Screening for health-related quality of life and its determinants in Fabry disease: A cross-sectional multicenter study

BACKGROUND Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. In order to improve health care of FD-patients, knowledge of its predictors is important. The aim of our study was to evaluate health-related quality of life (HrQol) in FD and to identify its independent determinants by exploring a wide range of demographic, social and clinical parameters. RESULTS In this cross-sectional multicenter study, 135 adult patients with FD were recruited at three specialized European centers in Germany and Switzerland. Demographics, social status and clinical parameters as well as data on HrQol (EQ5D, EQ VAS) and depression were collected by means of self-reporting questionnaires and confirmed by medical records. HrQol and its predictors were evaluated by univariate and multivariate regression analyses. The study population consisted of 78 female and 57 male FD patients (median age 48 yrs) of whom 80.7% (N = 109) were on enzyme replacement therapy (ERT) and 10.4% (N = 14) were on chaperone treatment. Univariate analysis revealed various factors reducing HrQol such as age > 40 years, classic phenotype, organ involvement (kidney and heart disease, stroke/transient ischemic attack (TIA), gastrointestinal disturbances), depression, and burning limb pain. However, only the following factors were identified as independent predictors of decreased HrQol: classic phenotype, kidney and heart disease, stroke/TIA, depression, and burning limb pain. ERT and chaperone therapy were independent determinants of increased HrQol. CONCLUSIONS Modifiable factors, such as burning limb pain and depression, identified as independent predictors of HrQol-deterioration should be addressed in programs aiming to improve HrQol in FD. A multidisciplinary approach is essential in FD-patients since diverse organ involvement prominently compromises HrQol in affected patients. Our findings showed that the classic phenotype is a strong predictor of worsening HrQol

Characterization of rubber particles and rubber chain elongation in Taraxacum koksaghyz

<p>Abstract</p> <p>Background</p> <p>Natural rubber is a biopolymer with exceptional qualities that cannot be completely replaced using synthetic alternatives. Although several key enzymes in the rubber biosynthetic pathway have been isolated, mainly from plants such as <it>Hevea brasiliensis</it>, <it>Ficus spec. </it>and the desert shrub <it>Parthenium argentatum</it>, there have been no <it>in planta </it>functional studies, e.g. by RNA interference, due to the absence of efficient and reproducible protocols for genetic engineering. In contrast, the Russian dandelion <it>Taraxacum koksaghyz</it>, which has long been considered as a potential alternative source of low-cost natural rubber, has a rapid life cycle and can be genetically transformed using a simple and reliable procedure. However, there is very little molecular data available for either the rubber polymer itself or its biosynthesis in <it>T. koksaghyz</it>.</p> <p>Results</p> <p>We established a method for the purification of rubber particles - the active sites of rubber biosynthesis - from <it>T. koksaghyz </it>latex. Photon correlation spectroscopy and transmission electron microscopy revealed an average particle size of 320 nm, and ¹³C nuclear magnetic resonance (NMR) spectroscopy confirmed that isolated rubber particles contain poly(<it>cis</it>-1,4-isoprene) with a purity >95%. Size exclusion chromatography indicated that the weight average molecular mass (<inline-formula><graphic file="1471-2091-11-11-i1.gif"/></inline-formula>w) of <it>T. koksaghyz </it>natural rubber is 4,000-5,000 kDa. Rubber particles showed rubber transferase activity of 0.2 pmol min^-1mg^-1. <it>Ex vivo </it>rubber biosynthesis experiments resulted in a skewed unimodal distribution of [1-¹⁴C]isopentenyl pyrophosphate (IPP) incorporation at a <inline-formula><graphic file="1471-2091-11-11-i1.gif"/></inline-formula>w of 2,500 kDa. Characterization of recently isolated <it>cis</it>-prenyltransferases (CPTs) from <it>T. koksaghyz </it>revealed that these enzymes are associated with rubber particles and are able to produce long-chain polyprenols in yeast.</p> <p>Conclusions</p> <p><it>T. koksaghyz </it>rubber particles are similar to those described for <it>H. brasiliensis</it>. They contain very pure, high molecular mass poly(<it>cis</it>-1,4-isoprene) and the chain elongation process can be studied <it>ex vivo</it>. Because of their localization on rubber particles and their activity in yeast, we propose that the recently described <it>T. koksaghyz </it>CPTs are the major rubber chain elongating enzymes in this species. <it>T. koksaghyz </it>is amenable to genetic analysis and modification, and therefore could be used as a model species for the investigation and comparison of rubber biosynthesis.</p

Complement activation and cellular inflammation in Fabry disease patients despite enzyme replacement therapy

Defective α-galactosidase A (AGAL/GLA) due to missense or nonsense mutations in the GLA gene results in accumulation of the glycosphingolipids globotriaosylceramide (Gb3) and its deacylated derivate globotriaosylsphingosine (lyso-Gb3) in cells and body fluids. The aberrant glycosphingolipid metabolism leads to a progressive lysosomal storage disorder, i. e. Fabry disease (FD), characterized by chronic inflammation leading to multiorgan damage. Enzyme replacement therapy (ERT) with agalsidase-alfa or -beta is one of the main treatment options facilitating cellular Gb3 clearance. Proteome studies have shown changes in complement proteins during ERT. However, the direct activation of the complement system during FD has not been explored. Here, we demonstrate strong activation of the complement system in 17 classical male FD patients with either missense or nonsense mutations before and after ERT as evidenced by high C3a and C5a serum levels. In contrast to the strong reduction of lyso-Gb3 under ERT, C3a and C5a markedly increased in FD patients with nonsense mutations, most of whom developed anti-drug antibodies (ADA), whereas FD patients with missense mutations, which were ADA-negative, showed heterogenous C3a and C5a serum levels under treatment. In addition to the complement activation, we found increased IL-6, IL-10 and TGF-ß1 serum levels in FD patients. This increase was most prominent in patients with missense mutations under ERT, most of whom developed mild nephropathy with decreased estimated glomerular filtration rate. Together, our findings demonstrate strong complement activation in FD independent of ERT therapy, especially in males with nonsense mutations and the development of ADAs. In addition, our data suggest kidney cell-associated production of cytokines, which have a strong potential to drive renal damage. Thus, chronic inflammation as a driver of organ damage in FD seems to proceed despite ERT and may prove useful as a target to cope with progressive organ damage

Fabry Disease: The Current Treatment Landscape

Fabry disease (FD) is a rare X-linked lysosomal storage disease based on a deficiency of α-galactosidase A (AGAL) caused by mutations in the α-galactosidase A gene (GLA). The lysosomal accumulation of glycosphingolipids, especially globotriaosylceramide (G

Mechanisms of Neutralizing Anti-drug Antibody Formation and Clinical Relevance on Therapeutic Efficacy of Enzyme Replacement Therapies in Fabry Disease

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A (AGAL/GLA) gene. The lysosomal accumulation of the substrates globotriaosylceramide (G

Neutralizing anti-drug antibodies in Fabry disease have no obvious clinical impact?

Abstract Fabry disease (FD) is a rare X-linked disorder caused by a deficiency of lysosomal α-galactosidase A activity. Treatment with recombinant enzyme replacement therapy is available since 2001 and the effects of anti-drug antibodies (ADA) on therapy efficacy and disease outcome in affected patients have been controversially reported. In this letter we discuss the importance of adequate measurements of neutralizing ADAs and appropriate longitudinal analysis to determine therapy efficiency and clinical outcome in patients with FD

Neutralizing anti-drug antibodies in Fabry disease have no obvious clinical impact?

Fabry disease (FD) is a rare X-linked disorder caused by a deficiency of lysosomal α-galactosidase A activity. Treatment with recombinant enzyme replacement therapy is available since 2001 and the effects of anti-drug antibodies (ADA) on therapy efficacy and disease outcome in affected patients have been controversially reported. In this letter we discuss the importance of adequate measurements of neutralizing ADAs and appropriate longitudinal analysis to determine therapy efficiency and clinical outcome in patients with FD