section 20.3
Lipoprotein-Associated Disorders
443
may completely prevent apo B synthesis, although other
possibilities exist. Since it is transmitted as an autosomal
recessive trait, heterozygotes cannot be detected without
an affected offspring.
In
h ypobetalipoprotein en ia
the plasma LDL level is de-
creased (10-20% of normal), but that of HDL is normal,
and that of VLDL is mildly lowered. Of 23 affected in-
dividuals from the four known affected families, one had
central nervous system dysfunction and fat malabsorption.
The others had mild or no pathological changes. The dis-
ease is inherited as an autosomal dominant trait. The be-
nign nature of this condition is in sharp contrast with the se-
riousness of hyperbetalipoproteinemia. In the latter, LDL
cholesterol concentrations are two to six times normal,
and patients are predisposed to premature atherosclerosis.
In another form of hypobetalipoproteinemia, the patient
synthesized apo B-48 and secreted chylomicrons but did
not produce apo B-100 or secrete VLDL.
F am ilial a p o lip o p ro tein A -Ia n d C -Illd eficien cy
is char-
acterized by mild corneal opacification, coronary artery
disease, marked HDL deficiency, and a normal ratio of
free cholesterol to esterified cholesterol in plasma in
all probands, also yellow orange, lipid-laden plaques on
the trunk, eyelids, neck, chest, anus, and backs of sev-
eral affected individuals. The LDL is often found to be
triacylglycerol-rich. The mode of inheritance is autoso-
mal codominant.
HDL deficiency with planar xanthomas was identified
in a 48-year-old Swedish woman who had a history of
yellow discoloration of skin around the eyes and groin.
She also exhibited hypothyroidism, angina pectoris, facial
neuralgia, and corneal opacification. Both eyelids were
thickened and infiltrated with small firm nodules. Moder-
ate hepatomegaly was noted. Plasma triacylglycerol and
VLDL cholesterol levels were elevated, LDL cholesterol
was normal, and HDL cholesterol was very low. LCAT
activity and the ratio of free cholesterol to total choles-
terol was normal. Apo A-IMiiano is the result of a sub-
stitution of cysteine for arginine at residue 173 of apo
A-I. This mutation apparently results in enhanced up-
take and hepatic catabolism of HDL. No evidence of
coronary artery disease, corneal opacification, xanthomas,
or hepatosplenomegaly has been reported. Plasma con-
centrations of HDL and apo A-I are greatly reduced.
Triacylglycerol is elevated, and both LDL and HDL
are triacylglycerol-rich in affected kindred. LCAT ac-
tivity is normal. The mode of inheritance is autosomal
codominant.
F am ilial h ypoalph alipoprotein em ia
has been identified
in several kindreds with a history of accelerated coronary
disease. Plasma lipid and lipoprotein values were all nor-
mal except for reduced levels of HDL cholesterol (50% of
normal). Slight reductions in apo A-II were reported (78%
of normal), but apo A-I was normal, as were LCAT and
hepatic lipase activities.
Tangier d isea se
is an autosomal recessive disorder. In
the homozygous state it is characterized by the absence
of plasma HDL cholesterol and deposition of choles-
terol esters in the reticuloendothelial system with hep-
atosplenomegaly, enlarged tonsils with yellowish orange
color, enlarged lymph nodes, and peripheral neuropathy.
Patients with Tangier disease, despite low levels of HDL
cholesterol, are not uniformly at risk for coronary artery
disease. The molecular basis for Tangier disease is a de-
fect of cholesterol efflux from cells. The defect has been
localized to mutations in a specific ABC 1-transporter pro-
tein. Defective export of cholesterol from cells, partic-
ularly from tissue macrophages causes accumulation of
cholesteryl esters. Plasma apo A-I levels in Tangier dis-
ease undergoes rapid clearance since nascent HDL is not
made due to lack of cholesterol efflux from the cells.
L C A T deficien cy
is due either to absence of the enzyme
or to synthesis of defective enzyme. LCAT catalyzes the
following reaction:
Phosphatidylcholine (lecithin) + cholesterol —»•
cholesteryl ester + 1 -acylglycerolphosphocholine (lysolecithin)
This reaction is responsible for formation of most of the
cholesteryl ester in plasma. The preferred substrate is
phosphatidylcholine, which contains an unsaturated fatty
acid residue on the 2-carbon of the glycerol moiety. HDL
and LDL are the major sources of the phosphatidylcholine
and cholesterol. Apo A-I, which is a part of HDL, is a
powerful activator of LCAT. Apo C-I has also been impli-
cated as an activator of this enzyme; however, activation
may depend on the nature of the phospholipid substrate.
LCAT is synthesized in the liver. The plasma level of LCAT
is higher in males than in females. The enzyme converts
excess free cholesterol to cholesteryl ester with the simul-
taneous conversion of lecithin to lysolecithin. The prod-
ucts are subsequently removed from circulation. Thus,
LCAT plays a significant role in the removal of choles-
terol and lecithin from the circulation, similar to the role
of lipoprotein lipase in the removal of triacylglycerol con-
tained in chylomicrons and VLDL. Since LCAT regulates
the levels of free cholesterol, cholesteryl esters, and phos-
phatidylcholine in plasma, it may play an important role
in maintaining normal membrane structure and fluidity in
peripheral tissue cells.
Primary deficiency of LCAT, initially found in three
Norwegian sisters, is rare and is inherited as an autoso-
mal recessive trait. Manifestations include corneal opacity,
normocytic anemia due to decreased erythropoiesis and
