Improved ways to screen for patients with Fabry disease, involving optometry in a multidisciplinary approach

Purpose: Fabry disease is considered a rare disease, based on its prevalence. It is recognized, however, that there are many individuals aff ected who are unscreened. This article aims to demonstrate how optometrists can help to defi ne improved ways to screen patients aff ected by this rare metabolic disorder, in a multidisciplinary perspective. Methods: A screening model, based on continuous education for optometrists was developed. Under this model, suspect patients identifi ed by optometrists are referred to Université de Montréal's vision clinic (EOUM) for further testing and assessment. Should ocular manifestations and/or case history prove relevant to these rare diseases, a urinary test is then performed to fi nd related biomarkers. When suspicions narrow to probable Fabry disease, the subjects are referred to metabolic disorder specialists for complete DNA testing and medical follow-up of their condition. Results: Continuous education lectures were given across Quebec, reaching nearly 60% of the province’s optometrists. Sixteen months following the model's implementation, ten suspected patients were referred. Of these, two new Fabry patients were confi rmed, leading to the diagnosis of fi ve other relatives with the disease. Two additional persons, diagnosed as Fabry patients, but lost to medical follow-up for many years, were once again placed under the care of Fabry experts. To this point, because of optometric involvement, seven new patients of Fabry were diagnosed and two were brought back under experts care.  Conclusion: Continuous education lectures were given across Quebec, reaching near 60% of the province’s optometrists. Sixteen months following the model's implementation, ten suspected patients were referred. Of these, two new Fabry patients were confi rmed, leading to the diagnosis of fi ve other relatives with the disease. Two additional persons, diagnosed as Fabry patients, but lost to medical follow-up for many years, were once again placed under the care of Fabry experts. To this point, because of optometric involvement, seven new patients of Fabry were diagnosed and two were brought back under experts care

A biobank management model applicable to biomedical research

BACKGROUND: The work of Research Ethics Boards (REBs), especially when involving genetics research and biobanks, has become more challenging with the growth of biotechnology and biomedical research. Some REBs have even rejected research projects where the use of a biobank with coded samples was an integral part of the study, the greatest fear being the lack of participant protection and uncontrolled use of biological samples or related genetic data. The risks of discrimination and stigmatization are a recurrent issue. In light of the increasing interest in biomedical research and the resulting benefits to the health of participants, it is imperative that practical solutions be found to the problems associated with the management of biobanks: namely, protecting the integrity of the research participants, as well as guaranteeing the security and confidentiality of the participant's information. METHODS: We aimed to devise a practical and efficient model for the management of biobanks in biomedical research where a medical archivist plays the pivotal role as a data-protection officer. The model had to reduce the burden placed on REBs responsible for the evaluation of genetics projects and, at the same time, maximize the protection of research participants. RESULTS: The proposed model includes the following: 1) a means of protecting the information in biobanks, 2) offers ways to provide follow-up information requested about the participants, 3) protects the participant's confidentiality and 4) adequately deals with the ethical issues at stake in biobanking. CONCLUSION: Until a governmental governance body is established in Quebec to guarantee the protection of research participants and establish harmonized guidelines for the management of biobanks in medical research, it is definitely up to REBs to find solutions that the present lack of guidelines poses. The model presented in this article offers a practical solution on a day-to-day basis for REBs, as well as researchers by promoting an archivist to a pivotal role in the process. It assures protection of all participants who altruistically donate their samples to generate and improve knowledge for better diagnosis and medical treatment

Le consentement libre et éclairé dans la recherche en génétique humaine: réalité ou utopie

Résumé: L 'avancement fulgurant de nouvelles techniques de biologie moléculaire a permis un essor majeur de la recherche en génétique humaine: l' identification de gènes responsables de maladies génétiques, la connaissance de leur pathogénie, l' apport d' un traitement, et le désir de vaincre et de prévenir ces maladies. Par contre, ladite recherche a aussi mené à une problématique d ' envergure face au respect de l' autonomie, de l' intégrité et de la dignité du sujet participant tout au long du projet. De fait, la recherche en génétique humaine devrait être un partenariat sujet-chercheur. Malheureusement, le sujet se retrouve souvent mal informé lors du recrutement, ne comprend pas le formulaire de consentement, ou n ' a pas saisi toutes les utilisations possibles de son ADN. L ' auteur présente le rôle que devraient jouer le chercheur et son équipe pour s'assurer d ' un choix informé de la part du sujet, garantir sa protection et respecter la confidentialité des données tout au long du projet de recherche. L ' implication déterminante du comité d ' éthique de la recherche y est aussi soulevée, particulièrement dans l' aspect éducationnel des chercheurs et dans le suivi du projet de recherche en génétique . Finalement, des principes fondamentaux sont proposés pour responsabiliser les chercheurs et les comités d ' éthique de la recherche et leur permettre d'atteindre un but commun: obtenir un "réel" consentement libre et éclairé dans un projet de recherche en génétique humaine.||Abstract: The considerable advancement of molecular biology techniques has given way to major developments in human genetic research such as: the identification of genes responsible for genetic diseases , the understanding of their pathogeny, the possibility of treatment and the desire to conquer and prevent those diseases. However genetic research has also brought forth major problems regarding autonomy, integrity and dignity of the participant. Human genetic research should be a partnership between the researcher and the human subject. Unfortunately, the participant is often illinformed when being recruited by the researcher or he may also Jack a full understanding of the consent form or the eventual uses of DNA samples collected throughout the project. The author presents the role that should be played by the researcher and the research ethics committee in order to guarantee an informed choice by the human subject and ensure his protection as weil as data confidentiality throughout the project. The importance of the educational role of the ethics research committee towards the researcher, as weil as the follow-up of the research project is presented. Finally, fundamental principles are proposed in order for the researcher as weil as the research ethics committee to attain a common goal, which is to ensure an informed consent in ali human genetic research projects

Association entre le génotype et l'excrétion du globotriaosylcéramide chez les patients atteints de la maladie de Fabry et la gestion de biobanques dans la recherche en génétique humaine

La maladie de Fabry est une maladie métabolique héréditaire liée au chromosome X et est causée par un déficit de l'enzyme l'[alpha]-galactosidase A. Plus de 350 mutations ont été répertoriées chez les patients atteints. L'incidence de la maladie de Fabry est variable à travers le monde: entre 1:3 100 en Italie à 1:833 000 au Portugal, avec une moyenne évaluée à 1:40 000. Les hommes hémizygotes présentent une expression clinique très variable et sont souvent atteints plus sévèrement que les femmes hétérozygotes, qui peuvent aussi manifester des symptômes. Un biomarqueur est excrété de façon prédominante dans l'urine de ces patients, le globotriaosylcéramide (Gb[indice inférieur 3]), un glycosphingolipide qui provient des cellules épithéliales rénales. Nous avons entrepris l'élaboration d'une méthode d'analyse du biomarqueur Gb[indice inférieur 3] dans l'urine déposée sur papier filtre de patients hémizygotes et hétérozygotes atteints de la maladie de Fabry, en utilisant la spectrométrie de masse en tandem couplée à la chromatographie en phase liquide. Suite au développement et à la validation de cette méthodologie, nous l'avons raffinée et améliorée de façon à pouvoir analyser simultanément le Gb[indice inférieur 3] et la créatinine (multiplex) à l'intérieur d'un temps plus court, soit en 2.6 minutes. Le dosage de la créatinine permet de normaliser les valeurs obtenues du Gb[indice inférieur 3]. Cette méthodologie répond à plusieurs impératifs cliniques: permettre un dépistage à haut risque de la maladie de Fabry et assurer le suivi et le monitoring des patients atteints qui sont sous thérapie enzymatique de remplacement. Nous répondons aussi à la question concernant l'étude de faisabilité d'analyse du Gb[indice inférieur 3] sur l'ensemble d'une population donnée. Aussi, l'établissement d'un diagnostic précoce avant l'apparition de troubles cliniques irréversibles est potentiellement important pour le patient et permet d'offrir un conseil génétique. Des corrélations phénotype-génotype hautement significatives ont pu être établies avec les taux d'excrétion du Gb[indice inférieur 3], à savoir que l'excrétion du Gb[indice inférieur 3] urinaire est en corrélation directe avec les types de mutations à l'étude, le sexe du patient et le traitement. Par contre, il n'y a pas de corrélation significative entre l'âge du patient et l'excrétion du Gb[indice inférieur 3]. Nous avons pu constater que certaines mutations non-sens provoquent une excrétion plus forte du Gb[indice inférieur 3] urinaire que d'autres types de mutations. Aussi, par les différences des moyennes des moindres carrés, nous avons trouvé une corrélation significative au niveau de l'excrétion urinaire du Gb[indice inférieur 3] et des mutations faux-sens et non-sens, de même qu'au niveau des mutations non-sens et des mutations de jonctions d'épissage. Aucune différence significative n'a été relevée entre deux groupes de patients avec la même mutation faux-sens, l'un provenant d'une région de la Nouvelle-Écosse où il subsiste un effet fondateur et l'autre issu de plusieurs régions à travers le monde. En réponse aux interrogations d'ordre éthique, nous avons élaboré un modèle de gestion des biobanques dans la recherche institutionnelle qui répond à toutes les questions soulevées précédemment et assure donc la protection du sujet participant et la confidentialité des informations génétiques correspondantes. Compte tenu de la complexité et des conséquences de tout projet de recherche impliquant des biobanques, nous avons élaboré un processus de formation continue sur le thème des bonnes pratiques éthiques applicables aux biobanques. Ce processus implique l'investigateur principal, le personnel de recherche, le comité d'éthique et l'institution qui travaillent en synergie en vue d'assurer une participation informée du sujet

Assessment of plasma lyso-Gb(3)for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease

Purpose To assess the utility of globotriaosylsphingosine (lyso-Gb(3)) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat. Methods A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenableGLAvariants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb(3)and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb(3)and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb(3)and kidney interstitial capillary (KIC) globotriaosylceramide (Gb(3)) inclusions was assessed in treatment-naive patients. Results No significant correlations were identified between changes in lyso-Gb(3)and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb(3)levels nor the rate of change in lyso-Gb(3)levels during treatment predicted FACE occurrences in all patients or those receiving migalastat for >= 24 months. Changes in lyso-Gb(3)correlated with changes in KIC Gb(3)inclusions in treatment-naive patients. Conclusions Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb(3)may not be a suitable biomarker for monitoring treatment response in migalastat-treated patients.Medical Biochemistr

Therapeutic challenges in two adolescent male patients with Fabry disease and high antibody titres

Enzyme replacement therapy (ERT) has been shown to stabilize certain aspects of Fabry disease (FD). However, in some patients on ERT, high antibody titres have been documented, with limited clinical improvement in systemic manifestations and often with significant adverse drug reactions. We present two related adolescent males with a 4.5 kb GLA deletion, not amenable to chaperone therapy, leading to profound reduction in alpha-galactosidase A (alpha-gal A) enzyme activity. Over a 3-year period of ERT, increasing IgG antibody titres against alpha-gal A were noted. After starting ERT serial urine globotriaosylceramide (Gb(3)) measurements showed an upward trend from 333 to 2260 mu g/mmol creatinine for patient 1 and 1165 to 2260 mu g/mmol creatinine for patient 2. Markedly increased levels of urine and plasma globotriaosylsphingosine (Lyso-Gb(3)) analogues were also found. The patients experienced recurrent infusion-associated reactions necessitating premedication and prolonged infusion times. Over the 3-year period of ERT, the patients experienced continued malaise, gastrointestinal symptoms and neuropathic pain. In addition, they had increasing anxiety related to their disease and apparent lack of response to ERT which led to a decision to ultimately stop ERT. No other approved treatment options are currently available for these patients. It is possible that the rapid development of the high antidrug neutralizing antibody (ADA) titres is related to the large GLA deletion leading to virtually absent enzyme activity. It remains unclear if their symptomatology during the period of receiving ERT is related to lack of its efficacy, the rising ADA titres, or both. These two patients highlight the need for further research into the management of antidrug antibodies and additional therapeutic approaches for FD.Synopsis: The development of very high antidrug antibody titres in response to ERT in two related adolescent males with FD highlight the need for other therapeutic options for patients in whom ERT or other currently approved therapies does not meet their treatment needs.Medical Biochemistr

Glucosylsphingosine Is a Highly Sensitive and Specific Biomarker for Primary Diagnostic and Follow-Up Monitoring in Gaucher Disease in a Non-Jewish, Caucasian Cohort of Gaucher Disease Patients

Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD

An integrated systems biology approach to the study of preterm birth using "-omic" technology - a guideline for research

Preterm birth is the leading cause of neonatal mortality and perinatal morbidity. The etiology of preterm is multi-factorial and still unclear. As evidence increases for a genetic contribution to PTB, so does the need to explore genomics, transcriptomics, proteomics and metabolomics in its study. This review suggests research guidelines for the conduct of high throughput systems biology investigations into preterm birth with the expectation that this will facilitate the sharing of samples and data internationally through consortia, generating the power needed to study preterm birth using integrated "-omics" technologies. The issues to be addressed include: (1) integrated "-omics" approaches, (2) phenotyping, (3) sample collection, (4) data management-integrative databases, (5) international consortia and (6) translational feasibility. This manuscript is the product of discussions initiated by the "-Omics" Working Group at the Preterm Birth International Collaborative Meeting held at the World Health Organization, Geneva, Switzerland in April 2009