Lysosomal Storage Disorders Principles And Practice

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 LYSOSOMAL
STORAGE
DIS RDERS
Principles and Practice

Gregory M. Pastores
New York University School of Medicine, USA

World Scientific
NEW JERSEY • LONDON • SINGAPORE • BEIJING • SHANGHAI • HONG KONG • TA I P E I • CHENNAI
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LYSOSOMAL STORAGE DISORDERS

Principles and Practice
Copyright © 2010 by World Scientific Publishing Co. Pte. Ltd.
All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means,
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ISBN-13 978-981-4271-31-8
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Foreword

Over the past few decades we have seen remarkable progress in our
understanding of the lysosomal storage diseases (LSDs) thanks to many
physicians and scientists who have devoted their careers to unraveling the
clinical, biochemical and molecular intricacies of these rare disorders.
Dr Pastores has been both a witness and a contributor to the emergence of
this field close to the forefront of medical genetics. This concise guide is
a distillation of his experiences caring for patients, teaching medical
students, residents and fellows, conducting clinical trials and participation
in national and international meetings devoted to progress in the LSDs.
He begins by emphasizing that these disorders involve all age groups
and multiple organ systems so that physicians caring for both children and
adults and from all specialties need to be informed. Historical information
of each disorder and vignettes liven up the text. The complexity of diag-
nosis is simplified by an emphasis on clinical signs and a paradigm for
diagnostic testing. Guidance is given on biochemical and molecular test-
ing and prenatal diagnosis and screening for carriers. Laboratory pitfalls
such as pseudo-deficiency alleles and activator protein deficiencies are
addressed in this well-referenced and up-to-date monograph. Disease
mechanisms, a relatively new field of inquiry, are nicely summarized yet
there is much about pathogenesis of the LSDs that remains unknown.
However, what makes the LSDs of such great interest today are the mul-
tiple approaches to therapy, some already in use and others in clinical
trials and potentially promising. To measure treatment progress, disease-
specific scoring systems are needed as well as quality of life measures and
these are also well-covered. The many tables in this manual allow even

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vi Lysosomal Storage Disorders

the beginning student convenient shortcuts to differentiate the various

LSDs on clinical grounds.
Even though rare, the LSDs continue to spawn new insights into basic
molecular processes with the potential for wider applications to other
categories of genetic disease. Both new and established students of the
LSDs will find this book a roadmap not only for better case finding and
management but also a stimulus to continue the tradition of discovery that
is the lifeblood of academic medicine.

Edwin H. Kolodny, M.D.

Bernard A. and Charlotte Marden Professor of Neurology
Chairman, Department of Neurology
New York University School of Medicine
New York, USA
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Preface

We ought not to set them aside with idle thoughts or idle words about
‘curiosities’ or ‘chances’. Not one of them is without meaning; not one
that might not become the beginning of excellent knowledge, if only we
could answer the question — why is it rare or being rare, why did it in
this instance happen?

— James Paget (1882)

I had the good fortune of coming to Mount Sinai Medical Center

(MSMC), New York to complete my training in medical genetics, after
an initial period of grounding at the Mayo Clinic in Minnesota. At that
time (1990), enzyme therapy for Gaucher disease (GD) was in clinical
trials. As New York had a large Ashkenazi Jewish community and GD
was a prevalent and well-characterized disorder in this population,
patient recruitment would not be a problem. Furthermore, a physician at
MSMC (Gregory A. Grabowski) had up to that point devoted most of
his professional life to studying the disease. Thus, our group had antici-
pated being involved in the pivotal trials to evaluate the recombinant
form of glucocerebrosidase (the enzyme deficient in GD). When Greg
left for Ohio in 1991 to head the Division of Genetics at the Children’s
Hospital in Cincinnati, I took over the care of our GD patients and com-
pletion of the trials, which was then a collaborative effort between
MSMC and Norman Barton and Roscoe O. Brady at the National
Institutes of Health. Roscoe’s role was both vital and of special interest,

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viii Lysosomal Storage Disorders

as he had in the mid-60’s delineated the enzyme deficiency that was

shown to cause GD and proposed the feasibility of treatment by infusing
the protein, isolated from human placenta, into patients. These initiatives
were supported by Genzyme Corporation, and facilitated by Orphan
Drug legislation (established in 1983).
Subsequently, I was involved in other GD-related studies delineating
genotype–phenotype relationships, assessment of disease burden and
mapping therapeutic profile in patients on enzyme therapy. Then as now,
Robert J. Desnick, a leader in the field of lysosomal storage disorders
(LSD), headed the Department of Human Genetics. In 1997, I moved to
New York University to work with Edwin H. Kolodny whose interests
included two other LSDs; specifically Tay-Sachs and Anderson-Fabry
disease. The conjunction of these personalities and particular circum-
stances served as my introduction to the field, which to a large extent has
defined my own professional life. These events were to also play a role in
my personal life, as it enabled the happy occasion of meeting Derralynn
A. Hughes, a hematologist at the Royal Free Hospital who was involved
with caring for the London-based patients with GD and Anderson-Fabry
disease. Derralynn and I were married in 2008, and at the time this book
was written we have a daughter (Paloma).
Although my time at the Mayo Clinic was short, the individuals I met
and the genuine spirit of mutual respect and high standard of patient care
delivery I was to witness has formed a firm foundation, from which I was
to draw the needed strength to confront the challenges I have subsequently
had to deal with. In this regard, Virginia Michels was an excellent guide
and teacher. More recently, Gilles Lyon, a French physician with whom
Ed Kolodny and I co-authored a text entitled the Neurology of Hereditary
Metabolic and Molecular Diseases in Childhood (2006), has been a
source of inspiration.
I have been engaged in clinical practice and research in the field of
LSDs for the past 20 years, and I was involved in several of the seminal
trials to evaluate the safety and efficacy of various therapeutic options for
several of these conditions. I believe this gives me a unique perspective,
which I would now like to share with the readers of this book. Various
investigators focus on different aspects in relation to LSDs, some are
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Preface ix

primarily clinicians and others do only basic scientific investigations.

Thus, most books on the subject tend to be multi-authored, and can be
variable in scope and depth. I have attempted to fill what I perceive as a
gap in the existing literature: information in a single textbook which can
serve as a concise guide not only for the novice, but for the expert as well
whose focus or interest may be narrower than my personal experience.
Rapid progress is underway; thus, knowledge regarding pathophysi-
ology and treatment of the LSDs is constantly undergoing revision. I have
tried my best to present the most up-to-date information on the subject as
I understand it. I would appreciate any effort by the reader to call atten-
tion to inaccuracies or outdated information, so this can be addressed in
future editions of this monograph.
In closing, I would like to inscribe this book to my parents, Jovito C.
Pastores and Annie H. McCarthy; both were equally devoted to my
upbringing and education. My parents passed away within a span
of one year, shortly before and after my wedding. What I am I know
confidently has come from my parents; what I hope for and will become
I pray my wife and daughter will enable.
Also, I would like to express my gratitude to the patients who have
entrusted their care to me, and have given me the opportunity to develop
my clinical skills. My interactions with the patients and their extended
families have helped to enrich my life in several ways, because it has
allowed me to learn of cultures and traditions that have not been part of
my own upbringing. In entrusting their care to me, it is my fervent hope
that I have met with their expectations.
Thus far, it has been a great adventure and I look forward to partici-
pating in future studies to elucidate the pathophysiology of LSDs and the
development of treatment. Through the years I have interacted with and
learned from several colleagues, and I am most grateful for the privilege
and their mentorship.
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Contents

Foreword v
Preface vii
List of Abbreviations xiii
List of Figures xvii

1. Introduction 5
2. Clinical Perspectives 23
3. Diagnostic Confirmation and Screening 47
Protocols
4. Assessment of Disease Burden and Assignment 65
of Disease Severity
5. Pathophysiology and Biomarkers 99
6. Current and Emerging Therapies 125
7. Future Prospects 143

Disease Index 153

General Index 157

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List of Abbreviations

AAV Adeno-associated virus

ABR Auditory brain stem evoked response
ACE Angiotensin-converting enzyme
AD Alzheimer disease
AFD Anderson-Fabry disease
AGAL α-galactosidase A
AIMS Alberta Infant Motor Scale
ALLO Allopregnanolone
AMP Adenosine monophosphate
AMPA α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate
AMPK AMP-activated protein kinase
ARSA Arylsulfatase A
ATP Adenosine triphosphate
BBB Blood-brain-barrier
BDA Bayh-Dole Act
BDNF Brain-derived neurotrophic factor
BiP Immunoglobulin binding protein/GRP78
BiPAP Bi-level positive airway pressure
CADC Cortical apparent diffusion coefficient
CCL18 Chemokine (C–C motif ) ligand 18
CD3 Cluster of differentiation-3
Cho Choline
CHO Chinese hamster ovary
CHOP C/EBP homology protein
CLN3 Ceroid-lipofuscinosis, neuronal-3

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xiv Lysosomal Storage Disorders

CNS Central nervous system

CPAP Continuous positive airway pressure
CRIM Cross-reacting immunologic material
CSF Cerebrospinal fluid
CTSD Cathepsin D deficiency
CVS Chorionic villus sampling
DGJ Deoxygalactonojirimycin
DPP-IV Dipeptidyl peptidase IV
EBP Elastin binding protein
EMG Electromyography
ER Endoplasmic reticulum
ERG Electroretinography
ERT Enzyme replacement therapy
FAA Functional activities assessment
FEV1 Forced expiratory volume in the first second
FPSS Functional performance scoring system
FVC Forced vital capacity
GABA Gamma-aminobutyric acid
GAG Glycosaminoglycans
GALC Galactocerebrosidase
GauSS-I Gaucher disease Severity Score Index
Gb3 Globotriaosylceramide
GBA Glucocerebrosidase
GD Gaucher disease
GINA Genetic Information Non-discrimination Act
GlcCer Glucosylceramide
GluR2 Glutamate receptor subunit-2
HCII-TC Heparin co-factor II-thrombin complex
HGSNAT Heparan-α-glucosaminide N-acetyltransferase
HRQoL Health-related quality of life
HS Heparan sulphate
HSCT Hematopoietic stem cell transplantation
I2S Iduronate-2-sulfatase
IDUA α-L-iduronidase
IL-1α Interleukin-1α
ISSD Infantile sialic acid storage disease
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List of Abbreviations xv

IT Intrathecal
JNCL Juvenile neuronal ceroid lipofuscinosis
JNK2 c-Jun N-terminal kinase-2
KS Keratan sulfate
LCA Leukocyte common antigen
LAMP2 Lysosomal-associated membrane protein-2
LIMP1 Lysosomal integral membrane protein-1
LINCL Late-infantile neuronal ceroid lipofuscinosis
LOTS Late-onset Tay-Sachs disease
LSD Lysosomal storage disorder
LVH Left ventricular hypertrophy
LVMi Left ventricular mass index
lysoGb3 Deacylated globotriaosylceramide
MCOLN1 Mucolipin-1
M-CSF Macrophage colony-stimulating factor
MEP Maximal expiratory pressure
MIP Maximal inspiratory pressure
ML-II/III/IV Mucolipidosis type II/III/IV
MLC Megalencephalic leukoencephalopathy with
subcortical cysts
MLD Metachromatic leukodystrophy
MOS Medical outcomes study
MPS Mucopolysaccharidosis
MRI Magnetic resonance imaging
MRS Magnetic resonance spectroscopy
MS Mass spectroscopy
MSD Multiple sulfatase deficiency
MSSI Mainz Severity Score Index
mTOR Mammalian target of rapamycin
MWT Minute walk test
NAA N-acetylaspartate
NCL Neuronal ceroid lipofuscinosis
NCV Nerve conduction velocity
NEU Neuraminidase
NF-κB Nuclear factor kappa-light-chain-enhancer
of activated B cells
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xvi Lysosomal Storage Disorders

NFT Neurofibrillary tangles

NPC Niemann-Pick disease type C
NPD Niemann-Pick disease
NIHF Non-immune hydrops fetalis
ODA Orphan Drug Act
OLP Oligodendrocyte progenitor
PARC Pulmonary and activation-regulated chemokine
PFT Pulmonary function test
PPCA Protective protein/cathepsin A
QMT Quantitative muscle testing
REM Rapid eye movement
ROS Reactive oxygen species
SAP Sphingolipid activator protein
Sap-B/C Saposin B/C
SASD Sialic acid storage disorders
SCMAS Subunit C of mitochondrial ATP synthase
SD Sandhoff disease
SDB Sleep-disordered breathing
SELDI Surface-enhanced laser desorption/ionization
SERCA Sarco/Endoplasmic reticulum Ca2+-ATPase
SPECT Single photon emission computed tomography
SRT Substrate reduction therapy
SSI Severity score index
STAT Signal transducers and activators of transcription
SUMF1 Sulfatase modifying factor 1
TIMP Tissue inhibitor of metalloproteinase
TLC Thin layer chromatography
TMS Tandem mass spectrometry
TOF Time-of-flight
TRAP Tartrate-resistant acid phosphatase
TSD Tay-Sachs disease
UCHL-1 Ubiquitin carboxyl-terminal esterase L1
UPR Unfolded protein response
UPS Ubiquitin-proteasome system
VEP Visual evoked potential
VO2 Maximal oxygen uptake
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List of Figures

Figure 1.1. Schematic illustration of the sequential degradation 10

of the glycosaminoglycan dermatan sulfate.
Deficiency of distinct hydrolases gives rise to
individual disorders; the overlap in clinical
presentations among the conditions in this group
is partly explained by the disruption of a common
metabolic pathway.

Figure 1.2. Schematic illustration of the endolysosomal 11

system and the mechanisms involved in the
delivery of exogenous and endogenous ‘cargo’
to the lysosome for processing.

Figure 2.1. Characteristic features of MPS-I in a child: 32

thickened coarse hair, thick lips, short neck,
gibbus deformity, joint contractures, and
umbilical hernia.

Figure 2.2. Cherry-red spot: red macula surrounded by 34

a pale retina, reflecting the storage material
in the perifoveal ganglion cells.

Figure 2.3. Angiokeratomas in a patient with Anderson-Fabry 39

disease.

Figure 3.1. Vacuolated lymphocyte. 48

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xviii Lysosomal Storage Disorders

Figure 3.2. Filipin-stained cultured fibroblast: (a) normal 55

control, (b) patients with NPC. The increased
fluorescence intensity reflects the vacuolar
accumulation of unesterified cholesterol in the
perinuclear region of the NPC cells.

Figure 4.1. Leukodystrophy in a child with MLD, evident 66

on brain MRI as changes in white matter signal
in the periventricular area (arrow heads).

Figure 4.2. Imaging with contrast showing dilatation and 67

tortuosity of the blood vessels in the brain
posterior circulation of a patient with
Anderson-Fabry disease.

Figure 4.3. X-ray views which show (a) the bullet-shaped 72

phalanges and (b) anterior beaking of the
vertebra, consistent with dysostosis in a child
with an MPS disorder.

Figure 5.1. Schematic illustration of putative disease 102

mechanisms associated with lysosomal
storgage disorders.

Figure 5.2. Atypical histiocytes seen in bone marrow biopsy 102

from patients with Gaucher disease (a) and
Niemann-Pick disease (b).
Figure 6.1. Schematic illustration of the mechanism of 133
drug action for pharmacologic chaperones.