Wannerk, Michael L. Westl, Gabor E. Linthorsta, aInternal medicine,department of Endocrinology and Metabolism, Academic Medical CenterAmsterdam, Amsterdam, Netherlands, bDepartment of Pathology, AcademicMedical Center Amsterdam, Amsterdam, Netherlands, cInternal medicine,department of Nephrology, Academic Medical Center Amsterdam,Amsterdam, Netherlands, dDepartment of Haematology, Royal Free &University college medical school, London, UK, eCharles Dent MetabolicUnit, National Hospital for Neurology and Neurosurgery, London, UK,fMedical Genetics, Hospital São João, Faculty of Medicine of University ofPorto, Porto, Netherlands, gUnidad de Dialisis, IIS-Fundacion Jimenez Diaz,Madrid, Spain, hRenal Research Group, Haukeland University Hospital,Bergen, Norway, iDepartment of Internal Medicine, Division of Nephrology,Ghent University Hospital, Ghent, Belgium, jIndependent Medical Consul-tant, Manchester, UK, kDepartment of Medicine, Division of Nephrology,University of Würzburg, Würzburg, Germany, lDepartment of Nephrology,Dalhousie University, Halifax, NS, Canada

Fabry disease (FD) is an X-linked lysosomal disorder, characterizedby angiokeratoma, neuropathic pain, cornea verticillata, an- or hypo-hidrosis, and in males by absent or near absent α-galactosidase A(AGAL-A) activity and a very high (lyso)globotriaosylceramide (Gb3).The kidneys, heart and central nervous system are often affected.Screening for FD in patients with a single non-specific symptom such askidney disease reveals a large number of individuals with a geneticvariant of unknown significance in the α-galactosidase A gene, a highresidual AGAL-A activity and absent characteristic FD features. Theseindividuals possibly do not suffer from FD and have an uncertaindiagnosis of FD. Thus screening carries the risk of misdiagnosis andinappropriate counseling and treatment; a structured diagnostic ap-proach is warranted. We present a diagnostic algorithm on how toapproach an individual with kidney disease and an uncertain diagnosisof FD. A systematic review was performed to identify imaging andlaboratory criteria that could confirm or exclude FD. A modified Delphiprocedure was conducted among 11 FD experts with 2 online surveysand 1 telephonic survey. We aimed to reach consensus on the pre-selected criteria and criteria that were added by the experts. Criteriawere accepted in the algorithm with ≥75% agreement and no dis-agreement. To assess consensus, Cronbach’s α was calculated. Theinternational guideline on chronic kidney disease (KDIGO)was adoptedto define kidney disease. Full agreement was reached on the currentgold standard, defined as characteristic on electronmicroscopy (EM) ina kidney biopsy, in the absence of medication use that may inducesimilar storage. The criteria ‘renal cysts’ and ‘small kidneys’ on imaging,as well as the ‘Maltese Cross sign’, ‘immunohistochemical staining ofGb3’, ‘high Gb3’ (in the range of classical males) and ‘high proteinexcretion’ in urine were rejected as diagnostic criteria because of low oruncertain specificity. Since recent, yet unpublished, data suggest thaturinary Gb3 may be increased in other diseases as well, its specificitywas debated. There was no agreement that this criterion can confirm adiagnosis of FD, although 36% of the panelists indicated that ‘high urineGb3’, in the clinical context of FD, is sufficient. In addition, the ‘MalteseCross sign’ and ‘high Gb3’ in urine were selected as red flags, indicatingthat the presence of these features makes FD more likely, but furtherassessments are needed. Cronbach’s α increased from 0.85 to 0.97between rounds. Because data on prevalence in other kidney disordersis very limited, further researchwas recommended to gain insight in thespecificity of several items and ‘high Gb3’ in particular. In conclusion, inadults with kidney disease, with a GLA variant and an uncertaindiagnosis of FD, a kidney biopsy with EM analysis should be performedto confirm or reject the diagnosis of FD. Other criteria currently cannotsubstitute for a biopsy in these cases.

doi:10.1016/j.ymgme.2013.12.270

258Cornea verticillata as a diagnostic feature in classical andnon-classical Fabry disease: results from the Dutch cohortand a systematic literature review

Linda van der Tola, Marije L. Sminiab, Carla E.M. Hollaka, MariekeBiegstraatena, aInternal medicine, department of Endocrinology andMetabolism, Academic Medical Center, Amsterdam, Netherlands,bOphthalmology, Academic Medical Center, Amsterdam, Netherlands

Fabry disease (FD) is an X-linked lysosomal disorder. Screeningfor FD reveals a large number of individuals without a characteristicpattern of clinical and biochemical features and with a variant in theα-galactosidase A (GLA) gene. These individuals may have a non-classical phenotype or no FD at all. Diagnostic tools are thus neededto avoid unjustified labeling and treatment. Cornea verticillata (CV)is a characteristic feature of FD and eye examination may there-fore be a useful, non-invasive, tool in the diagnosis of FD. In order togain insight in the prevalence of CV in classical and non-classical/uncertain (NC) cases, we assessed the well characterized Dutch FDcohort and performed a systematic review of the literature. The adultFD cohort was assessed for the presence of CV with slit-lamp exam-ination. Data on concomitant medication were checked. Results werestratified by gender and phenotype (classical or NC, based upon pre-defined biochemical and clinical criteria). A systematic review wasperformed to assess prevalence of CV. NC cases were defined asindividuals with a GLA variant associated with a NC phenotype orlabeled as such by the author. Dutch cohort: 91 (30 males) classicalFD patients were investigated by slit-lamp examination with a CVprevalence of 86% (95% CI 77-92; 93% males, 95% CI 78-99, 82%females, 95% CI 70-91, 4 females used amiodarone). Of the 34(16 males) NC individuals, 4 (3 males) had CV (12%, 95% CI 3-27), allwith a definite NC FD phenotype (N1 individual with the same GLAvariant had characteristic storage in a biopsy). None of the patientswith a negative biopsy had CV. Literature review: Full texts of 19cohort and 2 screening studies were retrieved. In 14 cohort studies,data were not sufficient to identify NC patients. Here, pooled prev-alence (classical and NC combined) was 72% (n = 510, 257 males,age 1-78 years, range 36-96), gender specific prevalence could becalculated in 234 males (68%) and 234 females (63%). In 5 cohortsNC patients could be selected, while data on CV was only availablein 4 cohorts (65/135 NC, 18 males, age 1-72 years). CV was presentin 25% of NC patients (n = 16/65, 1 male, 1 unknown gender). 15 of16 NC patients with CV harbor the GLA variant IVS919G N A, the onlyGLA variant studied in 1 cohort. A biopsy was never reported. Pooledprevalence in the classical patients from these 4 cohorts was 83%(n = 58/70, 40 males, 91% of 35 males, 78% of 18 females). CVwas absent in individuals identified through screening (n = 29, 12males). In conclusion, CV has the highest sensitivity in classicallyaffected males. In the NC patients, CV was only present in cases ofa definite, biopsy proven, diagnosis of FD. Hence, CV may indicatea pathogenic GLA variant (in the absence of medication that mayinduce CV); if CV is absent, FD cannot be excluded. The lower andvariable prevalence of CV in the literature may be influenced by alarge, underestimated, number of NC patients.

doi:10.1016/j.ymgme.2013.12.271

259Innate immune system activation in MPS I canine vascular disease

Moin Veraa, Steven Lea, Shih-hsin Kana, Patricia Dicksona, RaymondY. Wangb, aLos Angeles Biomedical Research Institute at Harbor-UCLA,Torrance, CA, USA, bCHOC Children's, Orange, CA, USA

Abstracts S109