Wolman Disease and Its Treatment
Moshe Wolman, M.D.
Introduction
olman disease (WD) is a
rather rare autosomal re-
cessive disorder which
usually results in the death of af-
fected infants at the end of the first
trimester of life. The incidence of
the disease cannot be determined at
present because pediatricians in
different countries vary in their abil-
ity to diagnose it. WD was first de-
scribed in Israel,I,2 then in the
United States, after which it was re-
ported in most countries and ethnic
groups. Cases have been reported
from most Western and Central
European countries,&dquo; the Far
East,9,lO the Indian subcontinent,l
Canada,12 and other countries.
The disease appears to be more
prevalent in Iranian Jews as well as
in non:Jews13,14 and in the Arab
population of the Galilee, prob-
ably representing genetic isolates.
One reason the true incidence of
the disease cannot be ascertained
may be due to lack of awareness in
the medical profession in some ar-
eas ; thus, the disease was not re-
ported from the Eastern bloc
countries for many years. And
Department of Pathology
Tel AvivUniversity
Sackler Faculty of Medicine
Tel Aviv, Israel
Address correspondence to: Moshe
Wolman, M.D., Department of Pathology,
Tel Aviv University, Sackler Faculty of
Medicine, 69978 Tel Aviv, Israel
An article with similar contents was
published in Hebrew in Harefuah, August,
1994.
though four cases are
Israeli Arabs, the only
ported in Arabs outside Israel were
in Libyan twins studied in Hun-
gary 15 and, more recently, in a Jor-
danian infant studied in Saudi
Arabia.16 Furthermore, it appears
that the only case reported in a
black African has been described
in a black American
In countries where the medical
profession is aware of the
clinical cases longer re-
are no
ported by leading journals. The
occurrence of new cases can be
inferred from studies dealing with
specific aspects of pathogenesis,
biochemistry, or instrumental aids
to diagnosis, as in a case reported
from Turkey. 18
Clinical and
Radiographic Features
Infants with Wolman disease
are born after uneventful pregnan-
cies, often to consanguineous par-
ents. They are hospitalized in the
first 2 months of life because of
diarrhea, vomiting, feeding diffi-
culty, stunted growth, and failure
to thrive. Physical examination re-
veals severe abdominal distention
and hepatosplenomegaly. Radio-
graphic examination reveals calci-
fication of both adrenal glands.
The calcification appears to deline-
ate the outline of both glands, and
this sign appears to be pathogno-
monic for the disease, and for its
less severe counterpart, choles-
terol ester storage disease (CESD).
The only test needed to corrobo-
rate the diagnosis is a biochemical
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known in or histochemical demonstration
cases re- of deficient or minimal acid-
esterase activity in leukocytes or
dermal fibroblasts.
Biochemical Features
The hereditary biochemical
deficit underlying this disease is
lack of an enzyme responsible for
disease, splitting the two most hydrophobic
lipids of the body, triglycerides and
cholesterol esters, at a low pH.l9
The enzyme (EC 3.1.1.13) has
been called by different names ow-
ing to its wide spectrum of activity.
In addition to its capacity to split
short fatty-acid chain triglycerides
(used in histochemical and bio-
chemical tests), it also acts as a lipase,
splitting long-chain triglycerides. It
has also been called cholesterol
esterase because it can split choles-
terol esters into free fatty acids and
cholesterol. The enzymatic deficit
is also responsible for accumula-
tion of some uncommon lipid es-
ters in the tissues and possibly for
the accumulation of some glyceryl
ether lipids,2 which is probably of
little pathogenic importance. In
normal individuals, this enzyme is
present in lysosomes of all cells. In
affected individuals, storage occurs
mainly in cells with active metabo-
lism of lipid esters.
It is important to note that af-
fected cells contain an effective
mechanism of catabolizing lipid es-
ters. While they lack the lysosomal
enzyme and therefore the capacity
to degrade lipid that are
esters
transported into the lysosomes,
the affected cells do contain an
207
 esterasein the endoplasmic reticu-
lum that can split fatty esters in a
neutral pH. 21 In macrophages,
this enzyme can split both choles-
terol esters22 and triglycerides.23
Some authors claim that the neu-
tral enzyme activity is appreciably
lower in the fibroblasts of patients
with Wolman disease.24
Estimation of acid esterase ac-
tivity in affected cells reveals a
slight but noticeable enzyme activ-
ity (around 10% to 15% of normal).
Burton et al25 have demonstrated
that the extent of activity depends
on the test used, and
they suggest
that only one of two acid esterase
isozymes is deficient in WD. It is
also possible that the detectable
enzyme activity in cells of patients
with the disease represents mini-
mal activity at low pH levels of the
neutral esterase. 26
The lack of acid-esterase activ-
ity cells of patients with WD does
in
not cause complete absence of
lipolytic activity. The receptor-
mediated pathway of uptake of
cholesterol ester (ChE)-contain-
ing lipoproteins that are trans-
ported into and split in lysosomes27
is not the only path of ChE absorp-
tion. Some cholesterol ester is
taken up by bulk-phase pinocy-
tosis, and this fraction does not
contribute to intracellular stor-
age .2&dquo; Furthermore, two groups29,39
reported independently that in fi-
broblasts from patients with WD,
only the lipids of extracellular ori-
gin are stored, while locally syn-
thesized lipids are normally
hydrolyzed. These observations
are probably related to the fact that
the neutral lipase-esterase of WD
cells is not, or is only marginally,
affected.
Prenatal diagnosis of WD is fea-
sible and has been successfully per-
formed. Although histochemical
demonstration of absent acid
esterase activity in cultured em-
brvonal cells might be simplest, it
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208
is preferable to perform
tative biochemical assay on them. 31
Cholesterol ester storage dis-
ease is also caused by deficient acid
esterase-lipase activity in the cells,
but here activity is only moderately
lowered, and the deficit in esterase
activity occurs only in the acid
(lysosomal) enzyme;
ity at neutral pH does
be affected.32 In CESD, most lipid
storage is in the same sites as in WD
and is similar in constitution, but
the disease is benign and often
does not affect the life span, in
spite of severe hepatomegaly.33
Clinical
Significance and
Patho genesis of
Pathologic Changes
The significant path-
most
ologic changes in patients with WD
are in three domains: cells of the
phagocytic system throughout the
body, the mucosa and other layers
of the small intestine, and the ad-
renal cortex.
Cells of the reticulo-endothe-
lial system promote endocytosis of
lipoproteins in the spleen, lymph
nodes, and liver; because of the
enzyme deficit, these calls
rid themselves of the fatty esters.
They are transformed into foam
cells, filled with frankly sudano-
philic (i.e., hydrophobic) lipids,
accounting for the splenomegaly
and lymphadenopathy. A similar
situation in hepatocytes contrib-
utes the swollen Kupffers cells to
the marked hepatomegaly. Also,
histiocytes of the interstitium of
various organs of the body, in-
cluding the heart, blood vessels,
and brain, are affected by the
lipid-storage process.
An extreme degree of lipid stor-
age occurs in patients with WD in
the small intestine and particularly
in the mucosa. At autopsy, the in-
ner surface of the gut appears vel-
a quanti- vety and bright yellow. The appear-
ance is due to swelling and flatten-
ing of the villi caused by severe
infiltration of the lamina propria
with lipid-filled histiocytes. Similar
but less severe infiltration occurs in
the other layers of the intestine. In
CESD the changes are basically
lipolytic activ- similar but much less severe.
not seem to Striking changes are seen in
neurones of the myenteric plexus.
Although changes in neurones in
the central nervous system are
mostly minimal,35 the myenteric
plexus neurones are stuffed with
hydrophobic lipids and many neu-
rones seem to have died. The se-
vere damage to neurones of the
plexus may account for the promi-
nence of gastrointestinal symp-
toms in WD patients. The changes
were described independently by
Kamoshita and Landing36 and by
myself (with collaborators) .37 The
changes in the gut indicate that
feeding of esters, especially milk
feeding, plays a major role in
causing symptoms of the disease.
A group of Japanese scientists
more recently suggested that the
severe damage to the intestine
excludes any absorption of enteral
nutrition.38
cannot The mechanism by which lack of
acid lipase prevents migration of the
lipoproteins from the intestine is
probably the following: it was gener-
ally assumed39,40 that under normal
conditions triglycerides are ab-
sorbed from the intestinal lumen by
enterocytes and secreted by them
into the intercellular space and
hence into the lymphatics. A more
recent study4l has shown that the
greater part of triglycerides are not
transported from the intestinal mu-
cosa via the lymphatics. The authors
assumed that normally the
triglycerides are split in the entero-
cytes and the products are trans-
ported directly to the hepatic
portal system. They found that the
villi contain a lysosomal acid lipase.
Lack of this enzyme in WD entero-
cytes causes the clogging of the
mucosa by the unsplit and untrans-
ported triglycerides.
An extremely consistent fea-
ture ofWD42 is the peculiar calcifi-
cation of the adrenal glands caused
by foci of necrosis and calcifica-
tion, containing cholesterol and
fatty acid crystals situated at about
I mm from the capsule throughout
the adrenal cortices. The calcifica-
tion, which indicates fatty-acid
soaps in cells lacking acid lipase-
esterase, is due to the presence of
neutral esterase in these cells,43 as
in all other cells. In adrenocortical
cells bursting with hydrophobic
lipids and transformed into a ne-
crotic mass, the microsomal acid
lipase can come in contact with the
lipids originally contained in
lysosomes.
Treatment Modalities for
WD and CSD Suggested
by Other Authors
More than 20 years ago,
Crocker, Fisher, and Filler44 at-
tempted treatment of a WD patient
with low-residue feeding followed
by intravenous alimentation. Mey-
ers et a145 observed a halt in the
deterioration of a WD patient
treated with parenteral hyperali-
mentation. An in vitro attempt to
treat cultured WD and CESD fi-
broblasts by &dquo;feeding&dquo; them the
missing enzyme was successful. 46,47
Whether such an approach can be
effective in patients is question-
able, as the average half life of en-
docytosed acid lipase activity in
fibroblasts is 1 day. 48
A number of authors correctly
assumed that modalities of treat-
ment for WD can be usefully and
more easily tested on CESD, in
which the progression of changes
is much slower. Ginsberg et a149
found that lovastatin treatment of
a young girl suffering from CESD
decreased the amounts of stored
cholesterol esters and triglycerides.
This observation was confirmed by
some studies5o,51 but not by oth-
ers.52 Another group53 reported
good results from simvastatin com-
bined with cholestyramine and a
low-fat diet.
In one unpublished case, a WD
infant was treated with liver trans-
plantation, which led to remission
of symptoms for many months.
Krivit et all achieved temporary
improvement by treating WD in-
fants with bone marrow transplan-
tation. Dr. Krivit has advocated
(personal communication) proce-
dures that might decrease the
chance of graft vs host reaction in
patients treated with bone marrow
transplantation, and the use of
concomitant liver transplant in se-
lected cases.
Theoretical Basis of a
Suggested Treatment
Infants affected by WD appar-
ently suffer from and die of pro-
gressive stuffing with fats of the
intestine and its innervation. The
conclusion reached by Meyers et
a145 and Kikuchi et ap8 that death
in these patients is due to inanition
is probably correct. Thus, therapy
should be aimed at achieving two
main goals: (1) to avoid stuffing
the intestine with nontransport-
able and noncatabolizable lipids;
(2) to avoid similar clogging of
the phagocytes. At present, when
most patients run
course, adrenocortical replace-
ment therapy may not be impor-
tant, but this may change if
therapy allows WD patients, with
most of their adrenal fetal cortex
destroyed, to live beyond the first
3 to 6 months of life.
Avoidance of breast-feeding,
any other milk feeding, or admini-
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stration of a formula containing
lipid esters is imperative, as pre-
viously suggested .55 In an unpub-
lished case, the family and the
treating physician of an infant af-
fected by WD asked me to advise
them on the treatment. Although
dietary treatment was started in the
third month of life, it appears to
have halted progression of the
disease. The girl died at the age
of 171/2 months of an acute undi-
agnosed febrile illness with signs of
essential fatty acid (EFA) and anti-
oxidant deficiency. Induction of se-
vere EFA deficiency by the fat-poor
diet is not surprising in view of the
known needs of EFA in infants. 56
The problem of how to admin-
ister adequate amounts of EFA
without any fatty acid esters is not
easy to solve. Administration of
EFA bound to proteins, as I have
suggested,55 might be effective in
view of the study of Von Hoden-
berg et al57 on cultured macro-
phages, but the question of its
feasibility at present is open to
doubt. A simpler solution might be
based on the use of percutaneous
administration of these lipids. In
fact, daily cutaneous application of
sunflower oil (rich in unsaturated
fatty acids) was found to cure the
symptoms of EFA deficiency in
adults58 and infants.5g The find-
ings were confirmed by some work-
ers in the field but contested by
others .60,61 Data presented in an ex-
change of letters to the editor of
the journal of Pediatrics62 indicate
that percutaneous treatment with
sunflower or safflower oil corrects
an acute some, but not all, aspects of EFA
deficiency. It is probable that the
discrepant results obtained by per-
cutaneous treatment of EFA defi-
ciency might be due to the use of
different parameters of improve-
ment by the various authors. It is
further possible that the oils used
did not contain adequate amounts
of the higher unsaturated fatty
209
 acids that are known to be needed
by newborns.63
Percutaneous application of
oils rich in unsaturated (including
highly unsaturated) fatty acids ob-
viously spares the gut from being
clogged. It is not clear whether the
use of this route can help the body
to metabolize the absorbed lipid
esters. Available biochemical evi-
dence indicates that epidermal
cells contain, in addition to an al-
kaline and acid phospholipase,
triglyceride lipase 6 and that ab-
sorption of fatty acids through the
skin is rapid and associated with
formation of phospholipids and
triglycerides .65,66 It is possible that
in WD, triglycerides absorbed by
the skin will be metabolized in
the epidermis and in part trans-
ported to other organs in a meta-
bolizable form.
In a preliminary unpublished
study by Professor Aliza Tietz (Dvir)
and myself, we smeared labeled tri-
olein or oleic acid on the back skin
of rats. We found that absorption was
rapid and that most of the labeleled
acid moved to adipose tissues. The
fraction localized in the phagocytic
system (in the spleen) was mainly
included in phospholipids. Because
the metabolism of adipose tissue
and phospholipids is not apprecia-
bly affected in WD, the chances are
that percutaneous application of
fats is not likely to be a further
burden on the defective lipolysis.
Suggested Treatment
Modality
As every single day of milk feed-
ing adds to the severity of clogging
of the absorptive intestinal mu-
cosa, treatment should be started
as soon as diagnosis of WD is sus-
pected. Treatment should include
the following: (1) Stopping breast-
feeding or feeding with a formula
containing triglycerides and cho-
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210
lesterol esters and keeping the in- medad de Wolman en su forma aguda
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7. Bona Bracco G, Gallina MR, et al.
G,
diet should include all the needed
A caseof lipase deficiency: Wolmans
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ones. (2) Daily smearing of the
53.
skin of a different extremity with 8. Röytta M, Fagerlund AS, Toukkanen S,
a small amount (to start with, 10 et al.Wolmans disease: morphological,
to 50 j~L, for example) of sun- clinical and genetic studies in the first
flower or safflower oil or prefer- Scandinavian cases. Clin Genet. 1992;
42:1-7.
ably soy, canola, flax, cod liver, or 9. Konno T, Fujii M, Watanuki T, Koizumi
algal oil. The last-mentioned oils K. Wolmans disease: the first case in
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dose applied can be doubled 10. Ho FCS, Lin HJ, Chan WC. Wolmans
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14. Kamalian N, Dudley Jr AW, Beroukhim
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