Journal of Hepatology 1999; 31: 557-560
Printed in Denmark All rights reserved
Mmksgaard Copenhagen
Phosphomannose isomerase deficiency as a cause of congenital hepatic
fibrosis and protein-losing enteropathy
Tom J. de Koning’, Lambertus
‘Department of Metabolic Disorders, University Children’s Hospital ‘Her Wilhelmina Kinderziekenhuis’, Utrecht and 2Department of
Gastroenterology, University Hospital, Utrecht, The Netherlands
W
ITHIN JUST a few months, three different groups
have reported a potentially treatable inborn
error of glycoprotein metabolism presenting with con-
genital hepatic fibrosis and protein-losing enteropathy
(l-3). The disorder causes defective protein glycosyl-
ation due to a deficiency of the enzyme phosphoman-
nose isomerase (PMI). Inborn errors of metabolism
are not usually associated with a developmental dis-
order of the liver and protein loss in the gut. This de-
fect might lead to new insights in fetal development of
intrahepatic bile ducts and disorders like ductal plate
malformation.
Niehues et al. (1) reported a young male patient with
a severe protein-losing enteropathy, recurrent throm-
bosis and vomiting. Antithrombin III activity was re-
duced. Simultaneously, De Koning et al. (2) described
three adolescent siblings of a consanguineous family
with congenital hepatic fibrosis and recurrent episodes
of vomiting accompanied by diarrhea. A few months
later, Jaeken et al. (3) reported two additional patients
with diarrhea, protein-losing enteropathy and de-
creased activities of antithrombin III, piotein C and
protein S. Liver biopsy also showed congenital hepatic
fibrosis. In all the patients the same enzyme defect, viz
a deficiency of PMI, was found. However, the authors
of these papers were not the first to recognize this pecu-
liar combination of symptoms. The clinical phenotype
of protein-losing enteropathy, congenital hepatic fi-
brosis and antithrombin III deficiency was first de-
scribed by Pedersen & Tygstrup (4) in 1980. In their
original paper two siblings were reported with recur-
rent thrombosis, gastro-intestinal protein loss and con-
Correspondence: Lambertus Dorland, Department of
Metabolic Disorders, University Children’s Hospital, ‘Het
Wilhelmina Kinderziekenhuis’, KC 02.069.1, PO Box
85090, NL-3508 AB Utrecht, The Netherlands.
Tel: 31 302505318. Fax: 31 302504295.
Copyright 0 European Association
for the Study OJ the Liver 1999
Journalof Hepatology
ISSN 0168-8278
Editorial
Dorland’ and Gerard I? van Berge Henegouwen2
genital hepatic fibrosis. From the present papers, as
well as two recent abstracts (5,6), a clear clinical picture
of PM1 deficiency is emerging. The disorder is a gastro-
intestinal disease with juvenile onset, of variable sever-
ity, with life-threatening thrombosis or bleeding, ductal
plate malformation of the liver, which varies from mild
ductopenia to Caroli’s syndrome, associated with pro-
tein-losing enteropathy. The latter was not present in
all patients. It may easily be conceived that more
phenotypic deviations will be reported in this enzyme
defect, given the report of a patient with hyperinsul-
inemic hypoglycemia and PM1 deficiency (6). PM1 de-
ficiency is a defect in the biosynthetic pathway of pro-
tein glycosylation. This leads to hypoglycosylated pro-
teins and the disorder is categorized as a carbohydrate-
deficient glycoprotein syndrome (CDGS). The CDG
syndromes belong to the group of rapidly expanding
malformation syndromes, which were first described
by Jaeken et al. (7) in 1980. The first enzyme defect was
elucidated in 1994 for CDGS type II, viz a deficiency of
in Golgi localized N-acetylglucosaminyltransferase II
(8). Of this type of CDGS, only a few patients are
known. One year later, in 1995, phosphomannomutase
deficiency was identified as the cause of CDGS type Ia
(9). This is the most frequent CDGS type. Biochem-
ically, CDG syndromes are diagnosed by analyzing the
various isoforms of serum transferrin by isoelectric fo-
cusing. Unusual patterns of transferrin-glycosylation
are easily detected. Until recently, patients reported
with all CDG syndrome subtypes suffered from devel-
opmental malformations and functional defects of
many organ systems associated with neurological
symptoms. In contrast, the clinical presentation of pa-
tients with PM1 deficiency differs strongly from this.
So why did the three groups of investigators consider
a CDG syndrome in their patients? Niehues et al. (1)
found a deficiency of antithrombin III in their patient
and as this is a feature of the CDG syndromes, they
557
T. J. de Koning et al.

glucose proteins are divided into two basic types depending on

the linkage of the carbohydrate side chains to the pro-
1 glucokinase tein backbone. O-linked oligosaccharides are bound to
the hydroxyl group of serine or threonine via an N-
glucose-6-phosphate acetylgalactosamine residue, and the N-linked oligo-
saccharides are bound to the amide group of aspara-
1 phosphoglucoseisomerase gine via an N-acetylglucosamine residue. The CDG
syndromes affect the processing of the N-linked oligos-
fructose-6-phosphate accharides. In N-linked glycosylation, GDP-mannose
is the donor of dolichol-phosphate-linked sugars. The
1 PMI synthesis pathway of GDP-mannose starts with the
hexokinase synthesis of mannose-6-phosphate from fructose-6-
mannose + mannose-6-phosphate phosphate. Mannose-6-phosphate is subsequently con-
verted to GDP-mannose in two enzymatic steps (Fig.
1 PMM
1). PM1 catalyzes the conversion of fructose-6-phos-
phate to mannose-6-phosphate. The next step, the con-
mannose-l -phosphate version of mannose-6-phosphate to mannose- 1-phos-
phate, is catalyzed by a phosphomannomutase
1 GDP-mannose pyrophosphorvlase
(PMM). A deficiency of the latter enzyme (PMM) is
the main cause of the most frequent CDG syndrome
GDP-mannose type Ia (12). Deficiencies of both enzymes PM1 and
PMM lead to identical patterns of transferrin isoelec-
1 tric focusing with predominance of asialo- and disialo-
transferrin isoforms. However, the clinical phenotypes
1 are completely different, with the exception of the clot-
ting factor abnormalities (13). Congenital hepatic fi-
Dol-PP-GlcNAc, Man,
brosis has not been reported in other CDG syndromes,
except in PM1 deficiency (14). In two of the three
1 dolich yl glucos yltrans ferase papers, mutations in the PM1 gene were reported (1,3).
But, in the two patients investigated, only three of the
Dol-PP-GlcNAc, Man, Glc,
four mutated alleles were identified.
1 Recently a new CDG type was characterized as a
1 deficiency of dolichyl-P-Glc: Man9GlcNAcz-PP-dol-
ichyl glucosyl-transferase (15). This enzyme is involved
N-glycosylation in the transfer of glucose from dolichylphosphate-
glucose onto the lipid-linked oligosaccharide
Fig. 1. Munnose metabolism and protein glycosylation. Man9GlcNAcz-PP-Dol. This defect is localized in the
endoplasmatic reticulum. The clinical presentation is
milder than that of CDGS type Ia, but it is more severe
than PM1 deficiency. Transferrin isoelectric focusing is
considered this diagnosis. Billette de Villemeur et al. indistinguishable from PMM and PM1 deficiency.
(10) reported a patient with gastrointestinal symptoms Can we relate the phenotypic expression to the en-
and hypoglycosylation of transferrin as determined by zyme defect that was found? Little is known about the
isoelectric focusing. The latter publication and the pathogenetic mechanisms involved in CDG syndromes.
finding of persistently low albumin concentrations in All the CDG syndromes show abnormalities in circu-
their patients prompted De Koning et al. (2) to per- lating glycosylated proteins as clotting factors that re-
form transferrin isoelectric focusing. The patients de- sult in abnormal function (13). In PM1 deficiency, in
scribed by Jaeken et al. (3) were investigated because contrast to the other CDG syndromes, the organ dys-
of antithrombin III deficiency as well as because of the function and altered embryonic development are re-
paper of Billettte de Villemeur (10). stricted to the gastrointestinal system. Some of the
Protein glycosylation is involved in many biological symptoms observed in patients with PM1 deficiency re-
processes and the oligosaccharide units of glyco- semble those found in hereditary fructose intolerance
proteins serve a variety of functions (11). Glyco- (HFI). The symptoms of both PM1 deficiency and HFI

5.58

are confined to tissues with high fructose metabolism
like liver and gut.
A common pathogenetic mechanism could be pres-
ent, as a relationship between HFI and PM1 activity
was demonstrated by Jaeken et al. (16). Data from
studies in the rat indeed suggest a high metabolism for
mannose in intestinal mucosa (3) and specific trans-
porters for mannose have been reported (17,18).
Clearly a deficiency of PM1 leads to a dysfunction of
the intestinal mucosa, but in contrast to the liver no
structural abnormalities of the gut were found in PMI-
deficient patients, only ultrastructural abnormalities.
In the patient reported by Niehues et al. (1) electron
microscopy showed an enlarged endoplasmatic retic-
ulum with long tubular bundles, which might represent
precipitates of hypoglycosylated proteins. The response
to treatment, which will be discussed below, adds
further support to a functional defect.
The report of congenital hepatic fibrosis (CHF) in
all patients with PM1 deficiency in whom liver his-
tology was investigated suggests a disruption of normal
embryonic development of intrahepatic bile ducts. The
familial occurrence of CHF has long been recognized
(19). It is frequently associated with autosomal reces-
sive polycystic kidney disease (ARPKD), but has also
been reported in other liver disorders as Caroli’s dis-
ease, choledochus cysts and in many malformation
syndromes (20). Congenital hepatic fibrosis is one of
the disorders in a spectrum of developmental defects
of intrahepatic bile ducts known as ductal plate mal-
formation (21). Ductal plate malformation is the
morphological description of the persistence of an ex-
cess of embryological bile duct structures in the ductal
plate configuration. The pathogenesis of ductal plate
malformation was recently discussed in an excellent re-
view (22). Ductal plates are being formed in the 8th
week of gestation. After the formation of ductal plates,
ductal plates are remodelled from the 12th week on-
wards, followed by a maturation of intrahepatic bile
ducts until after birth. This very complex developmen-
tal process is accompanied by the expression of a num-
ber of proteins by hepatoblasts differentiating to bili-
ary structures. These proteins include cytokeratins,
tissue polypeptide antigen, biliary glycoprotein I, carci-
noembryonic antigen, epithelial membrane antigen and
carbohydrate antigens (22-24). Furthermore, epithelial
proliferation and apoptosis are involved in remodeling
of the ductal plate (22,25). Many of the proteins in-
volved are indeed glycosylated, although not all have
N-linked oligosaccharide chains (26). It is attractive to
speculate that hypoglycosylation of some of the pro-
teins is involved in the altered developmental patterns
observed in ductal plate malformation. Since it is an
PM deficiency
exceptional experiment of nature, PM1 deficiency
could serve as a model to investigate the importance
of protein glycosylation in the developmental processes
of intrahepatic bile duct formation. Hepatic fibrosis
can result from this and probably is only the conse-
quence of an early abnormal development of the ductal
plate.
Recognition of the enzyme defect involved offers a
potential treatment to the patients suffering from this
disorder. Niehues and colleagues (1) were able to cor-
rect the clinical and biochemical abnormalities in their
patient with oral administration of D-mannose. The
protein-losing enteropathy, clotting factor abnormali-
ties as well as the abnormal transferrin isoelectric fo-
cusing pattern improved with D-mannose in a dosage
of 150 mg/kg body wt 5 times a day. As shown in Fig.
1, mannose can be converted to mannose-6-phosphate
by the enzyme hexokinase, bypassing the metabolic
block. The mannose given by the oral route was well
tolerated. Although long-term follow-up data are lack-
ing and some concern exists about the use of mannose
in high dosages (27), treatment with D-mannose seems
very promising. This treatment regimen has already
been applied with success to other patients (6).
In conclusion, PM1 deficiency is a new and exciting
disorder of protein glycosylation presenting with
ductal-plate malformation, congenital hepatic fibrosis
and gastrointestinal symptoms. We think this defect is
the first in an emerging area of gastrointestinal dis-
orders associated with defects in protein glycosylation.
Patients with unexplained congenital hepatic fibrosis
and protein-losing enteropathy should have serum
transferrin isoelectric focusing screening for PM1 de-
ficiency.
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