disease is an X-linked lysosomal storage disorder that leads to abnormal accumulation of glycosphingolipids due to a deficiency of alpha-galactosidase A (AGAL). The consequences of these alterations on the targeting of membrane proteins are poorly understood. Glycosphingolipids are enriched in Triton-X-100- resistant lipid rafts [detergent-resistant membranes (DRMs)] and play an important role in the transport of several membrane-associated proteins. Here, we show that In fibroblasts of patients suffering from Fabry disease, the colocalization of AGAL with the lysosomal marker LAMP2 is decreased compared with wild-type fibroblasts concomitant with a reduced transport of AGAL to lysosomes. Furthermore, overall composition of membrane lipids in the patients' fibroblasts as well as in DRMs reveals a substantial increase in the concentration of glycolipids and a slight reduction of phosphatidylethanolamine (PE). The altered glycolipid composition in Fabry fibroblasts is associated with an intracellular accumulation and impaired trafficking of the Triton-X-100 DRM-associated membrane glycoprotein dipeptidyl peptidase IV (DPPIV) in transfected Fabry cells, whereas no effect could be observed on the targeting of aminopeptidase N (ApN) that is not associated with this type of DRM. We propose that changes in the lipid composition of cell membranes in Fabry disease disturb the ordered Triton X-100 DRMs and have implications on the trafficking and sorting of DRM-associated proteins and the overall protein-lipid interaction at the cell membrane. Possible consequences could be altered signalling at the cell surface triggered by DRM-associated proteins, with implications on gene regulation and subsequent protein expression.

  11. Viral skin diseases of the rabbit.

    PubMed

    Meredith, Anna L

    2013-09-01

    This article describes the viral skin diseases affecting the domestic rabbit, the most important being myxomatosis. Transmission and pathogenesis, clinical signs, diagnosis, treatment, and control are described and the article will be of interest to veterinary practitioners who treat rabbits. Shope fibroma virus, Shope papilloma virus, and rabbitpox are also discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Skin Manifestations of Inflammatory Bowel Disease

    PubMed Central

    Huang, Brian L.; Chandra, Stephanie; Shih, David Quan

    2012-01-01

    Inflammatory bowel disease (IBD) is a disease that affects the intestinal tract via an inflammatory process. Patients who suffer from IBD often have diseases that affect multiple other organ systems as well. These are called extraintestinal manifestations and can be just as, if not more debilitating than the intestinal inflammation itself. The skin is one of the most commonly affected organ systems in patients who suffer from IBD. The scientific literature suggests that a disturbance of the equilibrium between host defense and tolerance, and the subsequent over-activity of certain immune pathways are responsible for the cutaneous disorders seen so frequently in IBD patients. The purpose of this review article is to give an overview of the types of skin diseases that are typically seen with IBD and their respective pathogenesis, proposed mechanisms, and treatments. These cutaneous disorders can manifest as metastatic lesions, reactive processes to the intestinal inflammation, complications of IBD itself, or side effects from IBD treatments; these can be associated with IBD via genetic linkage, common autoimmune processes, or other mechanisms that will be discussed in this article. Ultimately, it is important for healthcare providers to understand that skin manifestations should always be checked and evaluated for in patients with IBD. Furthermore, skin disorders can predate gastrointestinal symptoms and thus may serve as important clinical indicators leading physicians to earlier diagnosis of IBD. PMID:22347192

  13. Managing Amphibian Disease with Skin Microbiota.

    PubMed

    Woodhams, Douglas C; Bletz, Molly; Kueneman, Jordan; McKenzie, Valerie

    2016-03-01

    The contribution of emerging amphibian diseases to the sixth mass extinction is driving innovative wildlife management strategies, including the use of probiotics. Bioaugmentation of the skin mucosome, a dynamic environment including host and microbial components, may not provide a generalized solution. Multi-omics technologies and ecological context underlie effective implementation.

  14. Managing Amphibian Disease with Skin Microbiota.

    PubMed

    Woodhams, Douglas C; Bletz, Molly; Kueneman, Jordan; McKenzie, Valerie

    2016-01-16

    The contribution of emerging amphibian diseases to the sixth mass extinction is driving innovative wildlife management strategies, including the use of probiotics. Bioaugmentation of the skin mucosome, a dynamic environment including host and microbial components, may not provide a generalized solution. Multi-omics technologies and ecological context underlie effective implementation.

  15. [Skin diseases in geriatric patients. Epidemiologic data].

    PubMed

    Makrantonaki, E; Liakou, A I; Eckardt, R; Zens, M; Steinhagen-Thiessen, E; Zouboulis, C C

    2012-12-01

    The incidence of skin diseases more common in older patients, e.g. inflammatory and autoimmune diseases, benign and malignant tumors and paraneoplastic syndromes, is increasing worldwide rapidly mainly due to early or lifelong UV-overexposure and to an aging population. In order to transform this demographic change into a chance a better understanding of the pathomechanisms of these diseases, an early diagnosis and therapy are essential steps. In addition, a joint effort to raise public awareness, patient education, preventive measures and consistent monitoring of high-risk groups is of great importance. In this article, the relationship between aging and associated skin diseases will be presented with a particular focus on the epidemiology and risk factors.

  16. Tropical skin diseases in British military personnel.

    PubMed

    Bailey, Mark S

    2013-09-01

    Skin complaints are common in travellers to foreign countries and are responsible for up to 25% of medical consultations by military personnel during deployments in the tropics. They also have relatively high rates of field hospital admission, medical evacuation and referral to UK Role 4 healthcare facilities. Non-infectious tropical skin diseases include sunburn, heat rash, arthropod bites, venomous bites, contact dermatitis and phytophotodermatitis. During tropical deployments skin infections that commonly occur in military personnel may become more frequent, severe and difficult to treat. Several systemic tropical infections have cutaneous features that can be useful in making early diagnoses. Tropical skin infections such as cutaneous larva migrans, cutaneous myiasis, cutaneous leishmaniasis and leprosy do occur in British troops and require specialist clinical management. This illustrated review focuses on the most significant tropical skin diseases that have occurred in British military personnel in recent years. Clinical management of these conditions on deployments would be improved and medical evacuations could be reduced if a military dermatology 'reach-back' service (including a telemedicine facility) was available.

  17. DANDRUFF: THE MOST COMMERCIALLY EXPLOITED SKIN DISEASE

    PubMed Central

    Ranganathan, S; Mukhopadhyay, T

    2010-01-01

    The article discuss in detail about the prevalence, pathophysiology, clinical manifestations of dandruff including the etio-pathology. The article also discusses in detail about various treatment methods available for dandruff. The status of dandruff being amphibious – a disease/disorder, and relatively less medical intervention is sought after for the treatment, dandruff is the most commercially exploited skin and scalp disorder/disease by personal care industries. PMID:20606879

  18. 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.

  19. Solid Lipid Nanoparticles as Non-Viral Vectors for Gene Transfection in a Cell Model of Fabry Disease.

    PubMed

    Ruiz de Garibay, A P; Solinís, M A; del Pozo-Rodríguez, A; Apaolaza, P S; Shen, J S; Rodríguez-Gascón, A

    2015-03-01

    Here, we demonstrate the ability of solid lipid nanoparticle-based non-viral vectors to increase the α-galactosidase A levels of the IMFE1 cell line, an in vitro model for target cells in Fabry disease. For this purpose, vectors containing the pR-M10-αGal A plasmid, which encodes the α-galactosidase A enzyme, were prepared; the in vitro transfection efficacy was studied in IMFE1 cells, and the results were confirmed by RT-PCR. The cellular uptake of the vectors, intracellular disposition of the plasmid, and probable endocytosis pathways of the nanoparticles were also analyzed. The vectors used for the studies carried protamine (P-DNA-SLN), dextran and protamine (D-P-DNA-SLN), or hyaluronic acid of two different molecular weights and protamine (HA150-P-DNA-SLN or HA500-P-DNA-SLN). The new formulations, which presented a particle size in the range of nanometers (from 218 nm to 348 nm) and a positive superficial charge, were able to increase α-galactosidase A activity up to 4-fold in comparison to non treated IMFE1 cells. The most efficient vectors were those that included HA, and no differences due to changes in the molecular weight of HA were detected. The observed lack of colocalization with each of the four different Nile Red-labeled vectors and transferrin or cholera toxin appears to indicate that clathrin- and caveolae-independent pathways may be involved in their cellular uptake. Additionally, colocalization with LysoTracker indicated that the formulations were exposed to lysosomal activity, which may be responsible for the release of the plasmid from the vector. In conclusion, we reveal the potential of SLN-based vectors to efficiently transfect an immortalized Fabry patient cell line.

  20. To see a world in a grain of sand: elucidating the pathophysiology of Anderson-Fabry disease through investigations of a cellular model.

    PubMed

    Pastores, Gregory M; Hughes, Derralynn A

    2009-02-01

    Thomaidis and colleagues have created a cellular model of Anderson-Fabry disease by 'silencing' alpha-galactosidase A (AGAL) activity in human tubular epithelial cells. Increased membrane globotriaosylceramide (Gb3/CD77) expression was observed; it is suggested that this finding may be potentially useful as a surrogate marker of disease severity. Decreased membrane Gb3/CD77 expression was observed following agalsidase-alpha treatment, providing evidence of changes in cellular phenotype in response to enzyme therapy.

  1. Air pollution and skin diseases: Adverse effects of airborne particulate matter on various skin diseases.

    PubMed

    Kim, Kyung Eun; Cho, Daeho; Park, Hyun Jeong

    2016-05-01

    Environmental air pollution encompasses various particulate matters (PMs). The increased ambient PM from industrialization and urbanization is highly associated with morbidity and mortality worldwide, presenting one of the most severe environmental pollution problems. This article focuses on the correlation between PM and skin diseases, along with related immunological mechanisms. Recent epidemiological studies on the cutaneous impacts of PM showed that PM affects the development and exacerbation of skin diseases. PM induces oxidative stress via production of reactive oxygen species and secretion of pro-inflammatory cytokines such as TNF-α, IL-1α, and IL-8. In addition, the increased production of ROS such as superoxide and hydroxyl radical by PM exposure increases MMPs including MMP-1, MMP-2, and MMP-9, resulting in the degradation of collagen. These processes lead to the increased inflammatory skin diseases and skin aging. In addition, environmental cigarette smoke, which is well known as an oxidizing agent, is closely related with androgenetic alopecia (AGA). Also, ultrafine particles (UFPs) including black carbon and polycyclic aromatic hydrocarbons (PAHs) enhance the incidence of skin cancer. Overall, increased PM levels are highly associated with the development of various skin diseases via the regulation of oxidative stress and inflammatory cytokines. Therefore, anti-oxidant and anti-inflammatory drugs may be useful for treating PM-induced skin diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Reflectance confocal microscopy for inflammatory skin diseases.

    PubMed

    Ardigò, M; Prow, T; Agozzino, M; Soyer, P; Berardesca, E

    2015-10-01

    Reflectance confocal microscopy evaluation of inflammatory skin diseases represents a relatively new indication that, during the last 5 years, has shown an increasing interest with consequent progressive increment of publications in literature. The success of RCM in this filed of dermatology is directly related to the high needing of non-invasive techniques able to reduce the number of skin biopsies and support the clinical diagnosis and patient's management. RCM demonstrated to visualize microscopic descriptors of inflammatory and pigmentary skin conditions with good reproducibility between observer and high grade of correspondence with optical histology. Moreover, RCM has shown to provide sufficient data to support clinical diagnosis and differential diagnosis of inflammatory and pigmentary skin diseases. Recently, several works published in literature have opened the prospective to use RCM also for therapeutic follow-up in order to monitor the improvement of the microscopic parameters and help to prevent treatment side effects. In this review article we present some examples of RCM application in inflammatory and pigmentary diseases.

  3. 9 CFR 311.6 - Diamond-skin disease.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Diamond-skin disease. 311.6 Section... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.6 Diamond-skin disease. Carcasses of hogs affected with diamond-skin disease when localized and not associated with systemic...

  4. 9 CFR 311.6 - Diamond-skin disease.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Diamond-skin disease. 311.6 Section... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.6 Diamond-skin disease. Carcasses of hogs affected with diamond-skin disease when localized and not associated with systemic...

  5. 9 CFR 311.6 - Diamond-skin disease.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Diamond-skin disease. 311.6 Section... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.6 Diamond-skin disease. Carcasses of hogs affected with diamond-skin disease when localized and not associated with systemic...

  6. 9 CFR 311.6 - Diamond-skin disease.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Diamond-skin disease. 311.6 Section... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.6 Diamond-skin disease. Carcasses of hogs affected with diamond-skin disease when localized and not associated with systemic...

  7. 9 CFR 311.6 - Diamond-skin disease.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Diamond-skin disease. 311.6 Section... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.6 Diamond-skin disease. Carcasses of hogs affected with diamond-skin disease when localized and not associated with systemic...

  8. Oxidative stress and autoimmune skin disease.

    PubMed

    Shah, Amit Aakash; Sinha, Animesh A

    2013-01-01

    Antioxidants play the important role in our body of neutralizing free radicals and peroxides that are formed during normal physiologic events. While these reactive oxygen species are necessary for numerous biological processes, when created in excess they can have deleterious effects. The skin as an organ is constantly under attack by reactive oxygen species from both endogenous and exogenous sources. The pathophysiology of many autoimmune diseases is unknown and recently oxidative stress has come to light as a possible triggering mechanism. Recent investigations attempting to link autoimmune skin diseases and oxidative stress have had varying degrees of success. In this article, we review the current literature regarding antioxidants in alopecia areata, pemphigus vulgaris and other blistering diseases, vitiligo, and psoriasis, and suggest possible future studies and treatment options.

  9. Immunology and Skin in Health and Disease

    PubMed Central

    Richmond, Jillian M.; Harris, John E.

    2014-01-01

    The skin is a complex organ that, in addition to providing a strong barrier against external insults, serves as an arena for a wide variety of inflammatory processes, including immunity against infections, tumor immunity, autoimmunity, and allergy. A variety of cells collaborate to mount functional immune responses, which are initiated by resident populations and evolve through the recruitment of additional cell populations to the skin. Inflammatory responses are quite diverse, resulting in a wide range of signs and symptoms that depend on the initiating signals, characteristics of the infiltrating cell populations, and cytokines that are produced (cytokines are secreted protein that allows for cell–cell communication; usually refers to communication between immune–immune cells or stromal–immune cells). In this work, we will review the skin architecture and resident and recruited cell populations and discuss how these populations contribute to inflammation using human diseases and treatments when possible to illustrate their importance within a clinical context. PMID:25452424

  10. Global cardiac alterations detected by speckle-tracking echocardiography in Fabry disease: left ventricular, right ventricular, and left atrial dysfunction are common and linked to worse symptomatic status.

    PubMed

    Morris, Daniel A; Blaschke, Daniela; Canaan-Kühl, Sima; Krebs, Alice; Knobloch, Gesine; Walter, Thula C; Haverkamp, Wilhelm

    2015-02-01

    The aim of this study was to test the hypothesis that in patients with Fabry disease, 2D speckle-tracking echocardiography (2DSTE) could detect functional myocardial alterations such as left ventricular (LV), right ventricular (RV), and left atrial (LA) dysfunction, even when conventional cardiac measurements are normal. In addition, we hypothesized that these global cardiac alterations could be linked to worse symptomatic status in these patients. Fifty patients with Fabry disease and a control group of 118 healthy subjects of similar age and gender were included. The myocardial function and structural changes of the LV, RV, and LA were analyzed by 2DSTE and cardiac magnetic resonance imaging. Patients with Fabry disease had significantly lower functional myocardial values of the LV, RV, and LA than healthy subjects (LV, RV, and LA strain -18.1 ± 4.0, -21.4 ± 4.9, and 29.7 ± 9.9 % vs. -21.6 ± 2.2, -25.2 ± 4.0, and 44.8 ± 11.1 %, respectively, P < 0.001) and elevated rates of LV, RV, and LA myocardial dysfunction (24, 20, and 26 %, respectively), even when conventional cardiac measurements such as LVEF, TAPSE, and LAVI were normal. LV septal wall thickness ≥15 mm, RV free wall thickness ≥7 mm, and LV longitudinal dysfunction were the principal factors linked to reduced LV, RV, and LA strain, respectively. In addition, but to a lesser extent, LV and RV fibrosis were linked to reduced LV and RV strain. Patients with reduced LV, RV, and LA strain had worse functional class (dyspnea-NYHA classification) than those with normal cardiac function. In conclusion, in patients with Fabry disease, 2DSTE analyses detect LV, RV, and LA functional myocardial alterations, even when conventional cardiac measurements are normal. These functional myocardial alterations are common and significantly associated with worse symptomatic status in Fabry patients. Therefore, these findings provide important evidence to introduce global myocardial analyses using 2DSTE in the early

  11. Twenty-four-month alpha-galactosidase A replacement therapy in Fabry disease has only minimal effects on symptoms and cardiovascular parameters.

    PubMed

    Koskenvuo, J W; Hartiala, J J; Nuutila, P; Kalliokoski, R; Viikari, J S; Engblom, E; Penttinen, M; Knuuti, J; Mononen, I; Kantola, I M

    2008-06-01

    Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A enzyme activity. Decreased enzyme activity leads to accumulation of glycosphingolipids in different tissues including endothelial cells and smooth-muscle cells and cardiomyocytes, and cardiovascular complications are common in the disease. Since 2001, specific enzyme replacement therapy (ERT) with alpha-galactosidase A has been available. It has been reported to improve clinical symptoms and quality of life. However, limited and controversial data on its efficacy to cardiac involvement have been published. Nine patients (5 male) with Fabry disease were included in an open-label prospective follow-up study of 24-month ERT. Comprehensive cardiovascular evaluation was performed by MRI, stress echocardiography and quality of life assessment. Plasma globotriaosylceramide decreased from 6.2 to 1.4 microg/ml during ERT (p<0.05). The only other measured parameters that changed significantly were resting heart rate that decreased from 79 to 67 bpm (p<0.01) and end-systolic volume that decreased by 12.4 ml (p<0.05). The other parameters consisting of quality of life, self-estimated cardiovascular condition, diastolic function, exercise capacity, ECG parameters, ejection fraction and ventricular mass did not change. ERT has only minimal effect on symptoms and cardiovascular morphology and function in Fabry disease. Therefore, effective conventional medical therapy is still of major importance in Fabry disease. Larger ERT studies are warranted, especially in women, to solve current open questions, such as the age at which ERT should be started, optimal dosage and intervals between infusions. Furthermore, longer follow-up studies are needed to assess the effects of ERT on prognosis.

  12. 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 (Gb3 ) 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.

  13. Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females.

    PubMed

    Gutiérrez-Amavizca, B E; Orozco-Castellanos, R; R Padilla-Gutiérrez, J; Valle, Y; Figuera, L E

    2014-08-28

    Fabry disease (FD) is an X-linked lysosomal storage disease caused by α-galactosidase A deficiency; in contrast to other X-linked diseases, heterozygous females can be as affected as men. The construction and analysis of a family pedigree is a powerful tool to aid clinicians in diagnosis, establishment of inheritance pattern, and early detection of potentially affected relatives. The present study highlights the importance of pedigree analysis in families with FD for identifying other possibly affected relatives and investigating the clinical manifestations. This clinical report included 12 Mexican index cases with confirmed FD diagnosis. We constructed and analyzed their pedigree, and diagnosed FD in 24 affected relatives. Clinical features were similar to those reported for other populations. Pedigree analysis further identified an additional 30 women as possible carriers. We conclude that pedigree construction and analysis is a useful tool to help physicians detect and diagnose relatives at risk for FD, particularly heterozygous females, so that they can receive genetic counseling and early treatment. Mexican families with FD were similar to other populations reported in the literature, and our findings confirmed that heterozygous females can have signs and symptoms ranging from subtle manifestations to the classical severe presentation described in males.

  14. GLA variation p.E66Q identified as the genetic etiology of Fabry disease using exome sequencing.

    PubMed

    Peng, Hao; Xu, Xiaojuan; Zhang, Lusi; Zhang, Xuehong; Peng, Hexiang; Zheng, Yu; Luo, Sanchuan; Guo, Hui; Xia, Kun; Li, Jiada; Yao, Hongliang; Hu, Zhengmao

    2016-01-10

    Fabry disease (FD) was an X-linked lysosomal storage disorder resulting from a deficiency in glycosphingolipid catabolism caused by mutations in the α-galactosidase A gene GLA. Variant FD patients did not present with classical symptoms during childhood and were undiagnosed or misdiagnosed with other kidney diseases, such as chronic glomerulonephritis (CGN). In this study, we utilized exome sequencing and Sanger sequencing identified the variation p.E66Q of GLA completely co-segregated with the disease phenotype in a Chinese family, which previously been diagnosed as possible CGN. Female patients exhibited preferential X-chromosome inactivation (XCI) of the normal p.E66 allele, as indicated by XCI analysis. By measuring α-Gal A activity, we found that male patients in the pedigree had just little enzymatic activity while female patients had residual enzymatic activity. These patients were diagnosed with renal variant FD in subsequent clinical review. Our results directly implicated the GLA mutation p.E66Q as the genetic etiology of the Chinese renal variant FD pedigree.

  15. Skin Diseases: Skin and Sun—Not a good mix

    MedlinePlus

    ... higher. A higher number means longer, stronger protection. Buy products with an SPF of 15 or higher. ... protection, too . The incidence of skin cancer in African Americans and other dark-skinned people is much lower ...

  16. 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

  17. Identification of an Allosteric Binding Site on Human Lysosomal Alpha-Galactosidase Opens the Way to New Pharmacological Chaperones for Fabry Disease

    PubMed Central

    den-Haan, Helena; Pérez-Sánchez, Horacio; Del Prete, Rosita; Liguori, Ludovica; Cimmaruta, Chiara; Lukas, Jan; Andreotti, Giuseppina

    2016-01-01

    Personalized therapies are required for Fabry disease due to its large phenotypic spectrum and numerous different genotypes. In principle, missense mutations that do not affect the active site could be rescued with pharmacological chaperones. At present pharmacological chaperones for Fabry disease bind the active site and couple a stabilizing effect, which is required, to an inhibitory effect, which is deleterious. By in silico docking we identified an allosteric hot-spot for ligand binding where a drug-like compound, 2,6-dithiopurine, binds preferentially. 2,6-dithiopurine stabilizes lysosomal alpha-galactosidase in vitro and rescues a mutant that is not responsive to a mono-therapy with previously described pharmacological chaperones, 1-deoxygalactonojirimycin and galactose in a cell based assay. PMID:27788225

  18. Human skin pigmentation, migration and disease susceptibility

    PubMed Central

    Jablonski, Nina G.; Chaplin, George

    2012-01-01

    Human skin pigmentation evolved as a compromise between the conflicting physiological demands of protection against the deleterious effects of ultraviolet radiation (UVR) and photosynthesis of UVB-dependent vitamin D3. Living under high UVR near the equator, ancestral Homo sapiens had skin rich in protective eumelanin. Dispersals outside of the tropics were associated with positive selection for depigmentation to maximize cutaneous biosynthesis of pre-vitamin D3 under low and highly seasonal UVB conditions. In recent centuries, migrations and high-speed transportation have brought many people into UVR regimes different from those experienced by their ancestors and, accordingly, exposed them to new disease risks. These have been increased by urbanization and changes in diet and lifestyle. Three examples—nutritional rickets, multiple sclerosis (MS) and cutaneous malignant melanoma (CMM)—are chosen to illustrate the serious health effects of mismatches between skin pigmentation and UVR. The aetiology of MS in particular provides insight into complex and contingent interactions of genetic and environmental factors necessary to trigger lethal disease states. Low UVB levels and vitamin D deficiencies produced by changes in location and lifestyle pose some of the most serious disease risks of the twenty-first century. PMID:22312045

  19. Fabry disease: a study of 6 hemizygous men and 5 heterozygous women with emphasis on dermatologic manifestations.

    PubMed

    Larralde, Margarita; Boggio, Paula; Amartino, Hernán; Chamoles, Néstor

    2004-12-01

    To determine the significance of the dermatologic and systemic abnormalities found in 11 patients with Fabry disease (FD) which is an X-linked lysosomal storage disorder caused by the partial or complete deficiency of the alpha-galactosidase A enzyme. This defect leads to the accumulation of uncleaved glycosphingolipids throughout vascular endothelium and visceral tissues. Case series. Pediatric Dermatology Division, Ramos Mejia Hospital (primary care center) and Laboratory of Neurochemistry (referral center for metabolic diseases). Eleven patients with FD were studied: 6 hemizygous men (mean age, 23.0 years) and 5 heterozygous women (mean age, 49.4 years). Mucocutaneous angiokeratomas (AKs) were found in 5 (83%) of 6 hemizygotes and 4 (80%) of 5 heterozygotes. The AKs appeared at an average age of 13 years, affecting predominantly genitalia, back, elbows, and other frequently traumatized areas. All the hemizygotes and none of the heterozygotes suffered from hypohidrosis. Angiokeratomas on the trunk and oral mucosa without sweat abnormalities were detected in 80% of heterozygous women. All hemizygotic men presented with acral pain in childhood. We emphasize the value of early recognition of AKs and hypohidrosis as diagnostic clues to FD, a severe and progressive disorder.

  20. Genetic Screening of Mutations Associated with Fabry Disease in a Nationwide Cohort of Juvenile Idiopathic Arthritis Patients.

    PubMed

    Gonçalves, Maria J; Mourão, Ana F; Martinho, António; Simões, Olívia; Melo-Gomes, José; Salgado, Manuel; Estanqueiro, Paula; Ribeiro, Célia; Brito, Iva; Fonseca, João E; Canhão, Helena

    2017-01-01

    Fabry's disease (FD) is a lysosomal storage disorder associated with an alpha-galactosidase A deficiency. The prevalence of FD among juvenile idiopathic arthritis (JIA) patients with established diagnosis is unknown, but as musculoskeletal pain may be an important complaint at presentation, misdiagnosed cases are anticipated. With this study, we aim to calculate the frequency of FD-associated mutations in a cohort of JIA patients. Children with JIA from a national cohort were selected. Clinical and laboratorial information was recorded in the Portuguese rheumatic diseases register (http://Reuma.pt). Molecular genetic testing to detect GLA gene mutations was performed. After the multiplex polymerase chain reactions technique for DNA amplification, direct sequencing of the complete sequence of GLA gene was completed. From a cohort of 292 patients with JIA (188 females, 104 males), mutations were identified in 5 patients (all female). Four patients had the mutation D313Y, a rare GLA variant, which is associated with low enzymatic levels in plasma, but normal lysosomal levels. One patient presented the missense mutation R118C, which was previously described in Mediterranean patients with FD. This is the first screening of FD mutations in a cohort of JIA patients. No "classic" pathogenic FD mutations were reported. The late-onset FD-associated mutation, R118C, was found in a frequency of 0.34% (1/292).

  1. Skin function and skin disorders in Parkinson's disease.

    PubMed

    Fischer, M; Gemende, I; Marsch, W C; Fischer, P A

    2001-01-01

    Cutaneous symptoms (seborrhoea and hyperhidrosis) in Parkinson's disease were investigated. In 70 treated patients with Parkinson's disease and 22 control subjects, non-invasive bioengineering methods (sebumetry, corneometry, pH) were carried out on the forehead, sternum and forearm. In addition, concomitant dermatoses and medication were recorded. 18.6% of the patients had seborrhoea on the forehead (>220 microg/cm2), 51.4% showed normal sebum values (100-220 microg/cm2) and 30% a sebostasis (<100 microg/cm2). Males has significantly higher sebum values than females. No relationship between the seborrhoea and the therapy for Morbus Parkinson was found. Patients with hyperhidrosis (n = 36) had significantly lower pH values (p < 0.05) on the forehead than those without hyperhidrosis. 22 patients (31.9%) reported a cold/hot flush and a further 13 (18.8%) had clinical rosacea. Seborrhoea is rare in treated Parkinsonian patients but hyperhidrosis is frequently found. Furthermore, a particular lack of vasostability (flush) appears to be an autonomic dysregulation in the skin related to Morbus Parkinson, which has not been studied to any extent to date.

  2. Infections and skin diseases mimicking diaper dermatitis.

    PubMed

    Van Gysel, Dirk

    2016-07-01

    Diaper dermatitis is a common condition that often prompts parents to seek medical attention. Irritant diaper dermatitis is by far the most common cause, but numerous potentially serious diseases can present with changes of the skin in the diaper area. The differential diagnosis can include psoriasis, metabolic disorders, rare immune diseases and infection. Clinical examination can be helpful in distinguishing the underlying cause. General screening laboratory tests, as well as select testing when a specific condition is suspected, can be used to challenge or confirm the putative diagnosis.

  3. Oedematous skin disease of buffalo in Egypt.

    PubMed

    Selim, S A

    2001-05-01

    This review covers a historical view and etiology of oedematous skin disease which affects buffalo in Egypt, the microbiology of Corynebacterium pseudotuberculosis causing the disease: its virulence; clinical signs; mechanism of pathogenesis; histopathology; mode of transmission; immunological aspects; treatment and control. It is concluded that C. pseudotuberculosis serotype II is the main cause of OSD and exotoxin phospholipase D and its lipid contents of the cell wall are the major causes of pathogenesis. After declaring the role of Hippobosca equina in transmission of the causative agent among buffaloes, control of OSD is now available.

  4. Enzyme replacement therapy in a patient of heterozygous Fabry disease: clinical and pathological evaluations by repeat kidney biopsy and a successful pregnancy.

    PubMed

    Iwafuchi, Yoichi; Maruyama, Hiroki; Morioka, Tetsuo; Noda, Seiko; Nagata, Hiroshi; Oyama, Yuko; Narita, Ichiei

    2017-10-10

    Fabry disease is a rare X-linked lysosomal storage disorder of glycosphingolipid catabolism caused by deficient activity of the lysosomal hydrolase alpha-galactosidase A (ɑ-Gal A). A 20-year-old woman was referred to our hospital because of proteinuria and persistent macroscopic hematuria. Based on the typical renal pathological findings, deficient activity of the ɑ-Gal A, and heterozygous mutation in the ɑ-Gal A gene, she was diagnosed with Fabry disease. After 1 year of enzyme replacement therapy with agalsidase alfa at 0.2 mg/kg every other week, the patient's proteinuria and hematuria were disappeared. In our patient, enzyme replacement therapy with agalsidase alfa was observed to be safe and well-tolerated during her pregnancy, with no significant negative effects on her or her child. Here, we report clinical and pathological evaluations of a patient through repeat kidney biopsy after 6 years of enzyme replacement therapy. Furthermore, we discussed the appropriate enzyme replacement therapy and its safety in pregnant women with Fabry disease.

  5. IgG4-related skin disease.

    PubMed

    Tokura, Y; Yagi, H; Yanaguchi, H; Majima, Y; Kasuya, A; Ito, T; Maekawa, M; Hashizume, H

    2014-11-01

    IgG4-related disease (IgG4-RD) is a recently established clinical entity characterized by high levels of circulating IgG4, and tissue infiltration of IgG4(+) plasma cells. IgG4-RD exhibits a distinctive fibroinflammatory change involving multiple organs, such as the pancreas and salivary and lacrimal glands. The skin lesions of IgG4-RD have been poorly characterized and may stem not only from direct infiltration of plasma cells but also from IgG4-mediated inflammation. Based on the documented cases together with ours, we categorized the skin lesions into seven subtypes: (1) cutaneous plasmacytosis (multiple papulonodules or indurations on the trunk and proximal part of the limbs), (2) pseudolymphoma and angiolymphoid hyperplasia with eosinophilia (plaques and papulonodules mainly on the periauricular, cheek and mandible regions), (3) Mikulicz disease (palpebral swelling, sicca syndrome and exophthalmos), (4) psoriasis-like eruption (strikingly mimicking psoriasis vulgaris), (5) unspecified maculopapular or erythematous eruptions, (6) hypergammaglobulinaemic purpura (bilateral asymmetrical palpable purpuric lesions on the lower extremities) and urticarial vasculitis (prolonged urticarial lesions occasionally with purpura) and (7) ischaemic digit (Raynaud phenomenon and digital gangrene). It is considered that subtypes 1-3 are induced by direct infiltration of IgG4(+) plasma cells, while the other types (4-7) are caused by secondary mechanisms. IgG4-related skin disease is defined as IgG4(+) plasma-cell-infiltrating skin lesions that form plaques, nodules or tumours (types 1-3), but may manifest secondary lesions caused by IgG4(+) plasma cells and/or IgG4 (types 4-7).

  6. Global skin diseases on Instagram hashtags.

    PubMed

    Braunberger, Taylor; Mounessa, Jessica; Rudningen, Kyle; Dunnick, Cory A; Dellavalle, Robert P

    2017-05-15

    Recently named one of the most influential phone applications, Instagram continues to grow in popularity [1]. Instagram consists of images and video posts, making it ideal for education and communication within the visual field of dermatology. In this study, we seek to determine the presence of dermatology-related content with regard to the most common cutaneous diseases of the world. We searched the account types and hashtags associated with the eight most common skin diseases globally as identified by the Global Burden of Disease (GBD) study by Hollenstein et al.: eczema, psoriasis, acne,pruritus, alopecia, decubitus ulcer, urticaria, andscabies [9]. The majority of Instagram accounts included patient experiences (n=73), private accounts(n=52), and disease advocacy and awareness groups(n=20), (total n=221). We further investigated over 2 million skin disease hashtags. The greatest numbersof hashtags were the following: #acne (n = 1,622,626),#alopecia (n = 317,566), and #eczema (n = 196,115). Our results demonstrate that patients interact withone another through Instagram. As social networking platforms become more frequently used as a source of information for patients and patient support, medical professionals must gain awareness of content available through Instagram and consider it as a means to educate the public.

  7. [Skin Diseases in Primary Psychiatric Disorders].

    PubMed

    Mavrogiorgou, P; Juckel, G

    2016-10-01

    Somatic diseases in psychiatric disorders are frequently seen in clinical practice. Several international studies have shown that patients with a primary psychiatric disorder are at increased risk for developing severe somatic comorbidities in comparison to the normal population. Whereas there has been accumulation of knowledge on cardiovascular comorbidities, the relationship between skin and psychiatric disorders is less understood. There are only a few systematic studies on this subject and, in addition, there is lack of knowledge about underlying neurobiological and immunological mechanisms. Impairments and disorders of the skin are often an (early) sign of a psychiatric disorder. Somatic treatment of skin diseases should be initiated as early as possible in patients with psychiatric disorders. This review article focuses on dermatological diagnoses that are related to primary psychiatric disorders such as psychotic and affective disorders as well as addiction disorders, and presents the most important aspects of epidemiology, symptomatology and possible pathophysiology. © Georg Thieme Verlag KG Stuttgart · New York.

  8. Bioevaluation of sixteen ADMDP stereoisomers toward alpha-galactosidase A: Development of a new pharmacological chaperone for the treatment of Fabry disease and potential enhancement of enzyme replacement therapy efficiency.

    PubMed

    Cheng, Wei-Chieh; Wang, Jen-Hon; Li, Huang-Yi; Lu, Sheng-Jhih; Hu, Jia-Ming; Yun, Wen-Yi; Chiu, Cheng-Hsin; Yang, Wen-Bin; Chien, Yin-Hsiu; Hwu, Wuh-Liang

    2016-11-10

    A unique molecular library consisting of all sixteen synthetic ADMDP (1-aminodeoxy-DMDP) stereoisomers has been prepared and evaluated for inhibitory activity against α-Gal A, and ability to impart thermal stabilization of this enzyme. The results of this testing led us to develop a novel pharmacological chaperone for the treatment of Fabry disease. 3-Epimer ADMDP was found to be an effective pharmacological chaperone, able to rescue α-Gal A activity in the lymphoblast of the N215S Fabry patient-derived cell line, without impairment of cellular β-galactosidase activity. When 3-epimer ADMDP was administered with rh-α-Gal A (enzyme replacement therapy) for the treatment of Fabry patient-derived cell lines, improvements in the efficacy of rh-α-Gal A was observed, which suggests this small molecule can also provide clinical benefit of enzyme replacement therapy in Fabry disease.

  9. Medicinal plants used in treatment of inflammatory skin diseases

    PubMed Central

    2013-01-01

    Skin is an organ providing contact with the environment and protecting the human body from unfavourable external factors. Skin inflammation, reflected adversely in its functioning and appearance, also unfavourably affects the psyche, the condition of which is important during treatment of chronic skin diseases. The use of plants in treatment of inflammatory skin diseases results from their influence on different stages of inflammation. The paper presents results of the study regarding the anti-inflammatory activity of the plant raw material related to its influence on skin. The mechanism of action, therapeutic indications and side effects of medicinal plants used for treatment of inflammatory diseases of the skin are described. PMID:24278070

  10. Oral mucosal manifestations of autoimmune skin diseases.

    PubMed

    Mustafa, Mayson B; Porter, Stephen R; Smoller, Bruce R; Sitaru, Cassian

    2015-10-01

    A group of autoimmune diseases is characterised by autoantibodies against epithelial adhesion structures and/or tissue-tropic lymphocytes driving inflammatory processes resulting in specific pathology at the mucosal surfaces and the skin. The most frequent site of mucosal involvement in autoimmune diseases is the oral cavity. Broadly, these diseases include conditions affecting the cell-cell adhesion causing intra-epithelial blistering and those where autoantibodies or infiltration lymphocytes cause a loss of cell-matrix adhesion or interface inflammation. Clinically, patients present with blistering, erosions and ulcers that may affect the skin as well as further mucosal surfaces of the eyes, nose and genitalia. While the autoimmune disease may be suspected based on clinical manifestations, demonstration of tissue-bound and circulating autoantibodies, or lymphocytic infiltrates, by various methods including histological examination, direct and indirect immunofluorescence microscopy, immunoblotting and quantitative immunoassay is a prerequisite for definitive diagnosis. Given the frequency of oral involvement and the fact that oral mucosa is the initially affected site in many cases, the informed practitioner should be well acquainted with diagnostic and therapeutic aspects of autoimmune dermatosis with oral involvement. This paper reviews the pathogenesis and clinical presentation of these conditions in the oral cavity with a specific emphasis on their differential diagnosis and current management approaches.

  11. Rapid preparation of (3R,4S,5R) polyhydroxylated pyrrolidine-based libraries to discover a pharmacological chaperone for treatment of Fabry disease.

    PubMed

    Cheng, Wei-Chieh; Wang, Jen-Hon; Yun, Wen-Yi; Li, Huang-Yi; Hu, Jia-Ming

    2017-01-27

    The rapid discovery of a pharmacological chaperone toward human α-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 × 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue α-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other α-Gal A mutants in COS7 cells. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. Replacement of α-galactosidase A in Fabry disease: effect on fibroblast cultures compared with biopsied tissues of treated patients

    PubMed Central

    Keslová-Veselíková, Jana; Hůlková, Helena; Dobrovolný, Robert; Asfaw, Befekadu; Poupětová, Helena; Berná, Linda; Sikora, Jakub; Goláň, Lubor

    2008-01-01

    The function and intracellular delivery of enzyme therapeutics for Fabry disease were studied in cultured fibroblasts and in the biopsied tissues of two male patients to show diversity of affected cells in response to treatment. In the mutant fibroblasts cultures, the final cellular level of endocytosed recombinant α-galactosidases A (agalsidases, FabrazymeTM, and ReplagalTM) exceeded, by several fold, the amount in control fibroblasts and led to efficient direct intra-lysosomal hydrolysis of (3H)Gb3Cer. In contrast, in the samples from the heart and some other tissues biopsied after several months of enzyme replacement therapy (ERT) with FabrazymeTM, only the endothelial cells were free of storage. Persistent Gb3Cer storage was found in cardiocytes (accompanied by increase of lipopigment), smooth muscle cells, fibroblasts, sweat glands, and skeletal muscle. Immunohistochemistry of cardiocytes demonstrated, for the first time, the presence of a considerable amount of the active enzyme in intimate contact with the storage compartment. Factors responsible for the limited ERT effectiveness are discussed, namely post-mitotic status of storage cells preventing their replacement by enzyme supplied precursors, modification of the lysosomal system by longstanding storage, and possible relative lack of Sap B. These observations support the strategy of early treatment for prevention of lysosomal storage. PMID:18351385

  13. 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.

  14. 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.

  15. Occupational skin diseases in automotive industry workers.

    PubMed

    Yakut, Yunus; Uçmak, Derya; Akkurt, Zeynep Meltem; Akdeniz, Sedat; Palanci, Yilmaz; Sula, Bilal

    2014-03-01

    Studies on occupational skin diseases in workers of the automotive industry are few. To investigate the prevalence of occupational skin diseases in workers of the automotive industry. Between September and December 2011, a total of 405 workers from the automotive repair industry in Diyarbakır were interviewed. They were active workers in the repair industry who had been employed for at least six months. Business owners, sellers of spare parts and accounting officers were not included. The employees were examined at their workplaces and the working conditions were observed. Detailed dermatological examination was performed. The mean age of the 405 workers who participated in the study was 27.7 ± 10.3. The mean working time of employees was 13.3 ± 10.4 years. All of the employees were male. Dermatological diseases were not detected in 144 out of 405 workers (35.6%) and at least one condition was diagnosed in 261 (64.4%). The most frequent diagnosis was callus, hyperkeratosis, clavus (27.7%), followed by nail changes (16.8%) and superficial mycoses (12.1%). Contact dermatitis was seen at a rate of 5.9%. Traumatic lesions such as hyperkeratotic lesions and nail changes were found most frequently. Traumatic lesions were common among individuals who did not use gloves. Most nail changes were localized leuconychia, a finding not reported in the studies on automotive industry workers. In accordance with the literature, irritant contact dermatitis was observed in patients with a history of atopy and who had been working for a long time. Occupational skin diseases comprise an important field in dermatology, deserving much attention. Further studies on occupational dermatology are necessary.

  16. Phototherapy and photochemotherapy of skin diseases

    SciTech Connect

    Parrish, J.A.

    1981-07-01

    One important aspect of photomedicine is the use of nonionizing electromagnetic radiation with and without exogenous photosensitizers to treat diseases. Phototoxicity (cell injury by photons) is a likely mechanism for phototherapy and photochemotherapy of several skin diseases. The mechanism of action for phototherapy of hyperbilirubinemia and of uremic pruritus appears to be photochemical alteration of extracellular metabolites. Psoriasis is an example of a disease benefitted by several forms of phototherapy and photochemotherapy with varying relative effectiveness and safety. Two successful forms of treatment are oral psoralen photochemotherapy and UVB plus topical adjunctive agents. New information about UVB therapy of psoriasis includes data about the therapeutic action spectrum and about the relative roles of various topical agents such as coal tar, mineral oil, ''lubricants'' and steroids. Although there are many surface similarities, phototherapy and psoralen photochemotherapy have fundamental differences which may alter longterm risks in quantitative and qualitative ways.

  17. 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.

  18. 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.

  19. Bodies in skin: a philosophical and theological approach to genetic skin diseases.

    PubMed

    Walser, Angelika

    2010-03-01

    This contribution evolved from my work in a European network and is dedicated to the rare genetic skin diseases. To gain a deeper knowledge about the question, what it means to suffer from a genetic skin disease, I have discussed the concepts of skin in philosophical and theological anthropology. Presuming that ancient interpretations of skin diseases (moral and cultical impurity) are still relevant today, feminist Christian theology shows the ways of deconstructing stigmatizing paradigma by using the body as a hermeneutic category. Skin becomes the "open borderline" of the human being, pointing out both the social vulnerability and the transcendent capacity of the human person.

  20. Skin diseases of the vulva: eczematous diseases and contact urticaria.

    PubMed

    Sand, Freja Lærke; Thomsen, Simon Francis

    2017-08-07

    Skin diseases in the vulvar area include a variety of disorders many of which have a chronic course with significant morbidity. It is important to be aware of the symptoms, signs and diagnostic tools in order to optimise treatment. Herein, the most common eczematous diseases of the vulvar area, i.e. lichen simplex chronicus, seborrhoeic dermatitis, atopic dermatitis, irritant contact dermatitis, and non-systemic and systemic allergic contact dermatitis are reviewed. Allergic contact urticaria is also described.

  1. Rituximab in severe skin diseases: target, disease, and dose

    PubMed Central

    Bennett, Daniel D; Ohanian, Maro; Cable, Christian T

    2010-01-01

    New clinical indications for rituximab seem to appear every day. This review will trace the use of this monoclonal antibody from lymphoid malignancy, to classic autoimmune disease, and specifically severe autoimmune skin diseases. The history leading to different dosing schema with associated pharmacokinetic data will be discussed. A case of livedoid vasculopathy (atrophie blanche) responding to rituximab will illustrate how the response to therapy can help to elucidate previously obscure pathophysiology. PMID:22291497

  2. Immunology and skin in health and disease.

    PubMed

    Richmond, Jillian M; Harris, John E

    2014-12-01

    The skin is a complex organ that, in addition to providing a strong barrier against external insults, serves as an arena for a wide variety of inflammatory processes, including immunity against infections, tumor immunity, autoimmunity, and allergy. A variety of cells collaborate to mount functional immune responses, which are initiated by resident populations and evolve through the recruitment of additional cell populations to the skin. Inflammatory responses are quite diverse, resulting in a wide range of signs and symptoms that depend on the initiating signals, characteristics of the infiltrating cell populations, and cytokines that are produced (cytokines are secreted protein that allows for cell-cell communication; usually refers to communication between immune-immune cells or stromal-immune cells). In this work, we will review the skin architecture and resident and recruited cell populations and discuss how these populations contribute to inflammation using human diseases and treatments when possible to illustrate their importance within a clinical context. Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

  3. Skin diseases among schoolchildren in Ghana, Gabon, and Rwanda.

    PubMed

    Hogewoning, Arjan; Amoah, Abena; Bavinck, Jan Nico Bouwes; Boakye, Daniel; Yazdanbakhsh, Maria; Adegnika, Akim; De Smedt, Stefan; Fonteyne, Yannick; Willemze, Rein; Lavrijsen, Adriana

    2013-05-01

    Skin diseases, especially skin infections, among schoolchildren in Africa can be a major health problem. The objective of this study was to determine the prevalences of skin diseases among children in rural and urban schools in three different African countries and to study the influence of socioeconomic level. Cross-sectional, population-based studies were performed in Ghana, Gabon, and Rwanda. Point prevalences of skin diseases were estimated on the basis of physical examination by at least one dermatologist. A total of 4839 schoolchildren were seen. The overall prevalence of schoolchildren with any skin disease was high and amounted to 34.6% and 42.0% in two Ghanaian studies, 45.8% in Gabon, and 26.7% in Rwanda. In children with skin diseases, skin infections represented the greatest proportion of disease, accounting for 14.7% and 17.6% of skin disease in the Ghanaian studies, and 27.7% and 22.7% in Gabon and Rwanda, respectively. Diseases with the highest prevalence were tinea capitis and bacterial skin infections, especially in rural areas and in schools serving children living at lower socioeconomic levels. The prevalences of skin diseases among African schoolchildren were high. Skin infections such as tinea capitis and pyoderma predominated. © 2013 The International Society of Dermatology.

  4. 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

  5. Using CRISPR/Cas9-Mediated GLA Gene Knockout as an In Vitro Drug Screening Model for Fabry Disease.

    PubMed

    Song, Hui-Yung; Chiang, Huai-Chih; Tseng, Wei-Lien; Wu, Ping; Chien, Chian-Shiu; Leu, Hsin-Bang; Yang, Yi-Ping; Wang, Mong-Lien; Jong, Yuh-Jyh; Chen, Chung-Hsuan; Yu, Wen-Chung; Chiou, Shih-Hwa

    2016-12-13

    The CRISPR/Cas9 Genome-editing system has revealed promising potential for generating gene mutation, deletion, and correction in human cells. Application of this powerful tool in Fabry disease (FD), however, still needs to be explored. Enzyme replacement therapy (ERT), a regular administration of recombinant human α Gal A (rhα-GLA), is a currently available and effective treatment to clear the accumulated Gb3 in FD patients. However, the short half-life of rhα-GLA in human body limits its application. Moreover, lack of an appropriate in vitro disease model restricted the high-throughput screening of drugs for improving ERT efficacy. Therefore, it is worth establishing a large-expanded in vitro FD model for screening potential candidates, which can enhance and prolong ERT potency. Using CRISPR/Cas9-mediated gene knockout of GLA in HEK-293T cells, we generated GLA-null cells to investigate rhα-GLA cellular pharmacokinetics. The half-life of administrated rhα-GLA was around 24 h in GLA-null cells; co-administration of proteasome inhibitor MG132 and rhα-GLA significantly restored the GLA enzyme activity by two-fold compared with rhα-GLA alone. Furthermore, co-treatment of rhα-GLA/MG132 in patient-derived fibroblasts increased Gb3 clearance by 30%, compared with rhα-GLA treatment alone. Collectively, the CRISPR/Cas9-mediated GLA-knockout HEK-293T cells provide an in vitro FD model for evaluating the intracellular pharmacokinetics of the rhα-GLA as well as for screening candidates to prolong rhα-GLA potency. Using this model, we demonstrated that MG132 prolongs rhα-GLA half-life and enhanced Gb3 clearance, shedding light on the direction of enhancing ERT efficacy in FD treatment.

  6. Using CRISPR/Cas9-Mediated GLA Gene Knockout as an In Vitro Drug Screening Model for Fabry Disease

    PubMed Central

    Song, Hui-Yung; Chiang, Huai-Chih; Tseng, Wei-Lien; Wu, Ping; Chien, Chian-Shiu; Leu, Hsin-Bang; Yang, Yi-Ping; Wang, Mong-Lien; Jong, Yuh-Jyh; Chen, Chung-Hsuan; Yu, Wen-Chung; Chiou, Shih-Hwa

    2016-01-01

    The CRISPR/Cas9 Genome-editing system has revealed promising potential for generating gene mutation, deletion, and correction in human cells. Application of this powerful tool in Fabry disease (FD), however, still needs to be explored. Enzyme replacement therapy (ERT), a regular administration of recombinant human α Gal A (rhα-GLA), is a currently available and effective treatment to clear the accumulated Gb3 in FD patients. However, the short half-life of rhα-GLA in human body limits its application. Moreover, lack of an appropriate in vitro disease model restricted the high-throughput screening of drugs for improving ERT efficacy. Therefore, it is worth establishing a large-expanded in vitro FD model for screening potential candidates, which can enhance and prolong ERT potency. Using CRISPR/Cas9-mediated gene knockout of GLA in HEK-293T cells, we generated GLA-null cells to investigate rhα-GLA cellular pharmacokinetics. The half-life of administrated rhα-GLA was around 24 h in GLA-null cells; co-administration of proteasome inhibitor MG132 and rhα-GLA significantly restored the GLA enzyme activity by two-fold compared with rhα-GLA alone. Furthermore, co-treatment of rhα-GLA/MG132 in patient-derived fibroblasts increased Gb3 clearance by 30%, compared with rhα-GLA treatment alone. Collectively, the CRISPR/Cas9-mediated GLA-knockout HEK-293T cells provide an in vitro FD model for evaluating the intracellular pharmacokinetics of the rhα-GLA as well as for screening candidates to prolong rhα-GLA potency. Using this model, we demonstrated that MG132 prolongs rhα-GLA half-life and enhanced Gb3 clearance, shedding light on the direction of enhancing ERT efficacy in FD treatment. PMID:27983599

  7. Home infusion program with enzyme replacement therapy for Fabry disease: The experience of a large Italian collaborative group.

    PubMed

    Concolino, D; Amico, L; Cappellini, M D; Cassinerio, E; Conti, M; Donati, M A; Falvo, F; Fiumara, A; Maccarone, M; Manna, R; Matucci, A; Musumeci, M B; Nicoletti, A; Nisticò, R; Papadia, F; Parini, R; Peluso, D; Pensabene, L; Pisani, A; Pistone, G; Rigoldi, M; Romani, I; Tenuta, M; Torti, G; Veroux, M; Zachara, E

    2017-09-01

    Fabry disease (FD) [OMIM 301500] is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in progressive multisystem accumulation of globotriaosylceramide (Gb3). Although the introduction of Enzyme Replacement Therapy (ERT) resulted in a variety of clinical benefits, life-long intravenous (IV) treatment with ERT with an every other week schedule, may interfere with daily life activities and impact on QoL. We report here a multicentric, observational, longitudinal data analysis on a large cohort of 85 Italian FD patients (45 males, 40 females) from 11 out of 20 Italian regions, who received a cumulative number of 4269 home infusions of agalsidase alfa. For the whole cohort, the average duration of home therapy was 1 year and 11 months (range 3 months-4 years and 6 months), and during this period, compliance to treatment (number of infusions performed vs scheduled) reached 100%. The EQ-5 VAS scale was administered to patients to evaluate the self-reported QoL, 58% of patients showing an increase of EQ-5 VAS score at follow up compared to baseline (home treatment start) or remaining stable. A mild increase of average disease severity, measured through Mainz Severity Score Index (MSSI), was found during hospital treatment (p < 0,007), while it remained stable between the first home therapy infusion and last follow up. Interestingly, 4 out of 7 (57%) patients, showing an improvement in FD-related clinical status after starting home therapy, had previously a sub-optimal compliance to treatment during the period of hospital treatment management. Only 4 adverse non serious reactions (0,093%) were reported totally in 2 patients during home treatment. We conclude that home infusions in eligible patients with FD are safe, contribute to improve treatment compliance and therapeutic clinical outcomes, and may have a positive impact on self-perceived QoL.

  8. Occupational skin disease in Victoria, Australia.

    PubMed

    Cahill, Jennifer L; Williams, Jason D; Matheson, Melanie C; Palmer, Amanda M; Burgess, John A; Dharmage, Shyamali C; Nixon, Rosemary L

    2016-05-01

    To describe the characteristics of patients with occupational skin disease (OSD) in a tertiary referral clinic in Victoria, Australia. A retrospective review was conducted of records from patients seen at the Occupational Dermatology Clinic in Melbourne, Australia between 1 January 1993 and 31 December 2010. Of the 2894 people assessed in the clinic during the 18-year period, 44% were women and 56% were men. In all, 2177 (75%) were diagnosed with occupational skin disease (OSD). Of the patients with a work-related skin condition, 45% (n = 979) were considered to be atopic. The most common diagnosis in those with OSD was irritant contact dermatitis (ICD) (44%), followed by allergic contact dermatitis (33%) and endogenous eczema (11%). Women were significantly more likely to have soaps and detergents (P < 0.001) and water/wet work (P < 0.001) as causes of their ICD than men. Men were significantly more likely to have oils and coolants (P < 0.001) and solvent exposures (P < 0.001) as causes of their ICD. Occupational groups with the highest incidence of OSD were the hair and beauty professions (70 per 100 000), followed by machine and plant operators (38 per 100 000) and health-care workers (21 per 100 000). We confirm the importance of occupational contact dermatitis as the most common cause of OSD, with ICD being the most common diagnosis. There are differences in the causes of ICD between our group of male and female workers. For the first time in Australia, rates of OSD in certain industries have been calculated. © 2015 The Australasian College of Dermatologists.

  9. Adipocytes in Skin Health and Disease

    PubMed Central

    Rivera-Gonzalez, Guillermo; Shook, Brett; Horsley, Valerie

    2014-01-01

    Adipocytes are intimately associated with the dermal compartment of the skin, existing in a specialized dermal depot and displaying dynamic changes in size during tissue homeostasis. However, the roles of adipocytes in cutaneous biology and disease are not well understood. Traditionally, adipocytes within tissues were thought to act as reservoirs of energy, as thermal, or as structural support. In this review, we discuss recent studies revealing the cellular basis of the dynamic development and regenerative capacity of dermal adipocytes associated with the hair cycle and following injury. We discuss and speculate on potential roles of dermal adipocytes in cutaneous biology with an emphasis on communication during hair follicle growth and wound healing. Finally, we explore how alterations in the dermal adipose tissue may support clinical manifestations of cutaneous diseases such as lipodystrophy, obesity, and alopecia. PMID:24591537

  10. Psoriasis: experiencing a chronic skin disease.

    PubMed

    Chrissopoulos, A; Cleaver, G

    1996-03-01

    Psoriasis is an incurable chronic skin disease that affects one in fifty people. Psychological factors play a role in the aetiology and experience of psoriasis but there is little pertaining to the psychological experience of psoriasis in research literature. In this study the phenomenological approach is used to describe the everyday experiences of a person with psoriasis. By using Giorgi's (1985) steps of data analysis a description of the lifeworld of the person with psoriasis was compiled. The description presented several essential components of the experience of psoriasis and the results emphasize the effects of the disease on the sufferer's life. Problematic interpersonal relationships, a negative selfconcept, fluctuating moods, loss of control, negativity and loneliness are a part of this experience. It is hoped that knowledge of the world of the psoriasis sufferer will assist the help professions to understanding and empathize with the suffering and limitations that psoriasis brings.

  11. Skin manifestations of chronic kidney disease.

    PubMed

    Robles-Mendez, J C; Vazquez-Martinez, O; Ocampo-Candiani, J

    2015-10-01

    Skin manifestations associated with chronic kidney disease are very common. Most of these conditions present in the end stages and may affect the patient's quality of life. Knowledge of these entities can contribute to establishing an accurate diagnosis and prognosis. Severe renal pruritus is associated with increased mortality and a poor prognosis. Nail exploration can provide clues about albumin and urea levels. Nephrogenic systemic fibrosis is a preventable disease associated with gadolinium contrast. Comorbidities, such as diabetes mellitus and secondary hyperparathyroidism, can lead to acquired perforating dermatosis and calciphylaxis, respectively. Effective and innovative treatments are available for all of these conditions. Copyright © 2015 Elsevier España, S.L.U. and AEDV. All rights reserved.

  12. Skin Diseases Modeling using Combined Tissue Engineering and Microfluidic Technologies.

    PubMed

    Mohammadi, Mohammad Hossein; Heidary Araghi, Behnaz; Beydaghi, Vahid; Geraili, Armin; Moradi, Farshid; Jafari, Parya; Janmaleki, Mohsen; Valente, Karolina Papera; Akbari, Mohsen; Sanati-Nezhad, Amir

    2016-10-01

    In recent years, both tissue engineering and microfluidics have significantly contributed in engineering of in vitro skin substitutes to test the penetration of chemicals or to replace damaged skins. Organ-on-chip platforms have been recently inspired by the integration of microfluidics and biomaterials in order to develop physiologically relevant disease models. However, the application of organ-on-chip on the development of skin disease models is still limited and needs to be further developed. The impact of tissue engineering, biomaterials and microfluidic platforms on the development of skin grafts and biomimetic in vitro skin models is reviewed. The integration of tissue engineering and microfluidics for the development of biomimetic skin-on-chip platforms is further discussed, not only to improve the performance of present skin models, but also for the development of novel skin disease platforms for drug screening processes. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Detecting the Effects of Fabry Disease in the Adult Human Brain with Diffusion Tensor Imaging and Fast Bound-Pool Fraction Imaging

    PubMed Central

    Underhill, Hunter R.; Golden-Grant, Katie; Garrett, Lauren T.; Uhrich, Stefanie; Zielinski, Brandon A.; Scott, C. Ronald

    2015-01-01

    Purpose To identify quantitative MRI parameters associated with diffusion tensor imaging (DTI) and fast bound-pool fraction imaging (FBFI) that may detect alterations in gray matter and/or white matter in adults with Fabry disease, a lysosomal storage disorder. Materials and Methods Twelve healthy controls (mean age ± standard deviation: 48.0±12.4 years) and ten participants with Fabry disease (46.7±12.9 years) were imaged at 3.0 T. Whole-brain parametric maps of diffusion tensor metrics (apparent diffusion coefficient (ADC) and fractional anisotropy (FA)) and the bound-pool fraction (f) were acquired. Mean voxel values of parametric maps from regions-of-interest within gray and white matter structures were compared between cases and controls using the independent t-test. Spearman’s rho was used to identify associations between parametric maps and age. Results Compared to controls, the left thalamus of Fabry participants had an increase in FA (0.29±0.02 vs. 0.33±0.05, respectively; p=0.030) and a trend towards an increase in ADC (0.73±00.02 vs. 0.76±0.03 μm2/s, respectively; p=0.082). The left posterior white matter demonstrated a reduction in f (10.45±0.37 vs. 9.00±1.84 %, respectively; p=0.035), an increase in ADC (0.78±0.04 vs. 0.94±0.19 μm2/s, respectively; p=0.024), and a trend towards a reduction in FA (0.42±0.07 vs. 0.36±0.08, respectively; p=0.052). Amongst all parameters, only f measured in the left posterior white matter was significantly associated with age in Fabry participants (rho= −0.71, p=0.022). Conclusions Parameters derived from DTI and FBFI detect Fabry-related changes in the adult human brain, particularly in the posterior white matter where reductions in myelin density as measured by FBFI appear age related. PMID:26018987

  14. Reduced Right Ventricular Native Myocardial T1 in Anderson-Fabry Disease: Comparison to Pulmonary Hypertension and Healthy Controls

    PubMed Central

    Pagano, Joseph J.; Chow, Kelvin; Khan, Aneal; Michelakis, Evangelos; Paterson, Ian; Oudit, Gavin Y.; Thompson, Richard B.

    2016-01-01

    Aims Anderson-Fabry disease (AFD) is characterized by progressive multiorgan accumulation of intracellular sphingolipids due to α-galactosidase A enzyme deficiency, resulting in progressive ventricular hypertrophy, heart failure, arrhythmias, and death. Decreased native (non-contrast) left ventricular (LV) T1 (longitudinal relaxation time) with MRI discriminates AFD from healthy controls or other presentations of concentric hypertrophy, but the right ventricle (RV) has not been studied. The aims of the current study were to evaluate native RV T1 values in AFD, with a goal of better understanding the pathophysiology of RV involvement. Methods and Results Native T1 values were measured in the inferior RV wall (RVI), interventricular septum (IVS), and inferior LV (LVI) in patients with AFD, patients with pulmonary hypertension, who provided an alternative RV pathological process for comparison, and healthy controls. A minimum wall thickness of 4 mm was selected to minimize partial volume errors in tissue T1 analysis. T1 analysis was performed in 6 subjects with AFD, 6 subjects with PH, and 21 controls. Native T1 values were shorter (adjusted p<0.05 for all comparisons), independent of location, in subjects with AFD (RVI-T1 = 1096±49 ms, IVS-T1 = 1053±41 ms, LVI-T1 = 1072±44 ms) compared to both PH (RVI-T1 = 1239±41 ms, IVS-T1 = 1280±123 ms, LVI-T1 = 1274±57 ms) and HC (IVS-T1 = 1180±60 ms, LVI-T1 = 1183±45 ms). RVI measurements were not possible in controls due to insufficient wall thickness. Conclusion Native T1 values appear similarly reduced in the left and right ventricles of individuals with AFD and RV wall thickening, suggesting a common pathology. In contrast, individuals with PH and thickened RVs showed increased native T1 values in both ventricles, suggestive of fibrosis. PMID:27305064

  15. 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.

  16. Screening patients with hypertrophic cardiomyopathy for Fabry disease using a filter-paper test: the FOCUS study.

    PubMed

    Hagège, Albert A; Caudron, Eric; Damy, Thibaud; Roudaut, Raymond; Millaire, Alain; Etchecopar-Chevreuil, Caroline; Tran, Thi-Chien; Jabbour, Firas; Boucly, Catherine; Prognon, Patrice; Charron, Philippe; Germain, Dominique P

    2011-01-01

    Patients with Fabry disease (FD) show left ventricular hypertrophy (LVH) mimicking hypertrophic cardiomyopathy (HCM) of sarcomeric origin and might benefit, if detected early, from specific enzyme replacement therapy. The prevalence of FD in patients with LVH of 13 mm or greater, screened using the leucocyte alpha-galactosidase A (α-gal A) activity test, a technique that is difficult to apply routinely, ranged from 0% to 6%. To screen systematically for FD in patients with a diagnosis of HCM (LVH ≥15 mm) in primary cardiology practice, a validated, physician-friendly α-gal A assay was used on dried blood spots using a filter paper test. A cohort of 392 adults (278 men) followed for HCM were screened for FD. A standard blood test was used for confirmation in nine men in whom the α-gal A result was 40% or less. Four men (1.5%; 1.8% of men ≥40 years vs 0% <40 years; all with α-gal A <30%), but no women, were diagnosed with FD. Index cases presented with diffuse but asymmetric LVH, with severe obstruction in one case and frequent high-grade atrioventricular conduction block necessitating a pacemaker in three cases. Family screening identified eight additional cases. Genotyping was performed successfully on DNA extracted from the filter papers. In male patients diagnosed as having HCM, pure FD cardiac variants are not exceptional and can be specifically identified using a simple filter-paper test. The sensitivity of this test is low in female patients.

  17. A comprehensive Fabry-related pain questionnaire for adult patients.

    PubMed

    Üçeyler, Nurcan; Magg, Barbara; Thomas, Phillip; Wiedmann, Silke; Heuschmann, Peter; Sommer, Claudia

    2014-11-01

    Pain may be the earliest symptom in Fabry disease and presents with a distinct phenotype including triggerable pain attacks, evoked pain, pain crises, and chronic pain. Current pain questionnaires do not reflect the special phenotype of Fabry disease-associated pain, which hampers its systematic evaluation as the basis of correct diagnosis and effective treatment. A questionnaire specifically designed to assess Fabry disease-associated pain is thus urgently needed. At the Würzburg Fabry Center for Interdisciplinary Therapy (FAZIT), Germany, we developed and validated the first face-to-face Fabry Pain Questionnaire (FPQ) for adult patients. The initial version of the FPQ was tested in a pilot study with 20 consecutive Fabry disease patients. The performance of the revised FPQ was assessed in a first (n=56) and second (n=20) validation phase in consecutive Fabry disease patients. For this, patients were interviewed at baseline and 2 weeks later. We determined the test-retest reliability and validity of the FPQ in comparison to data obtained with the Neuropathic Pain Symptom Inventory. The FPQ contains 15 questions on the 4 pain phenotypes of Fabry disease (pain attacks, pain crises, evoked pain, chronic pain) in childhood and adulthood, on pain development during life with and without enzyme replacement therapy, and on everyday life impairment due to pain. This first disease-specific questionnaire is a valuable tool for baseline and follow-up assessment of pain in Fabry disease patients and may guide treatment in this distinct pain phenotype.

  18. [Swinepox--skin disease with sporadic occurrence].

    PubMed

    Moorkamp, L; Beineke, A; Kaim, U; Diesterbeck, U; Urstadt, S; Czerny, C P; Rüberg, H; Grosse Beilage, E

    2008-04-01

    Swinepox virus infection results in an acute, mild or subclinical course and is characterised by typical poxvirus skin lesions in affected pigs. Additionally, sporadic vertical swinepox virus transmission leads to congenital generalised infection and subsequent abortion or stillbirth. The present report describes the occurrence of epidermal efflorescences in two piglets after intrauterine natural suipoxvirus infection. No clinical abnormalities of the gilt and littermates as well as in other pigs from this herd were present. One of the affected piglets was stillborn and submitted for necropsy, the other animal was alive at birth, but died 3 days later. Histologically, a proliferative to ulcerative dermatitis with epithelial ballooning degeneration and characteristic intracytoplasmatic inclusion bodies was observed. The pathomorphological and histopathological suspected diagnosis of a poxvirus infection was confirmed by electron microscopy. Furthermore, the agent was identified as suipoxvirus by polymerase chain reaction. As demonstrated here, obvious skin lesions in suipoxvirus infection leads to a suspected diagnosis in newborn piglets on macroscopic examination. However, further post mortem examinations, including electron microscopy as well as molecular techniques are essential for the identification of the aetiology and the exclusion of differential diagnoses. Because the disease only affected two pigs there was only a small economic loss. A valid diagnostic plays an important role in advising farmers and for herd health monitoring.

  19. Global burden of skin disease in the elderly: a grand challenge to skin health.

    PubMed

    Hay, R J; Fuller, L C

    2015-12-01

    Skin diseases, as estimated in the global burden of disease study 2010, are a significant health problem in all global regions and many of those analyzed in this study show an increasing burden over recent years, extending into old age. Some of the conditions which have the highest impact on the elderly include non-melanoma skin cancer and skin ulceration, but bacterial skin infection, fungal disease or pruritus are all significant problems. With predicted changes in demography and a higher proportion of individuals above the age of 80 in the coming years concentrating new resources on gathering better data and devising preventative, therapeutic and palliative strategies is a priority.

  20. Epidemiology of Skin Disease in an Automobile Factory*

    PubMed Central

    Newhouse, Muriel L.

    1964-01-01

    A survey was made of a random sample of workers from the machine shops, assembly lines, and stock and store departments of an automobile factory. Among the 1,223 men seen, representing 97% of the sample, the prevalence of non-infective skin diseases was 14·5%. Skin diseases were classified into four groups: `dermatitis' and `folliculitis' of occupational origin, endogenous `eczemas', and miscellaneous skin diseases. Slightly more than half of all the skin diseases seen were considered to be occupational in origin. In this population the prevalence of skin disease was more than four times that based on patients attending the factory medical department. An unsuspected cause of allergic dermatitis was found on the assembly lines, where the incidence of dermatitis was significantly higher than among the non-production workers. The prevalence of folliculitis was significantly higher among production than non-production workers. There was no significant difference in the prevalence of `eczema' or the miscellaneous skin diseases in the various occupational groups. Among European workers fair men were more prone to skin disease than darker men. In another factory, a West Indian and Asiatic group of workers had a significantly lower prevalence of skin diseases than a group of Europeans doing similar work. Folliculitis was more prevalent among the younger workers and those recently employed in the factory; there was no obvious association between age and length of service and the occurrence of other types of skin disease. PMID:14249898

  1. Skin diseases in geriatric patients: our experience from a public skin outpatient clinic in Siena.

    PubMed

    Rubegni, P; Poggiali, S; Nami, N; Rubegni, M; Fimiani, M

    2012-12-01

    With the progressive aging of the Italian population, geriatric health care has become a major issue for health authorities. However, little data is available regarding geriatric skin diseases. In order to provide rapid access to specialist help, in 2003 we created a dermatology clinic dedicated only to geriatric patients age 65 and older. To determine the characteristic pattern and the prevalence of various skin disorders among the geriatric patients seen at the clinic, we performed a retrospective and descriptive study of all skin diseases in patients seen in our office from January 2003 to December 2009. We evaluated: age, proportion and gender for all skin disease categories. A total of 2100 geriatric patients were examined. The male to female ratio was 1.4 to 1. The most common disorder was pruritus "sine materia" (18.9%) followed by benign tumors (13.5%); 9.1% of our patients presented with actinic keratoses and 13.2% with malignant tumors. As reported by others, the quality of life in patients with skin cancer was better than patients with rashes as skin cancer patients tended to wait longer before seeking specialist care. To improve the assessment of skin diseases, we often worked closely with The prevalence of skin diseases in our patients emphasized the importance of educating the elderly about sun protection, the early detection of skin cancer, the use of emollients and proper skin care in general.

  2. National Athletic Trainers' Association Position Statement: Skin Diseases

    PubMed Central

    Zinder, Steven M.; Basler, Rodney S. W.; Foley, Jack; Scarlata, Chris; Vasily, David B.

    2010-01-01

    Abstract Objective: To present recommendations for the prevention, education, and management of skin infections in athletes. Background: Trauma, environmental factors, and infectious agents act together to continually attack the integrity of the skin. Close quarters combined with general poor hygiene practices make athletes particularly vulnerable to contracting skin diseases. An understanding of basic prophylactic measures, clinical features, and swift management of common skin diseases is essential for certified athletic trainers to aid in preventing the spread of infectious agents. Recommendations: These guidelines are intended to provide relevant information on skin infections and to give specific recommendations for certified athletic trainers and others participating in athletic health care. PMID:20617918

  3. Nutrition and skin diseases in veterinary medicine.

    PubMed

    Hensel, Patrick

    2010-01-01

    Veterinarians are confronted with a variety of food and nutrition-related skin diseases, with cutaneous food adverse reaction the most common in small animal dermatology. In addition to canine atopic dermatitis, cutaneous food adverse reaction has been an area of interest for extensive research for the last decade. Nutritional deficiencies and toxicoses are rare these days due to commercially available high-quality diets; however, poorly stored diets, inadequate husbandry of exotic pets, or problems in a farm animal environment may result in zinc, vitamin A, vitamin C, and fatty acid, or copper deficiency. Inherited deficiencies due to abnormal zinc absorption through the gastrointestinal tract must be considered in Nordic breed dogs and goats. Copyright © 2010 Elsevier Inc. All rights reserved.

  4. [Dermatology of neonatal period--skin diseases undemanding of treatment].

    PubMed

    Brzeziński, Piotr

    2009-01-01

    The skin of newborns differs from adult skin in many aspects. It is in the developing age which makes it difficult to fulfill it's correct function. There are diseases which appear in the first month of the infants life and require treatment. Mild local therapy may be administered or extensive moisturization of skin changes. Common mild and easy passing skin syndromes are: vernix caseosa, cutis marmarotta, hyperplasia sebacea, milia, acne neonatorum, erythema toxicum neonatorum, transient neonatal pustular melanosis, and neonatal dermalia pustulosis.

  5. [Skin diseases among refugees and immigrants. Four exotic case reports].

    PubMed

    Poulsen, A G; Petersen, C S; Weismann, K

    2000-11-13

    The influx of immigrants from outside the Western world, has led to a wider spectrum of dermatological diseases seen by doctors in Denmark. We present four case histories, in which the disease was brought to Denmark from the patient's land of origin. Tropical diseases may present as a skin disease as such, or a generalised disease with skin manifestations, the commonest signs being ulcers, papules, exanthema, changes in pigmentation, and itching.

  6. The skin microbiome: Associations between altered microbial communities and disease.

    PubMed

    Weyrich, Laura S; Dixit, Shreya; Farrer, Andrew G; Cooper, Alan J; Cooper, Alan J

    2015-11-01

    A single square centimetre of the human skin can contain up to one billion microorganisms. These diverse communities of bacteria, fungi, mites and viruses can provide protection against disease, but can also exacerbate skin lesions, promote disease and delay wound healing. This review addresses the current knowledge surrounding the healthy skin microbiome and examines how different alterations to the skin microbial communities can contribute to disease. Current methodologies are considered, changes in microbial diversity and colonisation by specific microorganisms are discussed in the context of atopic dermatitis, psoriasis, acne vulgaris and chronic wounds. The recent impact of modern Westernised lifestyles on the human skin microbiome is also examined, as well as the potential benefits and pitfalls of novel therapeutic strategies. Further analysis of the human skin microbiome, and its interactions with the host immune system and other commensal microorganisms, will undoubtedly elucidate molecular mechanisms for disease and reveal gateways for novel therapeutic treatment strategies.

  7. Accurate quantification of sphingosine-1-phosphate in normal and Fabry disease plasma, cells and tissues by LC-MS/MS with (13)C-encoded natural S1P as internal standard.

    PubMed

    Mirzaian, Mina; Wisse, Patrick; Ferraz, Maria J; Marques, André R A; Gabriel, Tanit L; van Roomen, Cindy P A A; Ottenhoff, Roelof; van Eijk, Marco; Codée, Jeroen D C; van der Marel, Gijsbert A; Overkleeft, Herman S; Aerts, Johannes M

    2016-08-01

    We developed a mass spectrometric procedure to quantify sphingosine-1-phosphate (S1P) in biological materials. The use of newly synthesized (13)C5 C18-S1P and commercial C17-S1P as internal standards rendered very similar results with respect to linearity, limit of detection and limit of quantitation. Caution is warranted with determination of plasma S1P levels. Earlier it was reported that S1P is elevated in plasma of Fabry disease patients. We investigated this with the improved quantification. No clear conclusion could be drawn for patient plasma samples given the lack of uniformity of blood collection and plasma preparation. To still obtain insight, plasma and tissues were identically collected from α-galactosidase A deficient Fabry mice and matched control animals. No significant difference was observed in plasma S1P levels. A significant 2.3 fold increase was observed in kidney of Fabry mice, but not in liver and heart. Comparative analysis of S1P in cultured fibroblasts from normal subjects and classically affected Fabry disease males revealed no significant difference. In conclusion, accurate quantification of S1P in biological materials is feasible by mass spectrometry using the internal standards (13)C5 C18-S1P or C17-S1P. Significant local increases of S1P in the kidney might occur in Fabry disease as suggested by the mouse model.

  8. Flood-related skin diseases: a literature review.

    PubMed

    Tempark, Therdpong; Lueangarun, Saoraya; Chatproedprai, Susheera; Wananukul, Siriwan

    2013-10-01

    Flood is one of the most common natural disasters, which commonly occurs in all parts of the world. The effects of the disasters considerably become enormous problems to overall public health systems. Flood-related skin diseases are a portion of these consequences presenting with cutaneous manifestations and/or signs of systemic illnesses. We conducted a systematic literature review of research publications relating to flooding and skin diseases. The purpose of this review was to provide dermatologists as well as general practitioners with comprehensive conditions of flood-related skin diseases and suggested treatments. Moreover, we categorized these flood-related diseases into four groups comprising inflammatory skin diseases, skin infections, traumatic skin diseases, and other miscellaneous skin diseases in a bid to implement early interventions and educate, prevent, and efficaciously handle those skin diseases under such a catastrophic situation so that better treatment outcomes and prevention of further complications could be ultimately achieved and accomplished. © 2013 The International Society of Dermatology.

  9. [The notion of occupational skin disease. Medical and legal aspects].

    PubMed

    Elsner, P; Schliemann, S

    2015-03-01

    The different definitions of skin disease in medicine and in law are frequently confusing for dermatologists. While a skin disease may be defined medically referring to the definition of health by the WHO as a pathological condition of the skin leading to a disruption of the physical, mental and social well-being of the individual, legal definitions vary depending on the field of insurance law that is referred to. In the law of private health insurance, a skin disease is defined as an anomalous condition of the skin requiring medical treatment that exists independently of the subjective judgement of the insured person and needs to be objectively confirmed by a medical evaluation. In contrast, in the law of the social health insurance, the Federal Court of Social Justice defines disease as irregular physical or mental condition, deviating from the perception of a healthy human being that requires medical treatment or leads to inability to work. Substantial bodily disfigurement may be regarded as an irregular physical condition. In the law of the statutory accident insurance, occupational skin diseases are defined under clause 5101 of the occupational disease regulation as serious or repeatedly relapsing skin diseases that have forced a person to refrain from any work activities causal for the development, the aggravation or the recurrence of the disease. The Federal Court of Social Justice interprets the term "skin disease" from the protective purpose of the law, i.e. the protection against the economic and health consequences of the exposure to harmful agents and a thereby forced change of profession. This broad interpretation of the term "skin disease" leads to the recognition of diseases of the conjunctiva of the eye or diseases of the blood vessels of the skin due to cold damage as skin diseases according to clause 5101. For the correct treatment and possibly notification of occupational skin diseases in collaboration with various insurance carriers

  10. A Novel Missense GLA Mutation (p.G35V) Detected in Hemodialysis Screening Leads to Severe Systemic Manifestations of Fabry Disease in Men and Women.

    PubMed

    Veloso, Valeria Soares Pigozzi; Ataides, Thiago Lacerda; Canziani, Maria Eugênia Fernandes; Veloso, Mariana Pigozzi; da Silva, Nilzio Antônio; Barreto, Daniela Veit; Pereira, Edna Regina Silva; de Moura, Luiz Antonio Ribeiro; Barreto, Fellype Carvalho

    2017-09-12

    Fabry disease (FD), an X-linked lysosomal storage disorder, leads to accumulation of globotriaosylceramide. Screening in dialysis patients may identify genetic variants of unknown clinical significance. We aimed to characterize the pathogenicity of a novel GLA gene mutation identified during hemodialysis screening and the histologic findings of early Fabry nephropathy. One out of 108 male hemodialysis patients screened for FD presented low α-galactosidase A activity. A novel missense mutation (p.G35V) in the GLA gene was detected. Family screening identified 11 additional cases (8 women). Clinical investigation was conducted in 10 patients (index case and 9 relatives). Pathogenicity of the new mutation was investigated by clinical and laboratory tests, cardiac and cranial magnetic resonance imaging, and kidney biopsy. Cardiac manifestations were detected in most patient from both genders, such as left ventricular hypertrophy and short PR interval. White matter lesion was present in 3 women. Pulvinar lesion of the thalamus and ischemic stroke were detected in male patients. Abnormal glomerular filtration rate (GFR) and/or albuminuria were present in 5 patients (3 women). Renal biopsies (n = 7) revealed globotriaosylceramide deposits in different cell types and foot processes effacement in all patients, including women with normal albuminuria. Despite a normal GFR, tubulointerstitial fibrosis ranging from 5 to 20% was present in young women and men with normal or high albuminuria, respectively. The novel missense mutation p.G35V leads to severe systemic manifestations of FD in men and women. Kidney histological changes, including tubulointerstitial fibrosis, may predate albuminuria and GFR changes in adult women. Novel non-invasive markers are required for early detection of Fabry nephropathy. © 2017 S. Karger AG, Basel.

  11. 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.

  12. [Role of IL-22 in the pathogenesis of skin diseases].

    PubMed

    Fujita, Hideki

    2012-01-01

    IL-22 is an IL-10 family cytokine that acts mainly on epithelial cells. It is produced by immune cell subsets, including CD4⁺ T cells, natural killer cells, and natural killer T cells. In the skin, IL-22 mediates keratinocyte proliferation and epidermal hyperplasia, inhibits terminal differentiation of keratinocytes, and induces the production of antimicrobial proteins. Although IL-22 production was initially linked with IL-17 expression in Th17 cells, IL-22 production can also occur in an apparently unique subset of cells that lacks the production of IL-17 and IFN-γ (Th22). Interestingly, Th22 cells express skin homing chemokine receptors CCR4 and CCR10. Indeed, Th22 cells reside in the normal skin and are shown to be enriched in the lesional skin of inflammatory skin diseases, indicating the importance of IL-22 in skin homeostasis and pathogenesis of skin diseases. Although psoriasis is the first example of an organ-specific immune disorder for which the role of IL-22 has been comprehensively studied, a growing body of evidence indicates that this cytokine also plays a critical role in the pathogenesis of atopic dermatitis. In this review, we discuss the role of IL-22 in the pathogenesis of skin diseases, particularly focusing on psoriasis and atopic dermatitis. Targeting IL-22 may have promise as a potential therapeutic for various skin diseases.

  13. Functions of the skin microbiota in health and disease

    PubMed Central

    Sanford, James A.; Gallo, Richard L.

    2014-01-01

    The skin, the human body’s largest organ, is home to a diverse and complex variety of innate and adaptive immune functions. Despite this potent immune system present at the cutaneous barrier, the skin encourages colonization by microorganisms. Characterization these microbial communities has enhanced our knowledge of the ecology of organisms present in normal skin; furthermore, studies have begun to bring to light the intimate relationships shared between host and resident microbes. In particular, it is apparent that just as host immunological factors and behaviors shape the composition of these communities, microbes present on the skin greatly impact the functions of human immunity. Thus, today the skin immune system should be considered a collective mixture of elements from the host and microbes acting in a mutualistic relationship. In this article we will review recent findings of the interactions of skin microbial communities with host immunity, and discuss the role that dysbiosis of these communities plays in diseases of the skin. PMID:24268438

  14. Regional distribution of ten common skin diseases in dogs.

    PubMed

    Sischo, W M; Ihrke, P J; Franti, C E

    1989-09-15

    We investigated the regional distributions of the most commonly diagnosed skin diseases in dogs from 17 North American veterinary teaching hospitals. Between January 1983 and December 1983, 11,456 diagnoses of skin disease were made. The 10 most common diagnoses were fleabite allergic dermatitis, skin cancer, pyoderma, seborrhea, allergy, demodectic acariasis (demodicosis), sarcoptic acariasis, immune-mediated skin disease, endocrine related skin disease, and acral lick dermatitis. Regional differences in the frequency of skin diseases were apparent. The northeast region had high frequencies of fleabite allergic dermatitis, allergy, and immune-mediated disease, and a low frequency of seborrhea. The midwest had a high frequency of seborrhea, and low frequencies of demodectic acariasis and allergy. In the plains region, low frequencies of fleabite allergic dermatitis, pyoderma, seborrhea, allergy, and demodectic acariasis were detected. In the west, the frequencies of fleabite allergic dermatitis, skin cancer, pyoderma, seborrhea, and acral lick dermatitis were high, whereas few dogs had allergic disease and sarcoptic acariasis. The southwest had high frequencies of fleabite allergic dermatitis and demodectic and sarcoptic acariasis. Fleabite allergic dermatitis, pyoderma, and demodectic and sarcoptic acariasis were frequently diagnosed in the southeast, but the number of dogs with seborrhea was low.

  15. Genetically modified skin to treat disease: potential and limitations.

    PubMed

    Krueger, G G; Morgan, J R; Jorgensen, C M; Schmidt, L; Li, H L; Kwan, M K; Boyce, S T; Wiley, H S; Kaplan, J; Petersen, M J

    1994-11-01

    Molecular definition of disease at the level of the gene and advances in recombinant DNA technology suggest that many diseases are amenable to correction by genes not bearing the defective elements that result in disease. Many questions must be answered before this therapy can be used to correct chronic diseases. These questions fall into safety and efficacy categories. Experience with transplanting cellular elements of skin or skin substitutes (defined as skin that possess the cell types and a dermal structure to develop into a functioning skin) to athymic rodents is considerable and is seen as a system where these questions can be answered. This paper reviews these questions and presents our early analysis of genetically modified cells in skin substitutes in vivo and in vitro. Experimental data demonstrate that both a matrix of woven nylon, housing a fibroblast generated collage, and dead dermis can be utilized to shuttle genetically modified human fibroblasts from the laboratory to an in vivo setting. Genetically modified fibroblasts do not migrate from the shuttle to the surrounding tissue. The survival of significant numbers, approximately 70%, of genetically modified fibroblasts for at least 6 weeks in these shuttles, supports this general approach as having clinical utility. It is also concluded that skin substitute systems can be used to generate a genetically modified skin in vitro that has the capacity to develop into functional skin in vivo. Further, as genetically modified keratinocytes differentiate there is increased production by the transgene, supporting the concept that keratinocytes have true potential as shuttles for therapeutic genes. This work demonstrates that transplantation of systems containing genetically modified cells of the skin can be used to experimentally define many aspects of gene therapy using skin before this technology is taken to the clinic. Examples include determining the effect of gene transduction and expression on

  16. Skin microbiota: overview and role in the skin diseases acne vulgaris and rosacea.

    PubMed

    Murillo, Nathalia; Raoult, Didier

    2013-02-01

    As the first barrier to environmental exposures, human skin has developed an integrated immune system to protect the inner body from chemical, physical or microbial insults. Microorganisms inhabiting superficial skin layers are known as skin microbiota and include bacteria, viruses, archaea and fungi. The microbiota composition is crucial in the instruction and support of the skin's immune system. Changes in microbiota can be due to individual, environmental or behavioral factors, such as age, climate, hygiene or antibiotic consumption, which can cause dysbiosis. The contribution of skin microbiota to disease development is known in atopic dermatitis, where there is an increase in Staphylococcus aureus. Culture-independent studies have enabled more accurate descriptions of this complex interplay. Microbial imbalance is associated with the development of various diseases. This review focuses on microbial imbalances in acne vulgaris and rosacea.

  17. Metamaterial-based sensor for skin disease diagnostics

    NASA Astrophysics Data System (ADS)

    La Spada, L.; Iovine, R.; Tarparelli, R.; Vegni, L.

    2013-05-01

    Skin absorption properties, under diseases conditions, are modified due to the structural variations of chromophores and pigments. The measurement of such different absorptions can be a useful tool for the recognition of different skin diseases. In this study the design of a multi-resonant metamaterial-based sensor operating in the optical frequency range is presented. The sensor has been designed, in order to have multiple specific resonant frequencies, tuned to the skin components spectral characteristics. A change in the frequency amplitude of the sensor response is related to the different absorption rate of skin chromophores and pigments. A new analytical model, describing the multi-resonant sensor behaviour, is developed. Good agreement among analytical and numerical results was achieved. Full-wave simulations have validated the capability of the proposed sensor to identify different skin diseases.

  18. The Diagnostic Value of Skin Disease Diagnosis Expert System.

    PubMed

    Jeddi, Fatemeh Rangraz; Arabfard, Masoud; Arabkermany, Zahra; Gilasi, Hamidreza

    2016-02-01

    Evaluation is a necessary measure to ensure the effectiveness and efficiency of all systems, including expert systems. The aim of this study was to determine the diagnostic value of expert system for diagnosis of complex skin diseases. A case-control study was conducted in 2015 to determine the diagnostic value of an expert system. The study population included patients who were referred to Razi Specialized Hospital, affiliated to Tehran University of Medical Sciences. The control group was selected from patients without the selected skin diseases. Data collection tool was a checklist of clinical signs of diseases including pemphigus vulgaris, lichen planus, basal cell carcinoma, melanoma, and scabies. The sample size formula estimated 400 patients with skin diseases selected by experts and 200 patients without the selected skin diseases. Patient selection was undertaken with randomized stratified sampling and their sign and symptoms were logged into the system. Physician's diagnosis was determined as the gold standard and was compared with the diagnosis of expert system by SPSS software version 16 and STATA. Kappa statistics, indicators of sensitivity, specificity, accuracy and confidence intervals were calculated for each disease. An accuracy of 90% was considered appropriate. Comparing the results of expert system and physician's diagnosis at the evaluation stage showed an accuracy of 97.1%, sensitivity of 97.5% and specificity of 96.5% The Kappa test indicated a high agreement of 93.6%. The expert system can diagnose complex skin diseases. Development of such systems is recommended to identify all skin diseases.

  19. Pattern of Skin Diseases in a Tertiary Institution in Kolkata

    PubMed Central

    Kar, Chinmay; Das, Sudip; Roy, Alok Kumar

    2014-01-01

    Background: There are very little elaborative studies in India about various patterns of skin diseases and various factors those influence the diseases in a tertiary institution. Aims: To find out the various patterns of skin diseases in relation to age, sex, occupation, and socio-economic status. To find out the magnitude of skin diseases and compare with other similar studies. Materials and Methods: Collection of data of all new skin cases in a specified period of one year and put on proforma for diagnosis. Few investigations were done for correct diagnosis. Results: It was found that skin OPD patients (new) were 4.16% of total new OPD patients, and male female ratio was 1.1:1. Among all patients (12910), infection was commonest (39.54%), followed by allergic skin disorder (29.20%). 25.05% patients were housewives, followed by students (23.21%). Study showed that 33.28% patients had per capita income of ` 361-720/month, and 22.35% patients were educated and/or studied up to class V. Conclusion: Pattern of skin diseases are mostly depend not only on environmental factors but also on occupation, socio-economic status, literacy, and age of the patients. PMID:24700954

  20. Non-infectious skin disease in Indigenous Australians.

    PubMed

    Heyes, Christopher; Tait, Clare; Toholka, Ryan; Gebauer, Kurt

    2014-08-01

    The burden of non-infectious skin disease in the Indigenous Australian population has not been previously examined. This study considers the published data on the epidemiology and clinical features of a number of non-infectious skin diseases in Indigenous Australians. It also outlines hypotheses for the possible differences in the prevalence of such diseases in this group compared with the general Australian population. There is a paucity of literature on the topic but, from the material available, Indigenous Australians appear to have a reduced prevalence of psoriasis, type 1 hypersensitivity reactions and skin cancer but increased rates of lupus erythematosus, kava dermopathy and vitamin D deficiency when compared to the non-Indigenous Australian population. This article profiles the prevalence and presentation of non-infectious skin diseases in the Indigenous Australian population to synthesise our limited knowledge and highlight deficiencies in our understanding. © 2013 The Australasian College of Dermatologists.

  1. Skin Diseases Take Big Slice Out of America's Health, Economy

    MedlinePlus

    ... gov/news/fullstory_163888.html Skin Diseases Take Big Slice Out of America's Health, Economy The sometimes ... each, the researchers found. Costs are also a big concern. In 2013, the United States spent $75 ...

  2. Skin Diseases: Questions for Your Health Care Provider

    MedlinePlus

    ... Issue Past Issues Skin Diseases Questions for Your Health Care Provider Past Issues / Fall 2008 Table of Contents ... Sun—Not a good mix / Questions for Your Health Care Provider Fall 2008 Issue: Volume 3 Number 4 ...

  3. Mitochondrial dysfunction: a neglected component of skin diseases.

    PubMed

    Feichtinger, René G; Sperl, Wolfgang; Bauer, Johann W; Kofler, Barbara

    2014-09-01

    Aberrant mitochondrial structure and function influence tissue homeostasis and thereby contribute to multiple human disorders and ageing. Ten per cent of patients with primary mitochondrial disorders present skin manifestations that can be categorized into hair abnormalities, rashes, pigmentation abnormalities and acrocyanosis. Less attention has been paid to the fact that several disorders of the skin are linked to alterations of mitochondrial energy metabolism. This review article summarizes the contribution of mitochondrial pathology to both common and rare skin diseases. We explore the intriguing observation that a wide array of skin disorders presents with primary or secondary mitochondrial pathology and that a variety of molecular defects can cause dysfunctional mitochondria. Among them are mutations in mitochondrial- and nuclear DNA-encoded subunits and assembly factors of oxidative phosphorylation (OXPHOS) complexes; mutations in intermediate filament proteins involved in linking, moving and shaping of mitochondria; and disorders of mitochondrial DNA metabolism, fatty acid metabolism and heme synthesis. Thus, we assume that mitochondrial involvement is the rule rather than the exception in skin diseases. We conclude the article by discussing how improving mitochondrial function can be beneficial for aged skin and can be used as an adjunct therapy for certain skin disorders. Consideration of mitochondrial energy metabolism in the skin creates a new perspective for both dermatologists and experts in metabolic disease. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. The role of antimicrobial peptides in chronic inflammatory skin diseases

    PubMed Central

    Majewski, Sławomir

    2016-01-01

    Antimicrobial peptides (AMPs) are effector molecules of the innate immune system of the skin. They present an activity against a broad spectrum of Gram-positive and Gram-negative bacteria as well as some fungi, parasites and enveloped viruses. Several inflammatory skin diseases including psoriasis, atopic dermatitis, acne vulgaris and rosacea are characterized by a dysregulated expression of AMPs. Antimicrobial peptides are excessively produced in lesional psoriatic scales or rosacea in contrast to the atopic skin that shows lower AMP levels when compared with psoriasis. The importance of the AMPs contribution to host immunity is indisputable as alterations in the antimicrobial peptide expression have been associated with various pathologic processes. This review discusses the biology and clinical relevance of antimicrobial peptides expressed in the skin and their role in the pathogenesis of inflammatory skin diseases. PMID:26985172

  5. Ex vivo gene therapy cures a blistering skin disease.

    PubMed

    Featherstone, Carol; Uitto, Jouni

    2007-06-01

    A recent publication that describes gene therapy treatment of a patient with an inherited blistering skin disease, epidermolysis bullosa, demonstrates for the first time that gene therapy can cure a disease of solid tissue. The treatment relies on ex vivo transduction of autologous epidermal stem cells with a normal copy of the defective gene, followed by reconstitution of the patient's skin with epithelial sheets that are grown from these genetically corrected cells. This approach holds promise for treatment not only of inherited disorders of the skin but also of other solid tissues that are becoming amenable to tissue engineering.

  6. Mortality from nonneoplastic skin disease in the United States.

    PubMed

    Lott, Jason P; Gross, Cary P

    2014-01-01

    The mortality burden from nonneoplastic skin disease in the United States is unknown. We sought to estimate mortality from nonneoplastic skin disease as underlying and contributing causes of death. Population-based death certificate data detailing mortality from nonneoplastic skin disease for years 1999 to 2009 were used to calculate absolute numbers of death and age-adjusted mortality by year, patient demographics, and 10 most commonly reported diagnoses. Nonneoplastic skin diseases were reported as underlying and contributing causes of mortality for approximately 3948 and 19,542 patients per year, respectively. Age-adjusted underlying cause mortality (per 100,000 persons) were significantly greater (P < .0001) for patients who were black/African American (3.4), women (1.4), and residing in the South (1.6). Most deaths occurred in patients ages 65 years and older (34,248 total deaths). Common underlying causes of death included chronic ulcers (1789 deaths/y) and cellulitis (1348 deaths/y). Errors in death certificate data and inability to adjust for patient-level confounders may limit the accuracy and generalizability of our results. Mortality from nonneoplastic skin disease is uncommon yet potentially preventable. The elderly bear the greatest burden of mortality from nonneoplastic skin disease. Chronic ulcers and cellulitis constitute frequent causes of death. Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  7. Treating skin disease: self-management behaviors of Latino farmworkers.

    PubMed

    Arcury, Thomas A; Vallejos, Quirina M; Feldman, Steven R; Quandt, Sara A

    2006-01-01

    Latino migrant and seasonal farmworkers experience high rates of skin disease that result from their working and living conditions. Knowledge of the ways farmworkers treat skin disease symptoms will provide a foundation for developing culturally appropriate health education, improving the delivery of health services, and improving occupational health policy for agricultural workers. The purpose of this paper is to describe skin disease self-management practices among Latino migrant and seasonal farmworkers in North Carolina. This analysis uses a qualitative design based on in-depth interviews with 30 Latino farmworkers (six females, 24 males). Computer assisted, systematic procedures are used to analyze the verbatim transcripts of these interviews. Participants shared a consistent set of health self-management actions in treating skin disease. These actions were within the domains of self-care and medical care. A model of skin disease self-management among Latino farmworkers includes the self-care actions of hygiene, use of home remedies and use of over-the-counter remedies, with farmworkers often combining different domains of self-care. While farmworkers acknowledge the benefits of medical care, they are also mindful of barriers to its use, including cost, transportation and language. The large percentage of farmworkers who experience skin problems indicates that health outreach workers who serve this population need to provide education on preventing and treating skin problems, and they need to recommend to farmworkers appropriate over-the-counter medicines for the treatment of these skin problems. Appropriate medical care for treating skin problems that are dangerous and reduce farmworkers' quality-of-life needs to be made available to this population.

  8. Lysosome-associated protein 1 (LAMP-1) and lysosome-associated protein 2 (LAMP-2) in a larger family carrier of Fabry disease.

    PubMed

    Pereira, Ester M; do Monte, Semiramis J H; do Nascimento, Fernando F; de Castro, Jose A F; Sousa, Jackeline L M; Filho, Henrique C S A L C; da Silva, Raimundo N; Labilloy, Anatália; Monte Neto, José T; da Silva, Adalberto S

    2014-02-15

    This study investigated the potential relationship between the expression levels of lysosome-associated membrane proteins (LAMP) 1 and 2 and responses to enzyme replacement therapy (ERT) in the members of a single family with Fabry disease (FD). LAMP levels were assessed by flow cytometry in leukocytes from 17 FD patients who received an eight-month course of ERT course and 101 healthy individuals. We found that phagocytic cells from the FD patients had higher expression levels of both LAMP-1 and LAMP-2, relative to the levels in phagocytes from the healthy controls (p=0.001). Furthermore, the LAMP-1 and LAMP-2 levels in phagocytes from the FD carriers continuously decreased with ERT administration to reach levels similar to those in healthy controls. We suggest that LAMP-1 and LAMP-2 could be used as additional markers with which to assess ERT effectiveness in FD.

  9. The expanding clinical spectrum of Anderson-Fabry disease: a challenge to diagnosis in the novel era of enzyme replacement therapy.

    PubMed

    Hauser, A C; Lorenz, M; Sunder-Plassmann, G

    2004-06-01

    Anderson-Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient alpha-galactosidase A activity. The conception of the disease has changed within the last decade. Studies of the last years have shown that the disease is not limited to the classical full-blown manifestation in affected males, which is well known since more than a century, but may also occur in carrier females. The phenomenology may differ in severity and kind of organ manifestation. Cardiac and renal variants with solely disease manifestation of these organs have also been described in an increasing number. It is likely that a spectrum exists regarding alpha-galactosidase A activity in both genders on the one hand, and an additional one regarding the severity and the number of organs affected on the other. The purpose of this review is to sharpen physicians' perception of this disease. Early and accurate diagnosis is mandatory considering that this disorder is now, after introduction of the novel enzyme replacement therapy, a treatable disease.

  10. Dupuytren Disease Infiltrating a Full-Thickness Skin Graft.

    PubMed

    Wade, Ryckie George; Igali, Laszlo; Figus, Andrea

    2016-08-01

    Although the role of the skin in the development and propagation of Dupuytren disease remains unclear, dermofasciectomy and full-thickness skin grafting (FTSG) appears to delay recurrence. In 2011, a 71-year-old, left-handed man presented with recurrent Dupuytren disease in the dominant hand. In 1991, he originally underwent a primary dermofasciectomy and FTSG for Dupuytren disease involving the palmar skin. Twenty years later, the left middle finger was drawn into flexion by a recurrent cord, and the old graft and adjacent palmar skin were clinically involved by fibromatosis. We performed a revision dermofasciectomy and FTSG. Microscopic analysis of the excised graft demonstrated dense infiltration of the entire skin graft by Dupuytren disease, with areas of active and burnt-out fibromatosis distinct from hypertrophic scarring. This report of Dupuytren fibromatosis infiltrating a skin graft raises questions about the pathophysiology of Dupuytren disease. Copyright © 2016 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

  11. A pseudo-outbreak of skin disease in British troops.

    PubMed Central

    Croft, A; Smith, H; Creamer, I

    1996-01-01

    When a newspaper report claimed that a serious outbreak of skin disease had occurred in British Army troops stationed at the Bocac Dam, in western Bosnia, all troops at the Bocac Dam location (n = 96), followed by a matched control group of troops (n = 91) at a nearby location, were examined by two investigators. 14% of the study population and 21% of the control group were found to have skin disorders. Most were complaints that are commonly encountered in general medical practice. There was a striking absence of skin infestations. The historical consultation rate for skin disorders had not increased. It was concluded that an outbreak of skin disease had not occurred in British troops guarding the dam. This epidemiological study shows that, even under conditions of modern field hygiene, up to one in five soldiers will have skin disease. Skin infestations, however, have become progressively less common during military campaigns this century, probably because of better personal hygiene, good preventive medicine practices and better access to effective health care. PMID:8976888

  12. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions.

    PubMed

    Hay, Roderick J; Johns, Nicole E; Williams, Hywel C; Bolliger, Ian W; Dellavalle, Robert P; Margolis, David J; Marks, Robin; Naldi, Luigi; Weinstock, Martin A; Wulf, Sarah K; Michaud, Catherine; J L Murray, Christopher; Naghavi, Mohsen

    2014-06-01

    The Global Burden of Disease (GBD) Study 2010 estimated the GBD attributable to 15 categories of skin disease from 1990 to 2010 for 187 countries. For each of the following diseases, we performed systematic literature reviews and analyzed resulting data: eczema, psoriasis, acne vulgaris, pruritus, alopecia areata, decubitus ulcer, urticaria, scabies, fungal skin diseases, impetigo, abscess, and other bacterial skin diseases, cellulitis, viral warts, molluscum contagiosum, and non-melanoma skin cancer. We used disability estimates to determine nonfatal burden. Three skin conditions, fungal skin diseases, other skin and subcutaneous diseases, and acne were in the top 10 most prevalent diseases worldwide in 2010, and eight fell into the top 50; these additional five skin problems were pruritus, eczema, impetigo, scabies, and molluscum contagiosum. Collectively, skin conditions ranged from the 2nd to 11th leading cause of years lived with disability at the country level. At the global level, skin conditions were the fourth leading cause of nonfatal disease burden. Using more data than has been used previously, the burden due to these diseases is enormous in both high- and low-income countries. These results argue strongly to include skin disease prevention and treatment in future global health strategies as a matter of urgency.

  13. Electrochemical Skin Conductance in Diabetic Kidney Disease.

    PubMed

    Freedman, Barry I; Smith, Susan Carrie; Bagwell, Benjamin M; Xu, Jianzhao; Bowden, Donald W; Divers, Jasmin

    2015-01-01

    There is a need to identify patients with diabetic kidney disease (DKD) using noninvasive, cost-effective screening tests. Sudoscan®, a device using electrochemical skin conductance (ESC) to measure sweat gland dysfunction, is valuable for detecting peripheral neuropathy. ESC was tested for association with DKD (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2)) in 383 type 2 diabetes mellitus (T2D)-affected patients; diagnostic thresholds were determined in 540 patients. Relationships between ESC with eGFR and urine albumin:creatinine ratio (UACR) were assessed in 202 European Americans and 181 African Americans with T2D. In 92 European American DKD cases and 110 T2D non-nephropathy controls, respectively, mean (SD) ages were 69 (9.7) and 61 (10.8) years, hemoglobin A1c (HbA1c) 7.4 (1.2) and 7.4 (1.3)%, eGFR 29.6 (12.2) and 87.8 (14.2) ml/min/1.73 m(2), and UACR 1,214 (1,705) and 7.5 (5.8) mg/g. In 57 African American cases and 124 controls, respectively, mean (SD) ages were 64.0 (11.9) and 59.5 (9.7) years, HbA1c 7.4 (1.3) and 7.5 (1.7)%, eGFR 29.6 (13.3) and 90.2 (16.2) ml/min/1.73 m(2), and UACR 1,172 (1,564) and 7.8 (7.1) mg/g. Mean (SD) ESC (μS) was lower in cases than controls (European Americans: case/control hands 49.5 (18.5)/62.3 (16.2); feet 62.1 (17.9)/73.6 (13.8), both p < 1.3 × 10(-6); African Americans: case/control hands 39.8 (19.0)/48.5 (17.1); feet 53.2 (21.3)/63.5 (19.4), both p ≤ 0.01). Adjusting for age, sex, body mass index and HbA1c, hands and feet ESC associated with eGFR <60 ml/min/1.73 m(2) (p ≤ 7.2 × 10(-3)), UACR >30 mg/g (p ≤ 7.0 × 10(-3)), UACR >300 mg/g (p ≤ 8.1 × 10(-3)), and continuous traits eGFR and UACR (both p ≤ 5.0 × 10(-9)). HbA1c values were not useful for risk stratification. ESC measured using Sudoscan® is strongly associated with DKD in African Americans and European Americans. ESC is a useful screening test to identify DKD in patients with T2D.

  14. Electrochemical skin conductance in diabetic kidney disease

    PubMed Central

    Freedman, Barry I.; Smith, S. Carrie; Bagwell, Benjamin M.; Xu, Jianzhao; Bowden, Donald W.; Divers, Jasmin

    2015-01-01

    Background There is a need to identify patients with diabetic kidney disease (DKD) using non-invasive, cost-effective screening tests. Sudoscan®, a device using electrochemical skin conductance (ESC) to measure sweat gland dysfunction, is valuable for detecting peripheral neuropathy. ESC was tested for association with DKD (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73m2) in 383 type 2 diabetes mellitus (T2D)-affected patients; diagnostic thresholds were determined in 540 patients. Methods Relationships between ESC with eGFR and urine albumin:creatinine ratio (UACR) were assessed in 202 European Americans (EA) and 181 African Americans (AA) with T2D. Results In 92 EA DKD cases and 110 T2D non-nephropathy controls, respectively, mean(SD) ages were 68.9(9.8) and 61.1(10.8) years, HbA1c 7.4(1.2) and 7.4(1.3)%, eGFR 29.5(12.2) and 87.7(14.1) ml/min/1.73m2, and UACR 1227(1710) and 7.6(5.9) mg/g. In 57 AA cases and 124 controls, respectively, mean (SD) ages were 64.0(12.0) and 59.5(9.7) years, HbA1c 7.4(1.3) and 7.6 (1.7)%, eGFR 29.7(13.3) and 90.2(16.2) ml/min/1.73m2, and UACR 1172(1564) and 7.8(7.1) mg/g. Mean(SD) ESC (μS) was lower in cases than controls (EA: case/control hands 49.3(18.5)/62.4(16.2); feet 62.2(18.0)/73.4(13.9), both p<5.8×10−7; AA: case/control hands 39.8(19.0)/48.5(17.1); feet 53.2(21.3)/63.5(19.4), both p≤0.01). Adjusting for age, sex, BMI and HbA1c, hands and feet ESC associated with eGFR <60 ml/min/1.73m2 (p≤7.2×10−3), UACR >30 mg/g (p≤7.0×10−3), UACR >300 mg/g (p≤8.1×10−3), and continuous traits eGFR and UACR (both p≤5.0×10−9). HbA1c values were not useful for risk stratification. Conclusions ESC measured using Sudoscan® is strongly associated with DKD in AA and EA. ESC is a useful screening test to identify DKD in patients with T2D. PMID:26228248

  15. Long-term effect of antibodies against infused alpha-galactosidase A in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome.

    PubMed

    Rombach, Saskia M; Aerts, Johannes M F G; Poorthuis, Ben J H M; Groener, Johanna E M; Donker-Koopman, Wilma; Hendriks, Erik; Mirzaian, Mina; Kuiper, Sijmen; Wijburg, Frits A; Hollak, Carla E M; Linthorst, Gabor E

    2012-01-01

    Enzyme replacement therapy (ERT) with alpha-Galactosidase A (aGal A) may cause antibody (AB) formation against aGal A in males with Fabry disease (FD). Anti agalsidase ABs negatively influence globotriaosylceramide (Gb3) reduction. We investigated the impact of agalsidase AB on Gb3 and lysoGb3 and clinical outcome in Fabry patients on ERT. Adult male and female patients on ERT for at least one year were included. Urinary Gb3 was measured by HPLC, plasma lysoGb3 by LC-ESI-MS/MS and AB with a neutralization assay. Of the 59 patients evaluable patients, 0/30 females and 17/29 males developed anti-agalsidase antibodies (AB+). Only 3/17 males had transient (low) titers (tolerized). All AB+ patients developed antibodies during the first year of treatment. Change of agalsidase preparation (or dose) did not induce antibody formation. AB+ males had significant less decline in plasma lysoGb3 compared to AB- males (p = 0.04). Urinary Gb3 levels decreased markedly in AB- but remained comparable to baseline in AB+ males (p<0.01). (Lyso)Gb3 reduction in plasma and urine on ERT was correlated with LVmass reduction in females and development white matter lesions and stroke. In male patients antibodies against aGal A remained present up to 10 years of ERT. The presence of these antibodies is associated with a less robust decrease in plasma lysoGb3 and a profound negative effect on urinary Gb3 reduction, which may reflect worse treatment outcome.

  16. Zebrafish as a model system to study heritable skin diseases.

    PubMed

    Li, Qiaoli; Uitto, Jouni

    2013-01-01

    Heritable skin diseases represent a broad spectrum of clinical manifestations due to mutations in ∼500 different genes. A number of model systems have been developed to advance our understanding of the pathomechanisms of genodermatoses. Zebrafish (Danio rerio), a freshwater vertebrate, has a well-characterized genome, the expression of which can be easily manipulated. The larvae develop rapidly, with all major organs having largely developed by 5-6 days post-fertilization, including the skin which consists at that stage of the epidermis comprising two cell layers and separated from the dermal collagenous matrix by a basement membrane zone. Here, we describe the use of morpholino-based antisense oligonucleotides to knockdown the expression of specific genes in zebrafish and to examine the consequent knockdown efficiency and skin phenotypes. Zebrafish can provide a useful model system to study heritable skin diseases.

  17. Identification of Malassezia pachydermatis from healthy and diseased human skin.

    PubMed

    Prohic, Asja; Kasumagic-Halilovic, Emina

    2009-01-01

    Malassezia pachydermatis is the only species in the genus Malassezia that is classically considered to be zoophilic. This yeast is only occasionally isolated from human skin, although it has been found to cause septic epidemics, especially in neonates. The aim of our study was to investigate the prevalence of M. pachydermatis on the skin of patients with Malassezia-associated diseases and of healthy subjects. One hundred and sixty skin scrapings from patients with pityriasis versicolor (PV), seborrhoeic dermatitis (SD), psoriasis (PS) and healthy individuals, forty each, were inoculated into Sabouraud dextrose agar and into modified Dixon agar. The yeasts isolated were identified according to their macroscopic and microscopic features and physiological properties. M. globosa was the most commonly isolated species in lesional skin of PV (65%) and PS (55%), M. restricta in lesional skin of SD (27.5%), while M. sympodialis was the predominant species recovered from healthy skin, representing 30% of the isolates. Zoophilic species, M. pachydermatis was identified in only one case, from the lesional skin of SD. The results of our study confirm that M. pachydermatis is not a member of the normal human flora and its presence on human skin is rare and indicates transmission from an external source.

  18. The Diagnostic Value of Skin Disease Diagnosis Expert System

    PubMed Central

    Jeddi, Fatemeh Rangraz; Arabfard, Masoud; Arabkermany, Zahra; Gilasi, Hamidreza

    2016-01-01

    Background: Evaluation is a necessary measure to ensure the effectiveness and efficiency of all systems, including expert systems. The aim of this study was to determine the diagnostic value of expert system for diagnosis of complex skin diseases. Methods: A case-control study was conducted in 2015 to determine the diagnostic value of an expert system. The study population included patients who were referred to Razi Specialized Hospital, affiliated to Tehran University of Medical Sciences. The control group was selected from patients without the selected skin diseases. Data collection tool was a checklist of clinical signs of diseases including pemphigus vulgaris, lichen planus, basal cell carcinoma, melanoma, and scabies. The sample size formula estimated 400 patients with skin diseases selected by experts and 200 patients without the selected skin diseases. Patient selection was undertaken with randomized stratified sampling and their sign and symptoms were logged into the system. Physician’s diagnosis was determined as the gold standard and was compared with the diagnosis of expert system by SPSS software version 16 and STATA. Kappa statistics, indicators of sensitivity, specificity, accuracy and confidence intervals were calculated for each disease. An accuracy of 90% was considered appropriate. Results: Comparing the results of expert system and physician’s diagnosis at the evaluation stage showed an accuracy of 97.1%, sensitivity of 97.5% and specificity of 96.5% The Kappa test indicated a high agreement of 93.6%. Conclusion: The expert system can diagnose complex skin diseases. Development of such systems is recommended to identify all skin diseases. PMID:27046943

  19. The canine and feline skin microbiome in health and disease.

    PubMed

    Weese, J Scott

    2013-02-01

    The skin harbours a diverse and abundant, yet inadequately investigated, microbial population. The population is believed to play an important role in both the pathophysiology and the prevention of disease, through a variety of poorly explored mechanisms. Early studies of the skin microbiota in dogs and cats reported a minimally diverse microbial composition of low overall abundance, most probably as a reflection of the limitations of testing methodology. Despite these limitations, it was clear that the bacterial population of the skin plays an important role in disease and in changes in response to both infectious and noninfectious diseases. Recent advances in technology are challenging some previous assumptions about the canine and feline skin microbiota and, with preliminary application of next-generation sequenced-based methods, it is apparent that the diversity and complexity of the canine skin microbiome has been greatly underestimated. A better understanding of this complex microbial population is critical for elucidation of the pathophysiology of various dermatological (and perhaps systemic) diseases and to develop novel ways to manipulate this microbial population to prevent or treat disease.

  20. Disturbed skin barrier in children with chronic kidney disease.

    PubMed

    Wojtowicz-Prus, Elzbieta; Kilis-Pstrusinska, Katarzyna; Reich, Adam; Zachwieja, Katarzyna; Miklaszewska, Monika; Szczepanska, Maria; Szepietowski, Jacek C

    2015-02-01

    There are limited data on skin lesions in children with end-stage renal failure. The aim of the study was an evaluation of the skin barrier in children with different stages of chronic kidney disease (CKD). The prevalence of xerosis, its severity, as well as its link selected demographic factors, were examined. The study included 103 children: 72 with CKD stages 3-5 (38 on conservative treatment and 34 on dialysis) and 31 patients with primary monosymptomatic nocturnal enuresis as a control group. Initially, the study subjects described the localisation and severity of dry skin by themselves. Next, clinical evaluation of xerosis, non-invasive corneometric assessment of epidermis moisturising and the measurement of transepidermal water loss were performed. Most CKD children reported dry skin. The problem of xerosis was identified more frequently in patients on dialysis (67.6 %) than on conservative treatment (42.1 %) (p = 0.01). CKD patients divided according to skin dryness did not differ with regards to age, sex, initial kidney disease and CKD duration. Disturbed skin barrier is an important concern of children with CKD, intensifying as the disease progresses. This symptom occurs on early stages of CKD and it should be taken into consideration in the CKD management.

  1. Letter to Editor: Chemokine Network Involved in Inflammatory Skin Diseases.

    PubMed

    Shaik-Dasthagirisaheb, Y B; Conti, P

    2015-01-01

    Chemokines are low-molecular-weight chemotactic proteins that regulate the trafficking of leukocytes to inflammatory sites and may recruit inflammatory cells to the epidermis. Chemokines are produced by many immune cells such as macrophages, mast cells, T lymphocytes and others, in response to pro-inflammatory stimuli including IL-1, TNF and LPS. Immune cells which participate in inflammatory skin disorders, upon activation express several adhesive and immune receptors such as P-selectin, CD40 ligand, and Toll-like receptors on their surface, and generate cytokines/chemokines. Chemokines have crucial functions in inflammation, and cell dysregulations and they are recognized as potentially important in diverse skin pathologies associated with the severity of disease. Injection of chemokines in the rat skin provoke the recruitment of inflammatory cells, release of cytokines, and activation of transcription of histidine decarboxylase (HDC), the enzyme responsible for the generation of histamine from histidine, which may cause fatal anaphylactic shock. Therefore, the use of anti-chemokines for inflammatory skin diseases remains a promising therapeutic approach. However, the complete role of chemokines in inflammatory skin diseases remains to be further studied. Here we report the relationship between chemokines and skin inflammation. © 2015 by the Association of Clinical Scientists, Inc.

  2. 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.

  3. The skin in autoimmune diseases-Unmet needs.

    PubMed

    Kuhn, A; Landmann, A; Bonsmann, G

    2016-10-01

    Treatment of skin manifestations in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and dermatomyositis (DM) is based on the results of only few randomized controlled trials. The first-line treatment for disfiguring and widespread cutaneous involvement in SLE is antimalarials, but some patients are therapy resistant. Recently, the monoclonal antibody belimumab was approved for SLE as an adjunct therapy for patients with autoantibody-positive disease who despite standard therapy show high disease activity, intolerance of other treatments, or an unacceptably high need for corticosteroids. However, a validated skin score has not been used to confirm the efficacy of belimumab on mucocutaneous manifestations. In SSc, another multi-systemic progressive disease, involvement of the lung, kidney, and the heart is frequently treated with corticosteroids and immunosuppressives, but therapeutic modalities for cutaneous lesions, such as skin sclerosis and digital ulcers, are limited. In the past years, treatment with the endothelin-receptor antagonist bosentan has been proven to reduce the occurrence of new digital ulcers in SSc patients but has no or limited effect on healing of digital ulcers. DM is an idiopathic autoimmune disease characterized by inflammation of the muscles and skin, which is treated with immunosuppressives. Corticosteroids are the first-line treatment for muscle involvement in DM, but skin lesions often flare by reduction or discontinuation. In summary, there is a high unmet need for new therapeutic strategies focusing on skin involvement in systemic autoimmune diseases. Therefore, innovative designs of randomized controlled trials with validated skin scores are warranted to develop new therapeutic strategies for patients with cutaneous manifestations. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease.

    PubMed

    Oji, Vinzenz; Eckl, Katja-Martina; Aufenvenne, Karin; Nätebus, Marc; Tarinski, Tatjana; Ackermann, Katharina; Seller, Natalia; Metze, Dieter; Nürnberg, Gudrun; Fölster-Holst, Regina; Schäfer-Korting, Monika; Hausser, Ingrid; Traupe, Heiko; Hennies, Hans Christian

    2010-08-13

    Generalized peeling skin disease is an autosomal-recessive ichthyosiform erythroderma characterized by lifelong patchy peeling of the skin. After genome-wide linkage analysis, we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies, which leads to a complete loss of corneodesmosin. In contrast to hypotrichosis simplex, which can be associated with specific dominant CDSN mutations, peeling skin disease is characterized by a complete loss of CDSN expression. The skin phenotype is consistent with a recent murine Cdsn knockout model. Using three-dimensional human skin models, we demonstrate that lack of corneodesmosin causes an epidermal barrier defect supposed to account for the predisposition to atopic diseases, and we confirm the role of corneodesmosin as a decisive epidermal adhesion molecule. Therefore, peeling skin disease will represent a new model disorder for atopic diseases, similarly to Netherton syndrome and ichthyosis vulgaris in the recent past.

  5. Skin-specific drug delivery: a rapid solution to skin diseases?

    PubMed

    Sadik, Christian D; Zillikens, Detlef

    2013-09-01

    In this issue of The Journal of Investigative Dermatology, Kouno et al. achieve skin-specific drug delivery using an antibody to deliver substances in a highly specific manner to nontransformed cells. They make use of a nonpathogenic anti-desmoglein 3 autoantibody that had been derived from a patient with pemphigus vulgaris to deliver drugs to the surface of keratinocytes. This approach may turn out to be a new "magic bullet", thereby revolutionizing the therapy of skin disease. The authors then used a conjugate of this antibody with a new drug entity, TNF-related apoptosis-inducing ligand, to demonstrate, as a proof-of-principle, that their approach has the potential to facilitate the treatment of both cancerous and inflammatory skin diseases.

  6. Genetic skin diseases related to desmosomes and corneodesmosomes.

    PubMed

    Ishida-Yamamoto, Akemi; Igawa, Satomi

    2014-05-01

    The integrity of the epidermis depends on the cohesion between keratinocytes, and desmosomes are the main adhesion structures. When cells become cornified, desmosomes are modified and transformed into corneodesmosomes. Mutations in the genes encoding desmosomal components underlie several skin diseases including palmoplantar keratoderma and forms of epidermolysis bullosa, indicating the importance of desmosomes as mechanical stress-bearing structures. Other types of genetic defects in a desmosome component (desmoglein 1), a corneodesmosome component (corneodesmosin), and an inhibitor for proteases involved in corneodesmosome degradation (LEKTI) result in three clinically overlapping conditions: SAM syndrome, an inflammatory type of peeling skin disease, and Netherton syndrome. All three result in allergies to multiple allergens due to severe barrier impairment. Conversely, impaired corneodesmosomal degradation due to matriptase mutations could lead to ichthyosis. By discovering the diverse clinical phenotypes of these diseases, we can enrich our understanding of the multifunctional roles of desmosomes and corneodesmosomes in skin biology.

  7. MicroRNAs in Human Diseases: From Autoimmune Diseases to Skin, Psychiatric and Neurodegenerative Diseases

    PubMed Central

    2011-01-01

    MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression via degradation or translational repression of their target messenger RNAs (mRNAs). Recent studies have clearly demonstrated that miRNAs play critical roles in several biologic processes, including cell cycle, differentiation, cell development, cell growth, and apoptosis and that miRNAs are highly expressed in regulatory T (Treg) cells and a wide range of miRNAs are involved in the regulation of immunity and in the prevention of autoimmunity. It has been increasingly reported that miRNAs are associated with various human diseases like autoimmune disease, skin disease, neurological disease and psychiatric disease. Recently, the identification of mi- RNAs in skin has added a new dimension in the regulatory network and attracted significant interest in this novel layer of gene regulation. Although miRNA research in the field of dermatology is still relatively new, miRNAs have been the subject of much dermatological interest in skin morphogenesis and in regulating angiogenesis. In addition, miRNAs are moving rapidly onto center stage as key regulators of neuronal development and function in addition to important contributions to neurodegenerative disorder. Moreover, there is now compelling evidence that dysregulation of miRNA networks is implicated in the development and onset of human neruodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Tourette's syndrome, Down syndrome, depression and schizophrenia. In this review, I briefly summarize the current studies about the roles of miRNAs in various autoimmune diseases, skin diseases, psychoneurological disorders and mental stress. PMID:22194706

  8. MicroRNAs in Human Diseases: From Autoimmune Diseases to Skin, Psychiatric and Neurodegenerative Diseases.

    PubMed

    Ha, Tai-You

    2011-10-01

    MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression via degradation or translational repression of their target messenger RNAs (mRNAs). Recent studies have clearly demonstrated that miRNAs play critical roles in several biologic processes, including cell cycle, differentiation, cell development, cell growth, and apoptosis and that miRNAs are highly expressed in regulatory T (Treg) cells and a wide range of miRNAs are involved in the regulation of immunity and in the prevention of autoimmunity. It has been increasingly reported that miRNAs are associated with various human diseases like autoimmune disease, skin disease, neurological disease and psychiatric disease. Recently, the identification of mi- RNAs in skin has added a new dimension in the regulatory network and attracted significant interest in this novel layer of gene regulation. Although miRNA research in the field of dermatology is still relatively new, miRNAs have been the subject of much dermatological interest in skin morphogenesis and in regulating angiogenesis. In addition, miRNAs are moving rapidly onto center stage as key regulators of neuronal development and function in addition to important contributions to neurodegenerative disorder. Moreover, there is now compelling evidence that dysregulation of miRNA networks is implicated in the development and onset of human neruodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Tourette's syndrome, Down syndrome, depression and schizophrenia. In this review, I briefly summarize the current studies about the roles of miRNAs in various autoimmune diseases, skin diseases, psychoneurological disorders and mental stress.

  9. Functions of the skin microbiota in health and disease.

    PubMed

    Sanford, James A; Gallo, Richard L

    2013-11-30

    The skin, the human body's largest organ, is home to a diverse and complex variety of innate and adaptive immune functions. Despite this potent immune system present at the cutaneous barrier, the skin encourages colonization by microorganisms. Characterization these microbial communities has enhanced our knowledge of the ecology of organisms present in normal skin; furthermore, studies have begun to bring to light the intimate relationships shared between host and resident microbes. In particular, it is apparent that just as host immunological factors and behaviors shape the composition of these communities, microbes present on the skin greatly impact the functions of human immunity. Thus, today the skin immune system should be considered a collective mixture of elements from the host and microbes acting in a mutualistic relationship. In this article we will review recent findings of the interactions of skin microbial communities with host immunity, and discuss the role that dysbiosis of these communities plays in diseases of the skin. Copyright © 2013. Published by Elsevier Ltd.

  10. Signaling by reactive oxygen and nitrogen species in skin diseases.

    PubMed

    Afanas'ev, Igor B

    2010-06-01

    For many years the formation of reactive oxygen and nitrogen species (ROS) and (RNS) in living organisms has been considered to be dangerous phenomenon due to their damaging action on biomolecules. However, present studies demonstrated another important activity of ROS and RNS: their signaling functions in physiological and pathological processes. In this work we discuss the new data concerning a role of ROS and RNS in many enzymatic/gene cascades causing damaging changes during the development of skin diseases and pathological disorders (skin cancer, the toxic effects of irradiation on the skin, and skin wounding). It has been suggested that the enhancement of ROS formation in tumor cells through the inactivation of mitochondrial MnSOD or the activation of NADPH oxidase leads to apoptosis and might be applied for developing a new cancer therapy. On the other hand ROS overproduction might stimulate malignant transformation of melanoma. Role of ROS signaling is also considered in the damaging action of UVA, UVB, and IRA irradiation on the skin and the processes of wound healing. In the last part of review the possibility of the right choice of antioxidants and free radical scavengers for the treatment of skin disease is discussed.

  11. Over-the-counter topical skin products--a common component of skin disease management.

    PubMed

    Vogel, Curt A; Balkrishnan, Rajesh; Fleischer, Alan B; Cayce, Kimberly A; Feldman, Steven R

    2004-07-01

    Over-the-counter (OTC) products are widely recommended by physicians and utilized by the public for the treatment and prevention of disease. The use of OTC drugs has been studied extensively, but the patterns of physician recommendations for OTC topical skin products and the characteristics associated with patients receiving such recommendations remain unclear. We aimed to look at patterns of OTC topical skin product recommendations by physician specialty, patient demographics, geographical region, diagnosis, and metropolitan status to determine whether there are differences in the utilization of these products in the treatment of dermatologic conditions. We analyzed office-based physician visits for OTC topical skin product recommendations recorded in the 1995 to 2000 National Ambulatory Medical Care Survey (NAMCS). From 1995 to 2000, there were an estimated 36 million physician recommendations for OTC topical skin products. Although dermatologists were responsible for 53.8% of recommendations, pediatricians had the largest proportion of recommendations per prescription recommendation (OTC/Rx=0.58). Women patients, white patients, patients younger than 20 years, urban residents, and those living in the Southern United States received greater numbers of OTC topical skin product recommendations. Of the leading products recommended, hydrocortisone (27.6%), anti-infectives (23.4%), and moisturizers (13.4%) were the most common. OTC topical skin product recommendations by US physicians are substantial, particularly among dermatologists and primary care physicians. Physician specialty, gender, race, and age appear to be factors associated with those recommendations.

  12. Animal models of skin disease for drug discovery

    PubMed Central

    Avci, Pinar; Sadasivam, Magesh; Gupta, Asheesh; De Melo, Wanessa CMA; Huang, Ying-Ying; Yin, Rui; Rakkiyappan, Chandran; Kumar, Raj; Otufowora, Ayodeji; Nyame, Theodore; Hamblin, Michael R

    2013-01-01

    Introduction Discovery of novel drugs, treatments, and testing of consumer products in the field of dermatology is a multi-billion dollar business. Due to the distressing nature of many dermatological diseases, and the enormous consumer demand for products to reverse the effects of skin photodamage, aging, and hair loss, this is a very active field. Areas covered In this paper, we will cover the use of animal models that have been reported to recapitulate to a greater or lesser extent the features of human dermatological disease. There has been a remarkable increase in the number and variety of transgenic mouse models in recent years, and the basic strategy for constructing them is outlined. Expert opinion Inflammatory and autoimmune skin diseases are all represented by a range of mouse models both transgenic and normal. Skin cancer is mainly studied in mice and fish. Wound healing is studied in a wider range of animal species, and skin infections such as acne and leprosy also have been studied in animal models. Moving to the more consumer-oriented area of dermatology, there are models for studying the harmful effect of sunlight on the skin, and testing of sunscreens, and several different animal models of hair loss or alopecia. PMID:23293893

  13. Animal models of skin disease for drug discovery.

    PubMed

    Avci, Pinar; Sadasivam, Magesh; Gupta, Asheesh; De Melo, Wanessa Cma; Huang, Ying-Ying; Yin, Rui; Chandran, Rakkiyappan; Kumar, Raj; Otufowora, Ayodeji; Nyame, Theodore; Hamblin, Michael R

    2013-03-01

    Discovery of novel drugs, treatments, and testing of consumer products in the field of dermatology is a multi-billion dollar business. Due to the distressing nature of many dermatological diseases, and the enormous consumer demand for products to reverse the effects of skin photodamage, aging, and hair loss, this is a very active field. In this paper, we will cover the use of animal models that have been reported to recapitulate to a greater or lesser extent the features of human dermatological disease. There has been a remarkable increase in the number and variety of transgenic mouse models in recent years, and the basic strategy for constructing them is outlined. Inflammatory and autoimmune skin diseases are all represented by a range of mouse models both transgenic and normal. Skin cancer is mainly studied in mice and fish. Wound healing is studied in a wider range of animal species, and skin infections such as acne and leprosy also have been studied in animal models. Moving to the more consumer-oriented area of dermatology, there are models for studying the harmful effect of sunlight on the skin, and testing of sunscreens, and several different animal models of hair loss or alopecia.

  14. Scabies: a ubiquitous neglected skin disease.

    PubMed

    Hengge, Ulrich R; Currie, Bart J; Jäger, Gerold; Lupi, Omar; Schwartz, Robert A

    2006-12-01

    Scabies has been a scourge among human beings for thousands of years. Its worldwide occurrence with epidemics during war, famine, and overcrowding is responsible for an estimated 300 million people currently infested. Scabies refers to the various skin lesions produced by female mites, and their eggs and scybala that are deposited in the epidermis, leading to delayed-type hypersensitivity reaction. Recent immunological findings such as cross-reactivity with house dust mite allergens and an altered T-helper-1/T-helper-2 pattern contribute to a better understanding of the pathomechanism. Furthermore, progress in molecular biology and cloning of relevant antigens could enable the development of a diagnostic ELISA system and candidate vaccines in the near future. Typical and atypical clinical presentations with pruritus as a hallmark of scabies occur in young, pregnant, immunocompromised, and elderly patients and include bullous and crusted (Norwegian) manifestations as well as those masked by steroid use (scabies incognito). This article reviews scabies management strategies in developed countries and resource-poor communities as well as typical complications, including the emergence of resistance and drug-related adverse events. Other problems such as post-scabies eczema and reinfestation, and newer treatments such as ivermectin are also discussed.

  15. Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients.

    PubMed

    Young-Gqamana, Brandy; Brignol, Nastry; Chang, Hui-Hwa; Khanna, Richie; Soska, Rebecca; Fuller, Maria; Sitaraman, Sheela A; Germain, Dominique P; Giugliani, Roberto; Hughes, Derralynn A; Mehta, Atul; Nicholls, Kathy; Boudes, Pol; Lockhart, David J; Valenzano, Kenneth J; Benjamin, Elfrida R

    2013-01-01

    Fabry disease (FD) results from mutations in the gene (GLA) that encodes the lysosomal enzyme α-galactosidase A (α-Gal A), and involves pathological accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Migalastat hydrochloride (GR181413A) is a pharmacological chaperone that selectively binds, stabilizes, and increases cellular levels of α-Gal A. Oral administration of migalastat HCl reduces tissue GL-3 in Fabry transgenic mice, and in urine and kidneys of some FD patients. A liquid chromatography-tandem mass spectrometry method was developed to measure lyso-Gb3 in mouse tissues and human plasma. Oral administration of migalastat HCl to transgenic mice reduced elevated lyso-Gb3 levels up to 64%, 59%, and 81% in kidney, heart, and skin, respectively, generally equal to or greater than observed for GL-3. Furthermore, baseline plasma lyso-Gb3 levels were markedly elevated in six male FD patients enrolled in Phase 2 studies. Oral administration of migalastat HCl (150 mg QOD) reduced urine GL-3 and plasma lyso-Gb3 in three subjects (range: 15% to 46% within 48 weeks of treatment). In contrast, three showed no reductions in either substrate. These results suggest that measurement of tissue and/or plasma lyso-Gb3 is feasible and may be warranted in future studies of migalastat HCl or other new potential therapies for FD.

  16. Zoonotic skin diseases of dogs and cats.

    PubMed

    Moriello, Karen A

    2003-12-01

    Although there are over 250 zoonotic diseases, only 30-40 of them involve dogs and cats. Transmission of zoonotic infections occurs via bites, scratches or touch; exposure to saliva, urine or feces; inhalation of particles or infectious aerosols; contact with a transport or intermediate host (e.g. ticks, fleas); or exposure to contaminated water, soil or vegetation. This paper summarizes the most important common zoonotic dermatological diseases of dogs and cats. The most common dermatological zoonoses are flea and tick infestations and the diseases they transmit; dermatophytosis; and mite infestations (Sarcoptes and Cheyletiella). Prevention of zoonotic infestations or infections can be accomplished easily by the use of routine flea and tick control, screening of new pets for dermatophytosis, and routine hand-washing.

  17. Psychological factors in skin diseases: stress and skin: facts and controversies.

    PubMed

    Orion, Edith; Wolf, Ronni

    2013-01-01

    Psychological stress (PS) has long been related to many common skin diseases and conditions, thought to be the cause of their onset or aggravation. Although clinical experience is often in concordance with this notion, apparently scientific proof can sometimes be challenging rather than straight forward. Although many data have been published, it appears that not enough good statistical evidence exists to support them. The difficulty in validating beyond a doubt the stress-skin interactions has rendered some skepticism among physicians. The gap between clinical expertise and problematic clinical research data has led scientists to bypass the need to tackle the question directly by searching the evidence in basic science.

  18. [Incidence of skin manifestations of Lyme disease in Croatia].

    PubMed

    Kansky, A; Balić-Winter, A; Bolanca-Bumber, S; Skerlev, M

    1992-01-01

    In the study, the most relevant historical data concerning Lyme-borreliosis are shortly reviewed. The most frequent skin manifestations, i.e. erythema cronicum migrans (ECM), lymphocytoma cutis (LCC) and acrodermatitis chronica atrophicans (ACA) are described. The clinical course of Lyme disease and the chronologic review of the most significant data on the disease are given. The frequency of skin manifestations of Lyme-borreliosis in various areas of Croatia from 1988 to 1989 based on the reports of dermatologists throughout Croatia is presented. According to our results, it can be concluded that skin manifestations of Lyme-borreliosis are much more frequent in the central and western parts of Croatia than elsewhere. The authors hope that the use of a fluorescent method for detecting antibodies to Borrelia burgdorferi since 1989 in the Serologic Laboratory of the Department of Dermatology, Salata, Zagreb will lead to more precise results about this disorder in the future.

  19. Anti-BlyS antibody reduces the immune reaction against enzyme and enhances the efficacy of enzyme replacement therapy in Fabry disease model mice.

    PubMed

    Sato, Yohei; Ida, Hiroyuki; Ohashi, Toya

    2017-02-02

    Formation of antibodies against a therapeutic enzyme is an important complication during enzyme replacement therapy (ERT) for lysosomal storage diseases. Fabry disease (FD) is caused by a deficiency of alpha-galactosidase (GLA), which results in the accumulation of globotriaosylceramide (GL-3). We have shown immune tolerance induction (ITI) during ERT in FD model mice by using an anti-B lymphocyte stimulator (anti-BlyS) antibody (belimumab). A single dose of the anti-BlyS antibody temporarily lowered the percentage of B cells and IgG antibody titer against recombinant human GLA. Administration of a low maintenance dose of the anti-BlyS antibody suppressed the B cell population and immunotolerance was induced in 20% of mice, but antibody formation could not be prevented. We then increased the maintenance dose of the anti-BlyS antibody and immunotolerance was induced in 50% of mice. Therapeutic enzyme distribution and clearance of GL-3 were also enhanced by a high maintenance dose of the anti-BlyS antibody.

  20. Gene editing for skin diseases: designer nucleases as tools for gene therapy of skin fragility disorders.

    PubMed

    March, Oliver P; Reichelt, Julia; Koller, Ulrich

    2017-03-07

    The current treatment of inherited blistering skin diseases, such as epidermolysis bullosa (EB) is largely restricted to wound care and pain management. More effective therapeutic strategies are urgently required and targeting the genetic basis of these severe diseases is now within reach. Here we describe current gene editing tools and their potential to correct gene function in monogenetic blistering skin diseases. We present the features of the most frequently used gene editing techniques TALEN and CRISPR/Cas9, determining their preferential application under specific genetic conditions, including the type of mutational inheritance, the targeting site within the gene or the possibility to specifically target the mutation. Both tools have traits beneficial in specific situations. Promising developments in the field engender gene editing as a potentially powerful therapeutic option for future clinical applications. This article is protected by copyright. All rights reserved.

  1. Various applications of microRNAs in skin diseases.

    PubMed

    Jinnin, Masatoshi

    2014-04-01

    microRNA (miRNA) is a family of non-coding RNAs, which consists of 19-25 nucleotides and regulates the expression of approximately 30% of human protein-coding mRNAs. miRNAs can bind to complementary sequences of the three prime untranslated regions of target mRNAs, leading to the modulation of gene expression. By altering target expression, miRNAs can affect various cellular activities including cell proliferation and cell development in vitro or carcinogenesis and immune response in vivo. A lot of researches have paid attention to the possibility that miRNAs play a role in the pathogenesis of various human disorders including skin diseases. For example, miR-29a down-regulation is thought to mediate the posttranscriptional up-regulation of collagens, which contributes to the tissue fibrosis in scleroderma. In addition, recent studies indicate that extracellular miRNA levels may be useful for the diagnosis and/or the estimation of disease activity of skin diseases. miR-150 levels were significantly decreased in sera of scleroderma patients, and were inversely correlated with the prevalence of pitting scars/ulcers and the incidence of anti-topoisomerase I antibody. Currently, the therapeutic value of miRNAs for the treatment of human diseases is under evaluation in animal models. let-7a can be overexpressed in the mouse skin by intermittent intraperitoneal miRNA injection, and skin fibrosis induced by bleomycin in mice can be improved by the supplementation of let-7a. This paper discusses the possible applications of miRNAs in the clarification of pathogenesis, diagnosis, evaluation of disease activity and treatment of skin diseases. Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  2. Children with Rare Chronic Skin Diseases: Hemangiomas and Epidermolysis Bullosa.

    ERIC Educational Resources Information Center

    Jones, Sheila Dove; Miller, Cynthia Dieterich

    The paper reports on studies involving children having the rare chronic skin diseases of hemangiomas and epidermolysis bullosa (characterized by easy blistering). One study compared the self-concept and psychosocial development of young (mean age 46 months) children (N=19) with hemangiomas with 19 children without hemangiomas. Findings indicated…

  3. The nature and consequence of Karl Marx's skin disease.

    PubMed

    Shuster, S

    2008-01-01

    From an analysis of the original correspondence, it has been possible to establish that Karl Marx's incapacitating skin disease was hidradenitis suppurativa, not 'boils' as was universally assumed at the time and since; the psychological effect of this illness on the man and his work appears to have been considerable.

  4. Children with Rare Chronic Skin Diseases: Hemangiomas and Epidermolysis Bullosa.

    ERIC Educational Resources Information Center

    Jones, Sheila Dove; Miller, Cynthia Dieterich

    The paper reports on studies involving children having the rare chronic skin diseases of hemangiomas and epidermolysis bullosa (characterized by easy blistering). One study compared the self-concept and psychosocial development of young (mean age 46 months) children (N=19) with hemangiomas with 19 children without hemangiomas. Findings indicated…

  5. Multidimensional two-photon imaging of diseased skin

    NASA Astrophysics Data System (ADS)

    Cicchi, R.; Sestini, S.; De Giorgi, V.; Massi, D.; Lotti, T.; Pavone, F. S.

    2008-02-01

    We used combined two photon intrinsic fluorescence (TPE), second harmonic generation microscopy (SHG), fluorescence lifetime imaging microscopy (FLIM), and multispectral two photon emission detection (MTPE) to investigate different kinds of human cutaneous ex-vivo skin lesions. Morphological and spectroscopic analyses allowed to characterize both healthy and pathological skin samples, including tumors, as well as to discriminate between healthy and diseased tissue, in a good agreement with common routine histology. In particular, we examined tissue samples from normal and pathological scar tissue (keloid), and skin tumors, including basal cell carcinoma (BCC) and malignant melanoma (MM). By using combined TPE-SHG microscopy we investigated morphological features of different skin regions, as BCC, tumor-stroma interface, healthy dermis, fibroblastic proliferation, and keloids. The SHG to autofluorescence aging index of dermis (SAAID) score was used to characterize each region, finding differences between BCC, healthy skin, tumor-stroma interface, keloids, and fibroblastic proliferation. Further comparative analysis of healthy skin and neoplastic samples was performed using FLIM. In particular, BCC showed a blue-shifted fluorescence emission, a higher absorption at 800 nm excitation wavelength, and a slightly longer mean fluorescence lifetime. MM showed a lifetime distribution similar to the corresponding melanocytic nevus (MN) lifetime distribution for the slow lifetime component, and different for the fast lifetime component.

  6. 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.

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

    PubMed Central

    2014-01-01

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

  8. Tropical Skin Diseases in Children: A Review- Part I.

    PubMed

    García-Romero, Maria Teresa; Lara-Corrales, Irene; Kovarik, Carrie L; Pope, Elena; Arenas, Roberto

    2016-05-01

    Because of travel and migration patterns, tropical skin diseases are now seen all around the world, not just in tropical or developing countries. Nutrition, housing, and environmental factors play an important role in these infectious diseases, so when they appear out of their normal environments, their classic presentation may vary. Tropical diseases can also present differently in childhood, making their recognition, diagnosis, and management a clinical challenge. Health care providers in developed countries need to be familiar with tropical skin diseases and be able to diagnose them in returning travelers or immigrants in order to optimize care. This article aims to review the epidemiologic, clinical, diagnostic, and therapeutic aspects of some of the most common tropical dermatologic conditions in children.

  9. 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.

  10. Toll-like receptors in skin infections and inflammatory diseases.

    PubMed

    Lai, Yuping; Gallo, Richard L

    2008-09-01

    The skin is the ultimate example of the function of innate immunity, it alerts the host of danger by many systems including sensing pathogen-associated molecule patterns (PAMPs) through Toll-like receptors and other pattern recognition receptors (PRRs), yet normally provides defense without inflammation. The skin responds rapidly to invading microbes by producing antimicrobial peptides or other antimicrobial intermediates before cytokine release results in inflammation. To achieve maximal immune responses for clearing invading microbes, the activation of select PRRs in skin then initiates and shapes adaptive immune responses through the activation of dendritic cells and recruitment of T cell subsets. Importantly, cross-talk between TLRs can influence this system in several ways including augmenting or suppressing the immune response. As a consequence of their pivotal role, TLR responses need to be tightly controlled by associated negative regulators or negative feedback loops to prevent detrimental effects from TLRs overactivation. This review focuses on describing the involvement of TLRs in the development of skin infections and inflammatory diseases, and highlights the potential application of TLR agonists or antagonists in these skin diseases.

  11. Autoimmune and infectious skin diseases that target desmogleins

    PubMed Central

    AMAGAI, Masayuki

    2010-01-01

    Desmosomes are intercellular adhesive junctions of epithelial cells that contain two major transmembrane components, the desmogleins (Dsg) and desmocollins (Dsc), which are cadherin-type cell–cell adhesion molecules and are anchored to intermediate filaments of keratin through interactions with plakoglobin and desmoplakin. Desmosomes play an important role in maintaining the proper structure and barrier function of the epidermis and mucous epithelia. Four Dsg isoforms have been identified to date, Dsg1–Dsg4, and are involved in several skin and heart diseases. Dsg1 and Dsg3 are the two major Dsg isoforms in the skin and mucous membranes, and are targeted by IgG autoantibodies in pemphigus, an autoimmune disease of the skin and mucous membranes. Dsg1 is also targeted by exfoliative toxin (ET) released by Staphylococcus aureus in the infectious skin diseases bullous impetigo and staphylococcal scalded skin syndrome (SSSS). ET is a unique serine protease that shows lock and key specificity to Dsg1. Dsg2 is expressed in all tissues possessing desmosomes, including simple epithelia and myocardia, and mutations in this gene are responsible for arrhythmogenic right ventricular cardiomyopathy/dysplasia. Dsg4 plays an important adhesive role mainly in hair follicles, and Dsg4 mutations cause abnormal hair