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1122 Part VIII: Monocytes and Macrophages Chapter 72: Gaucher Disease and Related Lysosomal Storage Diseases 1123

Some mutations result from recombinant events between the functional endoplasmic reticulum. 31,32 The investigation of the proteotoxic effect
gene and its pseudogene. Since 2000, approximately 20 of these mutated of the misfolded mutant enzyme in the endoplasmic reticulum has led
8
enzymes have undergone crystallography showing the divergence of lig- to the development of the new therapeutic modality of pharmacologic
ands in the active site and with various degrees of glycosylation. 23 chaperones (PCs). PCs are targeted to stabilize the mutated glucocere-
Among Ashkenazi Jews, the predominant mutation is N370S brosidase and allow its appropriate trafficking from endoplasmic reticu-
which accounts for approximately 75 percent of mutant alleles among lum to Golgi and, finally, to the lysosome.
Jewish patients and approximately 30 percent of the alleles among
non-Jewish patients. Homozygosity for N370S is characterized by
relatively milder phenotypes (although the phenotype is very het- CLINICAL FEATURES
24
erogenous and severe cases are seen ). N370S has heretofore been Three major types of Gaucher disease are differentiated clinically based
considered “protective” against the development of neuronopathic on absence (type 1) or presence of neurologic features (types 2 and 3).
33
features. The second common mutation found almost exclusively Table 72–1 summarizes key clinical, genetic, and demographic fea-
among Ashkenazi Jews is one that usually causes a severe phenotype. tures. Although it has been suggested that there is a phenotypic con-
Five or six common mutations account for approximately 97 percent tinuum, 34,35 it is still useful to think of Gaucher disease as three distinct
of alleles among Jews, but account for less than 75 percent of alleles forms to facilitate genetic counseling and management decisions.
among non-Jews. 8,25–27 Although controversial, premarital/prenatal There is variability in disease severity of all types of Gaucher dis-
screening for common mutations has become frequent among Ash- ease. Type 1 disease may be asymptomatic and be discovered in the
kenazi Jews. 28,29, course of population surveys of Ashkenazi Jews, or incidentally during
28
The second most common mutation is L444P, which when evaluation of an unrelated hematologic disorder.
homozygous accounts for most patients with the neuronopathic type 3
disease, and is the most prevalent mutation in Asians, Arabs, and Norr- Fatigue
bottnians. Patients with the unique variant of progressive calcifications Fatigue is a common complaint, usually not invariably related to ane-
of cardiac valves, type 3c, are uniformly homozygous for a point muta- mia, but also quite common in nonanemic patients and may be a result
tion D409H. 12 of elevated inflammatory cytokines. 36
Despite some relationship between specific mutations and the clin-
ical course, genotype–phenotype correlation is imperfect. Elucidation Organomegaly
of the three-dimensional structure of the glucocerebrosidase by crystal- In symptomatic patients, the spleen is typically enlarged, whether
37
lography has also not improved prediction of disease severity based on barely palpable or massively enlarged causing positional symptoms,
the location of mutations in the native protein. 30 such as early satiety or abdominal discomfort. Splenic infarction and
The majority of the mutations cause glucocerebrosidase mis- subcapsular hematoma are uncommon. Hepatomegaly is usually asymp-
folding, which may lead to early degradation of the enzyme in the tomatic, but it may cause abdominal discomfort and in splenectomized

TABLE 72–1. Characteristics of the Three Types of Gaucher Disease
TYPE 1 TYPE 2 TYPE 3
Subtype Asymptomatic Symptomatic Neonatal Infantile 3a 3b 3c
Common N370S/N370S N370S/other Two null or One null and None L444P/L444P D409H/D409H
genotype or 2 mild or 2 mild recombinant one severe
mutations mutations mutations mutations
Ethnic Ashkenazi Jews Ashkenazi Jews None None None Norrbottnians, Palestin-
predilection Asians, Arabs ian Arabs,
Japanese
Common None Hepatosple- Hydrops fetalis; SNGP, strabis- SNGP; myoclo- SNGP; hepa- SNGP; car-
presenting nomegaly, congenital mus, opistho- nic seizures tosplenomeg- diac valves’
features hypersplenism, ichthyosis tonus, trismus aly growth calcifications
bleeding, bone retardation
pains
CNS None None Lethal Severe SNGP; slowly SNGP; grad- SNGP;
involvement progressive ual cognitive brachycephalus
neurologic deterioration
deterioration
Bone None Mild to severe None None Mild Moderate to Minimal
involvement (variable) severe; kypho-
sis (gibbus)
Lung None None to (rarely) Severe Severe Mild to Moderate to Minimal
involvement severe moderate severe
Life Expectancy Normal Normal/ Neonatal death Death before Death during Death in Death in early
near-normal age 3 years childhood mid-adulthood adulthood

SNGP, supranuclear gaze palsy.

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