Vanessa Ferreira, PhD

President and Founder of the Portuguese Association for CDG and other Rare Metabolic Diseases (APCDG-DMR)

Member of the Spanish Association for CDG (AESCDG)

EUROGLYCANET CDG representative at European Platform for Rare Disease Registries (Epirare) DISCLAIMER

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OUTLINE

• INTRODUCTION ABOUT RARE DISEASES (RD) . Rare diseases as a public health priority

• THE PATIENT’S VOICE . APCDG-DMR: a non-profit organization . Congenital Disorders of Glycosylation (CDG)

• ACTIVITIES DONE BY APCDG-DMR

o To support families (Information & Empowerment) o Networking o Awareness amongst public and health care professionals o Education o Scientific and clinical research

WHAT IS A RARE DISEASE?

A rare disease in Europe is a disease affecting less than 1 in 2,000 citizens

In the United States, a rare disease is any disease or condition that affects 1 in 1,500 people

 29 million people affected in the EU

3 million people Spain 3 millions people in France (1 in 20) 600 000-800 000 people in Portugal 3.5 million people in the UK 1 million people in the Netherlands

25 million people USA

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 4 6,000 and 8,000 distinct rare diseases!

49 XXXXY 5p, Síndrome Acidemia Metilmalónica Homocistinuria, Tipo cbl C Acidemia Propiónica Acondroplasia Acondroplasia - Inmunodeficiencia Combinada Grave Adrenoleucodistrofia Agammaglobulinemia Ligada al Cromosoma X Aicardi Goutières, Síndrome de Alagille, Síndrome de Albinismo Alexander, Enfermedad de Alfa 1 Antitripsina, Déficit de Alpers, Enfermedad de Alport, Síndrome de Amaurosis Retiniana Congénita de Leber Amiloidosis Primaria Familiar Andrade, Enfermedad Anemia de Fanconi Angelman, Síndrome de Angioedema Hereditario Aniridia Apert, Síndrome de Arnold Chiari, Síndrome de Arteritis de Células Gigantes Artritis Crónica Juvenil Artritis Idiopática Juvenil Artritis Psoriásica Artrogriposis Múltiple Congénita Artrogriposis, Síndrome de Aspartilglucosaminuria Ataxia de Friedreich Ataxia de Marie Ataxia Espinocerebelosa del Tipo 1 (SCA1) Ataxia Espinocerebelosa SK3 Ataxia Hereditarias Ataxia Olivopontocerebelosa Ataxia Telangiectasia Atresia Aórtica Atresia Pulmonar con Comunicación Interventricular Atresia Pulmonar Septo Ventricular Intacto Atresia Tricúspide Atrofia Muscular Espinal Infantil Atrofia Muscular Espinal Proximal de Tipo 2 Atrofias Espinales Baller Gerold, Síndrome de Batten Spielmeyer Vogt, Enfermedad de Beckwith Wiedemann, Síndrome de Behçet, Enfermedad de Berardinelli Seip, Síndrome de Blefaroespasmo B-Oxidación Mitocondrial Braquicefalia Aislada Budd Chiari, Síndrome de Buerger, Enfermedad de C de Opitz, Síndrome Calambre del Escribano Calcinosis Canavan, Enfermedad de Cardiopatías Congénitas Carnitina, Síndromes por Déficit de Castleman, Enfermedad de Ceroido Lipofuscinosis Juvenil Ceroido Lipofuscinosis Neuronal Charcot Marie Tooth, Enfermedad de Chediak Higashi, Enfermedad de Churg Strauss, Síndrome de Cistinosis Cistinuria Cistitis Intersticial Citocromo C Oxidasa, Déficit de Citomegalovirus, Síndrome del Citrulinemia Coartación Aórtica Coffin Lowry, Síndrome de Coffin Siris, Síndrome de Colangitis Crónica Destructiva no Supurativa (CBP) Colangitis Primaria Esclerosante Coloboma del Iris Complejo Malformativo de Arnold Chiari Coproporfiria Hereditaria Corea de Sydenham Cornelia de Lange, Síndrome de Coroidemia Craneosinostosis Primaria Crecimiento, Problemas de Crigler Najjar, Síndrome de Cromosoma X Frágil, Síndrome de Crouzon, Enfermedad de Dandy Walker, Síndrome de Danon, Enfermedad de Defectos del Tabique Interauricular Defectos en la Biosíntesis de Testosterona Deficiencia Múltiple de Sulfatasas Déficit Congénito de HFE Déficit de 5a-reductora Deformidad de Sprengel Degeneración Macular Denys Drash, Síndrome de Depleccóon del ADN Mitocóndrial, Síndrome Dilatación Aórtica Disferlina, Ausencia de Disfonía Espasmódica Disgenesia Gonodal XY Dismetrías Óseas Displasia Ectodérmica Displasia Ectodérmica Tipo Berlin Displásia Espondofisária Displasia Ósea Displasia Ventricular Derecha Arritmógena (DVDA) Distonia Cervical Distonía Focal Distonía Multifocal Paroxística Distonía Neurodegenerativa Distonía Primaria Distonía que Responde a la Levodopa Distrofia Miotónica Distrofia Muscular Congénita Tipo Fukuyama Distrofia Muscular de Cinturas Distrofia Muscular de Duchenne y de Becker Distrofia Muscular de Emery Dreyfuss Distrofia Muscular de Landouzy Dejerine Distrofia Muscular Infantil Distrofias Musculares Doble Salida de Ventrículo Derecho Dolor Pélvico Crónico Duchenne Erb, Síndrome de Dumping, Síndrome de Ehlers Danlos, Síndrome de Ellis Van Creveld, Síndrome de Enanismo de Laron Epidermolisis Bullosa Epilepsia Mioclónica Progresiva Escafocefalia Esclerodermia Esclerosis Lateral Amiotrófica Esclerosis Tuberosa Espina Bífida Estenosis Pulmonar Valvular Estenosis Subaórtica Fija Exostosis Múltiple Extrofia Cloacal Extrofia Vesical Fabry, Enfermedad de Factor IX, Déficit de Fascitis Eosinofílica Fatiga Crónica, Síndrome de Felty, Síndrome de Fenilcetonúria o PKU Fibrodisplasia Osificante Progresiva Fibrosis Quística Fiebre Reumática Fucosidosis Galactosemia, Enfermedad de Gangliosidosis GM1 Gaucher Schlagenhaufer, Enfermedad de Gilles de la Tourette, Síndrome de Glicosilación, Defectos Congénitos de la Glucogenosis Gorlin, Síndrome de Granulomatosa Cronica, Enfermedad Granulomatosis de Wegener Hemiplejia Alternante Infantil Hemocromatosis Familiar Hemocromatosis Neonatal Hemofilia A Hemofilia C Hemoglobinopatía C - Forma Homocigota Hemoglobinopatía C Harlem Hemoglobinopatía D Hemoglobinopatía E Hemoglobinopatía Inestable Hemoglobinopatía J Hemoglobinopatía M con Hemólosis Hemoglobinopatía S Hemoglobinuria Paroxística Nocturna Hepatitis Autoinmune, Formas Mixtas de Hermansky Pudlak, Síndrome de Hidrocefalia Hiper-IgM, Síndrome de Hiperlaxitud, Síndrome de Hiperlisinemia Hiperostosis Frontal Interna Hipertensión Pulmonar Hipertensión Pulmonar Primaria o Idiopática Hipertensión Pulmonar Secundaria Hipocondroplasia Hipomagnesemia por Malabsorción Selectiva de Magnesio Hipopituitarismo Hipoplasia de las Celulas de Leydig Hipotonía Muscular Congénita Histiocitosis Tipo II Histiocitosis X Hormona del Crecimiento, Déficit de Hunter, Síndrome de Huntington, Enfermedad de Huntington, Enfermedad de (Variante de Wesphal) Hurle Scheie, Síndrome de Hurler, Enfermedad de I - Cell Ictiosis Vulgar Inmunodeficiencia Variable Común Insensibilidad a los Andrógenos, Síndrome de Insuficiencia Suprarrenal Primaria, Crónica, Adquirida Intolerancia Hereditaria a la Fructosa Isaacs, Síndrome de Jacobsen, Síndrome de Job, Síndrome de Joseph, Enfermedad de Joubert, Síndrome de Kawasaki, Síndrome de Kearns Sayre, Síndrome de Kennedy, Enfermedad de Kleine Levin, Síndrome de Klinefelter, Síndrome de Klippel Feil, Síndrome de Krabbe, Enfermedad de Leigh, Síndrome de Lesch Nyhan, Síndrome de Leucemia Linfocítica Crónica Leucodistrofia Leucodistrofia Metacromática Linfangioleiomiomatosis Lowe, Enfermedad de Lupus Discoide Eritematoso Lupus Eritematoso Sistémico Malformaciones Craneocervicales Manosidosis Marfan, Síndrome de Maroteaux Lamy, Síndrome de Marshall Smith, Síndrome de Mastocitosis Maullido del Gato, Síndrome del McArdle, Enfermedad de McCune Albright, Síndrome de McLeod, Síndrome de Melas, Síndrome de MERRF, Síndrome Miastenia Gravis Miller Dieker, Síndrome de Miocardiopatía Dilatada Idiopática Mitocondrial Mioneurogastrointestinal, Síndrome (MNGIE) Miopatía de Multicore Miopatía Mitocondrial Miopatía Nemalínica Miopatías Congénitas Miopatías Metabólicas Mitoconfrial, Enfermedad Mixta del Tejido Conectivo, Enfermedad de Moebius, Síndrome de Morquio, Enfermedad de Mucolipidosis Tipo 2 Musculares, Enfermedades Narcolepsia NARP, Síndrome de Natowicz, Síndrome de Nefronoptisis Neuramidasa, Deficiencia de Neurinoma del Acústico Neurofibromatosis Central Neurofibromatosis de Von Recklinghausen Neuromusculares, Enfermedades Neuropatía Motora Multifocal Nevus Nevus Gigante Congénito Niemann Pick, Enfermedad de Nonne, Síndrome de Noonan, Síndrome de Núcleo Central, Enfermedad de Nutrición Parenteral Oculo Cerebro Renal, Síndrome de Oftalmoplegia Externa Progresiva Osteogénesis Imperfecta Osteonecrosis Panhipopituitarismo Paraparesia Espástica Familiar Paraparesia Espástica Tropical Parry-Romberg, Síndrome de Pearson, Síndrome Pelizaeus Merzbacher, Enfermedad de Pénfigo Benigno Crónico Familiar de Hailey-Hailey Pénfigo Foliáceo Pénfigo Vulgar Penfigoide Ampollar Pénfigoide Bulloso Penfigoide Cicatricial Penfigoide Gestacional Persona Rígida, Sindrome de la Peutz Jeghers, Síndrome de Pfeiffer, Síndrome Picnodisóstosis Pierre Robin, Síndrome de Plagiocefalia Poems, Síndrome de Poland, Síndrome de Poliangeitis Microscópica Polineuropatía Amiloide Familiar (Tipo 1) Polineuropatía sensitivo-motora desmielinizante crónica Polineuropatías Poliquistosis Renal Autosómica Dominante (PQRAD) Poliquistosis Renal Autosómica Recesiva Pompe, Enfermedad de Porfiria Aguda de Doss Porfiria Aguda Intermitente Porfiria Cutánea Tarda Porfiria Eritropoyética Congénita Porfiria Hepática Variegata Post Polio, Síndrome de Prader Willi, Síndrome de Primarios Inmunitarios, Déficit de Prostatitis Crónica Proteus, Síndrome de Protoporfiria Eritropoyética Pseudo Hurler Polidistrofia Pseudoxantoma Elástico Púrpura de Schonlein Henoch Químico Múltiple, Síndrome Quiste Aracnoideo Quiste de Tarlov Rapp Hodgkin, Síndrome de Raynaud, Enfermedad Reiter, Síndrome de Retinosis Pigmentaria Retinosquisis Rubinstein Taiby, Enfermedad de Russell Silver, Síndrome de Sandhoff, Enfermedad de SanFilippo, Síndrome Santavuori, Enfermedad de Schwartz-Jampel, Síndrome de Sialidosis Síndrome de Rett Siringomielia Situs Inversus Cardiopatía Sjögren Primario, Síndrome de Sly, Síndrome de Smith Magenis, Síndrome de Sotos, Síndrome de Stargardt, Enfermedad de Stickler, Síndrome de Still del Adulto, Enfermedad de Takayasu, Enfermedad de Talasemia Mayor Talasemia Minor Tay Sachs, Enfermedad de Telangiectasia Hemorrágica Hereditaria Tetralogía de Fallot Tirosinemia Tipo I Transposición de Grandes Vasos Trisomia Cariotipo 47 XXX Turner, Síndrome de Usher, Síndrome de VACTERL Vasculitis Necrosante Generalizada Vasculitis Predominante Cutánea Ventrículo Único Von Gierke, Enfermedad de Von Hippel Lindau, Síndrome de Von Willebrand, Enfermedad de WAGR, Síndrome de Walker Warburg, Síndrome de West, Síndrome de Williams, Síndrome de Wilson, Enfermedad de Wiskott Aldrich, Síndrome de Wolff Parkinson White, Síndrome de Wolfram, Síndrome de X-Frágil, Síndrome Zellweger, Síndrome de

number of scientific publications about rare diseases continues to increase

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 5 CHARACTERISTICS OF RARE DISEASES

 Chronic  Patients are few and  Progressive geographically spread  Degenerative  Research is fragmented  Life-threatening  Resources are limited  Disabling  Experts are few  Lack or loss of autonomy  Specialised care centres for each  Difficult to manage disease cannot exist in every country

 Relevant information is little

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 6 RARE DISEASES ORIGINS

The cell 80% Genetic origins • Clinical manifestations • Causes • Populations they affect • Severity and age of onset Nucleus

DNA (Deoxyribonucleic acid) http://www.freedigitalphotos.net/images/view_photog.php?photogid=2888

• Bacterial or viral infections • Allergies Non-genetic origins • Environmental causes Suggestions that susceptibility • Degenerative or may be genetically determined proliferative basis

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 7 OUTLINE

• INTRODUCTION ABOUT RARE DISEASES (RD) . Rare diseases as a public health priority

• THE PATIENT’S VOICE . APCDG-DMR: a non-profit organization . Congenital Disorders of Glycosylation (CDG)

• ACTIVITIES DONE BY APCDG-DMR

o To support families (Information & Empowerment) o Networking o Awareness amongst public and health care professionals o Education o Scientific and clinical research

RARE DISEASES (RD) AS A PUBLIC HEALTH PRIORITY

EU Regulations on: Orphan Drugs (1999), Paediatric Use of Medicines (2006), Advanced Therapies (2007), Commission Communication (2008), Council Recommendation on Rare Diseases (2009), EU Directive on Cross Border Health Care establishes rare diseases as a public health priority in its Article 13 (Brussels, 21 February 2011).

http://ec.europa.eu/health/rare_diseases/policy/index_en.htm

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 9 Orphan Medicinal Product Regulation: development costs > expected return on investment 7,000-8000 rare medical conditions , less than 300 have therapies available to treat them

What are the EU incentives ? Market Exclusivity for 10 years after grant of EU marketing authorisation Fee Reductions: reduction of centralised regulatory fees via a special fund from EU budgetary authority Centralised Procedure: direct access to EMA centralised procedure for marketing authorisation EU-Funded Research grants from Community & Member State programmes Protocol Assistance: free scientific advice to optimise development

 Application for Orphan Designation demonstrate orphan criteria have been met:  life-threatening or debilitating nature of condition  medical plausibility  prevalence < 5 in 10,000 or unlikely to generate sufficient return on investment  no satisfactory methods exist or medicinal product will be of significant benefit  Diagnostic tool can apply for orphan designation

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 10 Annual Numbers of Orphan Designations and Marketing Authorizations in the EU

Orphan Designations

Number of Products

Marketing Authorizations

2010

Year

Source: EU Commission, Jan 2011 Orphan medicinal products on the market

Source: Dr Jordi Llinares, EMA, 2011 OUTLINE

• INTRODUCTION ABOUT RARE DISEASES (RD) . Rare diseases as a public health priority

• THE PATIENT’S VOICE . APCDG-DMR: a non-profit organization . Congenital Disorders of Glycosylation (CDG)

• ACTIVITIES DONE BY APCDG-DMR

o To support families (Information & Empowerment) o Networking o Awareness amongst public and health care professionals o Education o Scientific and clinical research

PORTUGAL

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 14 EURORDIS: European Organisation for Rare Diseases

 Founded 1997  461 members (45 countries)  Represents more than 4000 RD  Mission:Facilitate participation of patients in patient groups and to federate these patient groups with the goal of achieving a more powerful unified voice

EurordisCare1 EURORDIS IS PRESENT IN MANY EUROPEAN INSTITUTIONS AND PLATFORMS .Committee for Orphan Medicinal Products at the EMEA (COMP) .EMEA/Committee for Proprietary Medicinal Products (CPMP) Working Group with Patients’ Organisations .Rare Disease Task Force at Directorate General for Health and Consumer Protection .EU Health Policy Forum at DG Health and Consumer Protection .EU High Level Groups on Health Services and Medical Care EurordisCare2 and EurordisCare3

Different consortiums for patient organisations with a role in Healthcare issues

http://www.eu-patient.eu/ http://www.epposi.org/ http://www.patientsorganizations.org/ http://www.efgcp.be/ Examples of patient involvement in European Medicines Agency (EMA):

 Membership of the EMA Management Board  Membership of three scientific Committees: . COMP (Committee for Orphan Medicinal Products) . PDCO (Paediatric Committee) . CAT (Committee for Advanced Therapies)

 PCWP (Patients’ and Consumers’ Working Party)  Ad-Hoc participation in the activities of the Committee for Proprietary Medicinal Products (CHMP)  Review of Product Information (EPAR summary and package leaflet)  Membership of the Working Group on Clinical Trials in Third Countries  Patients act as observers in the Pharmacovigilance Working Party (PhVWP) PROFESSIONALIZED PATIENT:

•Conference Scholarship Opportunities directed to families and patients representatives: Genetic Diseases of Children: Advancing Research & Care V Congreso Internacional de Medicamentos Huérfanos y Enfermedades Raras

• th 6 DIA Patient Advocacy •EURORDIS SUMMER SCHOOL for patient advocates Fellowship Program in clinical trials and drug development

INFORMED PATIENT: Disease knowledge plus an expertise in the therapeutic field Data collection , Interpretation, Reports

•APIFARMA (Associação Portuguesa da Indústria Farmacêutica) training: Formação •L’École de l’ADN (Nîmes University, France) sobre Ensaios Clínicos

Health Technical Assessment (HTA) Summer School at the London School of Economics (LSE) .Should treatment A be reimbursed in a national healthcare system? .For which patients should it be provided? .For how long should patients receive the treatment? Understanding Health Technology Assessment (HTA): A guide Health Equality Europe OUTLINE

• INTRODUCTION ABOUT RARE DISEASES (RD) . Rare diseases as a public health priority

• THE PATIENT’S VOICE . APCDG-DMR: a non-profit organization . Congenital Disorders of Glycosylation (CDG)

• ACTIVITIES DONE BY APCDG-DMR

o To support families (Information & Empowerment) o Networking o Awareness amongst public and health care professionals o Education o Scientific and clinical research

Our organization in brief

• Founded in 2010 • Non-Profit Organization • 42 members (2 Honorary members) • 2 rare metabolic diseases covered Rosália Ferreira, Sandra Pinto, Vanessa Ferreira Social and Accessibility and Scientific and • 6 volunteers in Portugal, Advocacy Affairs Advocacy Affairs Management Spain, USA and Australia • EURORDIS (European Organisation for Rare Diseases) member Andrea Berarducci, Merell Liddle, • Annual budget and funding Filipe Oliveira CDG USA CDG Australia sources Website manager • Global voice to fight against impact of rare metabolic diseases

APCDG- DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 19

Basic Clinical Research Research

Causes?

Clinical Manifestations Medical Patient doctor

Congenital disorder of 2. glycosylation type 1A ? Rare Disease Gene BAD PROGNOSIS Mutation Premature aging Genetic counseling Prenatal diagnosis NO CURE

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 20 Vision and mission

Patient-centred research Basic To improve care Clinical Research Research FAMILIES

Medical doctor

•To support families •Scientific and clinical research (Information, & Empowerment) •Development treatments and Orphan Drugs •Networking •Advocacy RDs as Public Health • Awareness issue & policy development •Education

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 21 Associação Portuguesa CDG e outras Doenças Metabólicas Raras (APCDG-DMR)

Rare Metabolic Diseases Formed by: Mitochondrial diseases, Pyruvate Dehydrogenase Deficiency Board of directors; (PDH), Krebs cycle disorders, GLUT1 deficiency, defects of Executive Board; and carnitine transport, glycogenosis , Galactosemia , Frutosemia, Inborn errors of amino acid metabolism Finance Board. (, Aspartylglucosaminuria, , Maple syrup urine disease, , , , , Biotinidase deficiency, Medical-Scientific Ornithine carbamoyltransferase deficiency, Carbamoyl-phosphate Panel: synthase I deficiency disease, , Hyperargininemia, , , Nonketotic hyperglycinemia, , ), Gene expression regulation neurometabolic diseases, Peroxisomal diseases ( Zellweger Stem-cells field syndrome, rhizomelic chondrodysplasia punctata type 1, Infantile , Pipecolic acidemia, Hyperoxaluria type 1, Acyl- Cellular and neurobiology CoA oxidase deficiency, D-bifunctional protein deficiency, X-linked Regulation of the translation , Dihydroxyacetonephosphate control acyltransferase deficiency, Neonatal adrenoleukodystrophy, Development and growth , α-Methylacyl-CoA racemase deficiency, RCDP Type 2, control RCDP Type 3, Adult Refsum disease-1, ), Neurodevelopment Congenital Disorders of Glycosylation (CDG)

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 22 OUTLINE

• INTRODUCTION ABOUT RARE DISEASES (RD) . Rare diseases as a public health priority

• THE PATIENT’S VOICE . APCDG-DMR: a non-profit organization . Congenital Disorders of Glycosylation (CDG)

• ACTIVITIES DONE BY APCDG-DMR

o To support families (Information & Empowerment) o Networking o Awareness amongst public and health care professionals o Education o Scientific and clinical research

Congenital Disorders of Glycosylation (CDG): A booming disease of sugars

DNA mRNA nucleus P Phosphorylation cytoplasm Translation Protein formation Ac Acetylation

Protein Ub Ubiquitination Post-translational Modifications

Glycosylation

P Ac Ub

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 24 Functions: Transport (Example:Transferrin)

Structural (Example: collagens)

Immunologic (Immunoglobulins, histocompatibility Adapted from: Guia Metabólica antigens)

Cell attachment-recognition site (Example: various proteins involved in cell-cell (sperm-oocyte for Glycan example), Virus-cell,bacterium –cell, and hormone-cell interactions) + Regulation of development Protein Hemostasis (and Thrombosis)

Hormones (Example: Human Chorionic Gonadotropin Glycoprotein (HCG), Thyroid-stimulating hormone (TSH)

Affect folding of certain proteins (Calnexin, for example)

Interact with specific carbohydrates (Lectins, or antibodies for example)

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 25 Glycoprotein Correctly formed

Glycans are missing: Type I

Glycoprotein Uncorrectly formed Glycans are not correctly formed: Type II

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 26 Diagnosis of rare diseases is an important area of concern!

Several Specialists Several medical exams Underrecognized Delays in diagnosis

Without diagnosis patients and families cannot access effective  treatment, therapy , manage their condition and  access to social services

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 27 CDG DIAGNOSIS

• Transferrin isoelectric focusing (TF-IEF) Screening techniques: • Capillary zone electrophoresis (CZE) • High pressure liquid chromatography (HPLC)

• Measurement enzymatic deficiency or the genetic mutations Techniques for further • Lipid linked oligosacharides (LLO) (type I) investigation of CDGs: • Apolipoprotein (Apo) CIII (type II) • Glycan analysis (type II): mass spectrometry (ES-MS) or MALDI-TOF

Confirmation of CDG • enzymatic deficiency (few enzymes are measurable) diagnosis • or the genetic mutations: Exome Sequencing

1999-2009: oCDG I a – I g, …: 2009: PMM2-CDG (CDG-Ia) oCDG II a – II c, …:

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 28 CONGENITAL DISORDERS OF GLYCOSYLATION

Source: Dr Hudson Freeze laboratory webpage

Defects in protein N-glycosylation (n=16) Defects in protein O-glycosylation (n=7) Defects in lipid glycosylation (n=3) Defects in multiple glycosylation pathways and other pathways (n=17)

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 29 APCDG-DMR Retinitis Inverted nipples (CDGIa) pigmentosa Abnormal Strabismus Icthyosis Skin

fat pads Eyes (CDGIa; -Ic)

(CDG If) Coloboma (CDG Ia) Optical

atrophy

Bleeding tendency

Congenital nephrotic syndrome (CDGIa) Coagulation Renal ↓clotting factor XI activity ↑ FSH, LH and Laboratory prolactin

Cardiomyopathy (dylatedUNEXPLAINED or hypertrophic, (CDGIa and X)

Cycling vomiting Hydrops Heart Pericardial (CDGIb) fetalis SYNDROMEeffusion !!!!Gastrointestinal Chronic diarrhea

(CDG Ib)

Muscular Muscular hypotonia

Neurology Growth retardation Skeletal/Growth Failure to thrive

(Adapted from T. Marquard, 2003 , Eur J Pediatr and Dr Luísa Diogo,Coimbra,Portugal)

Specific treatment

• Specific treatment is available for only one CDG, namely PMI-CDG (CDG-Ib):

– simple daily oral mannose supplementation is an effective treatment for patients with this potentially lethal disorder

• Some patients with SLC35C1-CDG or leukocyte adhesion deficiency type II respond to simple supplementation of oral fucose (alleviates clinical symptoms)

• In PIGM-CDG that causes histone hypoacetylation, butyrate increases PIGM transcription and its supplementation was able to control seizures in one reported patient

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 32 Symptomatic treatments and preventive measures

Clinical feature

Failure to thrive Consider nasogastric tube or gastrostomy tube feeding Strabismus Glasses, patching, or surgery Stroke-like episodes Low doses of aspirin Oral motor dysfunction Consider consultation with a gastroenterologist/nutritionist Osteopenia Bisphosphonate therapy in severe forms Pericardial effusion Corticosteroids and salicylic acid, pericardial drainage Scoliosis/kyphosis Surgical treatment in severe forms True hypothyroidism L-thyroxine supplementation

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 33 OUTLINE

• INTRODUCTION ABOUT RARE DISEASES (RD) . Rare diseases as a public health priority

• THE PATIENT’S VOICE . APCDG-DMR: a non-profit organization . Congenital Disorders of Glycosylation (CDG)

• ACTIVITIES DONE BY APCDG-DMR

o To support families (Information & Empowerment) o Networking o Awareness amongst public and health care professionals o Education o Scientific and clinical research

Support families through such vital services as: o CDG International eNewsletter (3 languages): International o Access to scientific articles o Leaflets o Social network: . CDG united, CDG Family network, . AESCDG, . Les p’tits CDG, . Sindrome CDG o Skype (apcdgedmr) o Guide to understanding CDG (SP, EN and PTG) http://www.guiametabolica.org/sites/default/files/guia_practica_familias_CDG.pdf

Support families through such vital services as: o I LUSO-HISPANIC CDG MEETING, 21 -22 October, 2011 o Webpage (3 languages): http://sindromecdg.orgfree.com o Work in progress: o Expand Information: Model of Informative medical record o Interactive o Funds

Informative medical record: oSynonymous oClassification: MIM code, Orpha number oand code by OMS ICD10 (when it is applied) oFeatures of the disease: oDefinition oCauses oClinical spectrum oTreatment and management oNumber of population affected oBibliography oLaboratories of diagnosis oReference Medical doctor oPatients organisations Visibility

60 000 readers

3700 readers3700 readers OUTLINE

• INTRODUCTION ABOUT RARE DISEASES (RD) . Rare diseases as a public health priority

• THE PATIENT’S VOICE . APCDG-DMR: a non-profit organization . Congenital Disorders of Glycosylation (CDG)

• ACTIVITIES DONE BY APCDG-DMR

o To support families (Information & Empowerment) o Networking o Awareness amongst public and health care professionals o Education o Scientific and clinical research

Networking: Patient representatives at International level

• “Ethics on Rare Diseases Research” (28 October, 2009), Madrid, Spain. • 22 nd DIA Annual EuroMeeting Tutorial: Orphan Drugs (8 March, 2010), Mónaco. • 22 nd DIA Annual EuroMeeting (8-10 March), Mónaco. • 4th Annual Clinical Forum (11-13 October), Lisbon, Spain. • Europlan Conference, Orphan Drugs Group (5-6 November), Burgos, Spain. • V International Conference on Orphan Drugs and Rare Diseases (17-19 February, 2011), Sevilha, Spain. • VIII Basic Course on Inherited Diseases of Metabolism (22-24 March), Coimbra, Portugal. • 23 rd DIA Annual EuroMeeting Tutorial: Orphan Drugs in the EU; From designation to Marketing Authorisation (28 March), Geneva, Switzerland. • 23 rd DIA Annual EuroMeeting (28-30 March), Geneva, Switzerland. • Eurordis Membership Meeting (12-14 May), Amsterdam, Netherlands. • “Eurordis Summer School for Patient Advocates in Clinical Trials and Drug Development” (12-16 June), Barcelona, Spain • Health Technology Assessment Programme at London School of Economics (8 - 10 June), London, Uk. • 8th European Cytogenetics Conference (2-5 July), Porto, Portugal. • Glycosciences Conference (8-10 September), Lisboa, Portugal. • Inborn Errors of Metabolism and Neurodegeneration (3-5 November), Porto, Portugal. • European Medicines Agency: Patients and consumers training session on product information review (29 November), London, Uk. • EGAN/ROCHE strategy workshop:”Data sharing and therapy development: possibilities and pitfalls” (12-13 January, 2012), Basel, Switzerland. • European Conference on Rare Diseases and Orphan Products (23-25 May), Brussels,Belgium. • 26th International Carbohydrate Symposium (ICS2012) (22nd to 27th, July), Madrid, Spain.

Networking: Patient representatives at National level

Inborn Errors of Metabolism and Neurodegeneration (3-5 November,2011), Porto, Portugal. VII Social Responsability week, 2012, Lisbon, Portugal

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 40

Networking: Oral and poster presentations

2011:  “What’s CDG?” Rare Disease Symposia (22 January), Zaragoza, Spain.  “The Congenital Disorders of Glycosylation (CDG) networking” (2 June), Faculty of Medical Sciences, Universidade Nova de Lisboa, Portugal. Invited by Dr Paula Videira.  “Empowerment of Congenital Disorders of Glycosylation (CDG) patients’ voice” (31 May), Câmara Municipal do Seixal, GAMA department. Invited by Cristina Fernandes (GAMA coordinator)  “Flourishing opportunities to Congenital Disorders of Glycosylation (CDG) patients voice”, (8 July) Seixal, Portugal. Invited by Sofia Loução (Health Department at Câmara Municipal do Seixal).  “The Congenital Disorders of Glycosylation (CDG) non-profit organization” (8 July), “ Center Jacinto de Magalhães, National Institut of Health Ricardo Jorge, Porto, Portugal. Invited by Dr Dulce Quelhas.  “The role of patients in research”. Round table. Glycosciences Conference (8-10 September), Lisboa, Portugal. Invited by Professor Dr Amelia Rauter (Member of the Steering Committee and Executive for Glycochemistry of the ESF Research Network Euroglycoscience Forum and Secretary of IUPAC Division III Subcommittee on Biomolecular Chemistry).  “Empowerment of Congenital Disorders of Glycosylation (CDG) patients’ voice”. Poster presented at Inborn Errors of Metabolism and Neurodegeneration (3-5 November), Porto, Portugal.  “Empowerment of Congenital Disorders of Glycosylation (CDG) patients’ voice” (27-29 November), Book of abstracts, 22nd Joint Glycobiology Meeting, Lille, France.

2012:  “Congenital Disorders of Glycosylation from a patient advocate point of view” (17 January). Invited by Lysogene, Paris, France.  “Congenital Disorders of Glycosylation (CDG)” (30 January), Apifarma, Lisbon, Portugal. Invited by Apifarma.  “Empowerment of Congenital Disorders of Glycosylation (CDG) patients’ voice” European Conference on Rare Diseases and Orphan Products (23-25 May), Brussels, Belgium.  “Partnership amongst families, researchers and physicians to decipher CDG”: 26th International Carbohydrate Symposium (ICS2012) (22nd to 27th, July), Madrid, Spain.

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 41 OUTLINE

• INTRODUCTION ABOUT RARE DISEASES (RD) . Rare diseases as a public health priority

• THE PATIENT’S VOICE . APCDG-DMR: a non-profit organization . Congenital Disorders of Glycosylation (CDG)

• ACTIVITIES DONE BY APCDG-DMR

o To support families (Information & Empowerment) o Networking o Awareness amongst public and health care professionals o Education o Scientific and clinical research

Awareness amongst public and health care professionals: the Fairy-tale in then languages!

http://www.guiametabolica.org/ Awareness amongst public and health care professionals Paz Briones Mercedes Serrano

Belén Maria A Pérez- Vilaseca Dueñas Awareness amongst public and health care professionals Awareness amongst public and health care professionals

Andrea Berarducci, CDG USA http://www.cafepress.com/CDG_Community Awareness amongst public and health care professionals

23 of July 2012 11.00-11.30:J. Jaeken (Belgium): Congenital Disorders of Glycosylation (CDG): a booming disease family 11.30-12.00: V. Ferreira (Portugal): Partnership amongst families, researchers and physicians to decipher Congenital Disorders of Glycosylation (CDG). Awareness amongst public and health care professionals

Fairy-tales(5 in total) 57 leaflets Libraries Awareness amongst public and health care professionals

http://www.eurordis.org/content/living-cdg-two-stories-one-shared-hope Awareness amongst public and health care professionals

“CDG Kit” (EN, ES and FR)

CONGENITAL DISORDERS OF GLYCOSYLATION (CDG) Name, CDG patient representative Country

Collaborators: Andrea Berarducci, Bas Holten, Vanessa Ferreira Skype name: cdgawareness http://www.guiametabolica.org/sites/default/files/CDG_AWARENESS_AND_DISSEMINATION_ang.pdf Rare Connect Online Community: http://www.rareconnect.org/en/community/cdg OUTLINE

• INTRODUCTION ABOUT RARE DISEASES (RD) . Rare diseases as a public health priority

• THE PATIENT’S VOICE . APCDG-DMR: a non-profit organization . Congenital Disorders of Glycosylation (CDG)

• ACTIVITIES DONE BY APCDG-DMR

o To support families (Information & Empowerment) o Networking o Awareness amongst public and health care professionals o Education o Scientific and clinical research

Education

Escola Secundária de Caldas das Taipas (Guimarães) “Pôr os doentes em primeiro lugar” (Patient First Project) “PÔR OS DOENTES EM PRIMEIRO LUGAR”  Escola Superior de Saúde do Instituto Politécnico da Guarda: o To characterize the non-profit oganizations in Portugal  Play Decide Game: o A game that contributes to the improvement and enhancement of understanding of different issues related to Rare Diseases http://www.playdecide.eu/ Education

IGM- INSTITUTO DE GENÉTICA MÉDICA DOUTOR JACINTO MAGALHÃES,Porto, Portugal Education: To boost projects amongst universities

Meta-analysis and summaries in several languages

• Medicine, Biochemistry, Biology (genetics), psychology • Support therapies • Graphic designing (fairy-tale as video) • Media (Journalism) • Social care (Pharmaeconomy): Economic burden • Glycosciences eLearning course OUTLINE

• INTRODUCTION ABOUT RARE DISEASES (RD) . Rare diseases as a public health priority

• THE PATIENT’S VOICE . APCDG-DMR: a non-profit organization . Congenital Disorders of Glycosylation (CDG)

• ACTIVITIES DONE BY APCDG-DMR

o To support families (Information & Empowerment) o Networking o Awareness amongst public and health care professionals o Education o Scientific and clinical research

To boost and incentive scientific and clinical research

• Organisation of events to link researchers, clinicians and patients:  Potentiating collaborations amongst research laboratories (Javier Corral, University of Murcia , Spain)

• Writing research projects (Paula Videira Lab, Faculty of Medical Sciences - New University of Lisbon; Principal Investigator in CEDOC)

• Visibility  Scientific and Medical Conferences  CDG International eNewsletter

• Partnership with patient groups, researchers and medical doctors  CDG Online Community  Epirare

Partnership with patient groups, researchers and medical doctors: CDG Online community

http://www.rareconnect.org/en/community/cdg Partnership with patient groups, researchers and medical doctors: CDG Online community CDG patients group role: •Improved visibility for patient organization. •Play a role in communicating to the community. •Blog entries/Updates written by patient organization •Information •Research news •Policy developments •Events •Play a role in governance of the community. Recruiting Moderators & Volunteers

Family Referral Directory: connecting families that are living in the same region.

Many CDG experts participated (USA, France, Argentina, Spain, Netherlands, Italy, Belgium and Portugal) Partnership with patient groups, researchers and medical doctors: Epirare

• European Platform for Rare Disease Registries • European network to boost research, diagnosis and treatment • Natural history of the disease - Epidemiological research • Clinical research (patient recruitment for clinical trials) - Disease surveillance - Disease follow-up - Treatment evaluation (efficacy) - Treatment monitoring (safety) - Mutation database - Genotype-phenotype correlation - Benchmarking for improvement of quality of care and development of clinical care • Guidelines • Social planning

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 59 FAMILIES+RESEARCHERS+ PHYSICIANS: RESULT!

Eva Morava Marisa Giròs Lourdes Belén Dueñas Dirk Lefeber Paula Videira Hudson Freeze Carla Asteggiano Belén Pérez G Claúdio Dirk Lefeber Célia Cerdá Donna José Samuel Krasnewich Maria Prol Daisy Rymen

Rosália Marta Maria Vilaseca Mercedes Serrano Jaak Jaeken Paz Briones APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 60 TOWARDS A HOPE BY SUPPORTING RESEARCH

Support Research Calls Fellowships Patients as advisors: research driven by patients needs

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 61 PATIENTS’ PRIORITIES AND NEEDS FOR RARE DISEASE RESEARCH

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 62 Thanks to: The CDG Patient’s Voice

CDG-patients organizations or foundations CDG active patient representatives nucleus: Netherlands, UK, Ecuador, Brazil, Finland, Australia

“the little fighters foundation for a cure” Thanks to: The CDG Patient’s Voice

Links from different associations: Portugal: http://sindromecdg.orgfree.com/ Spain: http://webs.ono.com/aescdg/SINDROME_CDG/Bienvenidos.html France: http://www.lesptitscdg.org/ USA: http://www.cdgfamilynetwork.org/ Canada: http://www.thefog.ca/ http://thelittlefightersfoundation.com/ Germany: https://www.cdg-syndrom.de/ Denmark: http://www.cdgforeningen.dk/ Sweden: http://www.cdgs.se/

[email protected] Thanks to: Families and members

We are grateful to all Medical Doctors and Researchers that are changing the landscape of this rare metabolic disease all around the world! Their efforts are contributing to improve scientific and medical diagnosis, clinical manifestations and they are doing many efforts in order to find a treatment to CDG patients.

In Spain: In Portugal: Dr Belén P Dueñas Dr Elisa Teles, Dr Maria Vilaseca Dr Luísa Diogo, Dr Mercedes Serrano Dr Laura Vilarinho, Dr Paz Briones Dr Dulce Quelhas, Dr Marisa Giròs Dr Paula Garcia, Dr Belén pérez Dr Sílvia Sequeira, Dr Célia P Cerdá Dr Paula Videira, Dr Rafael Artuch Dr Esmeralda Martins

L F cartoon We are particularly grateful to: Professor Jaak Jaeken THINK METABOLIC, THINK CDG! INTERVIEW

The challenges that families face?

Facing a rare disease diagnosis: challenges

 Delays in order to obtain the precise and accurate diagnosis: Misdiagnosis Passing through all sort of medical tests and procedures before an accurate diagnosis

Understanding the diagnosis Feeling guilty

Lack and unavailability of scientific and medical information related to CDG (Language barrier) Scarcity of experienced physicians and medical centers specialized Struggling to identify and access available resources

Health care and social support services are designed for patients with common diseases Adult: follow-up done by family medical doctor for 10 years

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 69 Facing a Host of Unique Challenges

Lack Specialised care Sibling reaction centres Integration in Society, accessibility and symptomatic treatment Treatment

Educational Roadmap, delay Social integration diagnosis

Isolated, Adult phase Lack of information Professional integration, Lack support therapies, Lack of economic genetic counseling and psychologic support support future

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 70 How this activity helps the association?

S P Education E C Support Families: Awareness amongst I Inform, Communicate, public, health, F Train and Empowerment education and care I Patient professionals C Research Added Value:

a patient- PATIENT ADVOCACY centred To support the Healthcare G To advocate for better development and quality of life for O approval of legislation: patients and their supporting the rights and A families; specific needs in terms of L NATIONAL social support, infrastructure S UE and INTERNATIONAL and health care;

APCDG-DMR: Portuguese Association for CDG and other Rare Metabolic Diseases 72 Sources of photos:

• Slide 5: from the left to the right – http://www.freedigitalphotos.net/images/view_photog.php?photogid=1 499 – http://www.freedigitalphotos.net/images/view_photog.php?photogid=3 45 – http://www.freedigitalphotos.net/images/view_photog.php?photogid=8 09 – http://www.freedigitalphotos.net/images/view_photog.php?photogid=1 962 – http://www.freedigitalphotos.net/images/view_photog.php?photogid=7 39 – http://www.freedigitalphotos.net/images/view_photog.php?photogid=2 741 – http://www.freedigitalphotos.net/images/view_photog.php?photogid=2 280 – http://www.freedigitalphotos.net/images/view_photog.php?photogid=2 367