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Lysosomal Storage Disorders
Enables readers to gain both holistic and specific knowledge on the topic of Lysosomal Storage Disorders
In the past few decades, we have witnessed a ‘golden age’ of Lysosomal Storage Disorders (LSDs) clinical care, diagnosis, and research and this book is a well-timed review of the rapidly developing subject of LSDs. Contributions from many leading scientists and clinicians in the field provide the reader with a completely comprehensive overview of the subject. Topics covered in the book include:
- The general aspects of LSDs, with special attention paid to physiology and pathology
- Clinical and laboratory diagnosis, including newborn screening and the genetics of LSDs
- Individual LSDs, such as the various sphingolipidoses, mucopolysaccharidoses, glycogen storage disease, glycoproteinoses, galactosialidosis, and neuronal ceroid lipofuscinoses
- Other disorders of the lysosome, including those involving defects in the lysosomal membrane and in the emerging roles of the lysosome in cellular metabolism
- The existing and emerging treatments for LSDs
- Key patient issues such as availability and disease awareness, including in the Third World.
For researchers and industry professionals in the field of LSDs, this book serves as a completely comprehensive reference work to understand both theoretical concepts and how they may be used in practical applications. For students of LSDs, it provides a solid base of foundational knowledge and serves as a practical guide.
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Veröffentlichungsjahr: 2022
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Table of Contents
Cover
Title Page
Copyright Page
Contributors
Foreword
Preface to the First Edition
References
Preface to the Second Edition
PART 1: General Aspects of Lysosomal Storage Diseases
CHAPTER 1: Lysosomal Storage Diseases
Introduction
Historic clinical and scientific landmarks
Conclusion and aims of this book
References
CHAPTER 2: The Lysosomal System:
Introduction
Lysosomal structure, biogenesis, and function
Lysosomal positioning and contacts
Transcriptional regulation of lysosomal function
Lysosomal signaling and adaptation
Concluding remarks
Conflicts of interest
References
CHAPTER 3: The Lysosomal System
Lysosomal storage diseases: pathology
Concluding remarks
References
CHAPTER 4: Clinical Aspects and Clinical Diagnosis
Introduction
Clinical presentation
Making a diagnosis
References
CHAPTER 5: Laboratory Diagnosis and Monitoring of Lysosomal Storage Diseases
Introduction
Preliminary screening tests on urine or blood
Genetic testing
Diagnosis of lysosomal enzyme defects by measurement of enzymic activity
Diagnosis of defects in lysosomal membrane proteins
Diagnosis of the neuronal ceroid lipofuscinoses (NCLs)
Prenatal diagnosis
Biomarkers in monitoring the progress and treatment of disease
Cross‐reactive immunological material (CRIM)
Prospects
Acknowledgments
References
CHAPTER 6: Newborn Screening for Lysosomal Storage Diseases
Introduction
Newborn screening in the United States
Pilot NBS programs for LSDs
Analytical methods
Current challenges in NBS for LSDs
References
CHAPTER 7: Genetics of Lysosomal Storage Diseases
Introduction
Allelic heterogeneity
Non‐allelic heterogeneity
Genetic modifiers
Pseudogenes
Pseudodeficiency
Uniparental disomy
Genetic epidemiology
Epigenetics
Genetic counseling
References
CHAPTER 8: Classification of Lysosomal Diseases
Lysosomal storage diseases due to a deficiency of a lysosomal enzyme activity
Multiple enzyme deficiencies resulting from lysosomal protein processing defects
The mucolipidoses
Lysosomal disorders due to defects in lysosomal membrane proteins
Neuronal ceroid lipofuscinoses
Cathepsin defects
Diseases in the lysosomal metabolism of nucleic acids
Biogenesis of lysosome‐related organelles (LROs)
Acknowledgments
References
PART 2: The Individual Diseases
CHAPTER 9: Gaucher Disease
Gaucher disease
Epidemiology
Etiology and pathogenesis: genetic basis
Clinical forms
Type 1
Type 2
Type 3
Diagnosis
Biomarkers
Routine follow‐up of patients
Comorbidities
Intravenous enzyme replacement therapy (ERT)
Oral substrate reduction therapy (SRT)
Other treatment options: pharmacological chaperones (PCs) and gene therapy
Health‐related quality of life (HRQoL)
Summary
References
CHAPTER 10: Fabry Disease
Epidemiology
Genetic basis
Pathophysiology
Clinical presentation
Natural history
Laboratory diagnosis
Treatment
Treatment guidelines
References
CHAPTER 11: The Gangliosidoses
GM1‐gangliosidosis (OMIM #230500)
GM2‐gangliosidosis (OMIM #272800, #272750, #268800)
Genetics
Topology of lysosomal ganglioside catabolism
Pathophysiology
Laboratory diagnosis
Treatment
References
CHAPTER 12: Metachromatic Leukodystrophy and Globoid Cell Leukodystrophy
Case histories
Epidemiology
Genetics
Pathophysiology
Clinical presentation
Diagnosis by MRI
Laboratory diagnosis
Treatment
References
CHAPTER 13: Types A and B Niemann‐Pick Disease
Representative case histories
Epidemiology
Genetics
Pathophysiology
Clinical presentation
Natural history
Laboratory diagnosis
Treatment
Enzyme replacement therapy
References
CHAPTER 14: Niemann‐Pick Disease Type C
Case histories
Epidemiology
Genetic basis
Pathophysiology
Clinical presentation
Natural history
Clinical severity scales
Laboratory diagnosis
Treatment
References
CHAPTER 15: Other Lipidoses
15.1 Acid Ceramidase Deficiency:
Epidemiology
Genetic basis
Pathophysiology
Animal models
Clinical presentation
Natural history
Laboratory diagnosis
Treatment
References
15.2 Lysosomal Acid Lipase Deficiency
Introduction
Epidemiology
Molecular basis
LAL properties
Visceral lipid derangements in LALD
Lack of CNS effects in LALD
Lipoprotein and lipid abnormalities
Tissue and cellular involvement
Clinical presentation and natural history
Diagnosis
Treatment
Management and monitoring
References
CHAPTER 16: The Mucopolysaccharidoses
16.1 An Introduction
Epidemiology
Genetic and biochemical bases
Pathophysiology
Clinical presentation
Natural history
Laboratory diagnosis
Treatment
Final remarks
Acknowledgments
Reference
16.2 Mucopolysaccharidosis Type I (MPS I)
Introduction
References
16.3 Mucopolysaccharidosis Type II (MPS II)
Epidemiology and genetics
16.4 Mucopolysaccharidosis Type III (MPS III)
References
16.5 Mucopolysaccharidosis Type IV (MPS IV)
Clinical presentation
Mucopolysaccharidosis IVB
16.6 Mucopolysaccharidosis Type VI (MPS VI)
Clinical presentation
References
16.7 Mucopolysaccharidosis Type VII (MPS VII)
Introduction
Treatment
References
16.8 Mucopolysaccharidosis Type IX (MPS IX)
Diagnosis
Genetics
Treatment
References
CHAPTER 17: Pompe Disease
Case histories
Terminology
Epidemiology
Genetic basis
Pathophysiology
Clinical presentation
Natural history
Enzymatic and molecular diagnosis
Treatment
Acknowledgments
Further reading
CHAPTER 18: Glycoproteinoses
Epidemiology
Pathophysiology
Genetic basis
Clinical presentation
Laboratory diagnosis
Treatment
An example of glycoproteinosis: α‐Mannosidosis
Genetic basis
Pathophysiology
Clinical presentation
Natural history
Laboratory diagnosis
Treatment
Unresolved questions
References
CHAPTER 19: Defect in Protective Protein/Cathepsin A: Galactosialidosis
Epidemiology and clinical presentation
Genetic basis
Mouse model
References
CHAPTER 20: Multiple Enzyme Deficiencies
20.1 Defects in Transport
Epidemiology
Genetic basis
Pathophysiology
Natural history and clinical presentation
MLII‐related disease
Laboratory diagnosis
Treatment and disease management
References
20.2 Multiple Sulfatase Deficiency
Clinical presentation
Genetic basis
Biochemistry
Pathophysiology
Diagnosis
Treatment
References
CHAPTER 21: Lysosomal Membrane Defects
Introduction
Conclusions
Acknowledgments
References
CHAPTER 22: Neuronal Ceroid Lipofuscinoses
Case histories
Epidemiology
Genetic basis
Pathophysiology
Natural history
Laboratory diagnosis
Treatment
Treatment guidelines
References
Further reading
CHAPTER 23: Miscellaneous Disorders of the Lysosome: New Pathological Frontiers
Introduction
Defects in the lysosomal proteases, cathepsins
Diseases caused by defective nucleic acid metabolism in the lysosome
Other lysosomal disorders with disordered innate immunity
Syndromes due to defective equilibrative nucleoside transporter type 3 (hENT3)
SLC293A
Disorders of biogenesis of lysosomes and lysosomal‐related organelles
Treatment of disorders of lysosomal biogenesis
Conclusion
References
PART 3: Therapy and Patient Issues
CHAPTER 24: Current Treatment
General considerations
Supportive care and palliative treatment
Specific strategies for treating LSDs
Cell complementation
References
CHAPTER 25: Central Nervous System Aspects, Neurodegeneration, and the Blood–Brain Barrier
Introduction
CNS storage and neuropathology
Normal function of the blood–brain barrier
Therapeutic delivery across the blood–brain barrier
Development of the blood–brain barrier
Damage to the blood–brain barrier in lysosomal storage diseases
Current strategies and therapies for the LSDs
New treatment approaches for the neurological manifestations of MPSs
Alternative treatment approaches for the neurological manifestations of sphingolipidoses and other LSDs
Conclusions
Acknowledgments
References
Further reading
CHAPTER 26: Emerging Therapies
Introduction
Approaches to CNS enzyme delivery
Alternative enzyme variants for CNS targeting
Gene and cell‐based interventions
Indirect therapies
Combination therapies
Conclusions
References
CHAPTER 27: Lysosomal Storage Diseases in the Developing World
Introduction
Prevalence
Similarities and differences
Access to treatment
Challenges
Solutions
Trials and research
Future
References
CHAPTER 28: The Patient Perspective on Rare Diseases
Introduction
Rare disease challenges
A partnership for developing therapeutic solutions
Access to diagnosis, disease management, and treatment
Role of the patient organization
Setting the global stage
A coherent global network
Emerging communities: low‐ and middle‐income countries
Conclusion
References
Index
End User License Agreement
List of Tables
Chapter 1
Table 1.1 Historic landmarks in the study of lysosomal storage diseases. On...
Chapter 5
Table 5.1 Lysosomal enzyme defects associated with clinical indications, fo...
Table 5.2 Panel of lysosomal genes analyzed.
Chapter 6
Table 6.1 A summary of newborn screen pilot data.
Table 6.2 The current state of newborn screening for LSDs in the United Sta...
Chapter 8
Table 8.1 Classification of lysosomal storage diseases.
Chapter 9
Table 9.1 Subtypes of Gaucher disease and their characteristics.
Chapter 11
Table 11.1 Genetics and biochemistry of gangliosides.
Chapter 12
Table 12.1 Most common mutations found in patients with metachromatic leuko...
Chapter 13
Table 13.1 Typical clinical and laboratory findings of ASM‐deficient NPD.
Chapter 16a
Table 16.1 The classification of the mucopolysaccharidoses.
Table 16.2 Status of the specific therapies of the mucopolysaccharidosis – ...
Chapter 16d
Table 16.3 Outline of the typical progression of somatic and neurologic fea...
Chapter 18
Table 18.1 Disorders of glycoprotein degradation.
Chapter 19
Table 19.1 Galactosialidosis patients reported in the literature [4–26].
Chapter 20a
Table 20.1 Clinical findings and symptoms of mucolipidosis types II and III...
Chapter 20b
Table 20.2 Known human sulfatases.
Chapter 21
Table 21.1 Defects in lysosomal membrane proteins, mucopolysaccharidosis II...
Chapter 24
Table 24.1 Approved drugs for LSDs.
Chapter 25
Table 25.1 The basic mechanisms by which solute molecules may cross the BBB...
Table 25.2 Strategic therapeutic approaches for bypassing the BBB.
List of Illustrations
Chapter 1
Figure 1.1 The lysosome: a recycling center.
Figure 1.2 Formation of the lysosomal recognition marker, mannose‐6‐phosphat...
Figure 1.3 Genetic and cellular basis of lysosomal storage diseases (in red)...
Chapter 2
Figure 2.1 Schematic representation of the major lysosomal degradative pathw...
Figure 2.2 Major players and mechanisms controlling lysosomal positioning an...
Figure 2.3 TFEB is a master transcriptional modulator of autophagy and lysos...
Figure 2.4 The lysosome is a major cellular signaling hub. Several signaling...
Chapter 3
Figure 3.1 Storage accumulation of SCMAS in a cortical pyramidal neuron of t...
Figure 3.2 p62 localization to lysosomal storage bodies in the
Cln3
Δex7/8
...
Figure 3.3 Axonal spheroid pathology in the cerebellum of the
Mcoln1
−/−
...
Figure 3.4 Camera lucida drawings of Golgi‐impregnated cortical pyramidal ne...
Chapter 4
Figure 4.1 Infant with Mucolipidosis II (I-cell disease) day 1. Facial featu...
Figure 4.2 (a) Patient aged 18 months with MPS I (Hurler syndrome) gibbus de...
Figure 4.3 Cherry-red spot in 2-year-old infant with Tay–Sachs disease.
Figure 4.4 LSD signs and symptoms in the perinatal period and infancy.
Figure 4.5 LSD signs and symptoms in children and young adults.
Figure 4.6 LSD signs and symptoms in adults.
Chapter 5
Figure 5.1 Algorithms for diagnosis of lysosomal storage diseases. (a) More ...
Chapter 6
Figure 6.1 Principles of digital mictrofluidics (DMF) – electrowetting. Elec...
Figure 6.2 Ion formation and mass analysis in tandem mass spectrometry (MS/M...
Figure 6.3 Typical workflow for newborn screening (NBS) using MS/MS. A dried...
Figure 6.4 Algorithm for follow‐up of suspected Pompe disease cases identifi...
Chapter 7
Figure 7.1 Traditional monogenic and contemporary polygenic representation o...
Figure 7.2 The biochemical result of pathogenic variants in lysosomal storag...
Figure 7.3 Uniparental disomy. The left diagram shows a typical autosomal re...
Chapter 8
Figure 8.1 Functional lysosomal proteins.
Figure 8.2 Lysosomal catabolism of some glycosphingolipids.
Chapter 9
Figure 9.1 Most common Gaucher disease mutations in the β‐glucocerebrosidase...
Figure 9.2 Massive splenomegaly reaching into the true pelvis in a 20‐year‐o...
Figure 9.3 Erlenmeyer flask deformity.
Figure 9.4 Osteopenia in the femur.
Figure 9.5 Pathological fractures.
Figure 9.6 Vertebral fractures.
Figure 9.7 Biopsy of the parotid gland of a splenectomized 45‐year‐old male ...
Figure 9.8 Avascular necrosis of the hip with total hip replacement in the c...
Chapter 10
Figure 10.1 Typical angiokeratomas.
Figure 10.2 Typical facial dysmorphism in a patient with Fabry disease. Male...
Figure 10.3 Diagnostic pathway in Fabry disease.
Figure 10.4 The Fabry (
GLA
) gene.
Figure 10.5 Kidney biopsy: accumulation of globotriaosylceramide within the ...
Chapter 11
Figure 11.1 Storage histiocytes in bone marrow. (a): Light microscopic appea...
Figure 11.2 Genetics of GM2‐gangliosidosis. GAG – glycosaminoglycans; GM2A –...
Figure 11.3 Macular cherry‐red spot. The accumulation of ganglioside in gang...
Figure 11.4 (a) Model for enzymatic digestion of membrane‐bound GM2 by Hex A...
Chapter 12
Figure 12.1 Enzymes and activator proteins involved in degradation of sulfat...
Figure 12.2 Natural course of MLD. Typical course of gross motor function in...
Figure 12.3 Genotype/Phenotype correlation in MLD. Genotypes of patients are...
Figure 12.4 Natural course of MLD. Types of first symptoms in different onse...
Figure 12.5 MRI in MLD (T2w images axial) shows characteristic abnormalities...
Figure 12.6 MRI of infantile‐ and late‐onset Krabbe patients. MRI in GLD sho...
Chapter 13
Figure 13.1 (a) Typical H & E staining of a liver section from an acid sphin...
Chapter 14
Figure 14.1 NPC1 orchestrates redistribution of lysosomal cholesterol. In ad...
Figure 14.2 Schematic representation of the clinical aspects of Niemann‐Pick...
Figure 14.3 Algorithm for the laboratory diagnosis of Niemann‐Pick C disease...
Figure 14.4 Filipin staining of cultured skin fibroblasts in normal and Niem...
Chapter 15b
Figure 15.1 Schematic of the lysosomal acid lipase (LAL) functions in the ly...
Figure 15.2 Schematic of the modulation of cholesterol metabolism via brain ...
Figure 15.3 Schematic of clinical finding and course of infantile‐LALD and c...
Chapter 16a
Figure 16.1 Dysostosis multiplex observed in X‐rays of (a) hands and (b) spi...
Figure 16.2 Patient with MPS I, presenting the
visceral phenotype
. Noteworth...
Figure 16.3 Patient with MPS III B presenting the
neurodegenerative phenotyp
...
Figure 16.4 Patient with MPS IV A presenting the
skeletal phenotype
. Coarse ...
Figure 16.5 Algorithm for the laboratory diagnosis of the mucopolysaccharido...
Chapter 16b
Figure 16.6 A distinct lumbar hump is visible: (a) at the age of six months;...
Figure 16.7 A four‐year‐old boy with Hurler's disease: characteristic silhou...
Figure 16.8 (a) Ultrasound of the hip joint in a 19‐year‐old patient with th...
Chapter 16c
Figure 16.9 Photograph of a patient with MPS II at three years of age. Publi...
Chapter 16d
Figure 16.10 Clinical photograph of 14‐year‐old female with MPS IIIB, with t...
Figure 16.11 Axial CT scan of the brain of a MPS IIIB patient at 12 years ag...
Chapter 16e
Figure 16.12 Image shows the subtle changes that were noticed in the thoraci...
Chapter 16f
Figure 16.13 (a) At 14 years old (Sibling 1) and 11 years old (Sibling 2), b...
Figure 16.14 Skeletal X‐rays showing dysostosis multiplex. (a) Spine X‐ray s...
Figure 16.15 MRI of the cervical spine showing narrowing and compression of ...
Chapter 16g
Figure 16.16 Original patient described in case 1. (a) Patient at three mont...
Figure 16.17 Patient described in case 2. (a) Patient during the first infus...
Chapter 16h
Figure 16.18 MRI of the knee of an MPS IX patient. (a) Axial fluid‐sensitive...
Chapter 17
Figure 17.1 Extreme scapular winging in a patient with adult‐onset Pompe dis...
Figure 17.2 Muscle biopsy of a patient with Pompe disease. Routine staining ...
Chapter 18
Figure 18.1 Schematic representation of the enzymatic steps involved in the ...
Figure 18.2 (a) A lymphocyte with vacuolated lysosomes from a patient with
α
...
Figure 18.3 (a) Patient one year of age: note large head, prominent forehead...
Figure 18.4 Patient 28 years of age. Whole body, front (a) and side (b): not...
Chapter 19
Figure 19.1 Genomic organization of the
CTSA
gene. Purple boxes represent ex...
Figure 19.2 H&E staining of tissue sections from galactosialidosis (
Ctsa
‐kno...
Figure 19.3 Immunohistochemistry with PPCA antibody of tissue sections from ...
Figure 19.4 Immunohistochemistry of PPCA in systemic (liver, spleen, and kid...
Chapter 20a
Figure 20.1 Patient with ML II. Coarse facial features, long philtrum, short...
Figure 20.2 Patient with ML III gamma. Mildly coarsened facial features, sho...
Figure 20.3 Organization of the
GNPTAB
and
GNPTG
genes and their encoded α/β...
Chapter 20b
Figure 20.4 SUMF1 is both an essential and a limiting factor for the activit...
Chapter 21
Figure 21.1 Multiple functions of lysosomal membrane proteins.
Figure 21.2 Brief overview of diseases caused by mutations in lysosomal memb...
Chapter 23
Figure 23.1 Arylsulphatase G (ARSG)‐associated disease, Usher syndrome type ...
Figure 23.2 RNAseT2 deficiency with cystic leukoencephalopathy. Magnetic res...
Figure 23.3 Spondyloenchondrodysplasia with spasticity, cerebral calcificati...
Figure 23.4 Photomicrograph of vacuolated lymphocytes from a patient with Ch...
Figure 23.5 Photomicrograph of macrophages laden with cellular debris from a...
Chapter 25
Figure 25.1 Routes of transport across the BBB. RMT – receptor‐mediated tran...
Figure 25.2 The Blood-Brain Barrier Adult wild-type mouse C5&B1/6/.Electro...
Figure 25.3 The blood brain-barrier in an 8-10 month old MPSIII A mouse. The...
Figure 25.4 Commercially available therapies for treating lysosomal storage ...
Chapter 26
Figure 26.1 Figure of a cell, demonstrating the complex pathophysiological m...
Chapter 27
Figure 27.1 An illustration of a charitable access program for LSDs.
Guide
Cover Page
Title Page
Copyright Page
Contributors
Foreword
Preface to the First Edition
Preface to the Second Edition
Table of Contents
Begin Reading
Index
Wiley End User License Agreement
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Lysosomal Storage Disorders
A Practical Guide
SECOND EDITION
EDITED BY
Atul B. Mehta
Emeritus Professor of Haematology, University College London
Royal Free Hospital
London, UK
Bryan Winchester
Emeritus Professor of Biochemistry
UCL Great Ormond Street Institute of Child Health
University College London
London, UK
This second edition first published 2022© 2022 by John Wiley & Sons Ltd
Edition HistoryJohn Wiley & Sons Ltd (1e, 2012)
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Library of Congress Cataloging‐in‐Publication Data
Names: Mehta, Atul B., editor. | Winchester, Bryan, editor.Title: Lysosomal storage disorders: a practical guide / edited by Atul B.Mehta, Bryan Winchester.Other titles: Lysosomal storage disorders (Mehta)Description: Second edition. | Hoboken, NJ: Wiley‐Blackwell, 2022. | Includes bibliographical references and index.Identifiers: LCCN 2022000580 (print) | LCCN 2022000581 (ebook) | ISBN 9781119697282 (cloth) | ISBN 9781119697305 (Adobe PDF) | ISBN 9781119697251 (epub)Subjects: MESH: Lysosomal Storage Diseases | Lysosomes–pathologyClassification: LCC QH603.L9 (print) | LCC QH603.L9 (ebook) | NLM QU 265.5.L9 | DDC 571.6/55–dc23/eng/20220528LC record available at https://lccn.loc.gov/2022000580LC ebook record available at https://lccn.loc.gov/2022000581
Cover Design: WileyCover Image: © Kateryna Kon/Shutterstock
Contributors
Ida AnnunziataDepartment of GeneticsSt. Jude Children's Research HospitalMemphis, TN, USA
Andrea BallabioTelethon Institute of Genetics and Medicine (TIGEM), Naples, Italy;Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Naples, Italy;Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA
Manisha BalwaniDivision of Medical Genetics and GenomicsDepartment of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew York, NY, USA
Michael BeckClinical Science for LSDSphinCS GmbHHochheim, Germany
Clare BeesleyRare & Inherited Disease LaboratoryNHS North Thames Genomic Laboratory HubGreat Ormond Street Hospital for ChildrenLondon, UK
David J. BegleyInstitute of Pharmaceutical ScienceKings College LondonLondon, UK
Cinzia M. BellettatoMetabERNRegional Coordinating Center for Rare DiseasesUdine University HospitalUdine, Italy
Donna L. BernsteinLicensed Genetic CounselorSan Diego, CA, USA
Thomas BraulkeInstitute of Osteology & BiomechanicsUniversity Medical Center Hamburg‐EppendorfHamburg, Germany
Nicola Brunetti‐PierriTelethon Institute of Genetics and MedicinePozzuoli, Italy;Department of Translational Medicine;SSM School for Advanced StudiesFederico II UniversityNaples, Italy
Derek BurkeEnzyme UnitGreat Ormond Street Hospital for ChildrenLondon, UK
Barbara K. BurtonAnn & Robert H. Lurie Children's Hospital of ChicagoChicago, IL, USA
Joe T.R. ClarkeCentre Hospitalier Universitaire, Sherbrooke, QCUniversity of TorontoToronto, ON, Canada
Tanya Collin‐HistedInternational Gaucher AllianceDursley, UK
Jonathan D. CooperPediatric Storage Disorders LaboratoryDepartments of Pediatrics, Genetics & NeurologySchool of MedicineWashington University in St LouisSt. Louis, MO, USA
Timothy M. CoxDepartment of MedicineUniversity of Cambridge;Addenbrooke's HospitalCambridge, UK
James DavisonGreat Ormond Street Hospital NHS Foundation Trust;Great Ormond Street Hospital Biomedical Research CentreLondon, UK
Alessandra d'AzzoDepartment of GeneticsSt. Jude Children's Research HospitalMemphis, TN, USA
Robert J. DesnickDepartment of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew York, NY, USA
Graciana Diez‐RouxTelethon Institute of Genetics and MedicinePozzuoli, Italy;SSM School for Advanced StudiesFederico II UniversityNaples, Italy
Emily R. EdenInstitute of OphthalmologyUniversity College LondonLondon, UK
Deborah ElsteinGaucher UnitShaare Zedek Medical CenterJerusalem, Israel
Maria FullerGenetics and Molecular PathologySA Pathology at Women's and Children's Hospital;Adelaide Medical SchoolUniversity of AdelaideAdelaide, Australia
Jayne GershkowitzProfessional Patient Advocates in Life SciencesDanbury, CT, USA
Promita GhoshDepartment of Biochemistry & Medical GeneticsUniversity of ManitobaWinnipeg, MB, Canada
Volkmar GieselmannInstitut fur Biochemie und MolekularbiologieRheinische‐Friedrich‐Wilhelms UniversitatBonn, Germany
Roberto GiuglianiDepartment of GeneticsFederal University of Rio Grande do Sul (UFRGS),Medical Genetics ServiceHospital de ClinicasPorto Alegre, Brazil
Jack GoldblattGenetic Services of Western AustraliaSubiaco, Australia
Gregory A. GrabowskiDepartment of PediatricsUniversity of Cincinnati College of Medicine;Molecular Genetics, Biochemistry, and MicrobiologyDivision of Human GeneticsCincinnati Children's Hospital Medical CenterCincinnati, OH, USA
Paul HarmatzUCSF Benioff Children's Hospital OaklandOakland, CA, USA
Katie HarveyEnzyme UnitGreat Ormond Street Hospital for ChildrenLondon, UK
Simon HealesUCL Great Ormond Street Institute of Child Health, University College London, London, UKEnzyme Unit, Great Ormond Street Hospital for Children, London, UK
Chris HendrikszDepartment of PediatricsSteve Biko Academic UnitUniversity of PretoriaPretoria, South Africa
Derralynn HughesExperimental HaematologyUniversity College London;Lysosomal Storage DisordersRoyal Free London NHS Foundation TrustLondon, UK
Erin JozwiakUCSF Benioff Children's Hospital OaklandOakland, CA, USA
Priya S. KishnaniDivision of Medical GeneticsDepartment of PediatricsDuke University Medical CenterDurham, NC, USA
Ingeborg Krägeloh‐MannPediatric Neurology and Developmental MedicineUniversity Children's HospitalTübingen, Germany
Thierry LevadeLaboratoire de Biochimie MétaboliqueCentre de Référence en Maladies Héréditaires du MétabolismeInstitut Fédératif de BiologieCHU de Toulouse;INSERM UMR1037Cancer Research Center of Toulouse (CRCT)Université Paul SabatierToulouse, France
Dag MalmTromsø Centre of Internal Medicine (TIS)Tromsø, Norway
Jeffrey A. MedinDepartments of Pediatrics and BiochemistryMedical College of WisconsinMilwaukee, WI, USA
Atul MehtaEmeritus Professor of Haematology, University College LondonRoyal Free Hospital, London, UK
Matthew C. MicsenyiBiogenNeurodegenerative Disease ResearchCambridge, MA, USA
Kevin MillsTranslational OmicsGenetics & Genomic Medicine DepartmentUCL Great Ormond Street Institute of Child HealthLondon, UK
Sara E. MoleMRC Laboratory for Molecular Cell Biology;Great Ormond Street Institute of Child HealthUniversity College LondonLondon, UK
Adriana M. MontañoDepartment of Pediatrics;Department of Biochemistry and Molecular BiologySchool of MedicineSaint Louis UniversitySt. Louis, MO, USA
Nicole M. MuscholInternational Center for Lysosomal DisordersDepartment of PediatricsUniversity Medical Center Hamburg‐EppendorfHamburg, Germany
Gennaro NapolitanoTelethon Institute of Genetics and Medicine (TIGEM);Medical Genetics UnitDepartment of Medical and Translational ScienceFederico II UniversityNaples, Italy
Marvin NatowiczPathology and Laboratory MedicineGenomic MedicineNeurological and Pediatrics InstitutesCleveland ClinicCleveland, OH, USA
Øivind NilssenDepartment of Medical GeneticsDivision of Child and Adolescent HealthUniversity Hospital of North‐Norway;Department of Clinical Medicine‐Medical GeneticsUniversity of TromsøTromsø, Norway
Torayuki OkuyamaCenter for Lysosomal Storage DiseasesNational Center for Child Health and DevelopmentTokyo, Japan
Gregory M. PastoresDepartment of GeneticsUniversity College DublinDublin, Ireland
Marc C. PattersonDepartments of Neurology, Pediatrics, and Medical GeneticsMayo ClinicRochester, MN, USA
Roy W.A. PeakeBoston Children's HospitalHarvard Medical SchoolBoston, MA, USA
W.W.M. Pim PijnappelCenter for Lysosomal and Metabolic Diseases;Department of Pediatrics;Department of Clinical GeneticsErasmus MC, University Medical CenterRotterdam, The Netherlands
Frances M. PlattDepartment of PharmacologyUniversity of OxfordOxford, UK
Uma RamaswamiLysosomal Disorders UnitRoyal Free London NHS Foundation Trust;Department of Genetics and Genomics MedicineUniversity College LondonLondon, UK
Arnold J.J. ReuserCenter for Lysosomal and Metabolic DiseasesErasmus MC, University Medical CenterRotterdam, The Netherlands
Cornelia RudolphInternational Center for Lysosomal DisordersDepartment of PediatricsUniversity Medical Center Hamburg‐EppendorfHamburg, Germany
Paul SaftigBiochemical InstituteChristian‐Albrechts‐University KielKiel, Germany
Konrad SandhoffLIMES InstituteUniversity of BonnBonn, Germany
Maurizio ScarpaMetabERNRegional Coordinating Center for Rare DiseasesUdine University HospitalUdine, Italy
Edward H. SchuchmanDepartment of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew York, NY, USA
Angela SchulzDepartment of PediatricsUniversity Medical Center Hamburg‐EppendorfHamburg, Germany
Michael SchwakeBiochemistry III, Faculty of Chemistry, University of Bielefeld, Bielefeld, Germany
William S. SlyDepartment of Biochemistry and Molecular BiologySchool of MedicineSaint Louis UniversitySt. Louis, MO, USA
Young Bae SohnDepartment of Medical GeneticsAjou University HospitalAjou University School of MedicineSuwon, Republic of Korea
Hilde Monica Frostad Riise StenslandDepartment of Medical GeneticsDivision of Child and Adolescent HealthUniversity Hospital of North‐NorwayTromsø, Norway
Bob StevensMucopolysaccharidosis (MPS) SocietyAmersham, UK
George TimminsPardee RAND Graduate SchoolSanta Monica, CA, USA
Barbara Triggs‐RaineDepartment of Biochemistry & Medical GeneticsUniversity of Manitoba;Childrens Hospital Research Institute of ManitobaWinnipeg, MB, Canada
Anna Tylki‐SzymańskaDepartment of Paediatrics, Nutrition and Metabolic DiseasesChildren's Memorial Health InstituteWarsaw, Poland
Diantha van de VlekkertDepartment of GeneticsSt. Jude Children's Research HospitalMemphis, TN, USA
Ans T. van der PloegCenter for Lysosomal and Metabolic Diseases;Department of PediatricsErasmus MC, University Medical CenterRotterdam, The Netherlands
Marie T. VanierInstitut National de la Santé et de la Recherche Médicale;Hospices Civils de LyonLyon, France
Steven U. WalkleyThe Dominick P. Purpura Department of NeuroscienceRose F. Kennedy Intellectual and Developmental Disabilities Research CenterAlbert Einstein College of MedicineBronx, NY, USA
Melissa P. WassersteinMontefiore Medical CenterAlbert Einstein College of MedicineNew York, NY, USA
David A. WengerDepartment of NeurologyJefferson Medical CollegeThomas Jefferson UniversityPhiladelphia, PA, USA
Ruth E. WilliamsChildren's NeurosciencesEvelina London Children's HospitalGuy's and St Thomas' NHS Foundation TrustLondon, UK
Bryan WinchesterUCL Great Ormond Street Institute of Child HealthUniversity College LondonLondon, UK
Ari ZimranGaucher UnitShaare Zedek Medical CenterJerusalem, Israel
Foreword
Close to 75 years ago, lysosomes were first identified in Louvain, Belgium. It was soon appreciated by the discoverers that the membrane‐enclosed acid compartments contain various hydrolases that fragment macromolecules. Reflecting this notion, de Duve coined the name lysosomes for the organelles: literally, bodies (somos) of cleavage (lysein).
Thanks to the evolution of various technologies and the creative research of many, our insight into the composition of lysosomes, their cell biology, and their physiological relevance has increased tremendously. For example, the digestive nature of lysosomes is well known to be essential to cope with cellular pathogens. It has also become apparent recently that kinases at the surface of the organelles sense the cellular nutrient status and mediate regulatory responses in cellular metabolism and pathways such as phagocytosis, autophagy, and lysosome biogenesis. The crucial interplay between lysosomes and other cellular compartments is increasingly recognized.
Today there is ample appreciation for the importance of appropriate recycling to allow the sustainability of complex systems. This holds for our planet, the human body, and its constituent cells. Lysosomes fulfill a vital role in this recycling. This is best illustrated by the dramatic outcome of inherited deficiencies in lysosomal recycling in humans, collectively referred to as lysosomal storage diseases (LSDs).
In recent decades, we have witnessed a “golden age” of LSD clinical care, diagnosis, and research. The identification of disease‐causing mutations, even at the level of single cells, supports the diagnosis of many LSDs, assisted by the advanced detection of storage material as well as circulating biomarkers of storage cells. Increased insight into the composition of lysosomal enzymes and their catalytic mechanism as well as their delivery to lysosomes has formed a solid basis for the development of therapeutic interventions for LSDs caused by specific enzyme deficiencies. A breakthrough in this respect has been the design and application of enzyme replacement therapy (ERT) for Gaucher disease based on the seminal studies by Brady and colleagues. In combination with orphan drug legislation, the first successful ERT prompted a genuine interest from academic researchers and the pharmaceutical industry in designing therapies for LSDs. In addition to ERT, such approaches include substrate reduction therapies, enzyme enhancement therapies, and gene therapies. These developments, and the increased interest in LSDs in the clinic and society, have boosted the clinical care of LSD patients in expert centers worldwide.
This book is a well‐timed review of the rapidly developing LSD field. The editors have secured contributions from many expert scientists and clinicians. In Part 1, the general aspects of LSDs are addressed, with attention to physiology and pathology. The screening and diagnosis of LSDs are covered as well as clinical research and regulatory aspects. Part 2 focuses on individual LSDs such as the various sphingolipidoses, mucopolysaccharidoses, glycogen storage disease, glycoproteinoses, galactosidosis, neuronal ceroid lipofuscinoses, multiple enzyme deficiencies resulting from lysosomal protein processing defects, and miscellaneous disorders of the lysosome, including those involving defects in the lysosomal membrane. Central to Part 3 of this book are the existing and emerging treatments for LSDs, including related key patient issues such as availability and disease awareness.
To conclude, the golden age of LSD research has not ended but rather has only just started. Further generations of LSD researchers in the clinic, laboratory, and industry are needed to reach the goals relevant to patients and their families. The present book provides a solid knowledge base and practical guide for students of the LSDs.
Hans Aerts, Ph.D.
Preface to the First Edition
The concept of a lysosomal storage disorder is now almost 50 years old – an appropriate time, we feel, for a new review of the subject.
The term lysosome was coined by Christian de Duve [1], the discoverer of this organelle, to reflect its role as the major intracellular site for the enzymatic “lysis” of macromolecules so that they may be recycled. The concept of a lysosomal storage disorder was first proposed by H G Hers [2], following the discovery that one of the glycogen storage diseases (Pompe disease, acid maltase deficiency) was due to deficiency of a lysosomal enzyme. The concept of “cross‐correction,” formulated by Elizabeth Neufeld [3] and her group after the discovery that co‐cultured fibroblasts derived from two patients with different lysosomal storage disorders mutually corrected each other, led to the notion of “enzyme replacement therapy” (ERT). Roscoe Brady not only discovered the enzymatic basis for Gaucher disease and Fabry disease but also pioneered ERT for humans [4, 5].
The last two decades, however, have seen a huge expansion in research in this area which has substantially extended our understanding of both the scientific and the clinical basis of lysosomal storage disorders [6]. Thus, at a scientific level it is now very well recognized that lysosomes are part of an endosomal/lysosomal network which plays a critical role in a whole range of cellular processes including the recycling of membrane and other organelles, the turnover of molecules and ingested matter through endocytosis and phagocytosis, and an emerging role in apoptosis and autophagy. At a clinical level successful treatments have been employed which reduce substrate accumulation or promote substrate degradation but it is increasingly recognized that the protean multi‐system manifestations of these conditions result from pathologic processes over and above simple lysosomal storage and damage.
This book is the fruit of an ambitious project which aims to review both the scientific and the clinical aspects of lysosomal storage disorders. We perceive a need for an accessible volume giving an up to date overview of the subject. Even when effective treatments are available, there remains an urgent need to highlight awareness of the diseases so that early and appropriate treatment may be sought [7]. Furthermore, in a rapidly changing world, there is a real need to improve access to expensive treatments. The first section of the book reviews current understanding of the physiology and pathophysiology of lysosomal storage disorders and we again to attempt to classify the conditions. The second part of the book reviews individual diseases, and gives perspectives from patients and experts looking towards future therapeutic directions. The book is aimed at a wide audience including scientists, clinicians, health care workers and administrators, those working in the pharmaceutical industry, patients and their organizations.
We are highly indebted to Christine Lavery, the Founder and Chief Executive of the Society for Mucopolysaccharidosis Diseases (MPS Society, UK). Christine has been an integral part of the project from the very beginning, a partner during its production and a driver towards its completion. The extremely high regard in which she is held internationally has allowed us to assemble a glittering array of distinguished contemporary scientists and clinicians working in this area. Furthermore, all contributors and the editors have donated their royalties to the MPS society, which is dedicated to promote research into these diseases and to the support of patients and families who suffer from them. We are also grateful to Shire HGT which has made the project possible through an unrestricted educational grant given to the MPS Society. The Editors and contributors take full responsibility for the contents of the book and confirm that Shire HGT, the MPS Society and Wiley‐Blackwell have not had any role in influencing the content of the work.
We would also like to thank Elisabeth Dodds, Production Manager, Nick Godwin and Rob Blundell at Wiley‐Blackwell who have helped us at every stage of the project. Our distinguished contributors have made time in their busy schedules to prepare and revise their contributions and we thank them for their patience, timeliness, clarity and charity in delivering their chapters to us.
We would each like to acknowledge some, of our many, academic mentors. For Atul this has to be Lucio Luzzatto, a clinician and scientist who guided his early academic career, emphasizing the need for meticulous and reflective observation and record. Atul would also like to thank Victor Hoffbrand, who has provided invaluable encouragement during his career as a clinician, academic – and as a writer. Bryan would like to thank Don Robinson for introducing him to lysosomal storage diseases and giving him his first job, and Bob Jolly, who taught him the importance of linking pathology and biochemistry through the study of animal models. Finally, we would both like to thank our respective wives and families for their continuing forbearance and support.
Atul B. Mehta
Bryan Winchester
References
1 de Duve, C., Pressman, B., Gianetto, R. et al. (1955). Tissue fractionation studies: intracellular distribution patterns of enzymes in rat‐liver tissue.
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: 604–617.
2 Hers, H.G. (1963). Alpha glucosidase deficiency in generalised glycogen storage disease (Pompe disease).
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: 11–16.
3 Fratantoni, J.C., Hall, C.W., and Neufeld, E.F. (1969). The defect in Hurler and Hunter Syndromes II deficiency of specific factor involved in mucopolysaccharide degradation.
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4 Barton, N.W., Furbish, F.S., Murray, G.J. et al. (1990). Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease.
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5 Brady, R.O. (2006). Enzyme replacement therapy for lysosomal diseases.
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6 Cox, T.M. and Cachon‐Gonzales, M.B. (2012). The cellular pathology of lysosomal diseases.
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7 D'Aco, K., Underhill, L., Rangachani, L. et al. (2012). Diagnosis and treatment trends in mucopolysaccharidosis I; findings from the MPS I registry.
Eur. J. Pediatr.
Advance online publication.
Preface to the Second Edition
The past decade has seen major advances in the field of lysosomal storage diseases (LSDs) and their diagnosis and treatment. Particularly noteworthy has been a growing appreciation of the central role of the lysosome in cellular physiology, and this has led to the suggestion that the abbreviation LSD should perhaps refer to lysosomal system diseases. Increased substrate storage within lysosomes disturbs cellular homeostasis via diverse mechanisms and with often dramatic consequences.
The concept of a lysosomal storage disease is now almost 60 years old – an appropriate time, we feel, for a new review of the subject. We are delighted that so many of the authors from the first edition have contributed an update and that so many distinguished new contributors are included. We are particularly grateful that they have found time in their ever‐busy schedules, which have been almost overwhelmed by the demands of the Covid pandemic.
The editors and contributors have again agreed that all royalties will be donated to charities devoted to furthering knowledge of these conditions and patient advocacy. Royalties from this edition will be donated to the UK MPS Society.
We are very sad to note the passing of several key figures in the field who contributed to the first edition. We dedicate this second edition to the memory of Christine Lavery, who did a great deal to establish patient advocacy for families and sufferers of LSDs not only in the UK but worldwide. Professors Roscoe Brady and Ed Wraith, to whom many owe their lives, continue to be remembered by their friends and colleagues, respected by their peers, and revered by their patients.
We extend thanks to the many people who have made this edition possible. Terence Eagleton's enthusiasm and energy were driving forces in establishing the need for a new edition with a modified design that devotes chapters to each of the mucopolysaccharidosis (MPS) disorders and includes new chapters on LSDs in the developing world. Wiley has published this second edition without commercial sponsorship. Mandy Collison has patiently guided us over the past two years, despite many disruptions. We thank our wives, Kokila and Diana, who have allowed us to spend many hours in our studies indulging in the luxury of commissioning, reading, and editing much‐enhanced contributions from our distinguished panel of authors.
Atul B. Mehta
Bryan Winchester
PART 1General Aspects of Lysosomal Storage Diseases
CHAPTER 1Lysosomal Storage Diseases: Historic Landmarks and Scientific Principles
Atul Mehta1 and Bryan Winchester2
1 Emeritus Professor of Haematology, University College London, Royal Free Hospital, London, UK
2 UCL Great Ormond Street Institute of Child Health, University College London, London, UK
If I have seen further it is by standing on the shoulders of giants.
Isaac Newton (1642–1727)
Introduction
The study of the lysosome and its diseases has assumed profound scientific and clinical interest over the last 60 years and has accelerated since the publication of the first edition of this book. This chapter outlines historic landmarks in a story that begins with clinical descriptions of diseases of unknown pathogenesis. As we acquired basic knowledge of the pathology, the underlying biochemical disorders became apparent. The revolutionary impact of the recombinant DNA era quickly led to an understanding of the underlying genetics, and this has led to dramatic therapeutic developments. At several stages, however, individuals have had “eureka moments” that have shifted the paradigm. Ultimately, insights from observations of pathologically disordered lysosomes have shed light on basic cellular physiology and biochemistry, such that a more appropriate title for this book would be The Lysosome: Its Physiology and Associated Diseases. We may genuinely be at the dawn of a new age for the study of lysosomal biology.
Historic clinical and scientific landmarks
Ever since the first description, in 1881, of what we now know to be a lysosomal storage disease, clinical observation and description has been a key driver of scientific knowledge (Table 1.1). In addition to describing individuals, clinicians recognized not only that some (most) of these diseases affected more than one organ but also that central nervous system involvement was a key prognostic feature. They also recognized the familial (and therefore genetic) basis of these conditions, that genotype‐phenotype relationships were variable, and that certain ethnicities were more likely to be affected. Furthermore, in some cases the inheritance was likely to be sex‐linked and not autosomal.
Although only one Nobel Prize has been awarded within the lysosomal storage disease (LSD) field (Christian de Duve, 1974), several other scientists and clinician‐scientists working in the field have made equally distinguished contributions. As new methodologies and techniques (light and electron microscopy, ultracentrifugation, cell culture, organic chemistry, molecular biology and recombinant DNA) have become available, their application in this field of inquiry has been productive. Several animal models of these conditions occur naturally, and the creation of new animal models has further augmented the contributions made to human knowledge by the organisms that share our planet with us and that also depend on healthy lysosomes for cellular homeostasis.
Table 1.1 Historic landmarks in the study of lysosomal storage diseases. Only the first author is named, and many of these individuals worked as part of a team. It will not have escaped the reader's attention that many of the contributors to this book have themselves made contributions worthy of acknowledgement as “landmarks.” We apologize to those (contributors and others) whose names are omitted. Many of those named have been mentors whose mentees have gone on to make valuable contributions. For references, the reader is referred to several excellent reviews that focus on historic aspects of the LSDs and the MPS diseases.
Source: [1–9].
Year
Author
Description
1881
Warren Tay
Cherry‐red macular spot; developmental delay
1882
Phillipe Gaucher
Engorged macrophages; hepatosplenomegaly
1887
Bernard Sachs
Generalized neurodegeneration with cherry‐red macular spot
1898
William Anderson; Johannes Fabry
Angiokeratoma; renal failure; systemic disease
1897, 1903
R.D. Batten; Frederick Batten
Macular changes associated with cognitive deficiency in two brothers
1914 1927 1958 – further subclassification
Albert Niemann Ludwig Pick Alan Crocker
Hepatosplenomegaly Systemic disease Types A, B, and C
1917; 1919
Charles Hunter (Hunter syndrome); Gertrud Hurler (Hurler syndrome)
1932
Johannes Pompe
Cardiac hypertrophy; generalized muscle weakness; glycogen storage
1955
Christian de Duve
Discovery of the lysosome
1961 1962 1963 1968 1972
Sylvester Sanfilippo (Sanfilippo syndrome) Harold Scheie (Scheie syndrome); Luis Morquio; James Brailford (Morquio syndrome) Pierre Maroteaux; Emile Lamy (Maroteaux‐Lamy Syndrome) Konrad Sandhoff William Sly
Descriptions of MPS diseases
1963
Henri Hers
Pompe disease associated with lysosomal alpha glucosidase deficiency
1965
Ken Hashimoto
Abnormal lysosomal ultrastructure by EM in Fabry disease cells
1965
Roscoe Brady
Gaucher disease due to lysosomal beta‐gluco‐cerebrosidase deficiency
1967
Roscoe Brady
Fabry disease due to alpha galactosidase deficiency
1968
Elizabeth Neufeld
Cross‐correction of biochemical defects by co‐culture of cells in MPS I and MPS II
1972–1990
Stuart Kornfeld; Kurt von Figura; William Sly
Mannose‐6‐phosphate pathway
1990
Norman Barton; Roscoe Brady
Clinical effects of ERT for Gaucher disease
2000–2022
ERT for a range of LSDs; SRT for Gaucher disease; chaperone therapy; gene therapy for LSDs
EM – electron microscopy; ERT – enzyme replacement therapy; MPS – mucopolysaccharide diseases; SRT – substrate reduction therapy.
Central to this endeavor has been the development of effective treatments for these devastating diseases – and with treatment, the need for accurate molecular and biochemical diagnosis, clinical measurements with imaging and biomarkers, and pedigree analysis. Most of these diseases are enzyme deficiencies; and, appropriately, it is the success of enzyme replacement therapy for Gaucher disease that has been a major impetus behind new developments in this field. Paradoxically, however, it is the very limitations of the treatment (e.g. the need for regular intravenous injections; its short half‐life; the development of antibodies) that have meant these conditions have been fertile territory for some of the earliest applications of pioneering therapeutic approaches such as substrate reduction therapy for Gaucher disease (Chapter 9) and the use of pharmacologic chaperones and gene therapy for Fabry disease (Chapter 10).
Structure and function of lysosomes
The lysosomal system, which de Duve and his colleagues first described in the 1950s, is the main mechanism in eukaryotic cells for the catabolism of endogenous and exogenous macromolecules and the recycling of their constituents. It is also important for the processing of several essential metabolites and in cellular homeostasis through its interactions with other cellular compartments (Chapters 2, 3, and 23). The lysosome is a membrane‐bound cytoplasmic organelle containing a collection of catabolic enzymes, which collectively have the capacity to degrade all naturally occurring macromolecules to their constituent components. The lysosomal membrane, which plays a key role in the transport of material into and out of the lysosome and in interactions with other organelles, is protected from these degradative enzymes by a glycocalyx lining the inner membrane. Material to be broken down arising from outside the cell is delivered to the lysosome by the processes of phagocytosis and endocytosis, and material originating within the cell by autophagy together with some engulfment of the cytoplasm. Catabolism takes place in the lumen of the lysosome, which is maintained at an acidic pH by a specific proton pump in the lysosomal membrane. The low‐molecular‐weight digestion products pass through the lysosomal membrane, for reutilization by the cell, by a combination of passive diffusion and specific transporters. Partially digested material is not transported out of the lysosome, and any indigestible material is retained in the form of residual bodies (Figure 1.1).
Figure 1.1 The lysosome: a recycling center.
Figure 1.2 Formation of the lysosomal recognition marker, mannose‐6‐phosphate. For detailed reviews of the mannose‐6‐phosphate‐dependent and ‐independent pathways, see [10, 11].
There are over 50 lysosomal catabolic enzymes, the majority of which are soluble glycoproteins with hydrolase activity optimal at an acidic pH. Their inactive precursors are synthesized on ribosomes associated with the rough endoplasmic reticulum (ER) and transported to the lysosomes via the ER and Golgi compartment. During this process, they undergo partial proteolysis and glycosylation and acquire a specific lysosomal recognition marker, mannose‐6‐phosphate (M6P). The M6P marker is formed by a two‐step enzyme reaction in the Golgi (Figure 1.2). The M6P tagged proteins bind to two specific receptors (MPRs) in the Golgi, thereby separating the lysosomal proteins from other glycoproteins and delivering them to a pre‐lysosomal compartment. Here, dissociation of receptor and protein occurs, and the lysosomal enzymes are packaged for delivery to the lumen of the lysosome, where final maturation (particularly formation of the active conformation) occurs in the acidic environment. Both receptors recycle to the Golgi; but, crucially, one also goes to the plasma membrane. This enables extracellular M6P tagged lysosomal enzymes to be delivered to the lysosome by receptor‐mediated endocytosis. This is the basis of most forms of enzyme replacement therapy. Interestingly, a small proportion of the tagged lysosomal proteins is secreted by cells and can be taken up into cells and delivered to the lysosome by the MPR on the plasma membrane. This secretion‐recapture mechanism is the basis of enzyme replacement therapy by hematopoietic stem cell transplantation. The importance of the M6P marker is also illustrated by the diseases mucolipidosis II and III (MLII and MLIII), in which there is a failure to deliver lysosomal enzyme to the lysosome in some cell types. MLII and MLIII are caused by defects in the enzyme that catalyzes the first step in the formation of M6P, N‐acetylglucosamine‐1‐phosphotransferase (Figure 1.2). The elucidation of the M6P pathway, particularly by Elisabeth Neufeld, Stuart Kornfeld, Kurt von Figura, and collaborators, was a milestone in the understanding of lysosome function.
However, the presence of normal levels of lysosomal enzymes in some cells in patients with MLII and MLIII suggests that alternative routes for the transport of lysosomal enzymes exist. The integral lysosomal membrane protein, LIMP‐2, has been shown to be involved in the transport of β‐glucocerebrosidase, and sortilin can transport the saposins, prosaposin and GM2 activator protein, sphingomyelinase, and cathepsins D and H to the lysosome [10]. Lysosomal membrane proteins are delivered to the lysosome by different mechanisms, which depend upon their function not only in the lysosome but also in other cellular processes (Chapters 2, 3, and 21). Some cells express other plasma membrane receptors that transport appropriately labeled extracellular enzymes to the lysosome by receptor‐mediated endocytosis: e.g. the mannose receptor on macrophages has been exploited for the treatment of Gaucher disease.
Molecular, genetic, and cellular basis of LSDs
The metabolic pathways within the lysosome for the breakdown of the different classes of macromolecules have been established (see Part 2 of this book for details of the pathways for different macromolecules). The macromolecular substrates are broken down in a compulsory order of enzymic steps. Therefore, the absence of one enzyme's activity, due to a deleterious mutation in its gene, will result in blockage of the pathway and the resulting progressive accumulation or storage of partially digested material within the lysosomes. This is the basis of a lysosomal storage disease. The structure of the stored material will depend on which enzyme is blocked in which pathway, e.g. neutral sphingolipids with a terminal α‐galactosyl residue due to a deficiency of α‐galactosidase in the glycosphingolipid catabolic pathway in Fabry disease (see Figure 8.2). Some enzymes act in more than one metabolic pathway, leading to the heterogeneity of storage products. The absence of a non‐lysosomal cofactor for an enzymic step, e.g. a saposin in the catabolism of glycosphingolipids, can also lead to a block in the pathway (Chapters 9 and 11). Multiple deficiencies of enzymic activity in the lysosome can arise from defects in the proteins responsible for the post‐translational modification and transport of the lysosomal enzyme precursors, e.g. MLII/III (Chapter 20). A deficiency of the protective protein (cathepsin A) results in the secondary deficiency of both β‐galactosidase and α‐neuraminidase (Chapter 19). A defect in a specific lysosomal membrane transporter can lead to the paradoxical situation where an essential metabolite, the final digestion product, is sequestered within the lysosome and not available for use by the cell, e.g. cystine in cystinosis (Chapter 21). Defects in other lysosomal membrane proteins can also disrupt the catabolic process in different ways (Chapter 21). The clinical symptoms of a LSD are determined by which tissues and organs are affected by disruption of a particular lysosomal pathway and by the secondary cellular pathology resulting from the accumulation of storage material. As this accumulation is progressive, the severity and age of onset of a lysosomal storage disease will depend predominantly upon the nature of the mutation in the gene encoding the defective protein (Figure 1.3). LSDs are classified according to the function of the defective protein (Chapter 8).
Figure 1.3 Genetic and cellular basis of lysosomal storage diseases (in red) and potential therapies (in green). A mutation in the gene encoding a protein involved directly or indirectly in lysosomal catabolism will lead to the absence, a decreased amount, or a mutated form of that protein. Understanding the cellular consequences of these events has led to the development of therapeutic approaches.
The identification, cloning, and analysis of the genes encoding these defective lysosomal proteins have revolutionized the diagnosis of LSDs, the reliability of carrier detection, and genetic counseling (Chapters 5 and 6) and laid the foundation for novel therapies, including those for different types of mutations or even specific disease genotypes – individualized medicine (Figure 1.3).
Conclusion and aims of this book
The book begins with accounts of the structure and function of the lysosomal system. Its central role in diverse cellular processes is increasingly recognized. Mechanisms whereby defects in the system can lead to a lysosomal storage disease are described. This is followed by a general description of the clinical aspects of LSDs and their clinical and laboratory diagnosis. Part 1 concludes with a classification of LSDs based on the function of the defective protein. In Part 2, acknowledged experts discuss individual diseases or groups of diseases in great detail. The involvement of the lysosomal system in diseases that are not primarily storage diseases is also presented (Chapter 23). Part 3 presents accounts of current and future approaches to therapy, especially attempts to treat neuropathological aspects. To conclude, the impact of LSDs on patients and their families, including those in the developing world, is considered.
The editors would like to thank the authors profusely for freely sharing their experience and knowledge. None of the contributors or editors has received any form of sponsorship, commercial or otherwise, and any royalties will be donated to patient organizations through the good offices of the MPS Society (UK).
References
1 Vellodi, A. (2004). Lysosomal storage disorders.
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2 Klein, A.D. and Lysosomal, F.A.H. (2013). Storage disorders: old diseases, present and future challenges.
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3 Mehta, A., Beck, M., Linhart, A. et al. (2006). History of lysosomal storage diseases: an overview. In:
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