Gaucher disease is an uncommon autosomal genetic disorder
characterized by the deposit of large amounts of a lipid, glucosylceramide,
in the cells of the spleen, liver, and bone marrow.
The disease occurs because of a genetic fault in the production
of a specific enzyme, b-glucosidase, which ordinarily destoys the
lipid material.
Bone disease consists of a failure to remodel (Erlenmeyer-flask
deformity), osteopenia, and medullary and subchondral osteonecrosis,
all of which cause, in some patients, severe crippling and disability.
A major discovery was the capacity to modify the b-glucosidase
by mannose substitution, which allowed it to enter the cell and
destroy the lipid. This treatment has greatly altered the lives
of patients with this disease, and, when sufficient enzyme was given,
has greatly restored the patient’s osseous structure.
Gaucher disease is an uncommon disorder, but it offers a spectacular
model of the approach now being taken to define and treat many genetic
disorders, a number of which are orthopaedic in their manifestations.
Gaucher disease is a rare genetic disorder that is classified
as a lipid lysosomal storage disease. A product of cell-membrane
breakdown, glucosylceramide is stored in the lysosomal bodies of
the cells of the reticuloendothelial system as a result of a genetic
error in glucosylceramide-hydrolase (b-glucosidase) production.
The disease is transmitted as an autosomal recessive and most often
causes marked splenomegaly, hematological disorders, and bone abnormalities,
all of which may lead to serious functional impairment.
This Current Concepts Review describes the disorder in some detail,
with particular attention to the osseous manifestations. Although
the disease is uncommon, many orthopaedists see patients with osteonecrosis
or bleeding disorders and should be concerned about the possibility
that these findings may be manifestations of Gaucher disease. Of equal
importance, however, is an understanding of the extraordinary strides
made by scientists and clinicians in the treatment of this disease
over the 119 years since Gaucher first described it1. Not only can the disease now be
diagnosed with relative ease but patients who in the past were chronically
ill because of the visceral manifestations and severely disabled
by the osseous disease can now feel and look well and can live almost
normal lives. These remarkable achievements are unique in many ways
and are an essential part of this review. The lessons learned from
this disease will encourage us to critically examine other rare genetic
disorders and to apply similar systems that will allow effective
treatment in the future.
Gaucher disease was originally described in 1882 by a French dermatologist,
Phillippe Charles Ernest Gaucher, who reported the case of a patient
who had massive hepatosplenomegaly and findings suggestive of leukemia
but did not become ill or die1.
Gaucher believed the disease to be a "benign" leukemic
disorder. In 1924, Epstein described the presence of a lipid, cerebroside, in
the cells of patients with this disease and declared it to be a lipid
storage disorder2. The bone lesions,
which in many patients are quite striking, were first defined at
almost the same time, and necrotic segments and osteopenia were included
in the description3-5. Groen,
in 1948, was the first, as far as we know, to describe the genetic
transmission of the disorder, and he suggested that it was an autosomal
recessive disease6. In a landmark
discovery in 1965, Brady et al. defined the enzyme deficiency as
a failure of synthesis of glucosylceramide hydrolase (b-glucosidase),
which results in the accumulation of glucosylceramide (Fig. 1) in the lysosomal
bodies of the cells of the reticuloendothelial system7.
Perhaps the greatest accomplishment in the history of this disorder
was the result of work by the same team at the National Institutes
of Health. They initially tried to treat patients who had Gaucher
disease with the b-glucosidase enzyme, which represented the genetic
deficiency, but they discovered that it was not effective because
of the inability of the material to cross the cell barrier8-10. In 1991, Barton et al. reported on
the use of macrophage-targeted b-glucosidase, which was able to
cross the cell membrane and, once inside the cell, to destroy the
accumulated glucocerebroside in the lysosomal body11. This therapy made it possible to treat
patients with the disease effectively and, indeed, to restore them
to reasonably good health with use of regular intravenous administration
of the mannose-altered b-glucosidase12-18.
More recently, several investigators, including Ginns and Barranger,
have defined the genetic error in these patients19.
On the basis of these studies, attempts to eliminate the symptoms
of the disease by somatic gene therapy are now in progress at several
centers16,20-23.
Every twenty to thirty days, red and white blood cells are destroyed
and the chemical elements in the cell membrane are liberated (Fig. 2). Most of the
elements are either excreted or reutilized. One of these materials
is a complex glycosylated cerebroside lipid known as ceramide trihexoside7,24-27. It consists of a sphingosine
and a fatty acid (known as a ceramide) to which is attached, in linear
sequence, a glucose and two galactoses. In order for this material
to be reutilized or excreted, the three sugars must be chemically
removed. This is done first with a galactosidase and then with a
second galactosidase, which leaves a material consisting of ceramide
and glucose (glucosylceramide). If the patient cannot synthesize
sufficient glucosylceramide hydrolase (otherwise
known as b-glucosidase), the glucosylceramide is imbibed
by cells of the reticuloendothelial system (spleen, liver, and bone
marrow) and stored in the lysosomal bodies as quite distinct microtubular structures26,28. Because these tubules interfere with
programmed cell destruction, they confer on the cell a relative
degree of immortality so that the spleen and liver slowly enlarge
and the normal bone-marrow elements are replaced by the immortal
and characteristic Gaucher cells (Fig. 3)4,28,29.
Clinically, three forms of Gaucher disease are recognized and
are designated as types 1, 2, and 33,7,25,28.
Type 1 is the mild-to-moderately severe, slowly progressive non-neuronopathic
form seen most commonly in the United States, Europe, and particularly
Israel3,25,30. This
disorder is found most frequently in the Ashkenazi Jewish
population but may arise by spontaneous mutations and can be encountered
in any population group3,21,24,31-33.
As noted in Table I,
the findings are principally visceral, hematological, and osseous,
and the patients often have a long life because of the lowering
of the cholesterol level (the lipids are utilized in a different
system). Type 2 is the infantile form, which is fulminant and severe with
prominent neurological findings. Although the patients have visceral
and osseous disease, the neurological problems are dominant and
devastating and cause death usually by the age of two years24,28,34. There is no ethnic predilection,
and fortunately the disorder is rare. Type 3 is much less common
than type 1 and occurs most frequently in Swedish persons from Norrbotten.
In addition to the osseous, visceromegalic, and hematological problems,
these patients also have neurological problems but they are far
less severe than those seen in type 23,24,34.
The recent findings of the genetic errors in these patients are
of some importance (Table II). Five have been described for
type 13,30,35. Most of the patients
seen in the United States have an abnormality of the N370S allele,
which generally is associated with a milder disease course than are
the other abnormal alleles.
In untreated patients with Gaucher disease, a number of findings
are related to the increasing number of immortalized lipid-containing
cells of the reticuloendothelial system. It should be noted, however, that
for unknown reasons some patients with the same pattern of enzyme
failure have very mild disease whereas others have moderate or severe
manifestations and symptoms. In many cases, these individuals are
in the same family and have the identical genetic error. The explanation
for this is unknown but may be important in learning better ways
to control the disease28,33.
Although many symptoms and signs of Gaucher disease have been
reported, special emphasis should be placed on a few that are quite
striking and clearly related to the pathophysiology of the disorder:
splenomegaly, hepatomegaly, and hematological, pulmonary, and osseous
abnormalities.
The spleen in patients with Gaucher disease may be enormous36,37 (Figs. 4-A and 4-B). Splenic infarcts are common and
can be painful and at times life-threatening21,24,26,36.
Hypersplenism is common, with a resultant pancytopenia
and especially thrombocytopenia, leading at times to severe bleeding21,24,38,39. A hematocrit of 25% is
common in untreated patients with Gaucher disease, and many patients with
severe disease have a platelet count of <70,000/L
(<70 ¥ 109/L)38,40. It should be noted that these
values are often corrected quickly after splenectomy but later recur
as a result of progressive depletion of the normal marrow elements38,39. Hepatic disease is a late consequence
of Gaucher disease. Early in the course hepatomegaly is uncommon,
but after splenectomy the liver becomes more enlarged and may become
fibrosed and cirrhotic. This may lead to serious errors in metabolism,
further reduction in clotting factors, and, sometimes, death21,24,33,41,42. Pulmonary complications
are uncommon and limited in extent. They appear to occur with greater frequency
in patients with substantial liver disease43-47.
Although it is rare, secondary amyloidosis may be a very serious
problem48.
Laboratory studies performed for patients with Gaucher disease
who have not had a recent splenectomy or treatment with enzyme usually
reveal anemia, leukopenia, and thrombocytopenia21,24,37,38. In addition, patients
often have an increased acid-phosphatase concentration in the serum
(presumably related to the lysosomal location of the glucosylceramide)49. Of some interest is the presence
of increased angiotensin-converting enzyme of unknown cause50. Study of the glucosylceramide-hydrolase
concentrations in the white cells of the blood shows a deficit,
with levels often as low as one-tenth of the normal level26,37. An unusual finding in these
patients is an abnormally high level of plasma chitotriosidase,
which is presumably related to the abnormal macrophage activation
and is believed to be a reflection of the severity of the disease51. As indicated above, the cholesterol
level is often quite low because of the decrease in the amount of free
fatty acid available for production of this material. Examination
of the bone marrow is likely to show abnormal cellular elements
and Gaucher cells (often seen best on Wright stain)29. It should be noted that patients
with Gaucher disease may have benign hypergammaglobulinemia sometimes
associated with an elevated erythrocyte sedimentation rate52,53. This finding may be somewhat
confusing and of concern to the physician, since the neoplastic
process that occurs with the greatest frequency in patients with
Gaucher disease is myeloma54-56.
A matter of great concern in terms of surgical procedures is
that some patients with Gaucher disease may have a macrophage incompetence
for gram-positive bacteria57-59.
The cause is unknown but is presumed to be a diminution in the ability
of monocytes to destroy bacteria with their lysosomal enzymes57,58. The risk of infection after
surgery (prior to enzyme treatment) is often considerably greater than
that for other patients. Patients with Gaucher disease seem to have
an increased susceptibility to infection with some viruses, particularly
the Epstein-Barr virus. Also, symptoms and findings resulting from
this infection may persist much longer than those in other patients60.
The splenic, hematological, and hepatic manifestations of the
disease are disabling and, in some cases, life-threatening, but
the bone and joint manifestations often cause considerable distress
to patients with mild disease and even to those who are being treated
effectively with the enzyme. It should be noted, however, that the
bone disease may worsen after splenectomy, presumably because the
reservoir for the Gaucher cells is transferred from the enlarging
spleen to the bone marrow. In addition, pancytopenia similar to
that seen in patients with hypersplenism may develop, but, in the
case of Gaucher disease, it is related to the replacement of the
normal bone-marrow population61.
The pathogenesis of the osseous problems described below is, in
some cases, rather obscure. In addition, there are a number of factors
that currently are poorly defined and not well understood. These
include (1) an impairment and decrease in the number of osteoprogenitor
cells, leading to a severely diminished rate of osteosynthesis,
which results in a sometimes profound osteopenia with associated
lytic lesions and an increased risk of fractures; (2) marked suppression
of osteoclast activity, which leads to remodeling problems for young
bones (the Erlenmeyer-flask deformity) and poor fracture-healing
at all ages; (3) vascular compromise of unknown cause, resulting
in osteonecrosis of the medullary cavity especially affecting the bones
of the hip, knee, and shoulder (such problems may also occur as
an acute fulminant illness, which is termed the Gaucher
crisis); and (4) more frequent observation of osteomyelitis, septic
arthritis, and operative wound infections because of a macrophage
incompetence for gram-positive infection. The frequency of osteonecrosis in
these infected osseous segments makes perfusion with systemic antibiotics
much less effective and renders the disease virtually untreatable
in many cases.
It is evident that the presence of Gaucher cells in the marrow
is a major cause of most of the problems listed above, but the exact
mechanism by which the bone and bone cells are affected by their presence
is not clearly understood.
Failure to Remodel
The most prevalent abnormality in patients with Gaucher disease
is a failure of the distal part of the femur and the proximal part
of the tibia to remodel, resulting in the classic Erlenmeyer-flask
appearance (Fig. 5)21,28,62,63. This finding is noted
in approximately 80% of patients and is not a cause of
symptoms28. Although
rare in other disorders, it is not pathognomonic for Gaucher disease
and may be seen in some genetic metaphyseal and diaphyseal dysplasias.
Osteopenia
Decreases in medullary bone density and thinning of the cortices
are evident in almost all patients with Gaucher disease (Fig. 6)21,28,62. Cortical thinning due to
medullary expansion and moderately discrete lytic lesions are not
uncommon. Bone-densitometry measurements show a sharp reduction
in density compared with that of age-matched controls17,64-66, and measurements of cortical
thickness often show striking abnormalities64,67.
Fractures are common and sometimes difficult to treat, partly because
of the quality of the bone but also because of the bleeding tendency
and the risk of infection (Fig. 7)5,28,68.
Osteonecrosis
Death of bone because of vascular compromise occurs in many patients
with type-1 Gaucher disease and presents in two forms. The first
of these, medullary osteonecrosis, is sometimes asymptomatic5,28,62,69. Necrosis of medullary bone
causes the death not only of the osseous elements but also of the
marrow cells, which include a large number of Gaucher cells. Damage
to these cells releases the free fatty acid associated with the
sphingosine in the ceramide molecule. The major available counter-ion
for the released acid is calcium, which produces a calcium soap,
a material that is insoluble in body fluids69.
No enzymes are available to destroy this material so a medullary
area of markedly increased density, which, despite its appearance,
does not seem to strengthen the bone, may be seen for years (Fig. 8)28,69.
The second form of osteonecrosis, corticocancellous disease,
principally affects the femoral heads, distal parts of the femora,
proximal parts of the tibiae, or proximal parts of the humeri (Fig. 9-A)5,28,29,69-72. These subchondral lesions
often lead to pathological fracture and collapse of the osseous
end plate, which may result in disabling joint disease. The disorder
affects both adults and children. In children, the disorder closely
resembles Legg-Calvé-Perthes disease (Fig. 9-B). Regardless
of the age of the patient, the disease is often progressive, and
some patients may have such severe pain and disability that they
become wheelchair-bound at a young age28,70,71.
Osteonecrosis is more common in patients who have had a splenectomy73.
Osteonecrosis of either type may produce an acute and quite fulminant
pattern of pain and illness known as a Gaucher crisis5,28,62,74. Patients complain of severe
pain at the site, they are unable to move the affected part, and
they have a high fever, leukocytosis, and an elevated erythrocyte
sedimentation rate. Such findings are suggestive of acute osteomyelitis,
and the differential diagnosis is difficult5,75,76.
The current approach to this problem is to perform a technetium-99m
bone scan within two to three days following the onset of the crisis75-78. If the scan shows positive findings
over the site, the cause is much more likely to be osteomyelitis. If
it shows negative findings over the site, the presence of the bone
crisis is suggested.
Aspiration biopsies and cultures are also helpful, but, if possible,
it is wise to avoid open biopsy or irrigation. Wounds do not heal
well, and bleeding may be a serious problem. Although there is no known
way to decrease the speed and extent to which the crisis affects
the bone, oxygenation appears to be helpful and hyperbaric oxygen
therapy seems to have been of value in a few cases described anecdotally.
Unusual Manifestations
Several findings in patients with Gaucher disease are quite remarkable
and have no known genesis. The first of these is the presence of
benign hypergammaglobulinemia, which may be marked52-55,79. A great concern is the element
of doubt regarding the diagnosis that is created by the increased
prevalence of myeloma in patients with Gaucher disease46,55,56. This can be solved, in part,
by performing a bone-marrow biopsy and searching for Bence-Jones
protein and other markers of the more malignant disorder.
The second unusual feature is the collapse of midthoracic or
cephalad lumbar vertebrae (Fig. 10)5,28,62.
The vertebral damage may sometimes occur in multiple segments, leading
to curvature or kyphosis, sometimes with spinal cord compression. Patients
with this problem, particularly children, may show considerable
truncal shortening80.
Another unusual feature of Gaucher disease is the appearance
of the long bones on magnetic resonance imaging28,81-84. Because the medullary cavities
are filled with Gaucher cells instead of marrow or fat, the long bones
have a so-called salt-and-pepper pattern on T1-weighted magnetic
resonance images (Fig. 11). The cause of this change is not
clear, but it may be related to the shortening of the T1 relaxation time
of the Gaucher cells compared with that of the cells of the normal
marrow. The change does not seem to occur in epiphyseal sites and
often improves with enzyme treatment28,82,84.
Finally, one of the most bizarre osseous abnormalities in these
patients is the presence of a gaucheroma. These
abnormal collections of Gaucher cells and blood result in a markedly
expansile lesion of the bone and often appear as a massive destructive lesion
that resembles a giant-cell tumor or an aneurysmal bone cyst (Figs. 12-A and 12-B)85,86.
Patients with Gaucher disease should be carefully examined to
define the extent and character of the disease and hopefully to
predict future problems, but more importantly to define the need
for treatment. The protocol should include genetic studies to prove
the existence of the disease, general studies, and studies of the
bones.
Proof of the Existence of the Disease
Genetic studies to define the abnormal alleles have replaced
analysis of the cells and/or serum for glucosylceramide
hydrolase35. Similarly,
bone-marrow or liver biopsy to determine the presence of Gaucher
cells, formerly the principal means of establishing a diagnosis,
is rarely necessary.
General Studies
A careful history should be obtained and a physical examination
should be performed with special emphasis on the presence of visceromegaly.
Laboratory studies should include a complete blood-cell count; liver-function
tests; immunoelectrophoresis; and determination of the erythrocyte
sedimentation rate and the levels of electrolytes, calcium, phosphorus,
alkaline and acid phosphatase, and angiotensin-converting enzyme28,33,49,50,52. A radiograph of the
chest and a computerized tomography scan of the abdomen to estimate
the hepatic and splenic volumes are of considerable value in the
follow-up of patients during treatment21,24,28,44.
Studies of the Bones
A T1-weighted magnetic resonance image of both lower extremities,
a technetium-99m bone scan, bone densitometry (especially dual-energy
x-ray absorptiometry), calculation of cortical thickness, and determination
of the fat fraction at specific sites are valuable in defining the
extent of the bone disease and are particularly helpful in defining
the effect of treatment17,64,66,78,82-84.
It should be obvious that radiographs and other imaging studies
should be performed in relation to the patient’s symptoms.
Bone or joint pain related to infarcts should be carefully analyzed
by plain radiography, computerized tomography, and magnetic resonance
imaging. Magnetic resonance imaging is the most sensitive study
for finding bone abnormalities, but, as noted above, the image may be
sufficiently altered by the salt-and-pepper pattern as to be a source
of some confusion.
Until approximately twenty years ago, the treatment of Gaucher
disease was almost entirely supportive. Patients with a low hemoglobin
level were given iron or at times blood transfusions, and patients
with leukopenia were advised to avoid exposure to circumstances
involving a high risk of infection and to take antibiotics when
they felt ill. Patients were hospitalized when they had bone crises,
splenic infarcts, or serious bleeding episodes and were given supportive
care3,21,26. Splenectomy was virtually
mandatory in patients with a massive infarct or severe pancytopenia
or those in whom the spleen was so large as to be deforming or disabling3,16,24,31. The consequence of such
surgery was an increased number of cells in the bone marrow with
a resultant increase in bone disease and, more specifically, osteonecrosis61. Bone-marrow transplant was associated
with high rates of complications and death, which were related to
the ease with which patients with Gaucher disease are infected with
bacteria, and approaches such as plasmapheresis were thought to have
no value.
Bone disease was treated symptomatically62,63.
Fractures were managed with fixation devices, but they were associated
with a high complication rate, and patients with osteonecrotic destruction
of a joint who were thought to be at high risk for surgical complications
were treated conservatively. Joint replacement was performed, but
it was associated with serious drawbacks in terms of bleeding, high infection
rates, and occasionally death40,70,71,79.
Many patients with bilateral hip or knee disease were advised to
use a wheelchair rather than to risk surgery. Osteomyelitis and
septic arthritis were common and were treated with surgical débridement,
immobilization, and antibiotic therapy, but, because of the almost
inevitable presence of dead bone, they were very difficult to eradicate
and at times amputation was required57,75,76,87.
Enzyme Treatment
In a landmark discovery in 1965, Brady and his colleagues at
the National Institutes of Health described the enzyme deficiency
that allows the accumulation of the offending glucosylceramide in the
cells of the spleen, liver, and bone marrow7,9,26.
It seemed logical at this point to treat the patient with the enzyme
to determine if doing so could remove the accumulated lipid in the
lysosomal bodies of the cells. Initial trials with intravenous administration
of the enzyme showed a reduction in the concentration of glucosylceramide
in the serum, but, disappointingly, there was only a modest reduction
in the number of Gaucher cells or the concentration of acid phosphatase8,10. It became clear to Brady and
his coworkers that they had to get the enzyme inside the cell membrane
if the treatment was to be effective.
A second discovery was recorded when Brady, Barton, and their
scientific and clinical colleagues experimented with a mannose-substituted
b-glucosidase3,11,13,27,30,88,89.
This material could enter the cell and destroy not only the glucosylceramide
but also, in many cases, the offending cell. This led to a marked
reduction in the organ and body burden of the offending lipid. In a
number of clinical trials, the material (Ceredase [alglucerase];
Genzyme, Cambridge, Massachusetts), which was most readily obtained
by extraction and purification from placentas, was administered
intravenously every two weeks at a dose initially set at 60 U/kg
of body weight. Patients who received the enzyme felt better almost immediately
and reported weight gain, less bone pain, and reduced fatigue. Their
physicians noted that the patients had a reduction in acid phosphatase levels
and increased concentrations of white blood cells, platelets, and
hemoglobin over a twelve to twenty-week period. Splenic and hepatic
size, as measured on magnetic resonance images, was reduced during
the same period. Bone pain lessened, and crises became less frequent
in a matter of six to nine months6,15,28,33,49,64,90-92.
With use of recombinant-DNA technology, a similar agent known as
Cerezyme (imiglucerase; Genzyme) was developed and is currently
in use. Its action is identical to that of Ceredase, but it is much easier
to produce and has a more certain composition.
Although the condition of the bones improved with time, it was
of some concern that the improvement had not occurred at the same
rate as it had in other organs. With use of the standard dose of
Cerezyme (60 U/kg of body weight) every two weeks, substantial
improvement in bone densitometry, cortical thickness, and fat-fraction
data were not noted until well after one year of treatment89. Furthermore, recent studies have
shown that the improvement cannot be maintained if the dose is reduced
after two years of treatment, and currently it seems likely that
higher doses may be required if the initial success with regard
to the treatment of bone disease is to be maintained15,89. Several current trials of treatment
protocols with use of bisphosphonate in association with the enzyme
have shown some promise but have not yet been completed93,94. It is speculated that when the
marrow is restored sufficiently to allow the presence of osteoclasts (which
are markedly decreased in number in patients with untreated Gaucher
disease), more osteopenia is produced, especially in postmenopausal
women. The use of bisphosphonates seems to reduce this problem and
tends to increase the bone density.
Recently reported experimental studies utilizing gene transfer
to alter the body’s management of glucosylceramide are
of considerable interest19,20,23.
If the RNA coding for the enzyme can be introduced into the cell’s
DNA by reverse transcriptase, it is possible that these cells will
produce sufficient b-glucosidase to reduce the body’s burden
of the offending lipid16,18,20,22.
Initial animal studies have shown promise, and currently the genetic
therapy is being tried as an approach to the disease in at least
two centers. Thus far, some success has been achieved, but it appears to
have been relatively short-lived as the altered cells die and the
new cells do not seem to carry out the activity as effectively.
However, it is likely that this technology will help to provide
a better solution to the problem of Gaucher disease.
Several attempts have been made to vary the dose level in terms
of either the concentration given at each time-period
or a change in the time-period itself14,95,96.
Many of these protocols have been effective in maintaining the patients’ sense
of well-being, the reduction in splenic size, and the hematological parameters,
but evidence that none of these protocols leads to an improvement
in the bone findings has now accumulated89.
It should be evident from the foregoing discussion that the operative
management of patients prior to the introduction of enzyme therapy
was fraught with serious complications5,70,71,79.
It is important that a patient who requires surgery be treated with
increased amounts of Cerezyme for a reasonable period prior to the
operative procedure97. The anesthesiologist
should be alerted to the problems associated with poor aeration
in terms of precipitating a Gaucher crisis74 as
well as the threat of excessive bleeding in association with a diminished
platelet count or damage to the hepatic prothrombin-production system38,40,41. The patient should have transfusions
of blood and/or fresh platelets as necessary. Patients
sometimes wish to store their own blood prior to the surgery, and
this is acceptable, as is the preliminary use of materials such
as erythropoietin to enhance red blood-cell production. The patients
should receive prophylactic antibiotic therapy, preferably directed at
gram-positive organisms, prior to and for at least four to seven
days following the operation75.
Anticoagulants should not be administered unless there is some suggestion
that the patient has a risk of deep venous thrombosis. Patients
should be watched carefully during the first three months after
surgery, especially after hip or knee replacement, to be sure that
no complications occur.
A fairly well accepted sequential system for understanding and
treating genetic diseases involves six stages (Table IV).
Stage I: Description of the Clinical Syndrome
The syndrome was first described in 1882 in the remarkable report
by Gaucher1. Subsequent authors
have added much more information regarding the biological and biochemical characteristics,
but it is safe to say that the clinical definition of Gaucher disease
is well understood21,24,28,33 and
that the understanding of bone problems is reasonably well established
(although there are still some exceptions)17,21,28,62,64,65.
Stage II: Definition of the Pattern of Genetic
Transmission
The genetic transmission of Gaucher disease as an autosomal recessive
with frequent mutations was well known by the early part of the
twentieth century6,26.
Stage III: Identification of the Biochemical
Abnormalities
The biochemical abnormalities associated with Gaucher disease
were certainly known by the 1970s7,95.
Excessive concentrations of glucosylceramide in the serum and cells
was one of the cardinal findings noted and described by Brady and
his coworkers in the middle and late 1960s3,26,98.
Stage IV: Definition of the Biochemical Error
The identification of decreased production of glucosylceramide
hydrolase as the biochemical error associated with Gaucher disease
resulted from the prodigious efforts of Brady, Barton, Barranger,
Furbish, and the group at the National Institutes of Health in 19657,8. As a result of this landmark discovery,
patients now can be effectively treated with the enzyme and their
lives can be enormously improved and, in some cases, saved3,11,13,88. It should be noted, however,
that the very special discovery by Barton et al. that the mannose-substituted
enzyme could be introduced into the cell to target the macrophage
and destroy the glucosylceramide was a major contribution11.
Stage V: Identification of the Gene Error
The gene error associated with Gaucher disease has been identified.
The five abnormal alleles are known, and patients and their families
can be easily tested19,35.
Stage VI: Treatment by Genetic Alteration
Treatment of the disease by genetic alteration is currently in
progress experimentally and hopefully will be an effective way to
reduce the extent of the disease15,18,20,22 and,
with proper systems, perhaps to eliminate it completely.
An important aspect of this approach, and indeed the beauty of
it, is its methodical stepwise solution of a problem. Investigators
can have no greater joy than to solve a problem in such a superb
and orderly fashion. They should be, and indeed have been, honored
for this. Another aspect of this approach that is even more important
is its demonstration of a way of dealing with genetic diseases, in
particular, for the readers of The Journal, those
that affect the bones and are currently treated by orthopaedists. Table V shows an incomplete
list of an array of genetic disorders currently being treated by
orthopaedists and pediatricians with techniques that are based on analysis
of osseous structure, histological observation, or chemical alterations.
To date, although the genetic error has been found for most of these
disorders, we have no way of doing for patients with these diseases
what has been done for patients with Gaucher disease. However, there
is little doubt that similar advances in the understanding and treatment
of some of these disorders will occur in the not-too-distant future.
It is important for orthopaedic surgeons to understand the progress
that has occurred in relation to Gaucher disease. The treatment
of genetic bone diseases by molecular biological techniques has
a vast potential to alter the way that we treat our patients, and
we must maintain a familiarity with the steps and technology by
which advances can occur. That is the goal that we all wish to achieve
and the one that we must strive for.
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