Published to commemorate the first 5 years of the Fabry Outome Survey, this volume brings together contributions from leading experts in the field of lysosomal storage diseases (LSDs) in general and Fabry disease in particular in a single state-of-the-art publication. The first section covers general aspects of LSDs, with chapters on topics as diverse as the cellular pathophysiology of lysosomes, the development of enzyme replacement therapy (ERT), the central role played by patient groups, and the regulatory framework governing the treatment of orphan diseases. The second section describes the role of observational outcome surveys and the organization and development of FOS. The third and fourth sections draw largely, but not exclusively, from data in FOS. They describe the clinical features and natural course of Fabry disease and the multiple beneficial effects of ERT with agalsidase alfa on the function of affected organs and quality of life.

By the end of 2005, FOS contained comprehensive information on over 750 patients from 13 countries. This outcome survey has therefore been able to greatly extend the information previously available from limited small-scale clinical trials, and reflects the clinical picture of Fabry disease and its response to ERT with agalsidase alfa within the context of normal clinical practice.

Contents

• Foreword
• Contributors
• Preface
• List of abbreviations
• Section 1. General aspects of lysosomal storage diseases
  • 1. History of lysosomal storage diseases: an overview
    Atul Mehta, Michael Beck, Aleš Linhart, Gere Sunder-Plassmann, and Urs Widmer.
    • Introduction
    • Recognition of the lysosome as central to storage diseases
    • Treatment of LSDs
    • First description of Fabry disease
    • Conclusions
    • References
  • 2. Epidemiology of lysosomal storage diseases: an overview
    Maria Fuller, Peter J Meikle, and John J Hopwood.
    • Introduction
    • Genes and proteins
    • Incidence and prevalence
    • Burden of illness
    • Fabry disease
    • Newborn screening for Fabry disease and other LSDs
    • Conclusions
    • References
  • 3. Physiology of the lysosome
    Paul Saftig.
    • Introduction
    • Role of the lysosome in cell physiology
    • Role of lysosomal enzymes and membrane proteins
    • Trafficking of lysosomal enzymes
    • Enzyme replacement and chaperone therapies
    • Conclusions
    • Acknowledgements
    • References
  • 4. Cellular pathophysiology of lysosomal storage diseases
    Volkmar Gieselmann.
    • Introduction
    • Cellular pathophysiology
    • Effects of different mutations on pathophysiology
    • Factors influencing the clinical heterogeneity of LSDs
    • Conclusions
    • References
  • 5. Importance of glycosylation in enzyme replacement therapy
    Soumeya Bekri.
    • Introduction
    • Structure and synthesis of α-galactosidase A
    • Post-translational modifications
    • Glycosylation
    • References
  • 6. Animal models of lysosomal storage diseases: their development and clinical relevance
    Mark E Haskins, Urs Giger, and Donald F Patterson.
    • Introduction
    • The need for animal models
    • Gene knockout technology
    • Use of larger animal models
    • Clinical relevance to therapy
    • The α-galactosidase A knockout mouse
    • Conclusions
    • Acknowledgements
    • References
  • 7. General aspects of X-linked diseases
    Dominique P Germain.
    • Introduction
    • Random X-chromosome inactivation
    • Identification of X-linked inheritance
    • Identification of individuals heterozygous for X-linked diseases
    • Conclusions
    • References
  • 8. Laboratory diagnosis of lysosomal storage diseases
    Soumeya Bekri.
    • Introduction
    • Lysosomal enzyme function
    • Lysosome biogenesis
    • Heterogeneity of LSDs
    • Laboratory diagnosis of LSDs
    • Non-immune hydrops fetalis
    • Conclusions
    • References
  • 9. Biomarkers in lysosomal storage diseases
    Timothy M Cox.
    • Introduction
    • Categories of biomarker used in LSDs
    • Characteristics of ideal biomarkers for LSDs
    • Disease burden
    • New biomarkers for LSDs
    • Biomarkers in current use
    • Use of biomarkers in screening for LSDs
    • Discovery of new biomarkers for LSDs
    • Clinical evaluation of biomarkers
    • Conclusions
    • References
  • 10. Enzyme replacement therapy – a brief history
    Elizabeth F Neufeld.
    • Introduction
    • Corrective factors and recognition signals
    • Development of enzyme replacement therapy
    • References
  • 11. Regulatory framework for the treatment of orphan diseases
    Rashmi R Shah.
    • Introduction
    • Orphan drug legislation in the EU
    • Regulatory framework and processes in the EU
    • Five-year experience and achievements in the EU
    • Orphan drug legislation in the USA and Japan
    • Access and reimbursement
    • Conclusions
    • Acknowledgements
    • References
    • Useful websites for further information
  • 12. Role of patient support groups in lysosomal storage diseases
    Christine Lavery.
    • In the beginning
    • Making a difference
    • Advocacy and support
    • Fulfilling an educational role
    • Data collection
    • Lobbying and campaigning
    • Working in partnership
    • International collaboration
    • Conclusions
    • Reference
    • Patient support groups
  • 13. The patient's perspective of Fabry disease – a report from the German Fabry Patient Support Group
    Ditmar Basalla.
    • Introduction
    • Information from patients for patients
    • Information for physicians and specialized medical staff
    • Working at an international level
    • Outlook
    • References
• Section 2. Development of FOS - the Fabry Outcome Survey
  • 14. Formal trials versus observational studies
    Ravi Thadhani.
    • Introduction
    • Randomized clinical trials
    • Need for observational studies to evaluate healthcare
    • Importance of outcomes databases
    • Conclusions
    • Acknowledgements
    • References
  • 15. Organization and technical aspects of FOS – the Fabry Outcome Survey
    Elizabeth Hernberg-Ståhl.
    • History and aims
    • Organization of FOS
    • Data capture
    • Patient questionnaires
    • The FOS system
    • Protecting patient privacy
    • Usability
    • Data quality
    • Patient management
    • Role of FOS in pharmacovigilance
    • Publications arising from FOS
    • Conclusions
    • References
• Section 3. Fabry disease: clinical features and natural course
  • 16. Demographics of FOS – the Fabry Outcome Survey
    Michael Beck.
    • Patient demographics
    • Delay in diagnosis
    • Reported signs and symptoms in male and female patients
    • Children in FOS
    • Mortality
    • Enzyme replacement therapy
    • Conclusions
    • References
  • 17. Diagnosis of Fabry disease: the role of screening and case-finding studies
    Gere Sunder-Plassmann and Manuela Födinger.
    • Introduction
    • Who makes the diagnosis?
    • Screening and case-finding
    • Conclusions
    • References
  • 18. Biochemical and genetic diagnosis of Fabry disease
    Bryan Winchester and Elisabeth Young.
    • Biochemistry and structure of α-galactosidase A
    • Practical aspects of enzyme determination
    • Male patients with residual α-galactosidase activity
    • Prenatal diagnosis
    • Measurement of storage products
    • Methods of genetic diagnosis
    • Types of mutations/polymorphisms
    • Conclusions
    • Acknowledgements
    • References
  • 19. Natural history of Fabry disease
    Atul Mehta and Urs Widmer.
    • Classic Fabry disease
    • Fabry disease in women and children
    • Atypical variants of Fabry disease
    • Cause of death in Fabry disease
    • Conclusions
    • References
  • 20. The heart in Fabry disease
    Aleš Linhart.
    • Introduction
    • Pathogenesis of the cardiac involvement
    • Cardiac hypertrophy
    • LV function
    • Ischaemia and coronary events
    • Electrophysiological abnormalities and arrhythmias
    • Valvular involvement
    • Cardiac variant
    • Clinical symptoms
    • Treatment issues
    • Conclusions
    • References
  • 21. Renal manifestations of Fabry disease
    Gere Sunder-Plassmann.
    • Introduction
    • The progressive nature of renal involvement in patients with Fabry disease
    • Histopathology
    • Renal imaging
    • Renal replacement therapy in patients with Fabry disease
    • Conclusions
    • References
  • 22. Neurological manifestations of Fabry disease
    Raphael Schiffmann and David F Moore.
    • Vasculopathy and stroke
    • Peripheral neuropathy and hypohidrosis
    • Conclusions
    • References
  • 23. Nervous system manifestations of Fabry disease: data from FOS – the Fabry Outcome Survey
    Lionel Ginsberg.
    • Introduction
    • Ischaemic stroke
    • Vascular risk factors
    • Magnetic resonance imaging
    • Other CNS diseases
    • Peripheral neuropathy
    • Treatment
    • Conclusions and future prospects
    • References
  • 24. Dermatological and soft-tissue manifestations of Fabry disease: characteristics and response to enzyme replacement therapy
    Olivier Lidove, Roland Jaussaud, and Sélim Aractingi.
    • Introduction
    • Pathology of cutaneous lesions in Fabry disease
    • Sweating
    • Lymphoedema
    • Acroparaesthesia
    • Facial dysmorphia
    • Response to ERT
    • Conclusions
    • References
  • 25. Fabry disease and the ear
    Annerose Keilmann, Stefan Hegemann, Guido Conti, and Daniel Hajioff.
    • Introduction
    • Histopathology
    • Natural history of hearing loss in Fabry disease
    • Effects of ERT on hearing
    • Tinnitus
    • Vertigo
    • Conclusions
    • References
  • 26. Ophthalmological manifestations of Fabry disease
    Andrea Sodi, Alex Ioannidis, and Susanne Pitz.
    • Introduction
    • Common ocular findings
    • Occasional ocular findings
    • Prevalence and clinical significance of ocular manifestations
    • Enzyme replacement therapy
    • Future developments
    • Ocular manifestations in FOS –the Fabry Outcome Survey
    • Conclusions
    • References
  • 27. Pulmonary involvement in Fabry disease
    John D Aubert and Frédéric Barbey.
    • Historical background
    • Data from FOS
    • Potential mechanisms of airflow limitation in Fabry disease
    • Treatment
    • Future areas of research
    • Conclusions
    • References
  • 28. Gastrointestinal manifestations of Fabry disease
    Satish Keshav.
    • Introduction
    • Gastrointestinal features of Fabry disease
    • Pathophysiology
    • Natural course
    • Response to ERT
    • Outstanding questions
    • References
  • 29. Neuropsychiatric and psychosocial aspects of Fabry disease
    Matthias J Müller.
    • Introduction
    • Methods
    • Results
    • Discussion
    • Conclusions
    • References
  • 30. Fabry disease in females: clinical characteristics and effects of enzyme replacement therapy
    Patrick B Deegan, Frank Bähner, Miguel Barba, Derralynn A Hughes, and Michael Beck.
    • Introduction
    • Evidence for the effects of Fabry disease in female patients
    • FOS data
    • Relationship between X-inactivation, enzyme levels and disease severity
    • ERT in females
    • Conclusions
    • References
  • 31. Natural history and effects of enzyme replacement therapy in children and adolescents with Fabry disease
    Uma Ramaswami, Rosella Parini, and Guillem Pintos-Morell.
    • Introduction
    • Natural course of Fabry disease in children
    • FOS data
    • Discussion
    • Conclusions
    • References
  • 32. Measurement of disease severity and progression in Fabry disease
    Catharina Whybra, Frank Bähner, and Karin Baron.
    • Introduction
    • Mainz Severity Score Index
    • Development of a scoring system for use in FOS – the Fabry Outcome Survey
    • Discussion
    • Conclusions
    • References
  • 33. The genetic basis of Fabry disease
    Andreas Gal, Ellen Schäfer, and Imke Rohard.
    • Introduction
    • Classification and nomenclature of mutations
    • Polymorphisms and rare sequence variants of the GLA gene
    • The GLA gene and its mutations in Fabry disease
    • The gene product
    • References
  • 34. Genotype–phenotype correlation in Fabry disease
    Markus Ries and Andreas Gal.
    • Introduction
    • General and epidemiological considerations
    • Residual enzyme activity and phenotypic variants
    • Pharmacogenomics
    • Female heterozygotes
    • Genetic modifiers
    • Conclusions
    • Acknowledgements
    • References
• Section 4. Selected aspects of the clinical management of Fabry disease
  • 35. A multidisciplinary approach to the care of patients with Fabry disease
    Derralynn A Hughes, Sian Evans, Alan Milligan, Linda Richfield, and Atul Mehta.
    • Introduction
    • The multidisciplinary team approach
    • Holistic care
    • Home therapy
    • Conclusions
  • 36. Development of enzyme replacement therapy for Fabry disease
    Raphael Schiffmann and Roscoe O Brady.
    • Introduction
    • ERT using agalsidase alfa
    • ERT using agalsidase beta
    • Conclusions
    • References
  • 37. Enzyme replacement therapy and the heart
    Christoph Kampmann.
    • Introduction
    • Potential of ERT in relation to cardiac involvement
    • Evidence of the benefits of ERT on cardiac manifestations
    • Conclusions
    • References
  • 38. Effect of enzyme replacement therapy with agalsidase alfa on renal function in patients with Fabry disease: data from FOS – the Fabry Outcome Survey
    Andreas Schwarting, Gere Sunder-Plassmann, Atul Mehta, and Michael Beck.
    • Introduction
    • Difficulties with registry studies
    • Baseline characteristics of the patient cohort
    • Agalsidase alfa therapy and renal function
    • Discussion and conclusions
    • References
  • 39. Neurological effects of enzyme replacement therapy in Fabry disease
    Raphael Schiffmann and David F Moore.
    • Introduction
    • Effect of ERT on the vasculopathy of Fabry disease
    • Effect of ERT on the peripheral nervous system
    • Conclusions
    • References
  • 40. Effects of enzyme replacement therapy on pain and overall quality of life
    Björn Hoffmann.
    • Introduction
    • Pain in Fabry disease
    • QoL in Fabry disease
    • Considerations relating to pain reduction and improved HRQoL
    • Possible use of patient-reported outcomes as surrogate markers
    • Conclusions
    • References
  • 41. Safety of enzyme replacement therapy
    Frédéric Barbey and Françoise Livio.
    • Introduction
    • Definitions in FOS
    • Special reporting procedures in FOS
    • Results
    • Discussion
    • Conclusions
    • References
  • 42. Monitoring and follow-up of patients
    Atul Mehta, Michael Beck, Aleš Linhart, and Gere Sunder-Plassmann.
    • Introduction
    • Assessment of patients
    • Criteria for starting ERT
    • Follow-up of patients
    • Home therapy
    • Criteria for stopping treatment
    • Criteria for ERT in children under 18 years of age
    • Conclusions
    • References
  • 43. Possible future therapies for Fabry disease
    Roscoe O Brady and Raphael Schiffmann.
    • Introduction
    • Molecular chaperone therapy
    • Substrate reduction therapy
    • Gene editing
    • Gene therapy
    • Infusions of structurally modified α-galactosidase A
    • Therapies based on the downstream mechanism of disease
    • Conclusions
    • Acknowledgements
    • References
  • 44. Concluding remarks
    Atul Mehta, Michael Beck, Aleš Linhart, and Gere Sunder-Plassmann.

Supported by an unrestricted educational grant by Shire HGT.

The information contained in this publication does not necessarily reflect the opinions or recommendations of the publishers or sponsors. The dosages, indications and methods of use for the product(s) referred to by the authors may not necessarily be those indicated on the Summary of Product Characteristics or the US Prescribing Information for the product(s) and may reflect the clinical experience of the authors or may be derived from the pharmaceutical literature or other clinical sources. When diagnosing and treating patients, doctors should take into account the individual patient's condition(s) and should consult officially approved monographs such as the Summary of Product Characteristics or US Prescribing Information prior to following any procedures or treatments based on data presented in this book.