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1128 Part VIII: Monocytes and Macrophages Chapter 72: Gaucher Disease and Related Lysosomal Storage Diseases 1129

1.0 Figure 72–5. Color-coded fat fraction
measurements using quantitative chemi-
cal shift imaging in an adult patient with
type 1 Gaucher disease. Annual measure-
ments show increase in fat fraction with
specific therapy (mean value in 1994 =
0.11; mean value in 2001 = 0.45). (Used
with permission of Dr. Mario Maas, Aca-
demic Medical Center, Amsterdam, The
0.0 T = 0 T = 3 T = 7 Netherlands.)
FF = 0.11 FF = 0.24 FF = 0.45

Guidelines and/or expert opinions usually recommend the use of rel- was administered in a pilot study to adult type 1 patients ; clinical tri-
141
atively high doses. 127,128 Yet, it is evident that for most symptomatic als in type 3 patients are planned.
patients, there is no justification for doses higher than 30 to 60 U/kg per
month, and for patients with asymptomatic type 1 disease, ERT should Organ Transplantation
not be encouraged. 129 Because the macrophage is a derived from hematopoietic stem cells,
allogeneic hematopoietic stem cell transplantation should cure Gaucher
Substrate Reduction Therapy disease. Although some enthusiasm was expressed for this approach,
The possibility that decreasing the formation of glucocerebroside from the short-term risks of transplantation markedly limit the number of
130
ceramide and glucose, referred to as substrate reduction therapy (SRT), suitable candidates. Effective ERT further limits the appropriateness
might favorably impact disease parameters was proposed in the 1970s. of transplantation. Liver transplantation has been performed in a few
131
Oral miglustat (N-butyldeoxynojirimycin), a glucose analogue that patients with severe hepatic failure. 142
130
inhibits glucocerebroside synthase, has been licensed for treatment
of patients for whom ERT is not suitable or not a therapeutic option
according to the two preeminent regulatory authorities’ definitions. COURSE AND PROGNOSIS
This circumscribed approval stems from inferior efficacy of miglustat Age of onset, severity of clinical manifestations, and degree of progres-
relative to ERT and a problematic safety profile including peripheral sion are partially related to genotype. Patients homozygous for the N370S
neuropathies, tremor, and memory impairment. Miglustat is effective mutation tend to present with symptoms and signs at an older age with rel-
in reducing hepatosplenomegaly in Gaucher disease when given as atively milder manifestations, and usually have a relatively stable disease.
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100 mg, three times daily. Response to miglustat is dose-dependent; By contrast, compound heterozygotes for N370S and a “severe” mutation
lower doses yield suboptimal improvement without reducing frequency (such as N370S/84GG or N370S/L444P) usually present with the disease
of side effects. Miglustat has also been studied as maintenance therapy during childhood, and if untreated, progress continuously with both
133
133
in patients previously treated with imiglucerase. A practical advantage visceral and skeletal complications. 108,143,144 Patients homozygous for the
was that it could be considered in type 3 patients because as a small mol- L444P mutation will develop neuronopathic disease with deteriorating
ecule it crosses the blood–brain barrier and impacts neurologic signs. neurologic signs and symptoms and their life span is reduced. 65
Unfortunately, a clinical trial failed to achieve the end points and, hence, Although the genotype of the patient provides a benchmark for
there is no indication for this drug in neuronopathic Gaucher disease. prognosis, there is much variability in patients with the same genotype,
134
Another SRT, a ceramide analogue, eliglustat tartrate, has been including between siblings with the same genotype. The availability of
granted FDA approval. However, it has a more problematic safety profile ERT has changed the natural course of the disease allowing normal growth
compared to ERT (including cardiac events), the efficacy parameters. and development in most patients, even in those with “severe” genotypes.
135
The robust database derived from long-term followup from phase 2 and Nevertheless, some patients still develop skeletal complications despite
from three different phase 3 clinical trials indicates it can be useful. ERT and there is concern regarding development of associated diseases,
136
However, unlike miglustat, it cannot cross the blood–brain barrier and such as myeloma, other malignancies, or Parkinson disease. 120
should be targeted to type 1 patients only. Prior to the availability of ERT, patients with severe type 1 or type 3,
died at an early age because of liver disease, bleeding, or sepsis. With
Pharmacologic Chaperones the advent of ERT, typical causes of death are malignancy, cardiovas-
145
A new approach to lysosomal storage diseases is “chaperone ther- cular disease, and cerebrovascular disease. In type 2 disease, death
apy.” PC therapy is based on in vitro experiments showing that some usually results from neurologic complications within the first 4 years of
65
misfolded mutants of glucocerebrosidase are destroyed prior to their life ; there is also a lethal neonatal variant. Total absence of glucocere-
export from the endoplasmic reticulum to the lysosome. 137,138 Under brosidase may not be compatible with life.
these circumstances, a reversible inhibitor stabilizes the mutant
enzyme, enabling its passage to the lysosome without losing activity.
Clinical trials with the first PC for Gaucher disease, isofagomine tar- NIEMANN-PICK DISEASE
trate which had been shown to increase mutant enzyme activity in
139
cells, tissues, and healthy volunteers during the phase 1 trial, failed in HISTORY AND CLASSIFICATION
the phase 2 clinical trial when only 1 of 18 patients with type 1 showed In 1914, Niemann, a Berlin pediatrician, reported the case of an infant
a beneficial effect. 140 who died at age 18 months with a disorder that seemed atypical for
Another PC, ambroxol, an expectorant that is available without Gaucher disease because of its early onset and rapid course. In
146
prescription in many countries and has decades-long safety experience, 1927, Pick identified this as a unique disorder of rapid, progressive

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