section 19.2
Phospholipids and Glycosphingolipids in Clinical Medicine
413
1. Accumulation of a specific lipid in these disorders is
frequently accompanied by deposition of one or more
polysaccharides structurally related to the lipid.
2. Treatment is generally palliative or nonexistent.
Enzyme replacement therapy has proved useful in
some of these disorders. Because the exogenous
enzymes are unable to cross the blood-brain barrier,
their efficacy in the glycosphingolipidoses that have
neurological involvement is doubtful. Attempts to
modify the enzymes to overcome this difficulty offer
some hope.
3. Considerable progress has been made in the
identification of carriers and in prenatal diagnosis of
homozygotes. Thus, laboratory assays of enzyme
activity in leukocytes or cultured skin cells using
chromogenic or fluorogenic synthetic substrates have
dramatically reduced the incidence of
Tay-Sachs
disease.
Gaucher’s disease
is the most common lysosomal stor-
age disorder and also the most common inherited dis-
ease among Ashkenazi Jews, with a carrier frequency
of about 1 in 14. Four mutations in the gene encoding
for /J-glucocerebrosidase account for at least 90% of the
symptomatic patients. Gaucher’s disease has three forms
in which genetic effects appear to be due to errors in the
same or related genetic loci.
Type I, chronic nonneurono-
pathic
(adult), is the most common variety. It comprises a
heterogeneous group of patients characterized by the pres-
ence of hematological abnormalities (anemia, thrombocy-
topenia) and erosion of the cortices of long bones.
Type II,
acute neuronopathic,
usually appears before
6
months of
age and is fatal by 2 years. Mental damage is a primary
characteristic, and the disease progresses rapidly from its
onset.
Type III, subacute neuronopathic
(juvenile), com-
prises a heterogeneous group in which death occurs be-
tween infancy and about 30 years of age. The cerebral
abnormalities usually appear at least
2
years postnatally.
All
three
types
share
common
features:
hepato-
splenomegaly, Gauchers cells in the bone marrow (accu-
mulation of glucocerebroside in reticuloendothelial cells
in liver, spleen, and bone marrow), and autosomal reces-
sive inheritance. Some studies have shown a correlation
between the residual /i-glucocerebrosidase activity and
clinical severity, but the molecular basis for the genetic
heterogeneity is not known. The Gaucher cells obtained
from bone marrow aspirates exhibit a characteristic ap-
pearance of the cytoplasm owing to rod-shaped striated
inclusion bodies composed primarily of glucocerebroside.
Patients with Gaucher’s disease have elevated levels of
acid phosphatase activity in serum and spleen, increased
iron stores, increased angiotensin converting enzyme
activity, and a relative deficiency of clotting factor IX
(Chapter 36).
Enzyme replacement therapy with purified macro-
phage-targeted human /J-glucocerebrosidase in type I
Gaucher’s disease causes breakdown of stored glucocere-
brosides. This results in a reduction in the size of the
liver and spleen, in improvement in hematological abnor-
malities (anemia and thrombocytopenia), increased bone
mineralization, and decreased bone pain. Two sources
of human /J-glucocerebrosidase are available; one of
them is derived from human placenta (aglucerase) and
the other is synthesized by recombinant DNA technol-
ogy (imiglucerase). Both enzymes are modified in their
oligosaccharide side chains to expose terminal mannose
residues. Macrophages, through their mannose receptors,
internalize the modified enzyme.
Studies of cases of
GM\-gangliosidosis
have revealed
two distinct types. In
generalized gangliosidosis,
GMi and
desialo-GM i -gangliosidcs accumulate in brain and vis-
cera. The three /J-galactosidase activities isolated from
normal human liver all are absent. The disease begins at
or near birth, progresses rapidly, and ends fatally, usu-
ally by 2 years of age. In
juvenile GM\-gangliosidosis,
psychomotor abnormalities usually begin at about
1
year,
and death ensues at 3-10 years. Two liver /J-galactosidase
activities are absent, possibly accounting for the lack of
lipid accumulation in this organ. This enzymatic finding
supports the genetic separation into two forms.
GM
2
-gangliosidosis
is of two types: Tay-Sachs dis-
ease,
due
to
jJ
- hex oseam i n i dasc
A
(Hex-A)
defi-
ciency, and Sandhoff’s disease, due to deficiency of
/J-hexoseaminidase A and B (Hex-A, Hex-B). The rela-
tionship between these diseases is based on the subunit
composition of the two affected enzymes. Hex-A, a het-
eropolymer, consists of two a-chains (coded for on chro-
mosome 15), a /1-chain (coded for on chromosome 5), and
an activator protein. Hex-B is a tetramer of /3-chains. Mu-
tations at the a-locus give rise to Tay-Sachs disease. A
variant form can arise from mutation at the activator pro-
tein locus; however, it shows normal
in vitro
Hex-A activ-
ity with chromogenic substrates. Mutations at the /1-locus
yield
Sandhoff’s disease
and affect Hex-A and Hex-B,
both of which contain the /
1
-subunit.
Treatment of sphingolipidoses is primarily
symp-
tomatic and supportive. For example, in patients with
anemia due to Gaucher’s disease, thrombocytopenia as-
sociated with hypersplenism is relieved by splenectomy.
Infusion of appropriate purified human placental tissue
enzymes in patients with Gaucher’s disease and Fabry’s
disease reduced the accumulated glycolipids in the circu-
lation and liver. Recent advances in the cloning and am-
plification of human DNA segments in bacterial plasmids
