Mucopolysaccharidoses (MPS) represent a group of inheritable lysosomal storage diseases caused by mutations in the genes coding for enzymes involved in catabolism of different glycosaminoglycans (GAGs). They are clinically heterogeneous multisystemic diseases, often involving the spine. Bony abnormalities of the spine included in the so-called dysostosis multiplex and GAG deposits in the dura mater and supporting ligaments can result in spinal cord compression, which can lead to compressive myelopathy. Spinal involvement is a major cause of morbidity and mortality in some MPS (e.g., MPS IVA, VI, and I), and early radiological diagnosis is critical in preventing or arresting neurological deterioration and loss of function.

1. REVIEW PAPER
Spinal involvement in mucopolysaccharidoses: a review
Antonio Leone & Donato Rigante & Daniele Zaccaria Amato &
Roberto Casale & Luigi Pedone & Nicola Magarelli & Cesare Colosimo
Received: 15 October 2014 /Accepted: 21 October 2014 /Published online: 31 October 2014
# Springer-Verlag Berlin Heidelberg 2014
Abstract
Background Mucopolysaccharidoses (MPS) represent a
group of inheritable lysosomal storage diseases caused by
mutations in the genes coding for enzymes involved in catab-
olism of different glycosaminoglycans (GAGs). They are
clinically heterogeneous multisystemic diseases, often involv-
ing the spine. Bony abnormalities of the spine included in the
so-called dysostosis multiplex and GAG deposits in the dura
mater and supporting ligaments can result in spinal cord
compression, which can lead to compressive myelopathy.
Spinal involvement is a major cause of morbidity and mortal-
ity in some MPS (e.g., MPS IVA, VI, and I), and early
radiological diagnosis is critical in preventing or arresting
neurological deterioration and loss of function.
Discussion Management of MPS, however, requires a multi-
disciplinary approach because of the multiorgan nature of the
disease. Indeed in order to appreciate the relevance and nu-
ances of each other's specialty, radiologists and clinicians need
to have a background of common knowledge, rather than a
merely compartmentalized point of view. In the interest of the
management of spinal involvement in MPS, this review article
aims on one hand to provide radiologists with important
clinical knowledge and on the other hand to equip clinicians
with relevant radiological semiotics.
Keywords Mucopolysaccharidoses . Spine . Radiography .
CT . MR imaging
Introduction
Mucopolysaccharidoses (MPS) represent a rare group of
inherited metabolic diseases caused by genetic mutation of
specific enzymes involved in the sequential catabolism of
long-chain complex carbohydrates known as glycosaminogly-
cans (GAGs) or mucopolysaccharides. GAGs are components
of proteoglycans (glycosylated proteins that provide structural
integrity and function to connective tissues, providing hydra-
tion and swelling pressure to the tissue and enabling it to
withstand compressional forces) [1]. Dermatan sulfate, hepa-
ran sulfate, keratan sulfate, chondroitin sulfate, and hyaluronic
acid are the five identified GAGs in tissues. Enzyme deficien-
cy or malfunction results in the accumulation of partly de-
graded GAGs within the lysosomes of various cell types of
parenchymal and mesenchymal tissues. Excess intracellular
deposition progressively leads to cell, tissue, and multiorgan
dysfunction and ultimately results in premature death in the
majority of patients [2–5].
MPS were first described by Hunter in 1917 [6]. Many
similar cases were described during the following years. How-
ever, this family of diseases was not described as MPS until
the middle of the twentieth century, when the stored muco-
polysaccharides were isolated in tissues [7] and in urine [8] of
these patients. The specific enzyme deficiencies and genes
involved in MPS were subsequently identified [9], the last
being the gene for MPS III C only identified in 2006 [10]. To
date, seven distinct clinical types (I to IV, VI, VII, and IX) and
numerous subtypes of MPS have been described. Different
residual enzymatic activity can result in different phenotypes
of the same MPS type, from severe to attenuate [3, 5]. The
genetic basis, biochemical characteristics, and prominent clin-
ical features, as well as the eponym used for each disorder, are
summarized in Table 1 [3].
Awareness of the imaging appearances may help the radi-
ologist in facilitating early diagnosis and selection of an
A. Leone (*) :D. Z. Amato :R. Casale :L. Pedone :
N. Magarelli :C. Colosimo
Department of Radiological Sciences, Catholic University, School of
Medicine, Largo A. Gemelli, 1-00168 Rome, Italy
e-mail: a.leonemd@tiscali.it
D. Rigante
Institute of Pediatrics, Catholic University, School of Medicine,
Largo A. Gemelli, 1-00168 Rome, Italy
Childs Nerv Syst (2015) 31:203–212
DOI 10.1007/s00381-014-2578-1

2. effective treatment. To address correct identification of the
MPS type, however, correlation between imaging findings
and clinical manifestations is crucial. The aim of this review
article was to provide the required clinical knowledge that
radiologists need to know and the relevant imaging knowl-
edge that clinicians require in diagnosing spinal involvement
in MPS.
Clinical features
Individually, MPS are rare diseases, with data on the
incidence of individual types available for only a few
countries and regions. The overall incidence is estimated
as one in 22,000 births [9], but it is probably greatly
underestimated because the milder forms of MPS often
go unrecognized. All types are inherited as autosomal
recessive traits, except for MPS II (Hunter syndrome),
which is an X-linked recessive trait [10].
Clinical features and severity of symptoms vary widely
both among and within the seven major types of MPS,
including skeletal and joint abnormalities which can
result in dysmorphism and severe growth retardation,
hepatosplenomegaly, umbilical hernias, a different in-
volvement of visual, auditory, cardiovascular, respirato-
ry, central, and peripheral nervous systems, and distinc-
tive coarse facial features resembling the well-known
“gargoyles” (Fig. 1) [3, 11, 12]. The non-specific nature
of many symptoms and variable clinical presentations
frequently impede prompt and correct diagnosis. Patients
mostly appear normal at birth, and symptoms become
apparent around the age of 1 or 2. However, in most of
the patients with the severe phenotype, the symptoms
arise after birth and progress rapidly, whereas attenuated
phenotypes manifest in childhood or adolescence [2].
In relation to spinal involvement, vertebral, and skull base
anomalies, GAG deposits in the meninges and supporting
ligaments, as well as atlantoaxial subluxation and instability
can result in spinal cord compression with or without signs of
compressive myelopathy [12–15]. The thoracolumbar spine
andmore commonly the craniocervical junction are the two
major locations of spinal cord compression. Neurologic man-
ifestations of spinal cord compression at craniocervical junc-
tion suggest an upper motor neuron lesion consisting of gait
disturbance, hyperreflexia, spasticity, clonus, Babinski and
Hoffman signs, muscle weakness, and/or numbness (sensory
deficits) [15].
Compression at the thoracolumbar level causes similar
symptoms as those described for spinal cord compression at
craniocervical junction but are confined to the legs [15]. In
severe cervical spinal stenosis, a minor trauma can cause acute
traumatic quadriparesis or even medullary dysfunction lead-
ing to respiratory arrest [15].
Table 1 Classification of MPS
Type Eponym Deficient enzyme OMIM Gene (locus) Main clinical manifestations
I H Hurler α-L-iduronidase 607014 IDUA (4p16.3) Mental retardation, hydrocephalus, facial
dysmorphism, visceromegaly, joint stiffness,
corneal clouding (in increasing severity from
the Hurler-Scheie type to the Hurler type)
I H/S Hurler-Scheie α-L-iduronidase 607015 IDUA (4p16.3)
I S Scheie α-L-iduronidase 607016 IDUA (4p16.3) Joint contractures and stiffness
II Hunter Iduronate sulphatase 309900 IDS (Xq28) Hurler-like clinical picture, psycho-motor
regression, joint stiffness
III A Sanfilippo A Heparan N-sulphatase 252900 SGSH (17q25.3)
III B Sanfilippo B α-N-aceytylglucosaminidase 252920 NAGLU (17q21.2)
III C Sanfilippo C Acetyl-CoA α-glucosaminide
acyltransferase
252930 HGSNAT (8p11.21) Severe cognitive impairment with serious
behavioral changes before overt bone and
joint involvement
III D Sanfilippo D N-Acetylglucosamine-6-sulphatase 252940 GNS (12q14.3)
IVA Morquio A N-Acetylgalactosamine 6-sulphatase 253000 GALNS (16q24.3) Severe and distinctive skeletal dysplasia, joint
hyperlaxity, short stature, heart valvular
disease, preserved mental abilities
IV B Morquio B β-Galactosidase 253010 GLB1 (3p22.3)
VI Maroteaux-Lamy N-Acetylgalactosamine
4-sulphatase (aryl-sulphatase B)
253200 ARSB (5q14.1) Severe skeletal dysplasia, short stature, heart
valvulopathies, mild to severe corneal
clouding, preserved cognition
VII Sly β-Glucuronidase 253220 GUSB (7q11.21) Hydrops fetalis at birth, skeletal dysplasia,
short stature, corneal clouding, developmental
delay, hepatomegaly
IX Natowicz Hyaluronidase 601492 HYAL1 (3p21.31) Periarticular soft nodules, joint stiffness, short
stature, mild facial dysmorphism, preserved
cognition
OMIM online Mendelian inheritance in man
204 Childs Nerv Syst (2015) 31:203–212

3. Spinal involvement
Spinal involvement is a common and prominent feature in
patients with MPS IVA (Morquio A syndrome) [15–19], VI
(Maroteaux-Lamy syndrome) [15, 20, 21], and I (Hurler syn-
drome) [15, 22]; it has also been described in cases of MPS II
[23, 24], III (Sanfilippo syndrome) [25], and VII (Sly syn-
drome) [26]. In these patients, the pattern of musculoskeletal
abnormalities resulting from defective endochondral and
membranous growth throughout the body is known by the
term dysostosis multiplex [27]. In the spine, dysostosis mul-
tiplex includes flattening and elongation (platyspondyly) of
the vertebral bodies, wedge-shaped vertebral bodies with an-
terior beaking, resulting thoracolumbar kyphosis or even
gibbus deformity, and odontoid dysplasia (e.g., hypo- or
aplasia). Spinal stenosis and spinal cord compression are other
common features in patients with MPS and may even be the
first signs leading to disease diagnosis [28].
Bony anomalies
Evolution of vertebral abnormalities occurs over time. In early
childhood, the flattening of the vertebrae is not marked, and in
the lateral radiographs, the vertebral bodies have an oval
shape; anterior beaking of the vertebral bodies is also evident.
In late childhood, the thoracolumbar bodies grow very slowly
in height, the anterior beaking of the vertebral bodies, often
associated with posterior scalloping, persists particularly at the
thoracolumbar junction (Fig. 2), and the intervertebral disk
spaces are wide. In the adult, the anterior portion of many of
the vertebrae ossifies and gives a normal but flattened
rectangular configuration on lateral radiographs [29].
However, there is still anterior beaking in one or more
bodies at the thoracolumbar junction (Fig. 3). The height
of the bodies does not increase from late childhood. The
disk spaces remain wide [29].
Fig. 1 Gargoyle-like facial
features: a 9-year-old boy and b
12-year-old boy with Hunter's
syndrome and Sanfilippo's
syndrome, respectively. Note the
coarse faces with marked
craniofacial dysproportion, flat
noses, gapped teeth, and thick lips
(courtesy [written consent] of
respective parents)
Fig. 2 MPS type II in a 14-year-old boy. Sagittal reformatted CT image
of the thoracolumbar spine shows anterior beaking of some vertebral
bodies (arrows), thoracolumbar kyphosis, and posterior vertebral
scalloping (small arrows). Note retrolistesis of the beak-shaped L3
vertebra
Childs Nerv Syst (2015) 31:203–212 205

4. In the past, anterior beaking of the vertebral bodies has
been explained in terms of primary hypoplasia of the
involved vertebrae [29]. In 1970, Swischuk [30] suggested
that the deformity results from anterior herniation of the
nucleus pulposus into the superior aspect of the vertebra
below rather than from primary hypoplasia of the vertebral
body. In the young infant, the muscles have not as yet
developed their normal “tone.” Muscular hypotonia leads
to exaggeration of the already present spinal kyphosis, and
this, in turn, leads to increased stress on the thoracolumbar
intervertebral disks and a greater likelihood of anterior
nuclear herniation. In support of this hypothesis is the fact
that the anterior beaking of the vertebral bodies is also seen
in conditions characterized by generalized hypotonia but
no bone dysplasia (e.g., Down syndrome, phenylketonuria,
Niemann-Pick disease, Werdnig-Hoffmann disease) [30,
31]. However, Field et al. [27] examined specimens of
two children with MPS IH at postmortem and found that
the endplate formation was normal but that there was a
failure of ossification in the anterosuperior aspect of the
vertebral body. Tandon et al. [31], describing the spinal
problems in 12 patients with MPS type I, found that
anteroinferior beaking of the vertebral bodies and the
resulting kyphosis usually occur at the junction of the rigid
thoracic and mobile cervical and lumbar spines, suggesting
the importance of mechanical factors [31]. Therefore, there
may be more than one mechanism involved in anterior
beaking of the vertebral bodies. The posterior elements of
the vertebrae also have a grossly abnormal anatomy, and
failure of ossification appears to affect the primary centers
of the vertebral body and the two neural arches [31]. As a
result of hypoplasia of the superior vertebral facets, MPS
patients may have retrolisthesis of one of the relatively
small beak-shaped lumbar vertebrae (Fig. 2) or
spondylolisthesis of the vertebrae above a hypoplastic
beak-shaped vertebra at the thoracolumbar junction level.
The term spondylolisthesis refers to the forward slippage
(by any cause) of a vertebra on the subjacent one in the
sagittal plane. Backward vertebral slippage, a type of
spondylolisthesis, has been called retrolisthesis [32, 33].
The combination of an anterior beak and vertebral flatten-
ing at T12, L1, or L2 level is often responsible for
thoracolumbar kyphosis (Fig. 2); progressive lumbar gibbus
with kyphosis is commonly seen in MPS disorders, but it is
the commonest clinical problem in patients with MPS type I
[31]. In these patients, the apex of the kyphosis is usually
located at the L2 vertebra which has a prominent characteristic
anteroinferior beak, and the rate of progression of the kyphosis
is variable [31]. The etiology of the gibbus with vertebral
beaking is multifactorial and includes poor truncal muscle
tone, weight-bearing forces, growth disturbance, and anterior
disk herniation [34].
Abnormal development and maturation of cartilage and
bone due to the enzymatic block can give rise to incomplete
ossification of the odontoid process which leads to dens
hypoplasia/aplasia or os odontoideum. Hypoplasia/aplasia of
the odontoid process and resultant laxity of the transverse and
alar ligaments lead to atlantoaxial subluxation due to exces-
sive independent movement between the anterior arch of the
atlas and the dens [35]. During flexion, the anterior arch of the
atlas moves anteroinferiorly, while the odontoid process tilts
posteriorly. Therefore, a pincer-like effect is created by the
posterior arch of the atlas which indents the dorsal aspect of
the spinal cord as it translates forward relative to the axis [15].
The atlantodental interval (the distance between the
posteroinferior aspect of the anterior arch of C1 and the
most anterior aspect of the dens) is the imaging diagnostic
clue to anterior atlantoaxial subluxation. On lateral radio-
graphs of the cervical spine, an atlantodental interval great-
er than 3 mm in an adult and 5 mm in a child is considered
abnormal, and when it differs by more than 2 mm on
functional flexion-extension lateral views, there is
atlantoaxial instability. Cord compression is more likely
when the subluxation exceeds 9 mm [36].
Fig. 3 MPS IVA in a 21-year-old
man. a, b Sagittal reformatted CT
images of the lumbar spine (a)
and thoracolumbar junction (b)
show some typical thoracolumbar
spine changes including
platyspondyly, anterior beaking
within the midportion of the
vertebral bodies (small arrows in
a and b) and posterior scalloping
of the vertebral bodies (arrows in
a and b)
206 Childs Nerv Syst (2015) 31:203–212

5. The posterior atlantodental interval, which extends from
the posterior surface of the odontoid process to the anterior
surface of posterior arch of the atlas, may be a more reliable
radiographic predictor of spinal cord compression. In adults, a
posterior atlantodental interval less than 14 mm is indicative
of cord compression [37]. Vertical subluxation of the dens
through the foramen magnum also occurs in patients with
MPS. The definition of vertical atlantoaxial subluxation is
synonymous with other frequently used terms such as basilar
impression which refers to endocranial introflection of the
edges of the occipital foramen due to hypoplasia of the clivus
and occipital condyles [38]. As a consequence, the odontoid
process is displaced upwards, producing compression of the
spinal cord or bulbomedullary junction in the foramen mag-
num with cerebrospinal fluid and/or vascular compromise.
Several measurements are used to identify or confirm the
possible presence of basilar impression—for example, Cham-
berlain and Mcgregor lines. The Chamberlain line extends
from the posterior end of the hard palate to the posterior
midpoint of the occipital foramen. In a normal individual, this
line courses at least 3–4 mm above the tip of the dens. The
Mcgregor line extends from the posterior edge of the hard
palate to the occipital opisthion (the posterior lip of the fora-
men magnum); in a normal individual, the dens should not
project more than 4–5 mm above this line [38].
Os odentoideum consists of a smooth ossicle of bone
separated from a shortened odontoid process. Whether the
os odontoideum is congenital or traumatic in origin is of little
practical relevance because the net effect of atlantoaxial insta-
bility is the same [39]. The clinical importance of os
odontoideum is that because the os is fixed to the anterior
arch of C2 by the transverse ligament and moves with C1, it
indicates atlantoaxial instability and risk of spinal cord dam-
age from relatively minor trauma [39]. Dens hypoplasia and/
or os odontoideum are present in nearly all patients with MPS
IVA with varying degrees of cord compression due to peri-
odontoid soft tissue mass (composed of GAGs) (Fig. 4) and
indentation by the posterior arch of the atlas [40].
Spinal stenosis
Spinal stenosis describes a condition in which there is dimin-
ished space available for the neural and vascular elements in
the spine. It may be single-level (focal) or multilevel involving
the central spinal canal (central spinal stenosis) and/or the
intervertebral foramina and the lateral recesses of the central
spinal canal (lateral spinal stenosis) [41]. Spinal stenosis can
also be etiologically classified into developmental or acquired
types, although both mechanisms may be present in a given
patient. Developmental stenosis of the central spinal canal is
of two basic types: (1) hereditary-idiopathic spinal stenosis
and (2) spinal stenosis associated with disorders of skeletal
growth (e.g., achondroplasia, Down's syndrome, multiple
hereditary exostoses, and MPS) [12]. Acquired stenosis may
be a result of degenerative, traumatic, inflammatory, vascular,
postsurgical, and neoplastic conditions [41].
In MPS, spinal stenosis is mainly due to focal or multilevel
thickening of the connective tissues within the central spinal
canal, particularly of the meninges, posterior longitudinal
ligament, and flaval ligaments, due to GAG deposition [15].
Spinal cord compression
Spinal cord compression is a common feature in patients with
MPS [15–25]; it may involve multiple spinal cord levels, but
usually the craniocervical junction and thoracolumbar spine
(Fig. 4). Although spinal cord compression is believed to be
multifactorial, there are two main proposed etiopathologic
mechanisms. The first is related to central spinal canal stenosis
due to GAG deposits in the peri-odontoid tissue, supporting
ligaments, and meninges [12, 14, 20, 21]. The second mech-
anism is related to vertebral abnormalities, dysplasia of the
odontoid process, ligamentous laxity, and invagination of the
posterior arch of atlas leading to atlantoaxial subluxation and
instability [12, 14, 18, 28, 42].
Imaging evaluation
Radiography, CT, and magnetic resonance (MR) imaging of
the spine can be very helpful for screening patients with MPS,
optimizing the time for surgical intervention and for assessing
the impact of treatment [12–15].
Radiography
Systematic and careful imaging of the spine begins with
radiography. Anteroposterior and lateral radiographs of the
spine are typically included in the initial imaging evaluation
of suspected or diagnosed MPS. Detection of gross anomalies
of the spine such as os odontoideum, kyphoscoliosis,
platyspondyly, and anterior vertebral beaking is possible with
standard radiographic examination. The addition of functional
flexion-extension lateral views is important for the detection
and quantification of intervertebral instability. Because of its
simplicity, low expense, and wide availability, functional ra-
diography is the most widely used method in the imaging
diagnosis of intervertebral instability [33]. Unfortunately, the
presence of basilar invagination and enlarged mastoid pro-
cesses (e.g., in patients with MPS IVA) often obscures the C1-
2 level and limits the usefulness of the functional radiography
of the cervical spine in many patients [16]. Even though static
and functional radiography provides preliminary assessment
of the craniocervical junction, it does not provide direct visu-
alization of spinal cord and cartilagineous and ligamentous
Childs Nerv Syst (2015) 31:203–212 207

6. thickening resulting from accumulation of GAGs. Therefore,
in patients with suspected cord compression, MR imaging is
indicated to provide definitive visualization of the space avail-
able for the spinal cord and identify the presence of cord
damage. Radiographic follow-up examinations may be re-
quired to evaluate specific clinical problems such as
kyphoscoliosis.
CT
Advances in CT technology have led to the current generation
of multidetector CT scanners that boast faster acquisition,
increased anatomical coverage, higher spatial resolution, and
isotropic data acquisition. This has resulted in the improve-
ment in diagnostic accuracy, and the gain is perhaps best
exemplified by the surge in the detailed multiplanar reforma-
tions in spine imaging (Figs. 2 and 3). CT is more accurate
than radiography and MR imaging for demonstrating verte-
bral bony changes. Because of the advantage of speed over
MR imaging, CT may be the preferred imaging method when
cooperation may be limited, but sedation or anesthesia is non-
desirable. It is also used in presurgical planning in patients in
whom bony anatomy needs to be depicted accurately. Sagittal
reformatted CT images are critical for cervical imaging,
particularly for characterization of the odontoid process and
atlantoaxial articulation.
MR imaging
Although the bony changes are excellently demonstrated on
radiography and CT, MR imaging is generally considered to
be the most accurate imaging method for evaluating the soft
tissues, ligaments, meningi, spinal cord, and nerve roots [14,
15]. Therefore, MR imaging is currently by far the most
commonly used imaging modality for evaluating the compli-
cations of MPS (e.g., central spinal canal stenosis, spinal cord
compression, and myelopathy) (Fig. 4), defining the need for
surgical treatment, and monitoring the pathologic progression
of the disease (Fig. 5) [14, 15]. In patients with myelopathy,
signal hyperintensity on T2-weighted images at the level of
spinal compression might be due to edema, ischemia, or
gliosis/myelomalacia (Fig. 4). However, imaging myelopathy
does not always correlate with its signs and symptoms. In
most circumstances, the neurological deficits are usually less
severe than suggested by MR imaging [43].
Granted that a detailed discussion of MR imaging physical
phenomena is beyond the scope of this article (many excellent
review articles are available in the literature) [43, 44], the
Fig. 4 Multilevel spinal cord compression in a 24-year-old man with
MPS IVA and neurological manifestations of myelopathy. a, b Sagittal
T2-weighted MR images of the thoracolumbar (a) and cervical spine (b)
show spinal cord compression demonstrated by loss of cerebrospinal fluid
and diffuse central spinal canal stenosis being more evident at the thoracic
level (arrows in a). Central spinal canal stenosis is also evident at the
craniocervical junction with a small area of intramedullary increased
signal consistent with compressive myelopathy (arrow in b). Increased
signal intensity within the cervical and thoracolumbar cord from C3 to the
conus medullaris, consistent with edema, is clearly evident as well as mild
spinal cord thickening (small arrows in a and b). c Transverse T2-
weighted MR image passing through T4 vertebra confirms spinal cord
edema with central gray matter involvement (circle). d Transverse T1-
weighted MR image passing through T8 vertebra shows thickness of the
flaval ligament on the right encroaching on the dural sac (small arrows).
Note odontoid hypoplasia and localized thickening of the surrounding
tissue (asterisk in b) as well as thoracolumbar kyphosis, platyspondyly,
and sternum deformity (a)
208 Childs Nerv Syst (2015) 31:203–212

7. standard MR imaging protocol in MPS patients should rou-
tinely include spin-echo T1- and fast spin-echo T2-weighted
sequences obtained in the axial and sagittal planes. Since
spinal stenosis with concomitant loss of cerebrospinal fluid
(CSF) signifies spinal cord compression (Fig. 4), an additional
phase-contrast sequence may be a useful technique in demon-
strating CSF flow in some instances. Phase-contrast imaging
provides information about the phase (or direction) of flow
and the velocity (or magnitude) of flow [45]. When phase-
contrast sequences are obtained in the sagittal plane, the
absence of fluid pulsation anterior and posterior to the spinal
cord implies effacement of the CSF space and cord contact. In
these circumstances, demonstrating altered diffusion within
the spinal cord may be a method to detect compression and
impending myelomalacia prior to alteration of signal intensity
on T1- or T2-weighted images. Random motion of water
molecules (diffusion) in the presence of a strong magnetic
gradient results in MR signal loss as a result of the dephasing
of spin coherence. The application of a pair of strong gradient
to elicit differences in the diffusivity of water molecules
among various biologic tissues is known as diffusion
weighting [46]. Acute cord compression might cause diffu-
sion restriction, while chronic compression would cause in-
creased diffusivity. The application of MR diffusion-weighted
imaging (DWI) to the spinal cord has been challenged by the
relatively small region of interest, the more complicated and
inhomogeneous anatomy of the spine, the differences in mag-
netic susceptibility between adjacent air and fluid-filled
structures and the surrounding soft tissues, the CSF pulsatile
flow as well as the movement artifacts in a child. However,
advances in DWI techniques have resulted in higher-quality
images that are now able to depict pathologic abnormality
with improved sensitivity and specificity [47]. Diffusion ten-
sor imaging (DTI), which may be a sensitive method to detect
impending cord injury due to compression, has benefited from
the advances in DWI techniques as DWI images form the
foundation for DTI [47]. Recent advances in the design of
magnets and gradient coils have made possible the develop-
ment of open MR imaging systems, which provide new op-
portunities to investigate spinal kinematics, particularly verte-
bral instability. Flexion-extension MR imaging of the cervical
cord is becoming an important technique for clinical surveil-
lance and pre-surgical planning [48]; however, further studies
are required before the true management value of this tech-
nique can be determined [33]. A disadvantage of MR imaging
is that it may require sedation or anesthesia because many of
these patients are not very cooperative being in early child-
hood or intellectually challenged. Moreover, airway and car-
diac problems as well as cervical spine instability are common
in MPS patients. Thus, the risk of sedation and anesthesia
(e.g., cord compression resulting from atlantoaxial instability)
is substantially greater than in unaffected individuals.
In summary, spinal radiography is useful in suggesting
MPS as a possible diagnosis or supporting the diagnosis when
MPS is suspected. Spinal CT and MR imaging features are
critical for evaluating the complications of MPS (i.e., central
Fig. 5 Same patient as in Fig. 3.
Sagittal MR images obtained
7 days after suboccipital
craniotomy and C1 laminectomy.
a T2-weighted image of
cervicothoracic spine showing
significant regression of spinal
cord edema; focal areas of edema
(arrows) associated with mild
spinal cord thickening (small
arrows) persist at C4-7 and mid-
thoracic levels. b T2-weighted
image of cervical spine shows
partial regression of the small area
of intramedullary increased signal
due to compressive myelopathy
(arrow)
Childs Nerv Syst (2015) 31:203–212 209

8. spinal canal stenosis, spinal cord compression, and myelopa-
thy) and the need for surgical treatment.
Although a combination of anterior beaking and pos-
terior scalloping of the vertebral bodies is very typical for
MPS, no correlation between imaging findings and any
specific type of MPS has been found. Thus, it is not
possible to differentiate radiologically between MPS IV,
I, and VI which, compared with other forms of MPS, tend
to have greater spinal involvement. However, some points
in the differential diagnosis can be emphasized. Flattened
vertebrae throughout the entire thoracic region have never
been seen in patients with Hurler's syndrome. Patients
with MPS IV appear healthy at birth, and spinal abnor-
malities are prominent early childhood presentations [49].
The beak-shaped configuration of vertebral bodies of the
thoracolumbar junction and upper lumbar spine may be
identical in MPS I and IV; however, MPS I frequently
shows anterior beaking of the inferior aspect of the ver-
tebral body [30], whereas MPS IV shows anterior beaking
within the midportion of the vertebral body (Fig. 3). Both
MPS I and IV are associated with diffuse posterior verte-
bral scalloping, although the pathologic mechanism of
this finding is not known (Figs. 2 and 3).
Diagnosis
Early and accurate diagnosis can improve treatment out-
comes in MPS patients. Qualitative and quantitative de-
termination of urinary GAGs represents a simple screen-
ing test for patients presenting with clinical features sug-
gestive of MPS [2, 10]. The demonstration of an abnormal
pattern is diagnostic for an MPS disorder, and the pres-
ence of specific GAGs can suggest the most probable
MPS subtype; however, enzymatic activity assay is man-
datory to achieve definitive diagnosis. This is usually
possible through measuring enzyme activity in peripheral
blood leukocytes or cultured fibroblasts (skin biopsy) [2,
10]. Whenever the enzymatic activity assay is available,
the identification of the gene defect is not required for
diagnosis; it can be helpful for prenatal diagnosis and
identification of carriers in the family at risk [2, 10].
Prenatal diagnosis is performed on fresh or cultured cho-
rionic villus sampling [50] or cultured amniotic fluid. The
choice of the test—enzymatic and/or molecular genetic—
is based on the characteristics of the defect to be investi-
gated [51]. Carrier detection by genetic analysis is partic-
ularly important for MPS II which is inherited as X-linked
recessive trait [10]. In the other MPS types which are
inherited as autosomal recessive traits, the chance that
carriers will have children affected with MPS is very
small (unless the union is consanguineous) [2].
Treatment
Until recently, only supportive care was available for MPS
patients. The introduction of hematopoietic stem cell trans-
plantation has positively affected the natural history of some
MPS types (mainly MPS I, MPS VI, and potentially MPS VII)
[10, 52], but it is not routinely advocated in clinical practice
due to its high risk profile [53]. Intravenous enzyme replace-
ment therapy (ERT) is currently available for MPS I, II, and
VI and may be available for other forms of the disease in the
near future [10, 52]. The currently published clinical observa-
tions of ERT reveal that the deficient enzyme infusion can
modify the rate of disease progression in patients with pre-
existing disease but clearly does not lead to complete reversal
of all disease signs. Early treatment may significantly delay or
prevent the onset of the major MPS clinical signs and even
modify the natural history of the disease [10, 54]. Other new
treatment strategies are currently being investigated, including
gene therapy, intrathecal ERT, and molecular therapies such as
substrate reduction therapy which uses GAG biosynthesis
inhibitors [52, 53, 55]. Although these potential therapeutic
approaches may provide a better outcome for these devastat-
ing diseases in the near future, ERT remains the mainstay of
MPS treatment. Unfortunately, intravenous ERT is not likely
to provide enzyme across the blood–brain barrier in signifi-
cant amounts; therefore, surgery remains the standard treat-
ment for spinal cord compression and progressive
thoracolumbar kyphosis, although long-term outcomes are
unclear [15]. The primary aims of surgery are to restore
normal vertebral alignment, protect nerve structures, stabilize
the spine, and permit an acceptable degree of spinal mobility.
At the craniocervical junction, intervertebral instability,
intractable pain, cord compression, and definitive neurologi-
cal deficit require surgical treatment; it includes luxation re-
duction, stabilization by external fixation (e.g., halo vest), and
occipitocervical fusion [38, 56–58]. In cases of instability
coexisting with irreducible spinal cord compression,
osteosynthesis should be preceded by a decompression
procedure [38, 58, 59]. Atlantoaxial instability with resul-
tant myelopathy as well as spinal cord compression due to
peri-odontoid GAGs deposits have been so well described
in MPS IV that some authors have recommended prophy-
lactic fusion, often with decompression, at an early age
for these patients [16, 60].
Posterior occipitocervical fusion is the most common pro-
cedure and appears to be a satisfactory method of arresting the
downward clinical course in the majority of cases [59]. How-
ever, the choice of surgical approach as well as the extent of
surgery depends on the site of the instability and the site of
cord compression (Fig. 5) [15, 38, 56–59]. Therefore, it is
fundamental to obtain detailed documentation of the anatom-
ical–pathological and functional situation provided by preop-
erative radiography, CT, and MR imaging [38]. The anterior
210 Childs Nerv Syst (2015) 31:203–212

9. approach may allow a fusion procedure capable of preserving
the rotatory motion of the atlantoaxial junction [58]. The
posterior approach allows easier access to vertebral structures
and preserves the anterior visceral structures [38, 56, 57].
Patients with severe ventral spinal cord compression may
require one-stage anterior decompression and posterior
occipitocervical fusion [38, 58, 59].
Thoracolumbar spinal cord compression with myelopathy
is clearly an indication for surgery. Spinal decompression and
deformity correction are also required in MPS patients with
progressive and symptomatic kyphosis or gibbus deformity in
order to prevent further progression, preserve trunk balance,
and avoid neurological deficits and respiratory impairment
[61]. Although there is no consensus on the ideal surgical
approach and technique (each surgeon develops procedures
on the basis of clinical experience and opinion), it is generally
accepted that a decompression should be supported with in-
strumentation and fusion [15].
Conclusion
Spinal abnormalities which are prominent features of many
MPS types are chronic, progressive, often debilitating, and a
major cause of mortality. They may be evaluated by imaging
modalities such as radiography, CT, and MR imaging which
are also useful tools for surgical planning and follow-up. Early
diagnosis and timely treatment of spinal involvement are
critical in preventing or arresting neurological damage and
improving patient outcomes. However, diagnostic delays oc-
cur frequently especially for those patients with more attenu-
ated forms of the disease. Therefore, the availability of med-
ical resources, the correlation of clinical with imaging find-
ings, and a common knowledge base for treatment team
members (radiologists and clinicians) rather than a compart-
mentalized view are very important.
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