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6. LYSOSOMAL
STORAGE
DISRDERS
Principles and Practice

7. This page intentionally left blank This page intentionally left blank

8. NEW JERSEY • LONDON • SINGAPORE • BEIJING • SHANGHAI • HONG KONG • TAIPEI • CHENNAI
World Scientific
LYSOSOMAL
STORAGE
DISRDERS
Principles and Practice
Gregory M. Pastores
New York University School of Medicine, USA

9. British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library.
For photocopying of material in this volume, please pay a copying fee through the Copyright
Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to
photocopy is not required from the publisher.
ISBN-13978-981-4271-31-8
ISBN-10981-4271-31-4
Typeset by Stallion Press
Email: [email protected]
All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means,
electronic or mechanical, including photocopying, recording or any information storage and retrieval
system now known or to be invented, without written permission from the Publisher.
Copyright © 2010 by World Scientific Publishing Co. Pte. Ltd.
Published by
World Scientific Publishing Co. Pte. Ltd.
5 Toh Tuck Link, Singapore 596224
USA office: 27 Warren Street, Suite 401-402, Hackensack, NJ 07601
UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE
Printed in Singapore.
LYSOSOMAL STORAGE DISORDERS
Principles and Practice
Shelley - Lysosomal Storage Disorders.pmd 1/13/2010, 1:57 PM1

10. 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
v
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11. 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
FA
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12. vii
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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13. 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
FA
viii Lysosomal Storage Disorders
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14. FA
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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15. FA
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16. 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
xi
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18. 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
xiii
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19. 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
FEV
1 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-1
α Interleukin-1α
ISSD Infantile sialic acid storage disease
FA
xiv Lysosomal Storage Disorders
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20. 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
FA
List of Abbreviations xv
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21. 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 Ca
2+
-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
VO
2 Maximal oxygen uptake
FA
xvi Lysosomal Storage Disorders
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22. 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-Iin 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
xvii
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23. Another Random Document on
Scribd Without Any Related Topics

24. 261) Τινές προτείνουσιν Ιετόν, φρούριον της Σικελίας παρά
τον Κρίμηυον.↩
262) Οι Φωκείς, υπό των Αμφικτυόνων εις πρόστιμόν τι μέγα
καταδικασθέντες, και μη δυνηθέντες να πληρώσωσιν αυτό,
ελεηλάτησαν τον ναόν των Δελφών, Εκ τούτου προήλθεν ο
δεκαετής ιερός πόλεμος, όν κατέπαυσε Φίλιππος ο Μακεδών
εν έτει 344 π. Χ. Αρχηγοί των Φωκέων ήταν
αλληλοδιαδόχως ο Φιλόμηλος, ο Ονόμαρχος, ο Φαύλλος και
ο Φάλαικος.↩
263) Δηλαδή εζωγραφημένας διά της βαφής ήτις εξάγεται εκ
του οστράκου της πορφύρας.↩
264) Ήλεκτρον ήτον μέταλλον εκ χρυσού και αργύρου
μεμιγμένον. ↩
265) Πόλις άγνωστος της Σικελίας, δι' ό και γράφουσί τινες
Καυλωνίαν ή Γαλερίαν.↩
266) Λοχαγός του ιππικού.↩
267) Παρωδία της Ευριπίδου Μηδείας στοιχ. 214, όπου η
Μήδεια λέγει κλητικώς: «Κορίνθιαι γυναίκες,
εξήλθον δόμων», το δ' εξήλθον ενικώς εις πρώτον
πρόσωπον, περί εαυτής, εν ώ ενταύθα ο Εύθυμος ευφυώς το
παρώδησεν εις τρίτον πληθυντικόν πρόσωπον, εφαρμόζων
αυτό εις τους Κορινθίους.↩
268) Οι Συρακούσιοι φαίνεται ότι ήσαν τότε άξιοι των όσων
έπασχον, διότι ηθικώς ήσαν τόσον εξηχρειωμένοι, ώστε
εξεδικούντο επί γυναικών και παρθένων, φονεύοντες αυτάς
διά δικαστικής ανοσιουργίας.↩
269) Άλαβον γράφουσί τινες, διότι ούτω καλούμενον
σικελικόν ποταμόν αναφέρει ο Πτολεμαίος. Κατ' άλλας
γραφάς, Άμβολον.↩
270) Τινά χειρόγραφα φέρουσι «Λύκου.» ↩
271) Λευκανία, επαρχία της κάτω Ιταλίας.↩

25. 272) Αι εκκλησίαι του δήμου συνήρχοντο πολλάκις εις τα
θέατρα, ως τούτο, κατά τους μεταγενεστέρους χρόνους
εγίνετο και εν Αθήναις. ↩
273) Άραγε αντί απαχθείς, δεν είχε το κείμενον
απαγχθείς, λέγον ότι ζων εκρεμάσθη, και ορίζον ούτω τις
ήτον η ήν υπέστη ποινή των ληστών;↩
274) Ακράγας, την σήμερον Grigenti, πόλις περιέχουσα
αξιόλογα λείψανα αρχαίων μνημείων. Γέλα, την σήμερον
Terra nuova, αμφότεραι, εις την μεσημβρινήν παραλίαν της
νήσου.↩
275) Δηλαδή την επί του Πελοποννησιακού πολέμου
εκστρατείαν του Νικίου, εφ' ής δεινώς ηττήθησαν οι
Αθηναίοι.↩
276) Ελέα, πόλις της Λευκανίας, εν τη κάτω Ιταλία, άποικος
των Φωκαέων.↩
277) Η νήσος του Αιγαίου, η Ζέα.↩
278) Ο υιός του Κόνωνος, Αθηναίος στρατηγός.↩
279) Εξ αγνώστου χωρίου. ↩
280) Επίθετον του έρωτος. ↩
281) Θέλει να είπη, πόση χάρις επί των έργων του.↩
282) Ποιητής Κολοφώνιος, κατά τα 400 π. Χ. γράψας ποίημα
επικόν, επιγραφόμενον Θηβαΐς.↩
283) Διονύσιος, ζωγράφος περίφημος, εφάμιλλος του
Πολυγνώτου.↩
284) Κολοφών, πόλις της Ιωνίας εν τη μικρά Ασία.↩
285) Ίδ. Ραγκ. Ιστορ. της αρχ. καλλιτεχνίας, Τόμ. Α'. σ. 478
↩
286) Δηλ. της αυτομάτου τύχης, της μη βοηθουμένης υπ'
ανθρωπίνης φρονήσεως.↩

26. 287) Ίδ. ανωτ. ΚΓ.↩
288) Πόλις εις τα βόρεια κειμένη της Σικελίας. ↩
289) Η Αττική μνα ήτον 100, η δε σικελική 40 αττικών
δραχμών. ↩
290) Εξ Ομήρ. Ιλιάδ. Ω. 630.↩
291) Στίχος εξ αγνώστου τραγικού χωρίου. ↩
292) Ο Αβδηρίτης φιλόσοφος, ακμάσας περί Ολ. 72. ↩
293) Και εξ ετέρου χωρίου του Πλουτάρχου (Περί εκλελοιπ.
χρηστηρίων § 17), και εκ Κικέρωνος (Epist. ad C. Cassium)
εξάγεται ότι κατά το δόγμα του Δημοκρίτου και του
Επικούρου, εφέροντο εκ του περιέχοντος αέρος προς τους
ανθρώπους είδωλά τινα, ή εικόνες, χρηστά ή πονηρά,
αποτελούντα τας φαντασίας και τας ιδέας αυτών.↩
294) Ο Πυθαγόρας, φεύγων την πατρίδα του Σάμον, διότι
ετυραννείτο υπό του Πολυκράτους, ήλθεν εις Ιταλίαν, και
εσύστησεν εν Κρότωνι την φιλοσοφικήν αυτού σχολήν. Οι
Ρωμαίοι συγγραφείς τω αποδίδουσιν ως υιόν τον
Μάμερκον.↩
295) Γλυκύς.↩
296) Ίδ. βίον Νουμά. § Α.↩
297) Aedilitas.↩
298) Augures, οιωνοσκόποι. Την οιωνοσκοπίαν έλαβον οι
Ρωμαίοι παρά των Τυρρηνών.↩
299) ιός Σελεύκου του Καλλινίκου, βασιλεύσας της Συρίας
κατά τα έτη 246 — 210 π. Χ.↩
300) Οι πελέκεις, ή πελεκυφόροι, lictores, ήταν
σωματοφύλακες διδόμενοι έξ μεν εις τους στρατηγούς,
δώδεκα δ' εις τους υπάτους. ↩
301) Ούτω και ο Τίτ. Λίβιος. Κατ' άλλους Μνάσων.↩

27. 302) Όθεν παρ' ημίν η κάλτσα. Η λέξις δε ουχί λατινική,
αλλά του σικελικού ελληνισμού.↩
303) Δηλαδή γεωγραφικών θέσεων, προς δυσμάς, ανατολάς
κ.τ.λ. ↩
304) Κατά Τ. Λίβιον εξελέγη ύπατος εν έτει 572 α. κ, Ρ. (182
π. Χ.), και εξεστράτευσε κατά το επιόν έτος.↩
305) Από του ποταμού της Γενούης, μέχρι Μονάκου. ↩
306) Έχοντος τρεις παλμούς, τρία ζεύγη κωπίων.↩
307) Φίλιππον τον Γ', πατέρα του Περσέως.↩
308) Τον Πολιορκητήν.↩
309) Ίδ. Κοριολ. ο ΙΑ.↩
310) Πλοία φορτηγά. Ο Ωρεός, πόλις ές την βορείαν
παραλίαν της Ευβοίας. ↩
311) Πλοία πολεμικά, πέντε σειράς κωπών έχοντα.↩
312) Κατ' άλλους Ελίμεια ή Ελιμεία, ενικώς, πόλις της
Μακεδονίας, υπό την Απολλωνίαν.↩
313) Δαρδανείς, έθνος Θρακικόν κατά την Μοίσιαν, την νυν
Σερβίαν, μεταξύ Ορβήλου και Σκόδρου.↩
314) Έθνος Γερμανικόν κατά τας όχθας του Δουνάβεως. ↩
315) Κατά την άνω Αλβανίαν.↩
316) De divinatione I, 46.↩
317) Αμίππους τους λέγουσιν ο, Θουκυδίδης και ο
Ξενοφών, και ήσαν πεζοί συνοδεύοντες τους ιππείς, και
έτοιμοι ν' αναβώσι τους ίππους αυτών, άμα των ιππέων τις
έπιπτε (page).↩
318) Οι Μαιδοί, έθνος Θρακικόν πλησίον της Μακεδονίας
(Στράβ. 318). Εις τα χειρόγραφα φέρεται κακώς Μηδικήν.

28. ↩
319) Χιλίους, λέγει το κείμενον, υπονοούν τους στατήρας.
Είχε δ' ο χρυσούς στατήρ 2 δραχμών βάρος καν 20 δραχμών
αξίαν.↩
320) Ο Τ. Λίβυος (33) λέγει άνευ ασπίδος, διά να μη
κοιμώνται όρθιοι επ' αυτών. Τότε ενεωτέρισε και ως προς
την αλλαγήν των φυλακών. ↩
321) Οι και εφεκτικοί λεγόμενοι, και ζητητικοί και σκεπτικοί
φιλόσοφοι, οι του Πύρρωνος οπαδοί. ↩
322) Ναός του Απόλλωνος. Αλλ' ως πόλις της Μακεδονίας,
αναφέρεται υπό Στεφάνου του Βυζαντίου. ↩
323) Αναφέρεται και υπό Λιβίου, 44, 32.↩
324) Ημίσεια ώρα.↩
325) Λέγει τον Πύθιον Απόλλωνα, εις ού το ιερόν ην το
επίγραμμα αναγεγραμμένον.↩
326) Ο Ξεναγόρας λοιπόν εύρε το κάθετον ύψος του
Ολύμπου 6096 πόδας υπέρ το Πύνθιον. Το δ' ότι τα
υψηλότερα βουνά και αι βαθύτεραι θάλασσαι δεν
υπερβαίνουσι τους 6000 πόδας αποδείκνυται εσφαλμένον
υπό των νεωτέρων καταμετρήσεων. ↩
327) Πόλις της Πιερίας εν Μακεδονία, επί του Θερμαϊκού
κόλπου. ↩
328) Ο Τ. Λίβιος (Μ Δ, 37) δεν συμφωνεί προς ταύτα τα περί
της εκλείψεως.↩
329) Μακεδονικάς λόγχας μακράς 11, ή 15 πήχεις.↩
330) Μικράς στρογγυλάς ασπίδας.↩
331) Την Πύδναν, ως είπεν εν ΙΣΤ.↩
332) Ίδ. Φαβ. Μάξ. ΙΘ.↩

29. 333) Ίδ. και T. Liv. 44. Duac cohoriæ a parte Romanorum
erant, Peligna et Maruccina.↩
334) Την τρίτην περίπου μετά μεσημβρίαν.↩
335) Μόλις 17 ετών.↩
336) Οι Κρήτες είχον παρά τοις αρχαίοις κακήν υπόληψιν ως
ψεύσται. «Κρήτες αεί ψεύσται» έγραφεν ο Επιμενίδης 500
έτη π. Χ. και τον στίχον αυτού αναφέρει ο απόστολος
Παύλος.↩
337) Τους εν Σαμοθράκη λατρευομένους Καββείρους, οίτινες
υπό των Ελλήνων εθεωρούντο ως αυτοί οι Διόσκουροι. ↩
338) Σάγρας, ποταμός της Μεγάλης Ελλάδος, ρέων διά της
χώρας των Λοκρών. Ενταύθα οι Λοκροί, μυρίους έχοντες
στρατιώτας, ενίκησαν κατά κράτος τους Κροτωνιάτας,
έχοντας 130,000, και αυθημερόν έφθασε της νίκης η είδησις
εις Ολυμπίαν, Σπάρτην, Κόρινθον και Αθήνας.↩
339) Και εις Μυκάλην της εν Πλαταιαίς κατά Μήδων έπρεπε
να ειπή. Ίδ. Πολυαίνου. Στρατηγημ. Α, 33.↩
340) 20,000 στάδια αποτελούσι χιλίας ώρας.↩
341) Των Καββείρων δηλαδή ως ανωτέρω ο Περσεύς
εκάθησεν ικέτης.↩
342) Ακρωτήριον εις τα βόρεια της Σαμοθράκης.↩
343) Ως γνωστόν ο Φειδίας έπλασεν εν Ολυμπία
χρυσελεφάντινον το άγαλμα του Διός, όν περιγράφει
μεγαλοπρεπώς ο Όμηρος, Ο Αιμίλιος λοιπόν εννόει ότι
πρώτος διέγραψεν αυτόν ο Όμηρος, και την περιγραφήν
εκείνου ότι συνεπλήρωσεν ο Φειδίας.↩
344) Τινές υπώπτευαν υπερδεκαπλάσια.↩
345) Λιμήν και πόλις της Ηπείρου, επί των συνόρων της
Ιλλυρικής Μακεδονίας.↩
346) Τον Τίβεριν.↩

30. 347) Πλοίον δεκαέξ ζεύγη κωπίων έχον, κτήμα του βασιλέως
Περσέως.↩
348) Είδος ποτηρίων, εχόντων σχήμα κέρατος, κατά μίμησιν
των αρχαιοτάτων χρόνων, ότε τα κέρατα των ζώων
εχρησίμευον ως ποτήρια. Εντεύθεν, κατ' Αθήναιον (ΙΑ, 476)
και το κεράσαι.↩
349) Οδοιπορικόν. Διετήρησα την λέξιν του κειμένου, ως
κατάλληλον ίνα μείνη εν χρήσει, εκφράζουσα το γαλλικόν
marche.↩
350) Αντιγονίδες, Σελευκίδες και Θηρίκλεια, εκπώματα,
ούτως ονομασθέντα τα μεν από των δύο βασιλέων, τα δε
από του κατασκευάσαντος αυτά Θηρικλέους του Κορινθίου
(Αθήν. ΙΑ, 222, και 470.)↩
351) Ιλιάδ. Ω. 525-533.↩
352) Το νοτιανατολικόν ακρωτήριον της Ιταλίας, την
σήμερον Brindisi.↩
353) Τον θρησκευτικόν.↩
354) Carcere, η φυλακή, και του Σικελικού Κάρκαρον. ↩
355) Την των τιμητών, Censores.↩
356) Εις το κείμενον εγράφετο Λικίννιος Φιλόνεικος, ως αν η
δευτέρα λέξις ήτον της πρώτης επίθετον. Αλλ' ο Κοραής
έγραψε Λ. και Φιλόνεικος, διότι του Φιλονείκου τούτου
μνημονεύει ο Πλούταρχος και εν πολιτ. παραγγέλμ. §. 14.↩
357) Ο ιστορικός, Ίδ. Λυκ. Α.↩
358) Ο στρατηγός των Λακεδαιμονίων, όστις επί
Πελοποννησ. πολέμου εστάλη εις Συρακούσας και
κατέστρεψε τους Αθηναίους.↩
359) Τιμολ. §. ΙΑ.↩
360) Επαινετός μάλιστα διά τούτο είναι ο Τιμολέων. Δεν τον
κατέβαλε της τύχης καταφορά· αλλ' εβαρυθύμει δι' ό,τι

31. περιείχε στυγερόν και ανόσιον η ιδία αυτού πράξις, ήν τω
υπηγόρευσεν ηρωισμός πατριωτικός. ↩
361) Σύβαρις, πόλις της Ιταλίας, διαβόητος διά την
τρυφηλότητά της.↩
362) Στρατηγός Αθηναίος, νέους εισαγαγών κανόνας εις την
τακτικήν.↩
363) Στρατηγός των Λακεδαιμονίων, ο φονευθείς εις την εν
Αργινούσαις ναυμαχίαν.↩
364) Ο Στρατηγός του Αλεξάνδρου.↩
365) Τιμόθεος, υιός του Κόνωνος, και Χάρης, στρατηγοί των
Αθηναίων.↩
366) Ευριπ. Ικέτ. 864.↩
367) Νικομήδην λέγει τούτο εν Αποφθέγμασι.↩
368) Πολιτικήν μερίδα.↩
369) Λεοντιάδας, γράφει ο Ξενοφών.↩
370) Ακρόπολιν των Θηβών.↩
371) Επί Θρασυβούλου, μετά τον Πελοποννησιακόν
πόλεμον, κατά των τριάκοντα τυράννων.↩
372) Μία των ανωτάτων αξιών εν Θήβαις.↩
373) Η προ της Ελευσίνος πεδιάς, όθεν διέρχεται η οδός
προς τας Θήβας.↩
374) Μέλλων, κατά Ξενοφώντα. ↩
375) Στάλικας, λέγει το κείμενον, ό οι σχολιασταί
εξηγούσιν ως πασσάλους εφ' ών στηρίζουσι τα θηρευτικά
δίκτυα. Ίσως δε γενικώς τους θηρευτικούς πάλους. Σταλίκια
ονομάζει η συνήθεια τους οροθετικούς πασσάλους.↩
376) Ανώτατον ιερατικόν αξίωμα.↩

32. 377) Οι αρχαίοι δεν εκάθηντο, αλλ' ήταν κατακεκλιμένοι εις
τας τραπέζας. ↩
378) Ότε επεκράτει το δημοκρατικόν πολίτευμα εν Θήβαις,
οι ανώτατοι άρχοντες της πολιτείας ήσαν τρεις, καλούμενοι
Βοιωτάρχαι. ↩
379) Ούτως ωνομάζοντο οι υπό των Σπαρτιατών εις ξένας
πόλεις πεμπόμενοι διοικηταί.↩
380) Τα των Βοιωτών φρονούντων. ↩
381) Πλαταιαί η νυν Κόκλα. Θεσπιαί, το Ερημόκαστρον. ↩
382) Τανάγρα, το Κακοσάλεσι, άντικρυ της Ευβοίας, μεταξύ
Αττικής και Βοιωτίας.↩
383) Όπου σήμερον το χωρίον και μοναστήριον της
Σκριπούς. ↩
384) Διαίρεσις του σπαρτιακού στρατού.↩
385) Πλησιάζουσαν εις την Ορχομενίαν, προς τα
βορειανατολικά. ↩
386) Την Κωπαΐδα λίμνην, εις ήν εκρέει ο Μέλας, ενούμενος
μετά του Κηφισού.↩
387) Το υπέρ τον Ορχομενόν όρος. ↩
388) Ο Πλούταρχος, καίτοι ιερεύς του Απόλλωνος φαίνεται
όμως εφεκτικός.↩
389) Ίδ. Κάμιλλ. § . . .↩
390) Ο γνωστός Αρκάς ιστορικός, υιός του Λυκόρτα. Ο
αριθμός των αποτελούντων την μόραν φαίνεται ότι δεν ήτον
προσδιωρισμένος.↩
391) Ίδ. Λυκούργ. §ΣΤ.↩
392) Δηλαδή των συνδεδεμένων διά στενωτάτων δεσμών
φιλίας. ↩

33. 393) Φυλάς και φρατρίας, υποδιαίρεσιν των φυλών, γένη. ↩
394) Ιλιάδ. Β. 363.↩
395) Εν Βοιωτία και Φωκίδι ελατρεύετο ιδίως ο έρως, και
ετελούντο τα ερώτια. Ο έρως ούτος ην η θερμή φιλία των
νέων προς τους άνδρας παρ' ών εδιδάσκοντο τα μαθήματα
και ελάμβανον τα παραδείγματα της αρετής και ανδρείας. Ως
πρότυπον δε της τοιαύτης φιλίας προύκειτο αυτοίς ο
Ηρακλής και ο Ιόλαος. Τον άμωμον της φιλίας ταύτης
χαρακτήρα ανεγνώρισεν, ως κατωτέρω, αυτός ο Φίλιππος, ο
εχθρός των Θηβαίων. ↩
396) Ο Λάιος, πατήρ του Οιδίπου, ήρπασε τον Χρύσιππον
υιόν του Πέλοπος.↩
397) Την Αρμονίαν.↩
398) Λεύκτρα, χωρίον εις την Βοιωτίαν, ου μακράν των
Πλαταιών. ↩
399) Περί Μενοικέως ίδ. Ευριπ. Φοινίσσας. Περί Μακαρίας ίδ.
Ευριπ. Ηρακλείδ. Τα περί Φερεκύδου αλλαχόθεν άγνωστα. ↩
400) Ίδ. Θεμιστοκλ. §. ΙΓ ↩
401) Ο λιμήν της Βοιωτίας, άντικρυ της Χαλκίδος, όθεν
εξέπλευσαν οι Έλληνες κατά της Τρωάδος. Ίδε βίον
Αγησιλ.↩
402) Παραστάται (Ζευγίται εις το κείμενον) λέγονται οι
πλησίον αλλήλων ιστάμενοι στρατιώται· επιστάται δ' οπίσω
αλλήλων.↩
403) Αρχάς δεκεμβρίου.↩
404) Το Καλαμάκι εις τον Ισθμόν της Κορίνθου.↩
405) Πόλις της Θεσσαλίας.↩
406) Τον πατέρα του μεγάλου Αλεξάνδρου. ↩
407) Δηλαδή αγαθήν Τύχην.↩

34. 408) Ίδ. και Αλκιβ. Δ.↩
409) Τούτο σημαίνει ασπιδοφόρος. Ελέγετο δ' ούτω
χλευαστικώς διά τον μακρόν και δασύν πώγωνά του, όστις
εκάλυπτε το στήθος του ως ασπίς. (Αριστοφ. Εκκλησ. 71 και
Σχολ.)↩
410) Των Θεσσαλών Αχαιών. ↩
411) Η έκλειψις συνέβη κατά το έτος 364 ή 365 π. Χ.↩
412) Ιστορικός. Ίδ. Τιμολ. ΙΕ.↩
413) Εκ του Mars, του Άρεως.↩
414) Ιστορικός, Ίδ. Φάβ. Μάξ. ΙΘ.↩
415) Sorex Soricem, εκ του αιολικού Ύραξ, ο μυς.↩
416) Άλλοι γράφουσι Βιρδόμαρος· ούτω και οι πλείστοι των
Ρωμαίων συγγραφέων Virdomares ή Viridomares. Το δε
Βριτόμαρτος είναι εξελληνισμός κατά την Βριτόμαρτυν, την
θυγατέρα του Διός.↩
417) Μεταξύ Μεδιολάνου και Πλακεντίας. ↩
418) Ίδ. Β. Νουμά.↩
419) Ίδ. Ρωμύλ.↩
420) Ίδ. Ρωμύλ.↩
421) Ferire.↩
422) Ασσάριον ή Ας, ίσον αιγινητικώ οβολώ ή 1 2[3 του
αττικού οβολού. ↩
423) Ελλείπει ο αριθμός. ↩
424) Ιδέ Παύλ. Αιμύλ.↩
425) Ίδ. §. Α.↩

35. 426) Την Νεάπολιν, Νώλα, πόλις της αυτής επαρχίας. ↩
427) Τριακοσίους λέγει το κείμενον. Αλλ' ο Κοραής
προσέθηκεν την λέξιν χιλίους κατά Liv. ΧΧΙΙΙΙ, 46.↩
428) Πλοία έχοντα πέντε σειράς κωπίων.↩
429) Το χωρίον τούτο εις το κείμενον έχει πολλά τα
αμφιβαλλόμενα. ↩
430) Ειπών «Δος μοι πα στω, και ταν γαν κινήσω».↩
431) Πολύσπαστος μηχανή είναι η έχουσα πολλούς κοχλίας
(μακαράδες).↩
432) Όργανον έγχορδον, τριγωνικόν, είδος άρπης. ↩
433) Το τάλαντον ήτον βάρος είκοσι οκάδων περίπου. ↩
434) Μηχανή βέλη τοξεύουσα.↩
435) Τον εκατόγχειρα γίγαντα.↩
436) Το χωρίον φαίνεται παρεφθαρμένον. Ίδ. Πολύβ. ΙΙ.
270. Αθήν. ΙΔ, 634.↩
437) Mέρoς της διαίτης των αρχαίων ήτον ν' αλείφωνται διά
μύρων.↩
438) Ο λόγος ούτος είναι 2:1.↩
439) Ακρέλλας κατά Λίβ. XXIV, 35.↩
440) Ηλιακόν ωρολόγιον.↩
441) Μετά του Ιδομενέως κατά του Ιλίου εκ Κρήτης
συνεκστρατεύσαντος, υιού Μολιού και Μέλφιδος.↩
442) Ο Ρωμαϊκός τύπος του ονόματος του Οδυσσέως, ίσως
και εις ελληνικήν τινα διάλεκτον ανήκων.↩
443) Αι εκκλησίαι του δήμου πολλαχού εγίνοντο εις τα
θέατρα. ↩

36. 444) Ίδ. Φάβ. Μάξ. ΙΘ.↩
445) Πίνδ. Πύθ. Β. αρχ.↩
446) Απόσπασμα της απολεσθείσης τραγωδίας, της
επιγραφομένης Λικύμνιος.↩
447) Δηλαδή, πενιχρόν.↩
448) Ovatio.↩
449) Βακχικού αλαλαγμού.↩
450) Oves εκ του ενικού Ovis ουχί Ova, σημαίνον τα ωά. ↩
451) Σαυνίται ή Σαμνίται, λαός της μέσης Ιταλίας.↩
452) Τρίτης από της ανατολής του ηλίου.↩
453) Dicere.↩
454) Οι εν Ιταλία Λοκροί, εις την Καλαβρίαν, των Οζολών
αποικ. ↩
455) Lancea, ίσως εκ του λόγχη.↩
456) Ιστορικός ζήσας επί Τιβερίου.↩
457) Ο αυτοκράτωρ Αύγουστος, γράψας και ιστορίαν. ↩
458) Πόλις της Ρόδου. ↩
459) Ίδ. § Α. ↩
460) Του Αυγούστου.↩
461) Ίδ. Ρώμ. ΙΔ.↩
462) Ξενοφ. Kυρ. παιδ. Δ, α'.↩
463) Eις δράμα μη σωζόμενον.↩

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