Ital. J. Neurol.

ScL 1, 7-14, 1982

Urinary oligosaccharides in
lysosomal and other metabolic
disorders
Federico A., Guazzi G.
Clinica Neurologica dell'Universitd di Siena

This review describes the methods and results obtained in the study of the
urinary oligosaccharides in some metabolic disorders, lysosomal and other
metabolic disorders. Attention is focused especially on thin layer chromato-
graphy, which, being so simple, may be regarded as a useful method of
screening for these diseases.
Key-words: Oligosaccharides-lysosomal disorders-metabofic

Introduction Oligosacchariduria can now be detected easily

Oligosaccharides (OGS) are low molecular
weight carbohydrate chains composed of at least
three monosaccharide subunits. When covalent-
ly coupled to a protein moiety, they are called
glycoconjugates.
Recently in addition to the mucopolysacchari-
doses (diseases characterized by increased uri-
nary excretion of mucopolysaccharides) and
glycolipidoses (in which an impairment of gly-
colipid metabolism is present with abnormal
urinary glycolipid excretion and visceral stor-
age) a new group of disorders has been charac-
terized, known as glycoproteinoses or oligosac-
charidoses [21, 39, 45].
This is a heterogeneous group of syndromes
characterized by increased urinary excretion of
oligosaccharides, derived from a partial degra-
dation of glycoproteins.
Most of these syndromes were previously clas-
sified as mucolipidoses, though even in 1969,
when the term was proposed, it was criticized
because the storage of lipids and mucopolysac-
charides was not present as a characteristic find-
ing in all syndromes.
In mucopolysaccharidoses the storage of gan-
gliosides in CNS has been shown to be asso-
ciated to mucopolysaccharidoses.
The term glycoproteinoses or oligosacchari-
doses is justified by the presence of a specific
oligosaccharide excretion pattern, due to an
inherited defect.
by Thin Layer Chromatography (TLC) and this
technique is useful as a screening test, especially
as urine samples, after the addition of sodium
azide, can be sent by post.
In this paper we review all these syndromes and
report the biochemical methods for diagnosis.
Methods for detecting oligosacchariduria
Qualitative methods
Thin layer chromatography (TLC) on silica gel
is the simplest method for most of the major
screening tests.
In 1972 a one-dimensional TLC procedure on
silica gel was described by Palo and Savolainen
[29] for the screening of oligosaccharides in
aspartylglycosaminuria, using n-butanol/acetic
acid/water (50:25:25) as solvent. This method
was used by Humbel and CoUart [15] to detect
fucosidosis, mannosidosis and GM1 gangliosi-
dosis. 20-40 #1 of untreated 24h. urine was
deposited on silica-gel plates; chromatography
was usually developed overnight.
Fucose-containing oligosaccharides were better
separated by a second development with n-pro-
panol/nitromethane/water (100: 80:60) and gal-
acto-oligosaccharides were separed by using n
butanol/absolute ethanol/0.1 M HCI (10:100:-
The Italian Journal of Neurological Sciences

50) overnight with a single development [14].
Tsay and Marshall [48] suggest develop-
ment with n-butanol/acetic/water/ether
(90:60:10:20) for good separation of mono-, di-
and trisaccharides.
Sewell [34, 35] used the solvent system of Palo
and Savolainen [29] followed by the n-propa-
nol/nitromethane/water system of Humbel [14]
for 3 h. for detecting an increased number of
oligosaccharide-excreting disorders.
We used the solvent system of Humbel over-
night, using lactose as standard substance.
Oligosaccharides were detected by spraying the
TLC plate with a solution of orcinol in 50%
sulphuric acid followed by heating at 100 ~ C for
15' [15].
Quantitative methods
The methodology for quantitation and structu-
ral analysis of oligosaccharides was developed
by Strecker [39] in France, whose method in-
volves an initial deionisation of urine on Dowex
resin followed by sequential elution in pyridine
acetate buffer (pH 5.5), 1 mM-500mM. The var-
ious concentrated and lyophilized fractions
were analyzed by descending paper chromato-
graphy in pyridine/ethyl acetate/acetic acid/
water (50:50:10:30), developed for 10-20 days.
The exact structure of methylated oligosacchar-
ides was determined by gas chromatography
and nuclear magnetic resonance (NMR) spec-
trometry after enzymatic digestion with neu-
raminidase, fl-galactosidase, N-acetyl-fl-hexo-
saminidase, a - - and fl-mannosidase [41, 42,
43].
Another separation technique consists in sepa-
ration of high molecular weight constituents and
oligosaccharides by fractionation on Biogel P2
and Sephadex G25 eluted with water. The oligo-
saccharides are separated by a combination of
preparative zone electrophoresis [18] and de-
scending paper chromatography in varying mix-
tures of pyridine, acetic acid, ethyl acetate and
water.
We use gel filtration of urine on Biogel P2 and
sephadex G25 eluted with water followed by
TLC as previously described.
Normal oligosacchariduria
The TLC screening method shows no urinary
oligosaccharides bands below that of lactose
standard when normal urine is examined.
This may not be the case in neonates, in whom
some dark bands have been found. When the
screening test was repeated later, these uniden-
tified bands disappeared.
Pathological urinary oligosaccharide patterns
a-fucosidosis
Fucosidosis is a hereditary metabolic disorder
characterised clinically by progressive mental
deterioration and spastic tetraparesis and bio-
chemically by the absence of lysosomal a-L-
fucosidase. This deficiency first described by

TABLEI. Lysosomal metabofic with oligosacchariduria

Type Product stored and/or excreted Enzyme deficiency
Mucolipidosis I Sialyl Oligosaccharides a - Neuraminidase
Mucolipidosis II Glycopeptides-glycolipids Unknown
Mucopolysaccharides, Oligosaccharides
Mucolipidosis III Glycopeptides, Glycolipides, Unknown
Mucopolysaccharides, Oligosaccharides
Mucolipidosis IV Hyaluronic acid + gangliosides Ganglioside - a
Neuraminidase
Gangliosidosis GMI Ganglioside GMI + Keratansulfate - ,8 - Galactosidase
(various forms) + glycopeptide + Oligosaccharides -,8- Galactosidase and
a- Neuraminidase
-,8- Galactosidase and
,8- Fucosidase
GM2 Gangliosidosis va- Ganglioside GM2 + Globoside + Hexosaminidase A
riant O Oligosaccharides and B
or Sandhoff disease
Fucosidoasis Fucosphingolipid + Fucoglycopeptides a- L - Fucosidase
+ Keratansulfate
Mannosidosis Mannosialoligosaccharides a- Mannosidase
Aspartylglycosaminu ria Glycoasparagines Aspartylglycosamin
,8- amino-hydrase

Durand et al. [7] results in an accumulation of
fucose-containing sphingolipids, glycoproteins
and oligosaccharides, present in various tissues
[7, 49]. From the clinical point of view there are 3
forms of the disease distinguished by a more or
less early onset and a more or less rapid course
[331. Sewell [35] evidenced a typical pattern of
urinary oligosaccharides by means of TLC.
More sophisticated techniques have character-
ised 13 oligosaccharides from the urine of fuco-
sidosis patients [41] with fucose ( -1, 6) (-1,2),
(-1,3) as terminal sugar and glucose, galactose
and N-acetyl galactosamine as reducing su-
gars.
Mannosidosis
a-mannosidosis is an inborn error of metabo-
lism characterised by a deficiency of lysosomal
a-D-mannosidase. The clinical features are
mental retardation, coarse face, skeletal abnor-
malities and psychomotor retardation [5]. Olig-
osaccharides with high concentrations of man-
nose and N-acetylglucosamine have been iso-
lated from patients with this disease [27, 40].
Humbel and Collart [15] and Sewell [34] diag-
nosed mannosidosis from the typical TLC urine
pattern consisting of 6 bands, different from
those found in normal urine.
Aspartylglycosaminuria
This is a hereditary metabolic disorder charac-
terised by slowly progressive mental deteriora-
tion with onset in childhood [28] and by the
urinary excretion of aspartylglucosamine [17]
due to the reduced activity of N-aspartyl-et-
glueosaminidase [30].
Most of the patients have been described in the
Scandinavian countries.
Palo and Savolainen [29] were the first to use
TLC for evidencing the urinary oligosaccharides
in this syndrome. The value of TLC, because of
the typical OGS pattern, was demonstrated by
Humbel and Collart [15] and by Sewell [34].
GM1 Gangliosidosis
This disease may be characterised clinically by
gargoyle facies, corneal opacities, hepatosple-
nomegaly, skeletal changes and mental deterio-
ration with onset in early or late childhood or in
adulthood. These symptoms are more or less
severe according to the various clinical forms of
the disease. In adults gargoylism, hepatosple-
nomegaly and skeletal changes have hardly ever
Federico: Urinary oligosaccharides in metabolic disorders
been described. The disease is due to accumula-
tion of GM 1 ganglioside in the nervous system
and in other tissues through a deficiency of
GM1 ganglioside fl-D-galactosidase. An in-
creased amount of mucopolysaccharides, in tis-
sues and urine is present in this disease.
Wolfe revealed the presence of water-soluble
oligosaccharides in the liver. The same oligosac-
charides were later found in the urine [25, 26].
Urinary OGS screening by TLC is very useful
for the rapid diagnosis of GM1 gangliosidosis
[15, 34]. This method let us to suspect the disease
m 2 cases, one with early and the other with late
childhood onset, later confirmed by the enzyme
deficiency.
In another family, still under investigation, the
OGS pattern, different from that in the other,
classical forms, led us to pursue the enzyme
study, which highlighted a deficiency of fl-D-
fucosidase as well as the absence of fl-galacto-
sidase.
GM2 Gangliosidosis Variant 0
GM2 gangliosidosis, variant 0, or Sandhoff dis-
ease, is a lysosomal disease marked by a pro-
gressive psychomotor deficit, cherry-red spot in
the fundus oculi, hypacusis, myoclonic epilepsy
presenting in early infancy with death in the first
years of life. It is due to a deficiency of both A
and B components of fl-N-acetyl-hexosamini-
dase with storage of GM2 ganglioside and glo-
boside in the tissues [32].
Heavy excretion of OGS containing N-acetyl-
glucosamine and mannose in the urine has been
demonstrated [44]. Strecker et al. [42] have dem-
onstrated the presence of 7 different types of
urinary oligosaccharides.
The pattern of the urinary OGS revealed by
TLC in this disease is typical and hence the urine
test already points to the diagnosis (Federico et
al., in preparation).
No OGS changes have been found in GM2 gan-
gliosidosis (Tay-Sachs disease)
Mucopolipidoses
Mucopolipidoses are storage diseases, likewise
lysosomal, which present the clinical signs of
lipidoses and of mucopolysaccharidoses al-
though mucopolysaccharides have rarely been
found to be increased. Four types of mucopoli-
pidosis are known to date but new subtypes are
frequently being added.
The Italian Journal of Neurological Sciences
Mucolipidosis I or siafidosis
Mucolipidosis I is a congenital metabolic disor-
der marked by a slightly gargoyle facies,skeletal
dysplasia, cherry-red spot in the fundus oculi,
progressive myoclonic epilepsy and onset in ear-
ly childhood [38]. These patients have been
found to have a deficiency of neuraminidase [4]
and an abnormal urinary level of sialyl oligosac-
charides [23].
Numerous cases of cherry-red spot and myoclo-
nus syndrome have recently been reported [8, 9,
11, 31, 46]. Federico et al. [9], Rapin et al. [31]
and Thomas et al. [46] have reported cases of
onset in late childhood with no somatic or skel-
etal abnormalities and no visceromegaly. A case
described by Guazzi et al. [ 12] as "peculiar form
of MPSose" was recently diagnosed as sialidosis
because of the neuraminidase deficiency. In a
few cases, mostly Japanese, the neuraminidase
deficiency has been reported in association with
a fl-galactosidase deficiency (sialidosis, dys-
morphic form).
The urine of patients with this disorder has a
characteristic TLC oligosaccharide pattern [34].
12 distinct oligosaccharides have been purified
from the urine of such patients and their struc-
ture determined [9].
Mucolipidosis H (1-cell disease)
Mucolipidosis II or 1-cell disease is a congenital
metabolic disorder characterised by progressive
mental deterioration, hepatosplenomegaly,
skeletal and somatic changes similar to those
found in in mucopolysaccharidoses [20] and the
presence of characteristic cytoplasmic inclu-
sions in cultured cells. The lysosomal enzymes
are decreased in the cultured cells and increased
in the culture medium or in the serum of affected
patients due to a defect in the lysosome mem-
brane, which becomes incapable of recognising
and taking up the various acid hydrolases [24,
37].
Strecker [39, 43] has reported an increased
excretion of sialyl-oligosaccharides, combined
with an absence of leukocyte a-neuramini-
dase.
The urine of patients with mucolipidosis II pres-
ents no characteristic OGS pattern on TLC.
Mucolipidosis III (pseudo Hurler polydystro-
phy)
This has been described as a distinct nosograph-
ic entity by Maroteaux and Lamy [22]; charac-
terised by skeletal alterations, gargoyle facies,
10
corneal opacities, restriction of joint move-
ments. The urinary MPS are normal, the enzyme
activities are lowered in the cells but increased in
the serum [47]. In view of this it has been
regarded as a mild form of mucolipidosis II.
Strecker [43] showed and increase in oligosac-
charides, whose structure proved similar to that
reported in mucolipidosis II.
Mucolipidosis I V
This was described by Berman [2]. Gangliosides
and mucopolysaccharides are stored in the fi-
broblasts. The absence of ganglioside-neuram-
inidase [1] has recently been demonstrated but
the urinary oligosaccharides have never been
investigated.
Glycogen Storage Diseases
These are hereditary diseases, characterised by
normal or pathologic glycogen storage in skele-
tal muscle, cardiac muscle, kidney, brain, leuko-
cytes, fibroblasts and amniotic fluid cells, due to
a deficiency of specific enzymes concerned with
the metabolism of glycogen.
Hallgren et al. [13] reported abnormal excretion
of OGS in the urine of patients with Pompe
disease (glycogen storage disease, type II) origi-
nating from the partial degradation of glycogen.
Lennartson et al. [19] evidenced 3 types of OGS
in glycogenosis II and 4 in type III.
OGS variations demonstrable by TLC have
been reported by Tsay and Marshall [48] in
types II and V and by Sewell [35] in type VI).
Federico et al. [10] in a case of myopathy of late
onset with histochemically heteropolysacchar-
idic mega-inclusions and a normal glycogen
concentration found an abnormal OGS pattern
on TLC.
Collagen Disorders
Osteogenesis imperfecta
This disease, transmitted as an autosomal dom-
inant or recessive trait, is characterised by flab-
by ligaments, deafness, blue sclerae, bone ab-
normalities with frequent fractures, dental ab-
normalities and hernias. The biochemical defect
is not yet known, although there is evidence that
anomalies in the formation of the collagen
fibrils are involved in the pathogenesis of the
disease. Since the formation of the collagen
fibrils depends on interactions with the muco-
polysaccharides, they have been investigated in

several cases by many workers/9, [6-16]. Hurst
et al. [16] reported in cases of osteogenesis
imperfecta an abnormal excretion of non muco-
polysaccharidic interreacting with Alcian blue
material, suspected of being glycoproteins and/
or oligosaccharides. We have found an anoma-
lous pattern of urinary OGS in one family by
means of TLC (Federico et al. in prepara-
tion).
Marfan" s syndrome
This syndrome is transmitted as an autosomal
dominant trait. The clinical features are arach-
nodactyly, flabby ligaments, hernias, scarring of
the skin with keloids, ectopia lentis, cardiac
valve abnormalities. In one case we found an
abnormal urinary OGS pattern by means of
TLC.
Sommario:
Vengono descritti i metodi ed i risultati ottenuti nello studio degli oligosaccaridi urinari in alcune
malattie dismetaboliche di natura lisosomiale e non. Viene focalizzata l'attenzione in modo particolare
sulla cromatografia su strato sottile che, essendo una metodica semplice ed economica, pub essere
considerata un utile mezzo di screening per tali disturbi.
Address reprint requests to Dr. Antonio Federico
Istituto di Scienze Neurologiche, Universith degli Studi,
Facolth di Medicina e Chirurgia
Piazza Duomo, 2 - - 5 3 1 0 0 Siena, Italia
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