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Gaucher Disease: A Comprehensive Review

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 Critical Reviews'= in Oncogenesis, 18(3), 163~175 (2013)

Gaucher Disease: A Comprehensive Review

Barry E. Rosenbloom/-" & Neal J Weinreb2

'David Geffen School of Medicine at UCLA and Clinical Professor of Medicine at Cedars-Sinai, the
Comprehensive Gaucher Diagnostic and Treatment Center at Cedars-Sinai Medical Center, Beverly Hills,
California 90211; 2University of Miami Miller School of Medicine; University Research Foundation for Lysosomal
Storage Diseases, Boca Raton, Florida 33433, USA and the Dr. John T Macdonald Foundation, Department of
Human Genetics at the University of Miami Miller School of Medicine, Miami, Florida, 33144, USA

*Address all correspondence to: Barry E. Rosenbloom, MD; Clinical Professor of Medicine, David Geffen School of Medicine at
UCLA and Clinical Professor of Medicine at Cedars-Sinai, the Comprehensive Gaucher Diagnostic and Treatment Center at Cedars-
Sinai Medical Center, 9090 Wilshire Blvd, #200, Beverly Hills, CA 90211, E-mail: rosenbloomb@toweroncology.com.

ABSTRACT: Gaucher disease (GD) is an inherited error of metabolism due to a deficiency of glucocerebrosidase. This leads
to excessive storage of glucocerebroside in the liver, spleen, bone, and bone marrow. Patients develop anemia, thrombocytopenia,
hepatosplenomegaly, bone infarcts, aseptic necrosis of bone, and osteoporosis. There are three types of GD; types 2 and 3 have
neurological involvement. With the advent of enzyme replacement therapy and substrate reduction therapy, the natural history
of the disease has been has significantly changed, with a marked decrease in morbidity, especially for type 1patients. This article
reviews a broad spectrum of information regarding Gaucher disease, from the history of the disease to newer therapies still in
the investigational stage.

KEYWORDS: Gaucher; Glucocerebrosidase; Glucocerebroside; Enzyme replacement; Substrate reduction

ABBREVIATIONS

GD: Gaucher disease; GBA: acid f3-g1ucosidase; ERT: enzyme replacement therapy; SRT: substrate reduction therapy

I. INTRODUCTION II. HISTORY

Gaucher disease (GD) is an inborn error of
metabolism due to a deficiency of the lysosomal
enzyme glucocerebrosidase (acid 13-glucosidase, or
GBA).1 It is the most common of approximately
40 hereditary lysosomal storage disorders. The
disease is characterized by progressive lysosomal
storage of glucocerebroside (glucosylcerarnide)
in macrophages predominantly in bone, bone
marrow, liver, and spleen. Because GD is now
treatable with either enzyme replacement therapy
(ERT) or substrate reduction therapy (SRT), it
has attracted the interest of both researchers and
clinicians and its treatment has served as a para-
digm for treating similar diseases. Although the
disease was first described more than 125 years
ago, it has taken more than 100 years to find an
effective therapy.
In an 1882 medical school thesis, Dr. Phillipe Gau-
cher described a woman with an enlarged spleen that
contained unusual engorged cells, which he initially
and incorrectly thought to be malignant. When a
similar case was reported in 1885, the condition was
named Gaucher disease.e In 1904, Brill suggested
that the disease was inherited, and he showed that
the liver, lymph nodes and bones were involved.'
Eventually, GD was characterized as an hereditary
autosomal recessive disorder. Patients with neurologi-
cal involvement were first described in the 19205.4
In 1934, Aghion showed that reticuloendothelial
organs were infiltrated by the eponymic, and thought
to be pathognomic, Gaucher cells and had abnormal
accumulation of the glycosphingolipid glucocerebro-
side (glucosylceramide)." The biochemical basis for
the lipid storage in GD was resolved in the 19605
when Brady et aI. demonstrated that the biosynthetic

0893-9675i13iS35.00 © 2013 by Begell House, Inc. 163

164
pathways for glucocerebroside were normal in affected
patients but that the primary degradative pathway
via glucocerebrosidase was markedly but variably
defective." Subsequently, glucocerebrosidase ras
identified as a lysosomal enzyme, and patients 'fth
GD were thereafter described as having a lysosoral
storage disorder;" Using radio labeled natural substrate,
Kampine and Brady demonstrated that gIucoJer-
ebrosidase deficiency could be reliably detecte1 in
peripheral blood leukocytes (\VBC) from pati1nts
with GD.8 Subsequently, Beutler developed a ITlore
readily available assay for WBC acid !3-glucosi1ase
using an art.ificial fluorogenic substrate 4-]'VIU-~rta-
D-glucop)'Tanoside.9The Beutler assay, adaptedj for
modern technology, continues to be the gold standard
and is the only necessary procedure for the diagnf.sis
of GD. In the absence of medical indications 0 er
than confirmatory diagnosis, patients suspecte of
having G D may generally be spared the pain, .s-
comfort, and risk of invasive tissue examinations uch
as bone marrow and liver biopsies. U nfortunatel the
~'BC beta-glucosidase assay is insufficiently spe ific
for the purpose of identifying heterozygote car ers,
for family profiling, or for detection of at-risk cot ples
Subsequently, the glucocerebrosidase gene
(GBA1) was localized to chromosome 1, q2L1D
Sequencing studies revealed that GBAI co~ists
of 11 exons and a downstream pseudogene wfh a
55-bp deletion that is a significant contributor to
dysfunctional recombinant mutations.'! More Ihan
300 GBAl mutations and polymorphisms have een
reported.F DNA mutational analysis is essenti I for
carrier identification and for population screeni .In
the United States, prenatal screening for GD is ften
offered by obstetricians as a component of an" sh-
kenazi Jewish Panel" of genetic tests.P This pr~ tice
has generated controversy because marked hetdoge-
neity in the clinical severity of Gaucher pheno es
with a substantial population of genetically a:fficted
individuals with minimal, if any, clinical symp oms
poses a host of practical and ethical questions For
these reasons, routine high-throughput neo atal
screening for G D is currently not recommend d or
included in most state-mandated testing progfams.
Indications are that individuals with GD, regard-
less of clinical phenotype, may be at increased risk
Rosenbloom & Weinreb
for adverse outcomes late in life such as cancer and
Parkinsonism. This protocol introduces additional
complexities in the discussion of the rationale for
Gaucher screening, the more so because of the absence
of information as to whether initiation of treatment
either later or earlier in life will effectively lower the
risk of cancer or Parkinsonism.
Brady conceived of an intravenous enzyme
replacement therapy (ERT) as a possible treatment
for GD more than 40 years ago. In 1974, proof of
concept of ERT for GD was achieved when three
patients were treated with a limited quantity of puri-
fied human placental glucocerebrosidase, whereupon
plasma and hepatic glucocerebroside decreased.l"
Animal studies have shown that most of the infused
glucocerebrosidase is taken up by hepatocytes and
that only small amounts of the enzyme actually enter
macrophages (Kupffer cells).15 Glucocerebrosidase
is a 67-kDa glycoprotein containing approximately
7% carbohydrate." Reticuloendothelial uptake was
greatly improved after glucocerebrosidase was enzy-
matically deglycosylated to expose mannose residues
capable of binding to the macrophage mannose recep-
tors.'? After adding this step to a new purification
procedure for placental glucocerebrosidase, enzyme
infusions reduced liver glucocerebroside concen-
trations in 4 of 7 patients. IS The purification and
carbohydrate remodeling scheme was subsequently
adapted and scaled up for industrial production ..After
additional steps to eliminate risk of viral contamina-
tion, a small number of patients were treated with
rnannose-terminated placental glucocerebrosidase,
culminating in a seminal 12-patient trial.l" When
consistent improvements were noted in hematological
cytopenias, liver and spleen volumes, and surrogate
biomarkers, human placental glucocerebrosidase
(alglucerase) was approved by the FDA for treatment
of GD in adults and in children. However, although
alglucerase treatment was initiated in several hundred
patients within a couple of years ofits FDA approval,
it proved to be less than an ideal product.
Approximately 20,000 placentas were required
to extract enough glucocerebrosidase to treat one
patient for 1 year. Moreover, alglucerase contained
human serum albumin and a low level of protein
impurities such as human chorionic gonadotropin.
Critical Reviews" in Oncagenesis
Gaucher Disease: A Comprehensive Review 165

To ensure an adequate supply of enzyme and to of CD currently known and is usually considered
completely eliminate the potential risks with the use to be non-neuronopathic.! However, recent studies
of a human-tissue-derived product, a recombinant have called that distinction into question because by
human glucocerebrosidase (imiglucerase) expressed in the seventh to eighth decades of life, an intractable
Chinese hamster ovary (CHO) cells was developed. Parkinson-like syndrome, often with atypical fea-
Although the protein sequence ofimiglucerase differs tures including progressive dementia, is reported to
from that of alglucerase by a single amino acid, the occur in 5-10% of patients with otherwise typical
two proteins are enzymatically indistinguishable. In type 1 CD.25 Additionally, as many as 15-20% of
a randomized clinical trial, imiglucerase was shown adult type 1 patients may have subjective or objec-
to be therapeutically similar to alglucerase, and as a tive evidence of peripheral neuropathy-" However,
result, imiglucerase was approved in the United States there is as yet no evidence for an overlap between
in 1994 and throughout Europe in 1997.20 Also in type 1 and types 2 and 3 patients with respect to
1997, the completion of a large-scale manufacturing the hallmark manifestations of the neuronopathic
facility allowed nearly all patients to transition from phenotypes: abnormal eye movements (saccades)
alglucerase to imiglucerase. Imiglucerase is currently and myoclonic or generalized seizures. In Western
used in more than 90 countries worldwide. Early countries, type 1 disease occurs in 1175,000 births.
in 2010, following clinical trials in more than 100 However, in Jews of Ashkenazi (north-central and
patients, velaglucerase, a new recombinant gluco- eastern European) descent, the only ethnic group in
cerebrosidase derived from a cultured human fibro- whom the prevalence is markedly increased, it is seen
sarcoma cell line and with an amino acid sequence in approximately 1/600 individuals and the carrier
identical to the wild-type enzyme, was approved for rate is 1/15. In the United States, it is estimated that
commercial use by the FDA and EMA.21 Currently, there are approximately 12,000 individuals with the
throughout the world, 5,000-6,000 patients with disease, and approximately 66% are of Ashkenazi
CD are receiving imiglucerase, and approximately Jewish ethnicity;' However, due to a highly variable
1,000 are being treated with velaglucerase. Suc- penetrance, the disease appears to be symptomatic
cessful clinical trial results have also recently been only in approximately 50% of the Ashkenazi Jews
reported for taliglucerase, a third pharmacological who are genetically affected.27
glucocerebrosidase preparation produced in carrot Type 2 CD has its onset in infancy (so-called
cell cultures.F Taliglucerase is now also approved neuronopathic infantile, cerebral, or perinatal lethal
by FDA for commercial use in the United States. CD) and has an estimated prevalence of 1/150,000.
Oral substrate reduction therapy (SRT) with Accounting for 1% of all CD, affected infants have
N-butyldeoxynojirimycin (rniglustat) was approved a very short life expectancy of 2-3 years or less due
in 2003. Because the initial trial results with this to severe neurological consequences of the disease."
agent suggested that it might be relatively less effec- Type 3 CD is more prevalent than type 2 GD
tive than ERT, its use is officially restricted to those because of the considerably longer survival, and
patients who are unable and/or unwilling to receive accounts for approximately 5% of all patients with
ERT.23 A newer oral SRT agent called eliglustat is CD. Although it is panethnic, clusters have been
currently in clinical trials.P' well studied in Northern Europe, Egypt, and East
Asia'! In these areas, the proportion of CD patients
with neuronopathic disease is likely greater than
III. NOSOLOGY AND EPIDEMIOLOGY expected based on worldwide experience. Because
the spectrum of neurological involvement in patients
Traditionally, CD is recognized as having three major with type 3 G D is quite broad, it is conceivable that
phenotypic subcategories based on the presence or a significant number of type 3 individuals with mild
absence of early-onset central nervous system mani- eNS manifestations have been misclassified as hav-
festations. Type 1 disease constitutes 94% of all cases ing type 1 disease.

Volume 18, Number 32013

166
IV. PATHOGENESIS
GD is caused by a deficiency of lysosomal gluco-
cerebrosidase, a glyprotein enzyme necessary for the
metabolism of glucosylceramide.i? This ubiquitous
glycosphingolipid is the basic building block for
the complex globosides and gangliosides that are
important components of cell membranes, imbed-
ded receptors, and lipid rafts. A co-factor protein,
saposin C, is an essential activator for glucocerebro-
sidase, and along with a second transport protein,
lysosomal integral membrane, is necessary for the
successful transfer of GBA from the endoplasmic
reticulum to the lysosome.'? Rare cases of GD,
mostly neuronopathic in presentation, are attribut-
able to hereditary deficiency of saposin C.31 In the
usual patients with GD, deficiency of GBA leads
to intracellular accumulation of glucosylceramide as
well as other glycosphingolipids, including the gan-
glioside GM3, a significant signaling molecule, and
glucosylsphingosine, a potentially toxic lysolipid.32,33
Although elevated levels of glucosylceramide occur
in many cell types, lysosomal storage in macrophage
lysosomes is particularly prominent because of the
heavy substrate burden inherent in macrophage
phagocytic function.P" Because macrophages are more
commonly distributed in bone marrow, liver, spleen,
and lung than in other body sites, in patients with
GD these organs can accumulate 20-100 times the
normal levels of glucosylceramide."
The major manifestations of GD result from
the progressive accumulation of the glycolipid-laden
macrophages (Gaucher cells) in the various organs
and tissues noted previously. ffistologically, however,
the abnormal macrophages account for only a small
fraction of the increased volume of the liver and
spleen, in which much of the increased cell mass is
represented by an inflammatory hyperplastic cellular
component.P' All of the pathogenic pathways lead-
ing to organ damage have not yet been elucidated,
but certain findings are notable. Gaucher cells and
other immune-modulating cells secrete lysosomal
enzymes and cathepsins.F'ln addition, inflammatory
mediators, including interleukins 6, 8, and 10 and
macrophage inflammatory proteins 1 alpha and 1 beta,
are increased in the surrounding tissue and in the
Rosenbloom & Weinreb
peripheral blood.38 Gaucher cells themselves, at some
point in their evolution, phenotypically correspond
most closely to "alternately activated" macrophages,
which are associated with chronic inflammation,
healing processes, and fibrosia'? In patients with
neuronopathic types of GD, the deacylated form
of glucosylceramide, namely glucosylsphingosine,
is elevated in neuronal cells and may play a key
role as a neurotoxic agent by deregulating calcium
homeostasls.P
With respect to bone disease, both mineralized
bone and bone marrow are affected. Osteonecrosis,
medullary infarction, osteoporosis, and defective bone
remodeling are common in untreated GD patients,
and the bone marrow is infiltrated with GD cells,
leading to osteosclerosis and fibrosis. Patients often
do not achieve peak bone mass, which results in
subsequent osteopenia, osteoporosis, and increased
fracture risk. Children may have growth retardation
and delayed puberty. Aseptic necrosis of the shoulders
and hips are relatively common leading to subsequent
joint deformities and functional disability that may
not always be correctible with joint replacement
surgery." GD patients may experience severe acute
bone pain episodes due to infarction (bone crises)
as well as intractable chronic pain.
Although thrombocytopenia and anemia are in
large part a function of splenomegaly and hypersplen-
ism, bone marrow infiltration itself appears to con-
tribute to impaired hematopoiesis, a process that may
become irreversible once fibrosis and osteosclerosis
develop. There may also be an intrinsic defect in the
bone marrow that can impact cellular maturation.F
Bleeding in GD is most directly related to throm-
bocytopenia, but patients may have platelet defects
and other coagulation factor deficiencies, including
coincidental factor XI deficiency in Ashkenazi Jews
in whom this coagulopathy is relatively comrnon.f
V. GENETICS
Gaucher disease is inherited as an autosomal recessive
disorder. The gene for glucocerebrosidase (GBA1),
located on chromosome lq21, is 7.6 kb in length with
11 exons as well as a 5-kb pseudogene located 16
Critical Reviews ™ in Oncogenes is
Gaucher Disease: A Comprehensive Review
kb downstream. The latter is transcriptionally active,
although translationally nonfunctional and should be
recognized as separate from the GBAl gene when
molecular diagnoses are performed.P There are now
more than 300 GBA gene mutations listed in the
Human Gene Mutation database. More than 80%
of these alleles are single nucleotide substitutions,
whereas insertions, deletions, or other complex alleles
account for the remainder.F
In Western countries, three alleles account for
most of the mutations of GBA1: c.1226A>G (N370S),
c.1448T>C (L444P), and c.84dupG (84GG). N370S
accounts for 53%, L444P for 18%, and 84GG for
7%.44N370S alleles are commonly found in Ash-
kenazi Jews as well as in non-Jewish European
populations. A single N370S allele, regardless of
the second mutation, seems sufficient to avert clas-
sical neuronopathic disease. L444P, in the absence
of an N370S mutation, is more often, although not
invariably, associated with early-onset neurological
findings. L444P, although prevalent throughout
the world, is associated with a characteristic type 3
neuronopathic phenotype mostly seen in northern
Sweden and northern Europe.P The 84GG allele, a
frameshift mutation due to an insertion at position
84, is restricted to Ashkenazi Jews. This variant is a
non-protein producer and only occurs in a heteroal-
lelic state. It is presumed that the homozygous form
is lethal in utero.46
In Ashkenazis, N370S, L444P, and 84GG con-
stitute 94% of the mutant alleles, with N370S 70%
and the others 12% eacb.:" Among the non-Jewish
Europeans, N370S and L444P are responsible for
70% of the alleles. In Asian and Arab populations,
the N370S is rarely seen and the mutant allele fre-
quencies are much different. 47,48
VI. CLINICAL PRESENTATION
AIl types of GD generally have some degree of vis-
ceral involvement and bone disease, and there is the
potential for overlapping presentations. For example,
a child with type 3 disease may not have any neu-
rological symptoms until reaching adolescence and
as a result may be initially erroneously considered to
Volume 18, Number 32013
167
have type 1 disease. Such children may in fact actu-
ally have evidence of abnormal eye movements that
can be detected by careful neuro-ophthalmological
testing that is not typically included in routine
pediatric examinations.
Type 1 GD is present in more than 90% of all
known patients with GD. Despite the increased
prevalence among Ashkenazi Jews, because they are
such a small minority population worldwide, most
type 1 GD patients are in fact non-jewish."? Types
2 and 3 are panethnic and can be distinguished from
type 1 by the early onset of neurological involve-
ment. From the ICGG Gaucher Registry data, the
incidence of clinical characteristics for all GD types
include the following: splenomegaly 85%, hepato-
megaly 63%, anemia 34%, thrombocytopenia (with
or without bleeding manifestations) 68%, osteopenia
55%, fractures,7%, bone crises 7%, bone pain 33%
and growth retardation 36%.44
In type 2 disease (acute neuropathic), which
accounts for 1% of cases, in addition to the find-
ings noted in type 1 disease, the following clinical
characteristics have been reported: developmental
delay, hydrops fetalis, congenital ichthyosis, strabis-
mus, developmental delay, supranuclear gaze palsy,
bulbar palsy, paresis, hypertonia, rigidity, opisthoto-
nus, dysphagia, and seizures. The pathology shows
neuronal loss, gliosis, periadventitial Gaucher cells,
neuronophagia, with involvement of the frontal
cortex, thalamus, caudate,globus pallidus, pons, and
cerebellum.s? This disease variant, when not associ-
ated with neonatal death, is rapidly progressive over
a period of 2-3 years and is invariably fatal despite
any treatment known to date.
In type 3 disease, the following has been observed:
developmental delay, strabismus and supranuclear
gaze palsy, progressive dementia, myoclonus, corneal
opacities, and cardiovascular calcification.51 The
latter is associated with a unique phenotype found
in Arab, Iberian, and Japanese patients associated
with the D409H mutation. Another unique and
as yet unexplained finding in some type 3 patients
(Norrbottnian variant) is the development of a severe
gibbus deformity that is not associated with vertebral
skeletal involvement."
168
A. Type 1 Gaucher Disease: Clinical Course
Type 1 CD has a variable clinical course even among
siblings with the same genotype and in monozygotic
twins. 52 Those individuals with symptomatic disease
usually have significant visceral involvement, more
advanced bone disease, and more severe hematologi-
cal findings. Fatigue is common, and growth can be
delayed as well as puberty. 53 Patients in whom sple-
nectomywas performed because of severe cytopenias
or severe abdominal discomfort tend to have more
severe bone disease." Even apparently asymptomatic
patients often have signs of the disease including
anemia, thrombocytopenia, hepatosplenomegaly, and
bone abnormalities but may sometimes be discovered
only when quite elderly-54Age of presentation is vari-
able and presumably reflective of the clinical severity
of disease, and may to some degree be related to the
genotype. In the Gaucher Registry data base only 33%
of patients with the putatively "milder" homozygous
N370S genotype were diagnosed before the age of
20, compared to 65% of N370S compound hetero-
zvzotes
.0
in whom the disease is often more severe.
Splenomegaly is the most common visceral
disease manifestation. The spleen size can be
enlarged as much as 75-fold, but the median is
15.2 times normal.v Hepatomegaly frequently is
present, although sometimes not very pronounced.
However, liver volumes 2-3 times normal are not
uncommon." Although progressive hepatic fibrosis
can occur as part of the natural disease progression,
with the availability of definitive treatment, cirrhosis,
portal hypertension, and liver failure are now rarely
observed in the absence of a history of concurrent
hepatopathology such as chronic viral hepatitis.
Splenectomized patients tend to have more severe
liver disease. 56
Although splenectomy generally ameliorates
hematological cytopenias, without definitive treat-
ment, progressive bone marrow infiltration may
eventually cause recurrent anemia and thrombocy-
topenia. Upon enrollment in the ICGG Registry, in
patients with intact spleens, the mean hemoglobin
was 11.2 g/dL compared to 11.9 g/dL for those
who were post-splenectomy. For patients with intact
spleens, the mean platelet count was 99,OOO/IlL,with
Rosenbloom & Weinreb
26% having platelet counts less than 60,OOO/~lL.For
post-splenectomy patients the mean platelet count
was 242,OOO/IlL, and onIy 3% had platelet counts less
than 60,OOO/IlL.44 It is difficult to ascertain to what
extent anemia contributes to symptoms in affected
patients because complaints of fatigue are common
even in type 1 GD patients with normal hemo-
globin concentrations. There is no doubt however,
that from a historical perspective, some untreated
anemic patients were sufficiently impacted so as to
require repeated transfusions. On the other hand,
thrombocytopenic bleeding ranging from extensive
bruising and repeated episodes of epistaxis to serious
gastrointestinal, urological, obstetrical, CNS, post
traumatic, and post-surgical hemorrhage continue
to be significant, presenting manifestations in some
undiagnosed or untreated individuals.
Skeletal disease accounts for a good deal of the
morbidity associated with type 1 GD. Bone and joint
pain, sometimes associated with painful crises (due
to acute infarcts), can be debilitating." Avascular
necrosis can lead to joint collapse at the hip, knee, and
shoulder. Osteolytic lesions, pathological fractures,
and spinal compression fracture and extraosseous
masses (Gaucheromas) also contribute to morbidity.
In the Gaucher Registry data base, 63% reported a
history of bone pain, 8% bone crises, and 94% had
abnormal radiological findings. Bone disease was
worse in those patients who were post-splenectomy,
and bone disease was worse in surgically asplenic
patients who were diagnosed at an earlier age.57
Affected children tend to have poorer growth
velocity. Many children have heights that are less
than the 5th percentile for age and sex and 25%
are shorter than expected based upon mid-parental
height.58 More severe grovvth retardation usually was
associated with a greater degree of visceral involve-
ment. Puberty is delayed is 600Alof GD patients.v
Interstitial lung disease with severe hypoxemia,
due to proliferation of glycolipid-laden alveolar
macrophages can occur, but it is rare. Pulmonary
hypertension that is independent of infiltrative dis-
ease and due to occlusion of pulmonary capillaries
and cytokine-associated proliferative vascular lesions
also rarely occurs and represents a life-threatening
complication. 59 The hepatopuImonary syndrome
Critical Reviewst= in Oncogenesis
Gaucher Disease: A Comprehensive Review
due to abnormal shunting in the lungs also leads
to hypoxemia and ultimately to liver cirrhosis.s?
Pulmonary hypertension and the hepatopulmonary
syndrome are generally encountered in patients who
have had a splenectomy.
Although traditionally type 1 GD has been
considered non-neuronpathic, neurologic sequelae
are increasingly reported, predominantly in middle-
aged or elderly patients. An increased incidence of
polyneuropathy has been noted.26 For reasons yet
poorly understood, Parkinsonism is also increased in
Gaucher carriers with a variety of mutated Gaucher
alleles.s' However, Parkinsonism is also increased
to an extent greater than expected in patients with
type 1 GD itself-" These patients sometimes present
at an earlier age than the typical Parkinson patient
and have atypical disease manifestations such as
progressive dementia that may be relatively resistant
to standard Parkinson disease medications.
Evidence indicates that certain types of malig-
nancies are increased in patients with type 1 GD and
that there are also immune system abnormalities that
may theoretically contribute to increased cancer risk.
B. Laboratory Findings
Thrombocytopenia and anemia are the hallmark
findings of this disease. Leucopenia is also observed
but is rarely sufficiently severe to lead to infectious
complications. Liver function abnormalities may
occur but are rarely severe. Acute elevation of liver
enzymes may sometimes be attributable to cholecys-
titis as patients with type 1 GD often suffer from
concurrent cholelithiasis.V Surrogate biomarkers
including angiotensin converting enzyme, tartrate-
resistant acid phosphatase, CCL-18, and chitotriosi-
dase are usually elevated as is serum ferritin.63,64 The
magnitude of biomarker elevation does not correlate
with clinical severity, but changes from baseline may
be useful for monitoring the response to treatment.
Bone marrow sections, liver biopsies, and splenic
specimens show lipid-laden macrophages known
as Gaucher cells. Bone marrow Gaucher cells are
not pathognomonic for GD because cells similar in
appearance, which can be seen on light microscopy
(known as pseudo-Gaucher cells),have been reported
Volume 18, Number 3 2013
169
in various hematological conditions including chronic
myelogenous leukemia and thalassemia.v/"
c. Imaging Findings
From the Gaucher Registry,44,54the following find-
ings were reported:
1. The functionally insignificant Erlenmeyer flask
deformity of the distal femur, which is caused
by abnormal bone remodeling, was found in 46%
ofGD cases.
2. Fractures and lytic lesions were seen in 15% and
8% of GD patients, respectively.
3. Irreversible skeletal lesions were seen in 17% of
the N370S homozygous patients, and 26% of
N370S compound heterozygote patients.
4. Bone marrow infiltration was seen on MRI
in 40% of patients. However, this observation
almost certainly is distorted by under-reporting.
In other Gaucher population studies done under
controlled conditions, the prevalence of bone
marrow infiltration detected by MRI is much
higher, approaching 100%.
5. Bone infarcts and osteonecrosis were both present
on MRI in 25% of patients.
6. Osteopenia was seen on DEXA scanning in 42%
of patients.
D. Diagnosis
The diagnosis of GD is preferably established by
enzyme analysis supplemented by mutation analy-
sis. Peripheral blood leucocytes (WBC) all have
measurable glucocerebrosidase (GBA) activity, with
monocytes the most, and granulocytes the Ieasr.s?
Additionally, cultured skin fibroblasts can also be
used to measure GBA, but the latter technique is
used much less frequently in clinical settings.68 When
assaying peripheral blood 'NBC with the artificial
substrate, 4-methyurnbilliferyl-~- D-glucoside, type 1
patients usually have up to 10-15% residual activity.
However, there may be some overlap with carriers.
Residual enzyme activity is usually much less in
patients with types 2 and 3. The drawback of using
mutational analysis as the sole diagnostic technique
is that occasionally only one allele may be detected,
170
leading to the possibility that a patient may be mis-
identified as a carrier.
Bone marrow testing is not necessary solely for
the purpose of making the diagnosis of CD, but
sometimes it may be necessary when concurrent
hematological diagnoses such as MCUS, myeloma,
lymphoma, or myelodysplasia need either to be
excluded or evaluated.t? Prenatal diagnosis can be
performed on fetal cells from chorionic villous sam-
pling or amniocentesis. 70
E. Treatment
The treatment of CD was revolutionized with
the advent of enzyme replacement therapy (ERT)
more than 20 years ago. In the United States, three
FDA -approved products are commercially available:
imiglucerase, velaglucerase alfa, and taliglucerase.The
success ofERT has rendered therapeutic splenectomy
unnecessary except in very rare instances when a patient
has life-threatening hemorrhagic thrombocytopenia.
The goals of treatment are to improve the symptoms
of the disease, prevent irreversible changes in the bone,
and improve the quality of life of the CD patient."
Because bone disease leads to most of the morbidity,
early initiation of treatment rather than "watchful wait-
ing" is appropriate in patients, including children "nth
evident skeletal manifestations or with a risk profile
suggesting a high probability of bone complications.
Treatment should therefore be individualized for GD
patients based on careful and comprehensive initial
and serial assessments, preferably performed in cen-
ters of excellence. 72 The ICGG has proposed disease
monitoring schedules which can be used to determine
when dosage modifications should be considered.P
The dose of initial ERT for type 1 patients is
frequently based upon the extent of hematological
abnormalities, visceral abnormalities, and bone dis-
ease. In children, growth parameters (including those
reflecting malnutrition, growth retardation, impaired
psychomotor development, and fatigue) must also be
considered. 74 Therapeutic goals should he formulated
and discussed with patients (and/or parents) and
dose reductions can be considered when all clinically
important measurable goals have been met. Multiple
studies from individual centers, from clinical trials,
Rosenbloom & Weinreb
and from the ICGG Registry, show that abnormally
low hemoglobin concentrations usually increase to
near normal levels within 1 year of starting treatment.
Platelet counts typically increase significantly over the
first 2 years, and in patients who do not normalize
in that time, may continue to increase more slowly
for several years thereafter. Post-splenectomy patients
in general have more rapid hematological responses.
With respect to visceral disease, hepatomegaly typically
resolves within 2 years, and splenomegaly decreases
by 60%. However, patients who initially have mas-
sive splenomegalies may never decrease their splenic
volume to less than five times normal." More than
500;6 of patients with bone disease have significant
symptomatic relief, and well over 90% of patients
with a history of bone crises have no recurrence.i"
There is some evidence that women with type 1 GD
who are of child-bearing age may have increased risk
for spontaneous abortions. ERT appears to decrease
this risk. 77 Although a definitive study has not been
completed, a number of publications suggest that ERT
appears to be safe for use in pregnancy and, in fact,
its continued use may decrease pregnancy-associated
complications,includingperi-partum and post-partum
bleeding and potential acceleration of Gaucher bone
disease." Because infused glucocerebrosidases are
unable to permeate the blood brain barrier, ERT
should have little if any impact on the neurological
findings of patients with types 2 and 3 GD, even if
they are started sufficiently early in life, prior to the
onset of irreversible damage. However, in type 2 and
3 patients the other systemic disease manifestations
can improve, and sometimes neurological pathologies
stabilize for some time.79,80
Adverse effects of ERT can include fever, chills,
and flu-like symptoms during or shortly after the
infusion. The mechanism is thought to be immune-
mediated. IgE-mediated reactions are quite rare but
can be anaphylactoid. The use of anthistamines and
glucocorticoids as pre-medication is necessary for
some parients." Although approximately 13-15%
of patients develop IgG antibodies to imiglucerase,
in most instances the antibodies do not neutralize
glucocerebrosidase activity, prevent uptake by macro-
phages, or otherwise diminish the effectiveness of the
ERT. Occasionally, antibody positive individuals may
Critical Reviews" in Oncogenesis
Gaucher Disease: A Comprehensive Review
develop tolerance as treatment continues.P Although
imiglucerase, velaglucerase, and taliglucerase seem
generally comparable in terms of efficacy,there may
be differences in terms of antigenicity. Based on the
clinical trials for treatment naive patients, velaglucerase
appears to be the least antigenic (antibody develop-
ment in approximately 1%), taliglucerase intermediate
(6% antibody conversions), and imiglucerase the most
antigenic (13-15% conversions).83,84 It remains unclear,
however,whether these differencesare clinicallyimpor-
tant beyond the observation that antibody-positive
patients are more likely to have infusion reactions
than those who are antibody negative.
Commercial substrate reduction therapy (SRT)
is a treatment option for patients with type 1 GD
who refuse ERT or who are intolerant of it. SRT is
based on the concept that inhibition of synthesis of
gIucosylceramide should reduce intracellular substrate
burden sufficiently to allow clearance even by defec-
tive but partially active mutant glucocerebrosidase.
Miglustat (N -butyldeoxynojirimycin), an inhibitor
of glucosylceramide synthase, has been approved in
the United States and Europe for those with type
1where ERT is not suitable.F In the initial clinical
trial, after 1year, mig1ustat reduced liver and spleen
volumes by and 12 and 19%, respectively, with slight
improvement in anemia and thrombocytopenia.v
Further improvement was noted after longer peri-
ods of follow up. Gastrointestinal and neurologic
disturbances are the most common miglustat-related
adverse events reported in clinical studies. Gastroin-
testinal adverse events included diarrhea, moderate
weight loss of less than 10% of body weight, and
flatulence, which all tended to improve with time.
In addition, gastrointestinal disturbances resolved in
some patients who complied with recommendations
to follow a low carbohydrate diet during the first few
weeks of treatment with miglustat. Mild, transient
cases of tremor have been reported in patients treated
with miglustat in whom there was no corresponding
functional impairment and no impact of the tremor on
dexterity. The most common serious adverse reaction
was peripheral neuropathy. Patients should undergo
neurological examinations at the start of treatment
and every 6 months thereafter, and in those who
develop peripheral neuropathy the continued use of
Volume 18, Number 32013
171
miglustat should be reassessed. Miglustat may cause
fetal harm if administered to a pregnantwoman.lVlen
should maintain reliable contraceptive methods and
not plan to father a child while taking miglustat and
for 3 months after discontinuing.P
A newer, more specific glucosylceramide syn-
thase inhibitor, eliglustat tartrate, is chemically
different than miglustat and therefore may be less
likely to cause the gastrointestinal side effects that
have limited patient acceptability of miglustat. In a
phase 2 clinical trial in which eligible patients had
to have substantial splenomegaly and either anemia
or thrombocytopenia, eliglustat treatment reduced
liver and spleen volumes 17% and 38%, respectively,
and improved the mean hemoglobin by 1.6 Gldl and
platelet counts by 40% after 2 years.87 Increases in
bone mineral density were also observed." Phase 3
clinical trials of this agent in the treatment of naive
patients and in patients whose disease status appeared
to have stabilized after a minimum of 3 years of
ERT are now completely enrolled, and final results
are anticipated in approximately 2 years.
VII. CONCLUSION
Gaucher disease is a multisystem disease with phe-
notypic variation from a very mild variant to a very
severe and lethal variant. Type 2 disease is currently
treated only with palliative measures. Treatment
with ERT is highly beneficial for most patients with
type 1 GD, and it controls the non-neurological
consequences of type 3 GD. Oral therapies may
ultimately supplant intravenous treatment. With
successful treatment of the well- known reversible and
preventable causes of early-onset morbidity in GD,
attention is increasingly focused on annotating and
understanding the causes of adverse late outcomes
such as Parkinsonism and cancer, and, in particular,
plasma cell and other hematological malignancies.
ACKNOWLEDGMENT
Drs. Weinreb and Rosenbloom are supported by
Genzyme and Shire with Educational Grants and
Honoraria.
172
REFERENCES
1. Beutler E, Grabowski GA. Gaucher disease. In:
Scriver CR, Beaudet AL, Sly WS, Valle D, editors.
Metabolic and molecular bases of inherited disease.
New York: McGraw-Hill. 2001; 3635-68.
2. Gaucher PCE. De l'epithelioma primitive de las rate,
hypertrophie idiopathique de la rate sans leucemie.
[Academic Thesis} Paris, France; 1885.
3. Brill NE, Mandlebaum FS, Libman E. Primary
splenomegaly-Gaucher type. Mt Sinai Hosp
Reports; 1904, IV: 35-48.
4. Brady RO. Gaucher disease: past, present, and
future. In: Zimran A, editor. Gaucher disease.
1997;10:621-34.
5. Aghion H. Le maladie de Gaucher dans l'enface.
Faculte de Medecine. Paris, France; 1934.
6. Brady RO, Kanfer D, Bradley RM, Shapiro D.
Demonstration of a deficiency of glucocerebroside-
cleaving enzyme in Gaucher disease.J Clin Invest.
1966;7:1112-5.
7. Brady RO. Biochemicaland metabolicbasisof familial
sphingolipidoses. Semin Hematol. 1972;9: 273-84.
8. KampineJP,Brady RO,Kanfer]N,Feld M, Shapiro
D. Diagnosis of Gaucher's disease and Niemann-
Pick disease with small blood samples of venous
blood. Science. 1967;155:86-8.
9. Beutler E, Kuhl W. Detection of the defect of
Gaucher's disease and its carrier state in peripheral
blood leucocytes. Lancet. 1977;295:612-3.
10. Cormand B, Montfort M, Chabas A, Vilageliu L,
Gringerg D. Genetic fine localization of the beta-
glucocerebrosidase (GBA) and prosaposin (PSAP)
genes: implications for Gaucher disease. Human
Genet. 1997;100:75-9.
11. Horowitz M, Wilder S, Horowitz Z, Reiner 0,
Gelbart T, Beutler E. The human glucocerebrosi-
dase gene and pseudogene: structure and evolution.
Genomics.1989;4:87-96.
12. Human Gene Mutation Database (www.hgmd.
cf.ac.uk).
13. Levenson D. Expanded Ashkenazi Jewish prenatal
testing panel well received.AmJ Med Genet. 2010:
152A:fmviii-fmviii.
14. Brady RO, Pentchev PG, Gal AE, Hibbert SR,
Dekaban S. Replacement therapy for inherited
enzyme deficiency: use of purified glucocerebro-
sidease in Gaucher's disease. New Engl J Med.
1974;291:989-93.
Rosenbloom & Weinreb
15. Furbish FS, Steer q,Barranger JA,Jones EA,Brady
RO. The uptake of native and desialylated gluco-
cerebrosidase by rat hepatocytes and Kupffer cells.
Biochem Biophys Res Commun.1978;81:1047-53.
16. Pentchev PG, Brady RO, Hibbert SR, Gal AE,
Shapiro D. Isolation and characterization of gluco-
cerebrosidase from human placental tissue.J Biolog
Chern. 1972;248:5256-61.
17. Furbish FS, Steer C], Krett NL, BarrangerJA. Uptake
and distribution of placental glucocerebrosidasein rat
hepatic cells and effect of sequential deglycosylation.
Biochim Biophys Acta. 1981;673:425-34.
18. Furbish FS, Blair HE, Shiloach J, Pentchev PG,
Brady RO. Enzyme replacement therapy in Gau-
cher's disease: large scale purification of glucocer-
ebrosidase suitable for human administration. Proc
Natl Acad Sci USA. 1977;74:3560-3.
19. Barton NW, Brady RO, Dambrosia]M, DiBisceglie
AM, Doppelt SH, Hill SC, MAnkin HJ, Murray
GJ, Parker RI. Replacement therapy for inherited
enzyme deficiency: macrophage-targeted glucocer-
ebrosidase for Gaucher's disease. New Engl J Med.
1991;324:1464-70.
20. Grabowski GA, Barton NW, Pastores G, Dambrosia
]M, Banerjee TK, McKee MA, Parker C, Schiffman
R, Brady RO. Comparative efficacy of mannose
terminated glucocerebrosidase from natural and
recombinant sources.Ann Int Med.1995;122:33-9.
21. Zimran A, Altarescu G, Phillips M, Attias D,
Jmoudiah M, Deeb M, Wang N, Bhiranji K, Cohn,
GM, Elstein D. Phase ~ and extension study of
velaglucerase alfa replacement therapy in adults
with type 1 Gaucher disease: 48-month experience.
Blood. 2010;115:4651-6.
22. Zirnran A, Brill-Almon E, Chertkoff R, Petakov
M, Blanco-Favela F, Terreros Munoz E, Solono-
Meza SE, Amato D, Duran G, Giona F, Heitner R,
Rosenbaum H, Giraldo p,Mehta A, Park G, Phillips
M, Elstein D, Altarescu G, Szleifer M, Hashmueli
S, Avieza D. Pivotal trial with plant cell-expressed
recombinant glucocerebrosidase, taliglucerase alfa,
a novel enzyme replacement therapy for Gaucher
disease. Blood. 2011; 118:5767-73.
23. McCormack PL, Goa KL. Miglustat. Drugs. 2003;
63:2427-34; discussion 2435-6. Review.
24. Lukina E, Watman N,Arreguin EA, Dragosky M,
Iastrebneer M, Rosenbaum H, Phillips M, Pastores
GM, Kamath RS, Rosenthal DI, Kaper M, Singh
T, Puga AC, Petershmitt MJ. Improvement in
hematological, visceral, and skeletal manifestations
Crttical Reviews" in Oncogenesis
Gaucher Disease: A Comprehensive Review
of Gaucher disease type 1 with oral eliglustat tartrate
(Genz-112638) treatment- 2 year results of a phase
2 study. Blood. 2010;116:4095-8.
25. Rosenbloom B, Balwani M, Bronstein]M, Kolodny
E, Sathe S, Gwosdow AR, TaylorJS, Cole JA, Zirnran
A, Weinreb NJ. The incidence of Parkinsonism in
patients with type 1 Gaucher disease: data from
the ICGG Gaucher Registry. Blood Cells Mol Dis.
2011;46:95-102.
26. Biegstraaten M, Mengel E, Marodi L, Petakov N,
Niederau C, Giraldo P, Hughes D, Mrsic M, Mehta
A, Hollak CE, Van Schaik IN. Peripheral neuropathy
in adult type 1 Gaucher disease: a 2 year prospec-
tive observational study. Brain. 2010;133:2009-19.
27. Grabowski GA. Gaucher disease: gene frequencies
and genotype/phenotype correlations. Genet Test.
1997;1:5-12.
28. Mignot C, Doumrnar D, Marie I, De Villemeur TB,
French type 2 Gaucher disease Study Group. Type
2 Guacher disease: 15 new cases and review of the
literature. Brain Dev. 2006;28:39-48.
29. Messner MC, Cabot MC. Glucosylceramide in
humans. Adv Exp Med BIoI. 2010;688:156-64.
30. Atrian S,Lopez-Vinas E, Gomez- Puertas P, Chabas
H, Vilageliu L, Grinberg D. An evolutionary and
structure-based docking odel for glucocerebrosidase-
saposin C and glucocerebrosidase-substrate inter-
actions-relevance for Gaucher disease. Proteins.
2008;70:882-91.
31.
Tylki-Szymanska A, Czartory MT, Poorthis BJ,
Groener JA, Lugouska A, Millat G, Vaccaro AM,
Jurkiewicz E. Non-neuronopathic Gaucher diseasedue
to saposin C deficiency.Clin Genet. 2007;72:538-42.
32. G hauharali-van der Vlugt K, Langeveld M, Poppema
A, Kuuiper S, Hollak CE, Aerts JM. Prominent
increase in plasma ganglioside GM3 is associated
with clinical manifestations of type 1 Gaucher
disease. Clin Chirn Acta. 2008;389:109-13.
33. DekkerN, van Dussen L, Hollak CE, Overkleefr H,
Scheij S, Ghauharali K, van Breemen MJ, Farraz
MJ, Groener JE, Maas M, Wijburg FA, Speijer D,
Tylki-SzymanskA,Mistry PK, Boot RG,AertsJM.
Elevated plasma glucosylsphingosine in Gaucher
disease: relation to phenotype, storage cell markers,
and therapeutic response. Blood. 201l;1l8:e1l8-27.
34. Schaefer HE. The roles of macrophages in storage
diseases. Haematol Blood Transfus. 1981;27:121- 30.
35. Svennerholm L, Hakansson G, Mansson]E, Nilsson
O. Chemical differentiation of the Gaucher subtypes.
Prog Clin BioI Res. 1982;95:231-52.
Volume 18, Number 3 2013
173
36. Moran MT, Schfield JP, Hayman AR, Shi GP,
Young E, Cox TM. Pathologic gene expression
in Gaucher disease: up-reguation of cysteine pro-
teinases includinfg osteoclast cathepsin K. Blood.
2000;96:1969-78.
37. Allen MJ, Myer BJ Khokher AM, Rushton N,
Cox TM. Pro-inflammatory cytokines and the
pathogenesis of Gaucher's disease: increased release
of interleukin-6 and interleukin-l0. Qpart J Med.
1997;90:19-25.
38. Hollak CE, Evers L, Aerts JM, van Oers MH.
Elevated levels of M-CSF, sCD14 and IL8 in
type 1 Gaucher disease. Blood Cells Mol Dis.
1997;23:201-12.
39. Boven LA, van Meurs M, Boot RG, Mehta A, Boon
L, Aerts JM, LamanJD. Gaucher cells demonstrate
a distinct macrophage phenotype and resemble
alternately activated macro phages. Am J Clin Pathol.
2004;122:359-69.
40. Pelled D, Trajkovic-Budennec S, Lloyd-Evans E,
Sidransky E, Schiffman R, Futerman AH. Enhanced
calcium release in acute neuronopathic form of
Gaucher disease. Neurobiol Dis. 2005;18:83-8.
41. Deegan PB, Pavlova E, Tindall J, Stein PE, Bear-
croft P, Mehta A, Hughes D, Wraith JE, Cox TM.
Osseous manifestations of adult Gaucher disease in
the era of enzyme replacement therapy. Medicine.
2011;93:52-60.
42. Brotosin D, Tossier JP, Lapillonne T, Hermine 0, de
Villemeur TB, Cotoraci C. A cytometric study of red
blood cells in Gaucher disease reveals their abnormal
shape that may be involved with erythrophagocytosis.
Cytometry B Clin Cytom. 2011;80:28-37.
43. Spectre G, Roth B, Ronen G, Rosengarten D, Elstein
D, Zirnran A, VaronD, Revel-Vilk S. Platelet adhe-
sion defect in type 1 Gaucher disease is associated
with a risk of mucosal bleeding. Br J Haematol.
2011;153:372-8.
44. Charrow J,Andersson HC, Kaplan P, Kolodny EH,
Pastores G, Rosenbloom BE, Scott CR, Wappner
RS, Weinreb NJ, Zirnran A. The Gaucher registry:
demographics and disease characteristics of 1698
patients with Gaucher disease. Arch Intern Med.
2000;160:2835-43.
45. DaW N, Lagerstrom M, Erikson A, Pettersson U.
Gaucher disease type III (Norrbottnian type) is
caused by a single gene mutation in exon 10 of
the glucocerebrosidase gene. Am J Hum Genet.
1990;47:275-8.
174
46. Beutler E, Nguyen NJ, Henneberger MW, Smolec
]M, McPherson RA, West C, Gelbart T. Gaucher
disease: gene frequencies in the Ashkenazi Jewish
population. Am J Hum Genet. 1993;52:85-8.
47. Tajima A, Yokoi T, Ariga M, Ita T, Kaneshiro E,
Eto Y, Ida H. Clinical and genetic study ofJapanese
patients with type 3 Gaucher disease. Mol Genet
Metab. 2009;97:272-7.
48. El-Morsy Z, Khashaba MT, Soliman Oel-S, Yahia
S, El-Hady DA. Glucosidase acid beta gene muta-
tions in Egyptian children with Gaucher disease
and relation to disease phenotypes. WorldJ Pediatr.
2011;7:326-30.
49. Sobreira E, Pires RF, Cizmarik M, Grabowski GA.
Phenotypic and genotypic heterogeneity in Gaucher
disease type 1: a comparison between Brazil and the
rest of the world. Mol Benet Metab. 2007;90:81-6.
50. Gupta N, Oppenheim IM, Kauvar EF, Tayebi N,
Sidransky N. Type 2 Gaucher diease: phenotypic
variation and genotypic heterogeneity. Blood Cells
Mol Dis. 2011;46:75-84.
51. Cox TM, Schofield A. Gaucher disease: clinical
features and natural history. Bailleres Clin Haematol.
1997;10:657-89.
52. Lachmann RH, Grant IR, Halsall D, Cox TM.
Twin pairs showing discordance of phenotype in
adult Gaucher's disease. QJ Med. 2004;97:199-204.
53. Balwani M, Fuerstman L, Kornreich R, Edelman
L, Desnick RJ. Type 1 Gaucher disease: significant
disease manifestations in "asymptomatic" homozy-
gotes. Arch Intern Med. 2010;170:1463-9.
54. Fairly C, Zimran A, Phillips M, Cizmarik M, Yee J,
Weinreb N, Packman S. Phenotypic heterogeneity of
N370S homozygotes with type I Gaucher disease:
an analysis of798 patients from the ICGG Gaucher
Registry. J Inherit Metab Dis. 2008;31:738-44.
55. Kaplan P, Andersson HC, Kacena KA, Yee ]D.1he
clinical and demographic characteristics of nonneu-
ronopathic Gaucher disease in 887 children at diag-
nosis. Arch Pediatr Adolesc Med. 2006;160:603-8.
56. Lachmann RH, Wight DG, Lomas DJ, Fisher NC,
Schofield JP, Elias E, Cox TM. Massive hepatic
fibrosis in Gaucher disease: clinico-pathological
and radiological features. QIM. 2000;93:237-44.
57. Poll LW, vom Dahl S, Koch JA, Borner D, Will-
ers R, Cohnen M, lung G, Schere A, Niederau C,
Haussinger D, Modder U. Gaucher disease: MR
evaluation of bone marrow features during treatment
with enzyme replacement. Rofo. 2001;173:931-7.
Rosenbloom & Weinreb
58. Kauli R, Zaizov R, Lazar L, Pertzelan A, Laron Z,
Galatzer A, Phillip M, Yaniv Y, Cohen IJ. Delayed
growth and puberty in patients with Gaucher disease
type 1: natural history and effect of splenectomy
and/or enzyme replacement therapy. Isr Med Assoc
J. 2000;2:158-63.
59. Ross DJ, Spira S, Buchbinder NA. Gaucher cells
in pulmonary -capillary blood in association
with pulmonary hypertension. N Engl J Med.
1997;336:379-81.
60. Kim ]H, Park CH, Pai MS, Hahn MH, Kim MJ.
Hepatopulmonary syndrome in Gaucher disease
with right-to-Ieft shunt: evaluation and mea-
surement using Tc-99m MAA. Clin Nucl Med.
1999;24:164-6.
61. Goker-Alpan 0, Schiffman R, LaMarca ME,
Nussbaum RL, Mclnerney-Leo A, Sidransky E.
Parkinsonism among Gaucher disease carriers. I
Med Genet. 2004;41:937-40.
62. Taddei TH, Dziura J, Chen S, Yang R, Hyogo H,
Sullards C, Cohen DE Pastores G, Mistry PK.
High incidence of cholesterol gallstone disease in
type 1 Gaucher disease: characterizing the biliary
phenotype of type 1 Gaucher disease. J Inherit
Metab Dis. 2010;33:291-300.
63. Boot RG, van Breeman M], Wegdam W, Sprenger
RR, de long S, Speijei D, Hollak CE, van Dussen L,
Hoefsloot HC, Srnilde AK, de Koster CG, VissersJP,
Aerts JM. Gaucher disease: a model disorder for bio-
marker discovery.Expert Rev Proteomics.2009;6:411-9.
64. Stein P,Yu H,Jain D,Mistry PK. Hyperferritinemia
and iron overload in type 1 Gaucher disease. Am J
Hematol. 2010;85:472-6.
65. Saroha V, Gupta P, Singh M, Singh T Pseudogau-
cher cells obscuring multiple myeloma: a case report.
Cases J. 2009;2:9147.
66. Bain B], Lee L. Pseudo-Gaucher cells in sickle cell
anemia. Am J Hematol. 2010;85:435.
67. Wenger DA, Clark C, Sattler M, Wharton C.
Synthetic substrate beta-glucosidease activity in
leukocytes: a reproducible method for the identifi-
cation of patients and carriers of Gaucher disease.
Clin Genet. 1978;13:145-53.
68. Hultberg B, Sjoblad S, Ockerman PA. 4-Methy-
lumbelliferyl-beta-glucosidase in cultured fibroblasts
from controls and patients with Gaucher's disease.
Clin Chim Acta. 1973;49:93-7.
69. Beutler E, Saven A. Misuse of marrow examina-
tion in the diagnosis of Gaucher disease. Blood.
1990;76:646-8.
Critical Reviews" in Oncogenesis
 Gaucher Disease: A Comprehensive Review
70. Svennerholm L, Hakansson, Lindsten J, Wahlstrom
J, Dreborg C. Prenatal diagnosis of Gaucher disease.
Assay of the beta-glucosidase activity in amniotic .
fluid cellscultivated in two laboratorieswith different
cultivation condition. Clin Genet. 1981;19:16-22.
71. Pastores GM, Weinreb NJ, Aerts H, Andria G, Cox
TM, Giralt M, Grabowski GA, Mistry PK, Tylki-
Szymanska A. Therapeutic goals in the treatment
of Gaucher disease. Semin Hematol. 2004;41:4-14.
72. Andersson HC, Charrow J. Kaplan, Mistry P, Pas-
tores GM, Prakash-Cheng A, Rosenbloom BE, Scott
CR, Wappner RS,Weinreb NJ. Individualization of
long-term enzyme replacement therapy for Gaucher
disease. Genet Med. 2005;7:105-10.
73. Weinreb N], Aggio MC, Andersson HC, Andria
G, Charrow J, Clarke ]T, Erikson A, Giraldo P,
Goldblatt I. Hollak C, Ida H, Kaplan P, Kolodny
EH, Mistry P,Pastores GM, Pires R, Prakash-Cheng
A, Rosenbloom BE, Scott CR, Sobreira E, Tylki-
Szymanska A, Velodi A, vom Dahl S, Wappner
RS, Zimran A. Gaucher disease type 1: revised
recommendations on evaluations and monitoring
for adult patients. Semin Hernatol. 2004;41:15-22.
74. GrabowskiGA, Andria G, BaldellouA, Campbell PE,
Charrow ], Cohen J], Harris CM, Kaplan P, Mengel
E, Pocovi M, VellodiA. Pediatric nonneuronopathic
Gaucherdisease:presentation,diagnosisand assessment.
Consensus statements.Eur J Pediatr.2004;163:58-66.
75. Weinreb NJ, Charrow J, Andersson HC Kaplan P,
Kolodny EH, Mistry P,Pastores G, Rosenbloom BE,
Scott CR, Wappner RS, Zimran A. Effectiveness
of enzyme replacement therapy in 1028 patients
with type 1 Gaucher disease after 2 to 5 years of
treatment: a report from the Gaucher Registry, Am
J Med. 2002;113:112-9.
76. Poll LW,Maas M, Terk MR, Roca-Espiau M,Bembi
B, Ciana G, Weinreb NJ. Response of Gaucher bone
disease to enzyme replacement therapy. Br J Radiol.
2002;75 Suppll:A25-36.
77. Zimran A, Morris E, Mengel, Kaplan P, Belmatoug
N, Hughes DA, Malinova V, Heitner R, Sobreira
E, Mrsci M, Granovsky-Grisaru S, Amato D, vom
Dahl S. The female Gaucher patient: the impact
of enzyme replacement therapy around the key
reproductive events (menstruation, pregnancy and
menopause). Blood Cell Mol Dis. 2009;43:264-88.
78. Elstein Y, Eisenberg V, Granovsky-Grisaru S,
Rabinowitz R, Samueloff A, Zimran A, Eistein D.
Pregnancies in Gaucher disease: a 5-year study.Am
J Obstet Gynecol. 2004;190:435-4l.
Volume 18, Number 3 2013
View publication stats
175
79. Prows CA, Sanchez N, Daugherty C, Grabowski
GA. Gaucher disease: enzyme therapy in the
acute neuronopathic variant. Am ] Med Genet.
1997;71:16-2l.
80. Schiffmann R, Heyes MP, Aerts JM, Dambrosia
JM, Patterson MC, DeGaba T, Parker CC, Zirzow
GC, Olivr K, Tedeschi G, Brady RO, Barton NW.
Prospective study of neurological responses to treat-
mentwith macrophage-targeted glucocerebrosidase
in patients with type 3 Gaucher's disease. Ann
Neurol. 1997;42:613-2l.
8l. Ponce EjMoskovitz ], Grabowski. Enzyme replace-
ment in Gaucher disease type 1: effect of neutral-
izing antibodies to acid beta glucosidase. Blood.
1997;90:43-8.
82. Rosenberg M, Kingma W, FitzpatrickMA, Richards
SM. Immunosurveillance of alglucerase enzyme
therapy for Gaucher patients: induction of humoral
tolerance in seroconverted patients after repeat
administration. Blood. 1999;93:2081-8.
83. Sellos-Moura M, Barzegar S, Pan L, Shi P, Oom-
men S, Durant ], Ruiz ]A. Development of a panel
of highly sensitive, equivalent assays for detec-
tion of antibody responses to velaglucerase alfa
or irniglucerase enzyme replacement therapy in
patients with Gaucher disease.J Immunol Methods.
2011;373:45-53.
84. Cox T, Lachmann R, Hollak C, Aerts J, van Weely S,
Hrebicek M, Platt F, Butters T, Dwek R,Moyses C,
Gow I, Elstein D, Zimran A. Novel oral treatment
of Gaucher's disease with N -butyldeoxynojirimycin
(OGT 918) to decrease substrate biosynthesis.
Lancet. 2000;355:1481-5.
85. Zimran A, Elstein D. Gaucher disease and the clini-
cal experience with substrate reduction therapy. Phi-
losTrans R Soc London B BioI Sci.2003;358:961-6.
86. Hollak CE, Hughes D, va Schaik IN, Schwierin B,
Bembi B. Miglustat (Zavesca) in type 1 Gaucher
disease: 5 year results of a post-authorization safety
surveillance programme. Pharmacoepidemiol Drug
Saf.2009; 18:770-7.
87. Lukina E, Watman N,Arrequin EA,BanikazemiM,
Dragosky M, Iastrebner M, Rosenbaum H, Phillips
M, Pastores GM, Rosenthal DI, Kaper M, Singh
T, Puga AC, Bonate. A phase 2 study of eliglustat
tartrate (Genz-112638), and oral substrate reduc-
tion therapy for Gaucher disease type 1. Blood.
2010;116:893-9.