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1126 Part VIII: Monocytes and Macrophages Chapter 72: Gaucher Disease and Related Lysosomal Storage Diseases 1127

characteristic crinkles or striations. The cytoplasm is stained by the the risk of infection with encapsulated organisms. Partial splenectomy
periodic acid-Schiff technique. Electron microscopy demonstrates has not proved useful, with both regrowth of the remnant and risk of
cytoplasmic spindle- or rod-shaped, membrane-bound inclusion bod- osteonecrosis.
ies 0.6 to 4 μm in diameter, consisting of numerous small tubules, 130 When bone lesions result in fractures or osteonecrosis (see
to 750 Å in diameter, that are composed of twisted multilayers in nega- Fig. 72–3D), orthopedic procedures may be required. Joint replacement
tively stained preparations. 103 is generally uneventful, with good functional outcome and quality of
life. The success of arthroplasties is enhanced by adherence to preoper-
DIFFERENTIAL DIAGNOSIS ative protocols including assessment of bleeding tendency, prophylactic
use of antibiotic therapy, particularly in splenectomized patients, and
Diagnosis early post-operative ambulation. 108
The diagnosis of Gaucher disease should be considered in (1) any Deficiencies of iron, vitamin B , or vitamin D should be corrected
12
patient who presents with unexplained splenomegaly, thrombocytope- and calcium supplementation is recommended in patients with oste-
nia, frequent nosebleeds, anemia, acute or chronic bone pain; (2) chil- oporosis receiving bisphosphonates. Use of erythropoietin may be
109
dren with short stature for their age; and (3) nontraumatic avascular required for management of anemia because of marrow failure. 110
necrosis of a large joint at any age, especially if is associated with any of
the above features. Enzyme Replacement Therapy
A definitive diagnosis requires a reduced enzymatic activity The use of alglucerase, the first mannose-terminated, placental-de-
9
of β-glucocerebrosidase in leukocytes, 104,105 cultured fibroblasts, or rived enzyme, was approved in 1991, and the recombinant form,
amniocytes obtained during prenatal diagnosis. Measurement of glu- imiglucerase, albeit with one amino acid R495H that differs from the
cocerebrosidase levels is supplemented by mutational analysis. This wild-type protein owing to a cloning artifact in the original comple-
is important for prognosis, particularly in children, and for detection mentary DNA (cDNA), was introduced in 1994. Two intravenous
111
of carriers among affected families. While rapid polymerase chain preparations, one with the perfect native-enzyme sequence developed
reaction-based tests are often performed for five or seven common in a human cell line, velaglucerase alfa, and the other, a carrot root
112
mutations, especially among Ashkenazi Jews as a “first-pass,” it is highly cell-derived with the imiglucerase core sequence, taliglucerase alfa,
113
recommended to perform whole-genome sequencing to rigorously have completed phase 3 clinical trials and are available. Phase 2 clinical
106
establish the molecular diagnosis. trials with taliglucerase alfa are currently underway in which the same
Marrow aspiration as a means of diagnosis is only indicated when carrot cells, expressing taliglucerase alfa, are used as vehicle for oral
other hematologic diseases must be considered. 94,105 Gaucher cells delivery of the enzyme.
are often sparse and thorough examination under low-power may be The response to ERTs is most gratifying. 9,111–116 Decreased spleen
required to find them. Cells indistinguishable by light microscopy from and liver volumes and increased hemoglobin levels and platelet counts
typical Gaucher cells may also be seen in patients with other disorders usually occur within 6 months of therapy with biweekly doses between
such as chronic myelogenous leukemia, Hodgkin lymphoma, myeloma, 15 and 60 U/kg. Platelet counts in patients with massively enlarged
and acquired immunodeficiency syndrome. The latter patients do not spleens may require longer periods to respond, but improvement con-
lack the ability to catabolize glucocerebroside, but the great inflow of tinues within the first 2 years of therapy. Thereafter, patients treated with
globoside into phagocytic cells exceeds their capacity to hydrolyze glu- imiglucerase stabilize even while on the same dose. 116
cocerebroside, forming “pseudo-Gaucher cells.” The bone response is slower and less predictable. Osteonecrosis
Prenatal diagnosis can be established by examining cultured and lytic lesions do not respond to ERT. Quantitative chemical shift
amniocytes obtained by amniocentesis for measurement of glucocere- imaging, a sensitive modality to show changes in the marrow, includ-
brosidase activity or by examining amniocytes or chorionic villi DNA ing response to ERT (Fig. 72–5), is a resource available in only one
104
117
for known mutations. site worldwide and, hence, various other imaging modalities, espe-
cially MRI-based modalities, but also bone densitometry and plain
Heterozygote Detection radiographs, are used as needed to document skeletal status.
Heterozygotes for Gaucher disease have neither Gaucher cells in their ERT may or may not improve pathologic pulmonary findings.
marrow nor stigmata of Gaucher disease (other than the increased risk Because the enzyme is a large molecule, it does not cross the blood–
of Parkinson disease). Existence of a carrier state can be demonstrated brain barrier, and hence, does not impact neuronopathic features. 118,119
by reduced glucocerebrosidase activity to approximately 50 percent of All ERTs are safe, having few side effects that are usually tran-
normal values. However, regardless of methodology, enzyme activity sient. 112,113,120 Hypersensitivity reactions have been reported with each
among heterozygotes overlaps the normal range and hence definitive type of ERT, but only rare cases of anaphylaxis. Most patients with such
diagnosis of heterozygous status only can be made by mutational anal- reactions may continue ERT with or without premedication; it is advis-
ysis. Currently various methodologies are being developed to allow able to avoid the administration of glucocorticoids for this purpose
noninvasive prenatal diagnosis of monogenic diseases like Gaucher dis- because of an increased risk of osteonecrosis. For each ERT there is a
ease; the most promising of these is molecular analysis of cell-free fetal different percent of patients who may develop antibodies either shortly
DNA. 107 after initiation of treatment or over time.
Another side effect is weight gain with some concerns about
changes in insulin resistance and the development of metabolic syn-
THERAPY drome, including steatohepatitis. Because of the excellent safety
121
122
Symptomatic Treatment profile, many patients receive therapy at home and many female
Symptoms and signs related to massive enlargement of the spleen (e.g., patients are comfortable continuing with ERT during pregnancy and
pancytopenia, early satiety, abdominal discomfort, and growth retar- lactation. 123,124 The effects of treatment are unaffected by switching from
125
dation in children) can be resolved by splenectomy. However, because imiglucerase to velaglucerase alfa or taliglucerase alfa. 126
of the efficacy of ERT, splenectomy should only be a last resort as it The two major disadvantages of ERTs are the apparent lifetime
often induces progressive liver and bony complications, and increases dependency on intravenous infusions and the extremely high cost.

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