Lysosomal storage diseases - The horizon expands

Abstract

Since the discovery of the lysosome in 1955, advances have been made in understanding the key roles and functions of this organelle. The concept of lysosomal storage diseases (LSDs)-disorders characterized by aberrant, excessive storage of cellular material in lysosomes-developed following the discovery of α-glucosidase deficiency as the cause of Pompe disease in 1963. Great strides have since been made in understanding the pathobiology of LSDs and the neuronal ceroid lipofuscinoses (NCLs). The NCLs are neurodegenerative disorders that display symptoms of cognitive and motor decline, seizures, blindness, early death, and accumulation of lipofuscin in various cell types, and also show some similarities to 'classic' LSDs. Defective lysosomal storage can occur in many cell types, but the CNS and PNS are particularly vulnerable to LSDs and NCLs, being affected in two-thirds of these disorders. Most LSDs are inherited in an autosomal recessive manner, with the exception of X-linked Hunter disease, Fabry disease and Danon disease, and a variant type of adult NCL (Kuf disease). This Review provides a summary of known LSDs, and the pathways affected in these disorders. Existing therapies and barriers to development of novel and improved treatments for LSDs and NCLs are also discussed.

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1
Department of
Paediatrics and
Adolescent Medicine,
Biochemistry and
Molecular Genetics,
American University of
Beirut, POBox11‑0236,
Riad El‑Solh, 1107
2020, Beirut, Lebanon.
rb50@aub.edu.lb
Lysosomal storage diseases—the horizon
expands
Rose-Mary Naaman Boustany
Abstract | Since the discovery of the lysosome in 1955, advances have been made in understanding the
key roles and functions of this organelle. The concept of lysosomal storage diseases (LSDs)—disorders
characterized by aberrant, excessive storage of cellular material in lysosomes—developed following the
discovery of α‑glucosidase deficiency as the cause of Pompe disease in 1963. Great strides have since been
made in understanding the pathobiology of LSDs and the neuronal ceroid lipofuscinoses (NCLs). The NCLs are
neurodegenerative disorders that display symptoms of cognitive and motor decline, seizures, blindness, early
death, and accumulation of lipofuscin in various cell types, and also show some similarities to ‘classic’ LSDs.
Defective lysosomal storage can occur in many cell types, but the CNS and PNS are particularly vulnerable
to LSDs and NCLs, being affected in two‑thirds of these disorders. Most LSDs are inherited in an autosomal
recessive manner, with the exception of X‑linked Hunter disease, Fabry disease and Danon disease, and a
variant type of adult NCL (Kuf disease). This Review provides a summary of known LSDs, and the pathways
affected in these disorders. Existing therapies and barriers to development of novel and improved treatments
for LSDs and NCLs are also discussed.
Boustany, R.‑M.N. Nat. Rev. Neurol. advance online publication 13 August 2013; doi:10.1038/nrneurol.2013.163
Introduction
The lysosome, named after a Greek term that means
‘digestive body’, was discovered 58years ago by
DeDuve.
1
Normal functioning of the lysosome is
important for degradation of macromolecules and
homeostasis of the cell, but this organelle also has
a role in the processes of phagocytosis and antigen
presentation, which are necessary for regulation of
inflammation and control of autoimmunity. The
lysosome– endosomal system is intimately involved in
regulation of autophagy, apoptosis and cell death via
signal transduction and exocytosis—factors that are
all involved in inflammation, oncogenesis and neuro-
degenerative disease—as well as in receptor recycling
for regulation of neurotransmission, and in skin
pigmentation and bone biology.
Lysosomal storage diseases (LSDs) are hereditary
disorders. Most are inherited in an autosomal reces-
sive manner, although some are X-linked. LSDs are
often caused by mutations in genes encoding catabolic
enzymes that are involved in degradation of macro-
molecules. The substrate(s) of the defective enzyme(s)
build up over time, leading to excess cellular storage of
this material and to dysfunction in the nervous system
and eye, bone, muscle, and reticuloendothelial system.
Such perturbations of cellular processes ultimately lead
to cell death and organ-specific clinical manifestations.
The concept of lysosomal storage diseases (LSDs) was
developed in 1963, following the discovery that Pompe
disease was caused by a deficiency in α-glucosidase,
2
alysosome-associated enzyme that breaks down
starch in to glucose. Numerous defects of integral and
lysosome- associated membrane proteins have since
been described. Moreover, novel neuronal ceroid
lipofuscinoses (NCLs)—a groups of neurodegenera-
tive disorders that are similar to classic LSDs as they
are characterized by accumulation of cellular mat-
erial (namely, lipo fuscin) in bodily tissues—have also
been discovered. As such, the rubric of ‘LSDs’ now
encompasses around 50inherited metabolic disorders.
The CNS seems to be particularly vulnerable to LSDs:
most of these disorders manifest with neurological signs
(Tables1, 2 and 3) and, in some LSDs, the brain and/
or PNS is the sole affected organ, such as in Tay–Sachs
disease or metachromatic leukodystrophy, respectively.
3,4
Pathological threads that are common to LSDs and
NCLs are emerging. These shared features include: sec-
ondary storage of toxic metabolites; impaired lipid traf-
ficking; perturbed signalling; enhanced inflammation;
disturbed calcium homeostasis in endoplasmic reticulum
(ER); and stress and activation of the unfolded protein
response (UPR).
5,6
Collectively, these perturbations cul-
minate in dysregulated autophagy and other undesirable
outcomes of accelerated apoptosis and cell death.
5,7,8
Great
strides have been made in the discovery of genes and
proteins that are involved in LSDs and NCLs, and these
advances have led to excitement and anticipation regard-
ing direct approaches to therapy, such as replacement of
Competing interests
R.‑M.N. Boustany is an inventor on US patent applications
6,821,995; 8,003,327; and 8,242,086. See the article online
for full details.
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defective enzymes or genes. However, owing to unfore-
seen difficulties and variability of disease mechanisms
in each disorder, studies have found no improvement,
partial stabilization or limited improvement follow-
ing treatment in certain diseases. In Hurler disease, for
example, enzyme replacement improved organomegaly
and peripheral manifestations, but brain and bony disease
remained problematic.
9
Much work continues to be
done to clarify the pathophysiology of LSDs and NCLs,
advance our understanding of these diseases, and lead to
development of improved therapies. For now, screening
programmes, genetic counselling and prenatal diagnosis
remain the mainstays of LSD prevention.
This Review provides an overview of themes in known
LSDs—including classic LSDs, NCLs and other non-
classic LSDs—describing the pathobiology of disease,
and discussing evolving opportunities and novel targets
with regard to therapeutics that could improve outcomes
in patients with these disorders.
Lysosomal storage disorders
LSDs are commonly caused by dysfunction in lyso somal
components such as hydrolases, transporters and hydro-
lase activators, and lead to intralysosomal accumulation
of undegraded metabolites (Figure1). Disorders that are
caused by dysfunction of vesicular traffic and/or trans-
port within the endosome–lysosome system—such as
the mucolipidoses, NCLs and disorders presenting with
hypopigmentation, bleeding diatheses and immune
defects—can also manifest with defective lysosomal
storage. The descriptions of Tay–Sachs disease in 1881
10
and Gaucher disease in 1882 (two disorders now recog-
nized as LSDs) predated discovery of the lysosome in
1955.
8,11
The concept of LSDs was established by Hers
in1963 following the realization that Pompe disease
(now known as glycogen storage disease typeII) is
caused by deficiency of α-glucosidase, which leads to
accumulation of glycogen in lysosomes.
2
Key points
 The spectrum of lysosomal storage disease (LSD) includes defects in
degradative and synthetic enzymes, lysosomal membrane defects, the neuronal
ceroid lipofuscinoses (NCLs) and disorders of lysosome biogenesis and
endosome–lysosome traffic
 LSDs result in excess cellular storage and cell death in the CNS, PNS, lungs,
liver, bone, skeletal and cardiac muscle and the reticuloendothelial system;
symptomatology includes neurocognitive decline, seizures, blindness and
hepatosplenomegaly
 NCLs are typified by abnormal inclusions in brain, eye, liver, skin and the
reticuloendothelial system, with clinical manifestations such as neurocognitive
decline, blindness, seizures and early death
 Therapies involving enzyme replacement, substrate reduction and chaperone‑
mediated delivery, as well as haematopoetic and other stem‑cell therapies,
have had modest successes in the treatment of patients with LSDs
 LSDs and NCLs share pathological features: abnormal lipid trafficking,
dysregulation of apoptosis and autophagy, prolonged inflammation, disturbed
endoplasmic reticulum–cytosol calcium balance, cellular stress, and the
unfolded protein response
 The biological underpinnings of LSDs and NCLs partly explain the limited
success of ‘direct’ therapies for these disorders, but also provide novel targets
for therapeutic approaches
The signs and symptoms of LSDs vary depending
on disease type and other factors such as age at onset.
Some LSDs are evident at birth, such as β-glucuronidase
deficiency, or are diagnosed at 2–6months of age, such
as in infantile GM1-gangliosidosis, Krabbe disease or
Tay–Sachs disease. Other LSDs, such as metachromatic
leukodystrophy (MLD), become symptomatic in late
infancy or childhood, as with some of the mucopoly-
saccharidoses (MPSs). Although many LSDs present in
childhood, some manifest during the second decade or
adulthood, as exemplified by adult GM2-gangliosidosis.
Symptoms of LSD include failure to reach developmen-
tal milestones, visual disturbances, organomegaly (most
notable in Gaucher and Niemann–Pick disease), hyper-
splenism and anaemia, dysmorphic features and bony
disease (which typify MPSs), seizures and neuromotor
regression. Some of the late-onset (adult) forms have
psychiatric manifestations of depression or psychosis in
addition to neurological deficits, as seen in adult forms
of MLD and adult GM2-gangliosidosis. The neurological
and other complications that ensue over time in LSDs
cause substantial morbidity and diminished quality of
life for patients and their families, with death occurring
in early life in most cases.
4
Classification
In my opinion, the simplistic concept that LSDs arise from
monogenic defects in degradative pathways that lead to
lysosomal storage of sphingolipids, glycosphingo lipids,
MPS and oligosaccharides (or a combination thereof) no
longer holds. Initially, classification of LSDs was made
according to the nature of the accumulating storage
material—as in sphingolipidoses, mucopoly saccharidoses
and oligosaccharidoses.
7
This initial framework can
be applied to classic LSDs (described below) and has
enabled great progress to be made in identification of the
affected protein or gene in more than 50 dis orders. Aless
restrictive classification of disorders involving lysosomal
storage, however, allows inclusion of diseases that display
defects in cellular storage, synthetic enzymes, lysosome
membrane or other membrane proteins, and trafficking.
Under this proposed classification system, the horizon of
LSDs expands to include disorders that are characterized
by defects in synthetic processes (such as defective GM3-
synthase in GM3-gangliosidosis) or by trafficking defects
(Niemann–Pick disease, typeC1 [NPC1] and NPC2), as
well as including lysosomal membrane protein diseases
due to faulty lysosome-associated membrane protein 1
(LAMP-1), LAMP-2, or lysosome membrane protein II
(LIMP2), as in Danon disease and action myoclonus–renal
failure syndrome, respectively.
12
Under the new categori-
zation, NCLs can also be included in the LSD spectrum,
with lysosome biogenesis and endosome–lysosome traffic
disorders also warranting consideration under the rubric
of LSDs.
10,13
Classic LSDs
As mentioned above, classic LSDs were named accord-
ing to the nature of the accumulating substrate rather
than on the basis of the defective degradative enzyme or
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Table 1 | Classic lysosomal storage disorders
Disease type Neurological
involvement?
Defective enzyme or protein
Sphingolipidoses
Fabry disease Y
α‑Galactosidase A
Farber lipogranulomatosis N Ceramidase
Gaucher disease type I
Gaucher disease types II and III
N
Y
β‑Glucosidase
Saposin‑C activator
Niemann–Pick disease types A and B Y Sphingomyelinase
GM1‑gangliosidosis: infantile, juvenile and adult variants Y
β‑Galactosidase
GM2‑gangliosidosis (Sandhoff): infantile and juvenile
GM2‑gangliosidosis (Tay–Sachs): infantile, juvenile and adult variants
GM2‑gangliosidosis (GM2‑activator deciency)
Y
Y
Y
β‑Hexosaminidase A and B
β‑Hexosaminidase A
GM2‑activator protein
GM3‑gangliosidosis Y GM3 synthase
Metachromatic leukodystrophy (late infantile, juvenile and adult) Y Arylsulphatase A
Sphingolipid‑activator deciency Y Sphingolipid activator
Mucopolysaccharidoses
MPS I (Scheie, Hurler–Scheie and Hurler disease) Y
α‑Iduronidase
MPS II (Hunter) Y Iduronidase‑2‑sulphatase
MPS IIIA (Sanlippo A)
MPS IIIB (Sanlippo B)
MPS IIIC (Sanlippo C)
MPS IIID (Sanlippo D)
Y
Y
Y
Y
Heparan N‑sulphatase (sulphamidase)
N‑acetyl‑α‑glucosaminidase
Acetyl‑CoA; α‑glucosamide N‑acetyltransferase
N‑acetylglucosamine‑6‑sulphatase
MPS IVA (Morquio syndrome A)
MPS IVB (Morquio syndrome B)
Y
N
N‑acetylgalactosamine‑6‑sulphate sulphatase
β‑Galactosidase
MPS VI (Maroteaux–Lamy) Y N‑acetylgalactosamine‑4‑sulphatase
(arylsulphatase B)
MPS VII (Sly disease) Y
β‑Glucuronidase
MPS IX Y Hyaluronidase
Glycogen storage disease
Pompe (glycogen storage disease typeII) Y
α‑Glucosidase
Oligosaccharidoses
α‑Mannosidosis
Y
α‑Mannosidase
β‑Mannosidosis
Y
β‑Mannosidase
Fucosidosis Y
α‑Fucosidase
Aspartylglucosaminuria Y Aspartylglucosaminidase
Schindler disease Y
α‑N‑acetylgalactosaminidase
Sialidosis Y
α‑Neuraminidase
Galactosialidosis Y Lysosomal protective protein
Mucolipidosis II (I‑cell disease); mucolipidosis III Y Urine diphosphate‑N‑acetylglucosamine;
lysosomal enzyme N‑acetylglucosaminyl‑1‑
phosphotransferase
Integral membrane protein disorders
Cystinosis N Cystinosin
Danon disease Y Lysosome‑associated membrane protein 2
Action myoclonus–renal failure syndrome N Lysosome membrane protein 2
Salla disease Y Sialin
Niemann–Pick disease type C1 Y NPC‑1 , NPC‑2
Mucolipidosis IV Y Mucolipin
Additional disease types
Multiple sulphatase deciency Y Sulphatase‑modifying factor 2
Niemann–Pick disease type C2 Y NPC‑2
Wolman disease (infantile); cholesteryl ester storage disease N Lysosomal acid lipase
Galactosialidosis Y Cathepsin A
Abbreviations: MPS, mucopolysaccharidosis; NPC‑1, Niemann–Pick disease type C1 protein; NPC‑2, Niemann–Pick disease type C2 protein.
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hydrolase. Over time this classification has expanded to
include diseases caused by defects in lysosomal mem-
brane proteins that do not, therefore, follow the ‘classic’
naming approach (Table 1).
LSDs are rare: the aggregate frequency of these dis-
orders is estimated at 1 in 5,000 live births.
10
Some
LSDs have ethnic and/or geographical predilections; for
example, Tay–Sachs and Gaucher disease are prevalent in
Ashkenazi Jews.
4
Tay–Sachs is also common in the French
Canadian population and in those of Acadian descent,
4
whereas Salla disease and aspartylglucosaminuria are
associated with Finnish ancestry.
14,15
Severity and age of onset in LSDs are dictated by a
number of factors including: residual enzyme activ-
ity; mutant protein size; location of the mutation with
respect to catalytic site; distribution of tissue-specific
and cell-specific substrates; cell turnover rate; defective
protein expression; and other mechanisms that influence
the life span of the affected cells. Presence of residual
enzyme activity can result in mild and late-onset forms
of GM2-gangliosidosis such as the juvenile and adult
variants, juvenile or adult MLD, or the cardiac variant
of Fabry disease.
16,17
The NCLs
Reports of juvenile NCL preceded those of Tay–Sachs
disease by 55years, with the first case of juvenile NCL
being documented in 1826.
18,19
Most childhood subtypes
of NCL are characterized by a combination of cognitive
and motor decline, loss of vision, seizures and early
death.
20
In general, the NCLs are pathologically charac-
terized by storage of autofluorescent material (includ-
ing protein subunit C of mitochondrial ATP synthase
or saposins) within neuronal lysosomes,
21
which is
reminiscent of lipofuscin storage in the ageing brain
and other tissues. The various NCLs are characterized
by electron-dense ultrastructural features that are unique
to each disorder, and the aberrant storage is accompa-
nied by neuronal death and cerebral and/or cerebellar
corticalatrophy.
In 1896, Sachs coined the term ‘amaurotic familial
idiocy’ to describe Tay–Sachs disease.
3,6
This term was
subsequently used by Batten in 1903,
22
Vogt in 1905 and
1909,
12,23
Janský in 1908
24
and Bielschowsky in 1913,
25
as a unifying term to describe a group of disorders that
encompassed Tay–Sachs disease and juvenile and late-
infantile NCL. In 1939, however, Klenk identified dis-
tinct biochemical changes in brains from patients with
juvenile NCL
26,27
compared with in brains from patients
with Tay–Sachs or Niemann–Pick disease. Svennerholm
later confirmed that accumulation and altered structure
of gangliosides in the brains of patients with Tay–Sachs
disease were not evident in the brains of patients with
the other disorders.
28
14 distinct genetic NCL variants are now recog-
nized (Table2). The NCLs are caused by defects in
Table 2 | Human neuronal ceroid lipofuscinoses variants
Disease Eponym OMIM Clinical phenotype Gene Gene product
CLN1 Haltia–Santavuori 256730 Classic infantile, lateinfantile,
juvenile, adult*
CLN1
(PPT1)
PPT‑1
CLN2 Janský–Bielschowsky 204500 Classic late infantile,
juvenile*
CLN2
(TPP1)
TPP‑1
CLN3 Spielmeyer–Sjögren 204200 Juvenile* CLN3 CLN3 protein (battenin)
CLN4 Parry 162350 Adult autosomal dominant* CLN4
(DNAJC5)
DnaJ homologue subfamilyC
member 5
193
CLN5 Finnish variant late infantile,
variant juvenile (previously CLN9)
256731 Late infantile variant,
juvenile, adult*
CLN5 Protein CLN5
CLN6 Early juvenile (Lake Cavanaugh),
late infantile Costa Rican‑Indian
variant, adult Kuf type A
601780 Late infantile variant, adult*
(Kuf, type A)*
CLN6 Protein CLN6
CLN7 Turkish variant late infantile 610951 Late infantile variant*,
juvenile*, adult*
CLN7
(MFSD8)
Major facilitator superfamily
domain‑containing protein 8
CLN8 Northern epilepsy,
progressive EPMR
610003 Late infantile variant EPMR* CLN8 Protein CLN8
CLN10 Congenital 610127 Congenital classic*,
lateinfantile*, adult*
CLN10
(CTSD)
Cathepsin D
CLN11 Adult variant — Adult* CLN11
(GRN)
Progranulin
194
CLN12 Juvenile variant — Juvenile, Kufor–Rakeb
syndrome*
CLN12
(ATP13A2)
—
CLN13 Adult Kuf type B — Adult Kuf type* CLN13
(CTSF)
Cathepsin F
CLN14 Infantile — Infantile, progressive
myoclonus epilepsy 3*
CLN14
(KCTD7)
Potassium channel
tetramerization domain‑
containing protein 7
195
*These diseases have neurological involvement. Abbreviation: EPMR, epilepsy with mental retardation.
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Table 3 | Human lysosome‑related organelle disorders
Disorder Mutant
gene
Mutant
protein
Protein complex Clinical picture
Hermanski–Pudlak
disease types 1–8
HPS1
HPS2
HPS3
HPS4
HPS5
HPS6
HPS7
HPS8
HPS1
HPS2
HPS3
HPS4
HPS5
HPS6
HPS7
HPS8
BLOC‑3 AP‑3 adaptor
BLOC‑2
BLOC‑3
BLOC‑2
BLOC‑2
BLOC‑1
BLOC‑1
BLOC
Hypopigmentation of skin and/or eyes; bleeding diathesis;
progressive pulmonary brosis; accumulation of degraded
material in lysosomes
Griscelli 1 (or
Elejalde syndrome)
MYO5A Myosin VA Myosin VA–RAB27–
melanophillin
tripartite complex
Hypopigmentation of skin and hair; severe neurological
problems early in life; lack of melanocyte transfer from
melanocytes to keratinocytes
Griscelli 2 RAB27A Rab‑27 Myosin VA–RAB27–
melanophillin
tripartite complex
Hypopigmentation of skin and/or hair; immune defect
owing to decreased exotycosis of lytic granules in
cytotoxic T lymphocytes; lack of melanocyte transfer
from melanocytes to keratinocytes
Griscelli 3 MLPH Melanophillin Myosin VA–RAB27–
melanophillin
tripartite complex
Hypopigmentation of skin and/or hair; perinuclear
accumulation of melanosomes owing to ineffective
capturing of melanosomes by the actin network
Chediak–Higashi
disease
LY ST Lysosome
trafcking
regulator
LYST or lysosome
trafc regulator
Hypopigmentation of skin and/or hair; bleeding
diathesis; giant azurophilic granules
In children: life‑threatening skin and/or lung infections
owing to decreased cellular immunity
In adults: ataxia, cerebellar signs, neuropathy, autonomic
problems, seizures, cognitive impairment
Abbreviation: BLOC, biogenesis of lysosome‑related organelle complexes.
Early
endosome
Late
endosome
Recycling
endosome
Lysosome
Autophagy
Mitochondrion
Trans-Golgi
network
Nucleus
Lipid raft
Receptor
LigandAltered lipid content and
lipid raft stoichiometry
ER
ER stress
Unfolded protein
response
Proteasome
Unfolded
protein
Signalling
cascades
Neuronal
inammation and
glial activation
Demyelination
Autophagosome
vacuole
Lysosphingolipid
Lysosome
Endocytosis
Apoptosis
Figure 1 | Lysosomal storage and secondary mechanisms leading to cell death in neurons. Lysosomal storage in neurons is
accompanied by amplification of cellular processes with negative effects on neurons, glia, Schwann cells and the brain. These
processes include activation of ligand–receptor‑mediated signal transduction pathways, alteration of lipid trafficking and lipid‑
raft content and stoichiometry, heightened ER stress and a calcium‑mediated unfolded protein response, lysosphingolipid
storage, and glial activation with subsequent neuroinflammation and demyelination. These processes collectively culminate
to drive accelerated apoptosis and dysregulation of autophagy. Abbreviation: ER, endoplasmic reticulum.
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ceroid-lipofuscinosis, neuronal (CLN) proteins or CLN
genes, which was an unfortunate nomenclature choice
as ‘CLN’ is also used to refer to the cyclin genes, but the
nomenclature is now deeply embedded in NCL litera-
ture. Gene discovery for the NCLs began in 1995 with
identification of defects in endosomal–Golgi membrane
protein CLN3 as the cause of juvenile NCL (also known
as CLN3 disease).
29,30
Other defects in soluble lysoso-
mal proteins, namely, protein palmitoyl thioesterase 1
(PPT-1) and tripeptidyl peptidase 1 (TPP-1), have been
found to cause infantile and late-infantile forms of the
disease, respectively.
31
CLN6 and CLN8 are ER-resident
proteins that cause variant late-infantile forms of NCL,
and CLN6 defects also account for adult NCL (known as
Kuf disease type A).
31
Cathepsins D and F have now been
identified as the cause of congenital NCL and Kuf disease
type B, respectively.
18,31,32
Most NCLs are inherited in an autosomal recessive
manner, but some patients with the adult variant of
NCL show autosomal dominant inheritance.
31
Despite
a worldwide distribution pattern, the incidence of NCLs
varies depending on geographical location, ranging
from 1 in 14,000 people in Iceland to 1 in 67,000 in
Italy and Germany, with prevalence estimates ranging
from 1 per 1,000,000 in some regions to 1 in 100,000
in Scandinavian countries.
33
Scandinavian regions
have a high incidence of CLN3 disease and infantile
CLN1 disease, as well as epilepsy with progressive
mental retardation (also known as CLN8 disease or
Northern Epilepsy). Cases of variant late-infantile NCL
have been described in Costa Rica, Portugal, India,
USA, the Czech Republic (CLN6 disease) and Turkey
(CLN7disease).
31,32
Other disorders
From a pathobiological point of view, diseases of
lysosome- related organelle dysfunction and defects in
biogenesis and/or trafficking of endosomes and lyso-
somes can reasonably be included in the spectrum of
LSDs (Table3). One such disorder, Chediak–Higashi
disease, is caused by a defect in vesicular fusion.
11,34
Hermanski–Pudlak disease arises from problems in
exocytosis and mis-sorting of tyrosine-related proteins
from early endosomes to melanosomes, manifesting
with lung pathology secondary to loss of surfactant
phospholipid.
35
Griscelli syndrome is due to altered
vesicular trafficking.
36
These three disorders manifest
with lysosomal inclusions, varying degrees of albinism,
bleeding and/or immunity problems and, in the case of
Griscelli syndrome, neurodegeneration.
11
Common features of NCLs and LSDs
NCLs and classic LSDs are distinct genetic and biochem-
ical diseases, yet certain features bridge the two: both
cause neuronal storage defects and cell death in the brain,
with broadly similar manifestations of neurocognitive
decline, blindness, seizures and premature death. The
characteristic feature of storage of material within lyso-
somes supports the common grouping of these two dis-
orders. Another shared thread between LDSs and NCLs
is that four NCLs (namely, CLN1, CLN2, CLN10 and
CLN13 disease; Table2) are caused by defects in lyso-
somal enzymes, suggesting that some of the NCLs are
also amenable to enzyme or gene replacement therapy
or cell-based therapies.
Distinctions between LSDs and NCLs do, however,
exist. Most NCLs are caused by defects in insoluble
transmembrane proteins, whereas in classic LSDs most
defects involve degradative hydrolases, with accumula-
tion of related undegraded substrates in lysosomes. In
NCLs, the nature of the stored material is not directly
related to the defective protein, even in those caused by
defects in soluble enzymes such as in TPP-1, PPT-1 and
cathepsins.
37
This finding suggests that storage in classic
LSDs is more of a primary cause–effect phenomenon
whereas, in NCLs, lysosomal storage can be caused by
defects in secondary processes of membrane turnover or
altered endosome and/or lysosome trafficking.
Organ involvement
Which organs are affected in LSDs is thought to be par-
tially dependent on the nature of the substrates that accu-
mulate and their specific cellular distribution, as well
as the cell turnover rate in each tissue. Sphingolipids,
galactosylceramide and sulphatide are important com-
ponents of the brain and PNS, which could explain the
preferential involvement of the brain and nerves in these
diseases.
6
Other mechanisms that contribute to specific
organ pathology in LSDs are discussed below (under the
heading ‘Pathobiology of disease’).
In Gaucher disease, Niemann–Pick disease and the
MPSs, GM1-gangliosidosis and multiple sulphatase defi-
ciency, aberrant lysosomal storage manifests as hepato-
splenomegaly because the accumulating substrates in
these disorders are naturally present in the liver and
spleen. Deposition of glycosaminoglycans (GAGs) in
heart valves and connective tissues in part explains the
cardiomyopathy that is common in MPSs, particularly
Maroteaux–Lamy disease (MPS VI). Patients with this
disorder also develop fibroelastosis, pulmonary hyper-
tension, cardiac conduction system disorders and acute
heart failure.
38
Deposition of GAGs in dura and ligaments
can lead to cervical spinal cord strangulation and carpal
tunnel syndrome, respectively, and these complications
require surgical intervention.
39
Both entities can occur in
all MPSs, but are particularly severe in MPSVI.
40
Dysostosis multiplex—a disorder that is character-
ized by abnormal bone and/or cartilage growth with
deformities involving vertebrae, ribs and extremities—
is caused by deposition of GAGs in growth plates and
cartilage, leading to inflammation and tissue destruc-
tion. Signs of dysostosis multiplex are conspicuous in
patients with MPS who have short stature, scoliosis and
atlanto-occipital instability.
41
Pulmonary deposition of GAGs can lead to restric-
tive lung disease, as observed in Niemann–Pick disease,
typeB (NPB, the visceral form of this disease).
42
Severe
skeletal involvement in MPS I, II, IV and VI culminates
in restrictive lung disease in the MPSs.
43,44
In MPS IV, ele-
vation of antero-posterior diameter of the chest, pectus
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carinatum, widened ‘oar-shaped’ ribs and short thorax,
as well as kyphoscoliosis, are common.
43
Elevation of the
diaphragm owing to hepatosplenomegaly and inflex-
ibility of costo-vertebral joints can lead to inefficient
mechanical movements of the chest in patients with MPS.
Coarse facial features in patients with MPS I and II
result from infiltration of GAGs into mucosal and soft
tissues, and GAG deposition can restrict the airway.
Features of MPS I, II, VI and VII include a flat nasal
bridge, prominent cheek bones and supra-orbital ridges,
full lips, mouth-breathing and macroglossia, which all
predispose patients to pharyngeal collapse and obstruc-
tive sleep apnoea.
43
In severe cases of MPS I and II, GAG
deposition in the adenoids, tonsils and epiglottis can
contribute to upper-airway obstruction and laryngo-
malacia.
43
Lower-airway obstruction in MPSs increases
with age in MPS I, II, IV and VI.
45–48
The reticuloendothelial system (composed of bone
marrow, spleen and blood vessels) is often involved
in LSDs, with hypersplenism and anaemia being par-
ticularly prominent in Gaucher disease.
49
Cutaneous
manifestations, including ‘peau d’orange’ and peb-
bling of the skin, are seen in Hunter disease.
50
Coarse
hairand hirsutism—the latter being obvious as syn-
ophris andincreased facial and/or body hair—are
present in the MPSs.
51
Purplish, elevated lesions called
‘angiokeratoma corporis diffusum’ occur in a bathing-
trunk distribution in Fabry disease in prebubertal males,
and can provide an important diagnostic clue.
4
Corneal
clouding is present in most of the MPSs and varies in
severity, being least conspicuous in Hunter disease.
52
Conjunctival tortuosities and spokewheel-like lenticular
opacities are indicative of Fabry disease.
53
Neuropathology
Certain features of the brain, such as its limited capacity
for regeneration, high sensitivity of neurons to damage
and the need for prolonged neuronal survival,
54,55
mean
that this organ is particularly vulnerable to LSDs. The
brain and/or PNS are affected in most of the known LSDs
and NCLs (Tables1, 2 and 3) and are the sole affected
organ in Tay–Sachs disease, Krabbe disease, MLD and
the NCLs. As sphingolipids, phospholipids, galactosyl-
ceramide and sulphatide are important components of
the brain, excess storage of these compounds can lead
to neurological symptoms. Disruption of synaptic archi-
tecture and neuronal transmission can also contribute
to neuropathology in LSDs. In my view, a threshold of
neuronal loss, aggravated by chronic inflammation and
further neuronal loss, leads to neurological symptoma-
tology and progression, particularly in the setting of
very limited regenerative capacity in the brain and PNS.
Neuronal death in LSDs causes a range of symptoms
including neurocognitive delay, regression, blindness,
deafness, seizures, spasticity, contractures, movement
disorders and early death.
56,57
Blindness in patients with LSDs is attributable to depo-
sition of whitish lipids in the surrounding retina. The
absence of deposits in the macula gives a red appear-
ance, hence the name ‘cherry red spots’—a feature that
is charac teristic of the gangliosidoses, Niemann–Pick
disease type A (NPA) and NPB, and is observed in sia-
lidosis, mucolipidoses II and III and galactosialidosis.
58
In the NCLs, blindness can arise following retinitis pig-
mentosa owing to photoreceptor death, and retinitis
pigmentosa is also seen in Hunter disease and some of
the Sanfilippo disease variants.
59,60
Optic atrophy with
pale discs and attenuated retinal vessels occurs in MLD,
Krabbe disease and some other LSDs.
61–64
The PNS is affected in Fabry disease and manifests as a
painful small-fibre neuropathy at the extremities. Sensory
and motor neuropathy is common in Krabbe disease and
MLD, characterized by absence of deep-tendon reflexes
and slow nerve- conduction velocities. Pompe disease is
characterized by a progressivemyopathy.
65
The traditionally held view that neurological symp-
toms and signs of LSDs are only correlated with physical
and mechanical disruption of neurons that is second-
ary to the storage defect is not necessarily correct.
Pathogenesis in most CNS-related and PNS-related
LSDs involves neuronal dysfunction that is independ-
ent of neuronal storage.
7
The deleterious outcome in
Krabbe disease, for example, is not caused by accumu-
lation of galactosylceramide but is attributable to sec-
ondary increase in the lysosphingolipid psychosine.
66
In the MPSs, substrate accumulation in adjacent, non-
neural tissues can lead to neurological complications;
examples include carpal tunnel syndrome and spinal
cord compression in MPS I, VII and IV, and cerebro-
vascular stroke in some cases of Fabry disease.
67,68
Other
neuro logical complications in LSDs include hydro-
cephalus resulting from GAG deposition, collagen
proliferation in the meninges and/or arachnoid villi,
and histio cytic infiltration.
69–72
In MPS II and III, lyso-
somal storage occurs in neurons, which can lead to brain
atrophy.
73
Involvement of pyramidal tracts (such as in
juvenile MLD and Kuf disease, α and β-mannosidosis,
fucosidosis and many NCLs) or the cerebellum (in
α-mannosidosis and β-mannosidosis, sialidosis, juve-
nile GM2-gangliosidosis, CLN3 and CLN2 disease) are
evident in disparatediseases.
As each neuronal cell or glial cell subtype can syn-
thesize different sphingolipids, LSD pathologies can
be cell-specific, and different disorders can manifest
with diverse neurological syndromes.
74
Late-onset
GM2 disease type B, Gaucher disease typeIII and
NPC each present with distinct eye-movement dis-
orders. Limitation of upward gaze is a common finding
in NPC, and serves as a valuable clinical sign of this
disorder.
75
Parkinsonian features are seen in late-onset
GM1-gangliosidosis, Gaucher disease typeI and CLN3
(juvenile Batten) disease,
76,77
whereas Krabbe disease
and MLD are leukodystrophies with involvement of
long tracts and peripheral nerves.
78–81
Optic-nerve
atrophy and retinopathy are common in the NCLs and
some classic LSDs that profoundly affect the brain, optic
nerves and/or PNS, causing blindness, motor and/or
cognitive decline, intractable seizures, movement and
eye-movement disorders, and death.
26,59,60
The shared
features of these disorders suggest that the various
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proteins involved in NCLs operate in similar functional
pathways, or that common mechanisms of neuronal
dysfunction are involved in these disorders.
26
Pathobiology of disease
Our understanding of complex pathophysiological
processes underlying the LSDs and NCLs is increasing
exponentially, but is far from complete. Numerous mech-
anisms have emerged as contributors to disease propaga-
tion. These features are discussed below, with specific
LSD or NCL disease examples for each.
Activation of cell-death signalling
Some compounds associated with LSDs—such as
galacto sylceramide (GalCer) in Krabbe disease or
GAGs in the MPSs—act as ligands for signal transduc-
tion receptors. Aberrant storage of these molecules can,
therefore, alter activation of receptors or enzymes that
are involved in signalling cascades.
7,10
GAGs are similar
to lipopolysaccharide in that they activate Toll-like recep-
tor 4 (TLR4).
82–85
In animal models of MPS VI or VII,
chondro cytes secrete proinflammatory cytokines that
increase metalloprotease activity, leading to subsequent
cartilage degeneration and activation of TLR4 by GAGs.
82
Activation of this receptor leads not only to upregulation
of proapoptotic ceramide in the chondrocytes, thereby
causing cell death, but also to proliferation of synovial
cells owing to an increase in levels of sphingosine- 1-
phosphate. In Hurler disease, excess storage of heparin
sulphate can lead to modulation of signalling mediated
by fibroblast growth factor 2 and transforming growth
factor β, which contributes to neuronal cell death, neuro-
degeneration and bone pathology.
86
Apoptosis occurs at
an accelerated rate in a number of the NCLs, particularly
in CLN3 disease (discussed below).
87–89
Wild-type CLN5
and CLN8 proteins act as ceramide synthase activators,
which suggests a role for modulation of sphingolipid-
activated cell-death signalling pathways in CLN5 and
CLN8 disease.
32
Alteration of lipid content
Alterations of plasma membrane lipid content and lipid
raft stoichiometry can also affect receptor responses
and subsequent signalling events. This phenomenon is
observed in NPC1, in which cholesterol accumulation
in lysosomes leads to increased membrane fluidity and
decreased insulin signalling.
90–92
Furthermore, altered
trafficking of a short-acyl-chain derivative of lactosyl-
ceramide—an important component of lipid rafts—leads
to its aberrant accumulation in late endosomes and/or
lysosomes (as opposed to its usual localization in the
Golgi body). This pathological feature is observed in
GM1 and GM2 gangliosidosis, MPS IV, MLD, prosa-
posin deficiency and Fabry disease, as well as in NPA,
NPB andNPC.
93,94
In CLN3 disease, defects of CLN3 protein affect sphingo-
lipid stoichiometry in lipid rafts. As wild-type CLN3
protein aids in GalCer transport to lipid rafts,
95
defects
in CLN3 lead to impaired anterograde GalCer traffick-
ing from the Golgi body to lipid rafts. The consequent
reduction in GalCer content drives the generation of
proapoptotic ceramide, which activates caspase-8 and sub-
sequent executor caspases, and culminates in acceleration
of apoptosis.
88,89,95,96
Transfection of CLN3-deficient cells
with CLN3 cDNA can correct the GalCer deficit, as can
treatment of cells with exogenous GalCer: both treatment
approaches were shown to restore cell growth and to confer
resistance to apoptosis.
97
Exploration of the effect of defects
in lipids and lipid trafficking through exogenous modifi-
cation of these factors has uncovered exogenous GalCer
administration as a potentially beneficial therapy for CLN3
disease in Cln3 knock-in mice.
97
Lysosphingolipids—bioactive compounds that accu-
mulate alongside sphingolipids in sphingolipid degrada-
tion disorders—deserve special mention in this Review
given the devastating effect of alterations of these com-
pounds on the brain and PNS. Lysosphingolipids are
sphingolipids that contain a sphingoid-base free amino
group, the best studied of which is psychosine, a lyso-
sphingolipid that is derived from GalCer. Excessive
accumulation of psychosine is associated with Krabbe
disease:
98
psychosine inhibits cytokinesis via interaction
with the orphan G protein-coupled receptor 8 (TDAG8),
so excessive accumulation of this lipid results in genera-
tion of the multinucleated giant cells that are charac-
teristic of Krabbe disease.
99
Psychosine also inhibits
protein kinase C, a signalling molecule that attenuates
the response of Schwann cells and oligodendrocytes
to growth factors, so excessive cellular accumulation
of psychosine sensitizes these cells to apoptosis.
66,98
Furthermore, through activation of phospholipase A
2
,
psychosine drives an increase in arachidonic acid and
lysophosphatidylcholine, which leads to caspase-3 acti-
vation, apoptosis and subsequent demyelination in both
the CNS and PNS.
100,101
In Gaucher disease, glucosylsphingosine (another
lyso sphingolipid) accumulates in the brain and contrib-
utes to the neurodegenerative process in patients with
neuropathic forms of the disease.
102
In the gangliosidoses,
GM2 and GM1 accumulate in lysosomes,
103
whereas in
Fabry disease accumulation of lysoglobotriaosylsphingo-
sine causes proliferation of smooth muscle cells, result-
ing in thickening of the intima media and subsequent
vascular obstruction.
104
Prolonged inflammation
The reticuloendothelial system is the major storage site
in many LSDs, particularly Gaucher disease and NPA,
NPB and NPC.
105,106
Injury to neurons leads to activation
of microglia and release of inflammatory mediators from
these cells—a process that is aggravated by subsequent
activation of signalling cascades in response to cytotoxic
disturbances in the brain.
107,108
Glial activation is initially
a survival response and, in cases such as meningitis,
stroke or head injury, is a finite process that subsides
once the insult ends. In LSDs, however, an increasing and
lifelong storage load in neurons provides a constant stim-
ulus for glial activation and inflammation that ultimately
leads to neuronal destruction. Inflammation, although
secondary to the storage disorder, contributes to the
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neurodegenerative process in many LSDs and NCLs, and
is, therefore, a promising therapeutic target.
108,109
ER–cytosol calcium balance
In Gaucher disease, calcium release from the ER into the
cytosol is increased owing to activation of the ryanodine
receptor, driven by excess intracellular accumulation of
glucosylceramide (GluCer).
78
This process is evident in
the brain of patients with neuropathic Gaucher disease
types II and III.
78,110,111
In GM1-gangliosidosis and GM2-
gangliosidosis, reduction of calcium uptake by the ER can
occur owing to inhibition of the sarcoplasmic–ERcalcium
ATPase (SERCA) transporter. This transporter prevents
calcium-evoked cellular responses,
112
so its inhibition
aggravates neuronal apoptosis and contributes to neuro-
degeneration in GM2-gangliosidoses (Tay–Sachs and
Sandhoff disease) and in other LSDs that display GM2-
ganglioside accumulation.
112,113
Reduced expression of the
SERCA transporter is also evident in the cerebellum of an
NPA mouse model that is pathologically characterized by
accumulation of sphingomyelin.
114
Although cellular calcium-related regulatory mecha-
nisms are not yet fully elucidated, it is clear that glyco-
sphingolipids and phospholipids can modulate ER and
cytosolic calcium levels. These pathways could, there-
fore, lend themselves to therapeutic manipulation with
organelle- specific calcium channel blockers for treat-
ment of LSDs. Two such drugs that are currently used for
treatment of hypertension—diltiazem and verapamil—
are reported to have beneficial effects in fibroblasts
derived from patients with Gaucher disease, SanfilippoA
(MPSIIIA) or α-mannosidosis.
6
The unfolded protein response
Diminished ER calcium stores and other ER pertur-
bances activate the UPR, which initiates ER stress and
apoptosis.
115,116
Activation of the UPR has been described
in the brain and other organs in individuals with CLN1
disease, as well as in brains from patients with GM1-
gangliosidosis.
115,116
Clearly, accelerated apoptosis is
a recurring theme in LSDs, NCLs and other neuro-
degenerative disorders.
101,117,118
Notably, neurons that are
primed to die through apoptosis can be saved if interven-
tionoccurs before mitochondrial membrane depolari-
zation occurs.
119
Antiapoptotic agents that traverse the
blood–brain barrier (BBB) will, therefore, have an impor-
tant place in the drug armamentarium in treating LSDs
as well as neurodegenerative diseases such as Huntington
disease, Parkinson disease and Alzheimer disease.
Dysregulation of autophagy
Autophagy is a process that involves self- cannibalization:
cellular proteins are recycled and damaged organelles
are removed through their integration into autophago-
somes, with some being targeted for digestion via
autophagosome– lysosome fusion. These processes
function as a survival response during times of cel-
lular stress such as starvation
120,121
but, when taken to
the extreme, autophagy can promote apoptosis either
by acting alone or as an executor of programmed cell
death.
122
Dysregulation of autophagy has been implicated
in many neurodegenerative diseases, including classic
LSDs and CLN3 disease.
123,124
Given that the lysosome
and autophagosome are united for part of their journey
through the cell, the link between autophagy and LSDs is
to beexpected.
125,126
Altered lipid trafficking and autophagic vacuole flux
are two other mechanisms that cross paths with auto-
phagy. In autophagy-associated disorders, induction of
autophagy can be either inhibited or activated. Activation
of autophagy is visualized as an increase in conversion of
microtubule-associated protein 1A/1B-light chain 3 (LC3)
from the cytosolic form (LC3-I) to the autophagosome-
associated form (LC3-II), as well as an increase in the
level of an autophagy related protein, beclin1.
127
InCLN3-
deficient lymphoblastoid cells and fibroblasts, activationof
autophagy occurs downstream of caspase-8 activation and
apoptosis.
88
In cerebellar cells from Cln3-deficient mice,
addition of exogenous lithium diminishes the number of
LC3-II positive cells (that is, cells containing autophago-
somes) by restoring autophagic flux.
128
In multiple sul-
phatase deficiency and Sanfilippo A disease (MPS IIIA),
however, reduction of vacuole flux occurs secondary to
impaired lysosome–autophagosome fusion.
129
Autophagy
is activated in NPC,
127
CLN3 disease, Sandhoff disease,
GM1-gangliosidosis,
7,96,129
and in Pompe disease, in
which increased autophagy is linked to a disturbance of
trafficking of the enzyme α-glucosidase.
125
Therapeutic approaches
Enzyme replacement
Enzyme replacement therapies (ERTs) are currently
approved and in clinical use for non-neuropathic typeI
Gaucher disease, Fabry disease, Scheie syndrome (MPSIS),
Hurler–Scheie disease (MPS IS/H), Hunter disease
(MPSII), Maroteaux–Lamy syndrome (MPSVI) and
early-onset and late-onset Pompe disease.
9
Clinical trials
of ERTs are ongoing for α-mannosidosis, Wolman cho-
lesteryl storage disease, Morquio syndrome (MPSIVA)
and NPB.
130–133
The role and benefit of ERTs is beyond the
scope of the Review, but these topics have been extensively
reviewed elsewhere.
6,7,9,10
A multitude of clinical trials
using intra thecal recombinant enzymes are ongoing, most
notably for Sanfilippo A, Hurler disease, and MLD.
134–136
Combination therapies comprising peripheral ERT plus
bone marrow transplantation and/or intrathecal therapies
are also underinvestigation.
137,138
Substrate reduction therapy
The goal of substrate reduction therapy (SRT) is
to decrease glycosphingolipid synthesis to a level
that is manageable given the impaired degrada-
tive capacity of the cell. The imino sugar N-butyl-
deoxygalactonojirimycin (also known as miglustat)—a
competitive inhibitor of ceramide glucosyltransferase—
reversibly blocks GluCer synthase, the first step in glyco-
sphingolipid biosynthesis.
139,140
Miglustat has shown
potential for treatment of LSDs that are caused by storage
of GluCer or GluCer-based glycoshphingolipids; the
drug is approved for treatment of Gaucher I and III and
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NPC, and is effective in disease mouse models that are
characterized by accumulation of gangliosides (such
as models of GM1, GM2 and GM3-gangliosides).
141–144
One advantage of SRT and pharmacological chaperones
(discussed below) over other therapies is that they cross
the BBB. Drawbacks to SRT include adverse effects of
decreased glycosphingolipid synthesis such as flatulence,
cramps and diarrhoea, and development of numbness,
hand tremors and peripheral neuropathy, although many
of these effects dissipate with prolonged drug use.
6,142
Pharmacological chaperones
Pharmacological chaperones (PCs) are enzyme inhibi-
tors that can be given at suboptimal concentrations.
PCs stabilize the conformation of mutant proteins by
binding them, promoting their folding (thereby per-
mitting bypass of the ER quality-control system) and
enhancing their trafficking to Golgi and lysosomes,
which ultimately raises residual enzyme activity.
145
1-deoxygalactonojirimycin (also known as migalastat
hydrochloride) is a potent and specific active-site inhibi-
tor of α-galactosidase A that has shown beneficial effects
in murine models of Fabry disease.
145
This drug could
prove useful in patients with missense mutations that
cause misfolding of mutant α-galactosidase A, and is
currently in clinical trials for Fabry disease.
146
Combination therapy with ERT and migalastat hydro-
chloride has proved particularly effective in a murine
model of Fabry disease.
145
Eliglustat tartrate, an inhibitor
of β-glucosidase, is in phaseIII clinical trials for treat-
ment of Gaucher disease I, and is being tested either
alone or in combination with ERT.
147
Treatment with
the -iminosugar LABNAc—a noncompetitive inhibi-
tor of β-N-acetylhexosaminidase and pyrimethamine
(a mutation-specific inhibitor that enhances residual
hexosaminidase A)—led to elevation of enzyme levels
in cells from adult patients with Tay–Sachs disease.
148,149
Presymptomatic bone marrow transplantation
Haematopoetic stem-cell transplantation (HSCT)
has shown benefit in individuals with asymptomatic
Krabbedisease, and also some efficacy in patientswith
Hurler disease
63,150,151
and, anecdotally, in patients
withlate-onset forms of MLD. Stem-cell therapies, par-
ticularly neural stem-cell therapies, have proved benefi-
cial in animal models of LSDs, and are currently under
investigation in CLN2 disease.
152,153
Virally mediated gene therapies
Viral gene therapies have shown therapeutic benefit in
animal models of LSDs but have been difficult to imple-
ment in humans, as shown by the limited success of this
approach in patients with CLN2 disease.
154
Intracerebral
or intraventricular enzyme and/or gene and cell-based
therapies have proved effective in mouse models, but
their feasibility and efficacy in humans remain ques-
tionable.
37,154,155
A number of trials are, however, ongoing,
including: retroviral-mediated transfer and expression of
cDNA for glucocerebrosidase and α-galactosidase A in
human haematopoietic progenitor cells; a phaseI/II trial
of diaphragm delivery of the acid α-glucosidase gene via
a recombinant adeno-associated virus (AAV) vector in
patients with Pompe disease;
156
a phaseI/II open-label,
single-centre study of intracranial administration of a
replication-deficient AAV gene transfer vector express-
ing cDNA against human aryl sulphatase A to children
with MLD;
157
a phaseI/II clinical study of intracerebral
administration of AAV carrying cDNA against human
heparin-N-sulphamidase and sulphatase-modifying
factor 1 for treatment of Sanfilippo type A.
158
Stop-codon readthrough technology
Stop-codon readthrough technology is an emerging field
that could potentially be used to treat genetic diseases that
are caused by premature insertion of stop codons—genetic
shorthand markers that indicate where the gene ends.
These types of mutations result in shortened proteins with
poor function. Stop-codon readthrough technology uses
small molecules that cross the BBB and prompt the cell
to disregard the premature stop codon, thereby allowing
generation of a full and functional protein.
159
Hypothesis-driven therapies
Therapies aimed at restoration of normal biochemical
or cell biological processes are necessary for success-
ful treatment of disorders that are characterized by
defects in integral and nonsoluble structural mem-
brane protein that are not amenable to the therapies
described above. The antiapoptotic drug flupirtine
maleate is used for treatment of various forms of Batten
disease, although no formal trials of this drug have yet
been conducted.
119
Phosphocysteamine is a drug that
breaks ester linkages and, therefore, acts in place of the
missing enzyme in CLN1 disease or the infantile form
of NCL.
160
Notably, however, no definitive improvement
in patient outcome has been reported with this drug.
Nonsteroidal anti-inflammatory or immunomodula-
tory therapies have shown therapeutic benefit in mouse
models of a number of LSDs,
161
and mycophenolate
mofetil (another anti-inflammatory drug) has proved
beneficial in Cln3-deficient mice.
109
Various preclinical approaches to LSDs are also being
pursued. Genistein-mediated inhibition of GAG syn-
thesis is one suggested treatment for patients with MPS
disorders,
162
and use of δ-tocopherol to reduce lipid accu-
mulation has been proposed for NPC1 and Wolman cho-
lesterol storage disease.
163
Cholesterol storage in NPC1
inhibits Rab GTPases that normally activate exocytosis.
164
In cells derived from mice that lack the Npc1 protein,
treatment with methyl-β-cyclodextrin (a compound that
removes cholesterol from membranes), or overexpression
of Rab4, led to a reduction in lysosomal storage.
165
This
approach could be applicable to other LSDs that show
impaired exocytosis. Heat shock protein 70 has been
shown to stabilize lysosomes, and treatment of cells from
patients with Niemann-Pick disease with this compound
was found to reduce disease-associated pathology.
166
The BBB represents a formidable obstacle that thera-
pies targeting brain-specific pathologies must penetrate
(discussed below). One example of brain-specific LSD is
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MPS typeII (Hunter disease), which is caused by muta-
tions is iduronate 2-sulphatase (IDS). In an attempt to
overcome the BBB, researchers have developed a brain-
penetrating IgG–IDS fusion protein that can enter the
brain in mouse models of MPS.
167
Other approaches to
overcome tissue barriers are under investigation, and
include exploitation of glycosylation-independent lyso-
somal targeting in murine models of Pompe disease,
168
or addition of amino acid tags to drugs to enhance their
targeting to bone in mice with MPS VII.
169
Evolving therapies for NCLs
No approved therapies are available for the NCLs, which is
not surprising given that gene discovery in these disorders
did not begin until 1995.
In disorders caused by mutations in the soluble
enzymes TPP-1 and PPT-1—which are associated with
CLN2 disease and CLN1 disease, respectively—the
storage of material in lysosomes (subunit C of mito-
chondrial ATPase in CLN2 disease and saposins in CLN1
disease) is not a direct effect of the missing enzyme, but
occurs secondary to alterations in membrane turnover,
apoptosis and autophagy.
170
Nevertheless, ERT and stem-
cell therapies have been reasonably successful in animal
models of these disorders and are under development for
patients with these NCLs.
The substrates are known for some enzymes that are
deficient in NCLs—such as for cathepsin D in congenital
NCL and cathepsin F in adult Kuf ’s disease type B.
171–173
Cathepsin D is activated by proapoptotic ceramide and
tumour necrosis factor (TNF), and mediates downstream
events including cleavage of the BH3 interacting-domain
death agonist (BID; a pro-apoptotic member of the
BCL-2 protein family), release of cytochrome c, and acti-
vation of caspase-9 and caspase-3. These processes are all
hallmarks of apoptosis, providing yet another association
between an NCL variant due to a defective lysosomal
enzyme and apoptosis (Table2).
CLN3 disease presents a complex therapeutic problem
as it is caused by a membrane protein defect that is not
amenable to protein or gene replacement or stem-cell
therapies. Nevertheless, some valid and hypothesis-
driven therapeutic approaches have been postulated.
These include use of antiapoptotic agents (flupirtine
maleate),
119
anti-inflammatory strategies (mycophenolate
mofetil),
174
and the potential use of GalCer to correct per-
turbed lipid raft stoichiometry.
95
Lithium has also been
suggested as a therapy for CLN3: through a presumed
action of enhancement of autophagy, lithum treatment
led to reduction of lipid storage in cerebellar cells derived
from CLN3-knock-in mice.
128
The effect of lithium treat-
ment on nonspecific targets may, however, limit the use
of this treatment. Of the therapies described for CLN3
disease, only mycophenolate mofetil is in clinical trials.
174
Apoptosis and inflammation have been implicated in
CLN5 disease, which is caused by defects in a membrane
glycoprotein, and in CLN6 and CLN8 diseases, which
involve defects of ER-resident proteins. Antiapoptotic
and anti-inflammatory strategies are, therefore, poten-
tially feasible therapeutic options for these dis orders.
Therapeutic suggestions that remain in preclinical stages
include use of lipid-lowering drugs such as gemfibrozil
and feno fibrate—two treatments that have been shown
to upregulate TPP-1 in brain cells in a mouse model of
CLN2 disease.
175
Atherapeutic approach suggested for
disorders caused by premature stop-codon mutations is
inhibition of nonsense-mediated decay of mRNA tran-
scripts with the use of drugs such as ataluren or genta-
mycin. This approach was shown to work in lymphoblasts
from patients with CLN1 or CLN2 disease.
176
Obstacles to therapy
The formidable brain
The most challenging aspect of LSDs is that they often
cause pathology in the brain: irreversible neuronal cell
death, tissue loss and scarring are often already under
way by the time a diagnosis is made. Furthermore, the
brain presents problems with regard to drug delivery and
access. The BBB is a particular hindrance to ERT.
Other obstacles to therapy include the need for tar-
geted entry of drugs to specific cell types or lysosomes, as
well as for distribution of therapeutic compounds to sites
that are distant from the application area. Intracerebral
and intrathecal strategies have given positive results in
animal models but, given the invasive nature and poten-
tial neurosurgical complications of this type of therapy,
my enthusiasm for treatment of children with such
therapy is dampened, although not completely absent.
A perplexing issue is that available and emerging treat-
ments for LSDs have the potential to ameliorate progno-
sis considerably, but will never be total cures. Although
therapies might not dramatically improve the quality of
life of afflicted individuals, they could prolong survival.
Other tissue barriers
The brain is not the only tissue that presents challenges
to therapies for LSDs.
10,90
In NPCB, for example, lung
pathology is common, and such damage, once sustained,
is irreversible.
42
Bone and cartilage disease that devel-
ops due to LSDs in early childhood is also irreversible,
as observed in Morquio syndrome (MPS typeIV A),
other MPS disorders, and Gaucher disease typeI.
9
Early
and presymptomatic initiation of therapy can, however,
mitigate bone and cartilage destruction to some extent.
As described above, GAG storage in cartilage in the
MPSs activates the TLR4 signalling pathway, inducing
a TNF-driven inflammatory response.
82,85
Anti-TNF
antibody therapy in an animal model of MPS improved
growth-plate organization and diminished articular
chondrocyte cell death as well as synovial tissue hyper-
plasia.
177
In a rat model of MPS VI, combination therapy
with ERT and anti-TNF antibodies enhanced mobility
and tracheal morphology and increased bone growth.
177
Destruction of skeletal muscle, smooth muscle and
cardiac muscle in Pompe disease has been partially
resistant to ERT, even when treatment is initiated early.
178
This lack of efficacy has been attributed to the low number
of surface and lysosomal mannose-6-phosphate (M6P)
receptors in skeletal muscle, as these receptors were shown
to be required for the success of ERT in this model.
178
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The problem can be overcome, however, by increasing
the dose and frequency of application of ERT. A fusion
protein that binds α-glucosidase protein to insulin- like
growth factor 2—a molecule that improves efficiency of
enzyme binding to M6P receptors—is currently in clinical
trials.
179
Clenbuterol, a drug that enhances M6P receptor
expression, is also being considered for Pompe disease as
well as other LSDs.
180
Immunological resistance
Some patients with Gaucher, Fabry or Pompe disease
who were treated with ERT were found to develop IgG
antibodies against the enzyme over time.
181
This situation
arises in cases when the patient’s own antibodies even-
tually crossreact with the enzyme, or if they have never
encountered the enzyme and are ‘crossreactive immuno-
logical material’-negative and so mount strong antibody
responses to the initial ERT.
182
Increasing ERT dose or
more-frequent administration can restore efficacy of
the enzyme to normal levels.
9,183
Early use of immuno-
modulating agents such as rituximab, methotrexate or
intravenous immunoglobulin can also reduce the anti-
body response against the infused enzyme, but effec-
tiveness of ERT is often restored naturally after a short
period of time.
9
In cases that are resistant to rituximab,
methotrexate or intravenous immunoglobulin, treatment
with bortezomib can restore effectiveness of the infused
enzyme by attenuating the mounted antibody response
to the foreignprotein.
9
Timing of treatment
The fact that aberrant lysosomal storage can begin inutero,
before treatment can be initiated, presents another hin-
drance to successful therapy. Evidence of lysosomal
storage defects have been reported in chorionic villus and
amniotic fluid cells at 10weeks of gestation, suggesting
that pathological processes are initiated before the onset of
symptomatic disease.
184
In almost all instances, early diag-
nosis with prompt initiation of presymptomatic therapy
for defective soluble enzymes in the neonatal period, or
as early as possible, can improve outcomes.
Access to therapy
The prohibitive lifelong cost and availability of ERT to
few patients in a handful of countries raises several ethical
issues. The morbidity, mortality and costs associated with
ERT and stem-cell therapies demand implementation of
a treatment decision-making tree for specialists, insur-
ance companies and government-led health-care agencies
for the various LSDs. Such a decision- making tree has
been devised for Gaucher disease, and hopefully similar
decision-making approaches can be implemented for
other LSDs.
185
Another roadblock to treatment once therapies become
available is the difficulty of carrying out clinical trials
with sufficient statistical power, given the low number of
young children who present with these orphan diseases.
Adding further complexity, many children with these dis-
eases do not present until considerable and nonreversible
neurological impairment has occurred.
Expensive therapies such as ERT and stem-cell therapies
are possible only in countries with sufficient funds to help
parents cover the treatment costs. A 2006 study estimated
that these costs amount to $200,000–$300,000 per year.
186
More-recent estimates, however, place the cost of lifetime
ERT higher, at €150,000–€450,000.
187
Cost estimates for
bone marrow transplantation are variable and difficult to
ascertain, and no reliable estimates have been published.
These cost estimates do not take into account the personal
cost of morbidity and mortality from immunoablative pro-
cedures that are necessary for engraftment of the trans-
plant. Even in wealthy countries, however, the decision by
insurance companies to offer or deny financial support for
therapy presents challenging ethical and human dilemmas.
Conclusions
The past six decades have witnessed the discovery of
the lysosome and characterization of many LSDs and
novel NCLs, providing us with an evolving and expo-
nentially complex understanding of their pathobiology.
These advances have led to development of approved
therapies for a handful of LSDs, as well as many ideas for
develop ment of novel treatment options. At the very least,
study of the lysosome and its related diseases has helped
clarify vital cellular processes such as pH regulation,
188,189
calcium homeostasis, apoptosis, autophagy, inflamma-
tion, membrane and lipid trafficking, endocytosis and
exocytosis. This understanding has broadened the range
of therapeutic targets for LSDs and NCLs, other neuro-
degenerative disorders and cancer. Yet, possible strategies
to modify the course of these serious and deadly diseases
are far from perfect, and the reality of medicine is com-
plicated. Genetic screening programmes in at-risk popu-
lations, screening of newborns for treatable disorders,
provision of genetic counselling and prenatal diagnosis in
at-risk pregnancies and, more recently, pre-implantation
diagnosis, remain the best remedies we have to lessen the
burden that LSDs and NCLs present to society.
190
In a future and perfect universe—once screening for
disorders becomes universal and accurate bioinformatic
analysis of personalized genomic testing becomes afford-
able and accessible on a global scale—we could dream
of a world free of genetic diseases.
191,192
For now, at the
very least, we can aim for timely diagnosis to enable early
implementation of available and emerging therapies.
Review criteria
A search for original articles published between 1970 and
2013 and focusing on lysosomal storage diseases and the
neuronal ceroid lipofuscinoses was performed in MEDLINE
and PubMed. The search terms used were “lysosomal
storage diseases”, “neuronal ceroid lipofuscinoses”,
“lysosome‑related organelle diseases”, “enzyme
replacement therapy”, “chaperone‑mediated therapy”,
“virally mediated gene therapy” and “haematopoetic and
other stem‑cell therapies”, as well as “small‑molecule
therapies” alone and in combination. All articles identified
were English‑language, full‑text papers. I also searched
the reference lists of identified articles for further relevant
papers, as well as NIH webpages for relevant clinical trials.
REVIEWS
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Acknowledgements
The author is grateful to H. Maacaron for her valuable
assistance with the referencing of this manuscript.
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