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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2984_Библиотеки_им_академика_М_И_Перельмана
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In: Neurochemistry of Metabolic Diseases ISBN: 978-1-53618-339-9
Editor: Sankar Surendran © 2020 Nova Science Publishers, Inc.
Chapter 4
MUCOPOLYSACCHARIDOSIS TYPE VII/SLY
DISEASE: MOLECULAR MECHANISM
AND THERAPEUTIC EFFECT
Adriana M. Montano
Department of Pediatrics,
Department of Biochemistry and Molecular Biology,
School of Medicine, Saint Louis University,
St. Louis, MO, US
ABSTRACT
Mucopolysaccharidosis VII (MPS VII) also known as Sly disease, is
an ultra-rare lysosomal disorder, characterized by hepatosplenomegaly,
skeletal abnormalities and mental retardation. The most severe cases of
MPS VII are characterized by hydrops fetalis, a condition in which excess
fluid builds up in the body before birth. This disorder is caused by
deficiency of the lysosomal enzyme -glucuronidase (GUSB), causing
the accumulation of heparan, dermatan and chondroitin-4 and -6 sulfate
Corresponding Author’s Email: adriana.montano@health.slu.edu.
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Adriana M. Montano
104
in the lysosomes. To date, 63 distinct mutations in the GUSB gene
causing the disorder have been reported. The disease has three distinct
clinical presentations: (i) non-immune neonatal hydrops fetalis (NIHF);
(ii) Infantile or adolescent form with history of hydrops fetalis; and (iii)
Infantile or adolescent form without known hydrops fetalis. NIHF is the
most severe form of MPS VII disease and history of NIHF has been
reported in 48% of patients with MPS VII. The infantile form of MPS VII
with severe phenotype is characterized by short stature, generalized
skeletal dysplasia, coarse facial features, hepatosplenomegaly, umbilical
and/or inguinal hernia, heart and lung disease, and cognitive impairment.
There is no cure for this disorder, but two treatments have emerged as
gold standard since the disease was first reported in 1973. Several MPS
VII patients have undergone hematopoietic stem cell transplantation but
with high mortality and morbidity. Recently, first clinical trial of enzyme
replacement therapy (ERT) was conducted in 2018. Long-term
administration of ERT for at least 144 weeks in 12 patients revealed
several clinical benefits. Patients showed dramatic decrease in urinary
glycosaminoglycans (GAGs), and improvement in the multi-domain
responder index which measured motor function, mobility, pulmonary
function and visual acuity. Currently, experimental treatments are being
developed to tackle the limitations of the current therapies. Unmet needs
include neurologic and skeletal manifestations and, management of
secondary effects of GAG accumulation including inflammation.
1. INTRODUCTION
Mucopolysaccharidosis VII (MPS VII, Sly Disease, MIM 611499) is
an ultra-rare autosomal recessive disorder caused by the deficiency of the
lysosomal enzyme -glucuronidase (GUS, EC 3.2.1.31) [1]. Absence of
GUS enzyme results in the systemic accumulation of glycosaminoglycans
(GAGs), heparan sulfate (HS), dermatan sulfate (DS), chondroitin-4-
sulfate (C4S) and chondroitin-6-sulfate (C6S), causing cellular and organ
dysfunction [2].
MPS VII was first described in 1973 in an African American boy who
presented with unusual facial features at seven months of age. This patient
also suffered from frequent upper respiratory infections, developmental
delay by 30 months of age, hepatomegaly, and short stature [2]. MPS VII
patients exhibit a heterogeneous phenotype ranging from lethal hydrops
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Mucopolysaccharidosis Type VII/Sly Disease
105
fetalis to a milder phenotype [3, 4]. Most patients with the severe
phenotype have skeletal abnormalities, short stature, cardiac
manifestations, pulmonary involvement, hepatosplenomegaly, and
cognitive decline [3]. MPS VII remains an ultra-rare disease with an
estimated frequency of 1 in 300,000 to 2,000,000 live births. A total of 148
patients have been reported in several countries around the world [2, 5].
This low frequency may be partially explained by the large number of
misdiagnosed or non-diagnosed individuals due to the heterogeneity of the
disease. Recently, it was reported that almost half of the patients with MPS
VII have had a history of hydrops fetalis. The high rate of fetal demise due
to hydrops fetalis then suggests that a large portion of patients with MPS
VII may go undiagnosed [4]. Increased suspicion of MPS VII when a
patient present with hydrops fetalis will aid to provide early treatment and
improve outcomes.
Current diagnosis of MPS VII patients is delayed from months to years
unless the proband has a relative with the disorder. If there is no presence
of hydrops fetalis, MPS VII patients will exhibit signs and symptoms
around six months of age due to the presence of hepatosplenomegaly,
inguinal or umbilical hernias, skeletal abnormalities and/or abnormal
frequent respiratory infections. Therefore, implementation of newborn
screening is advisable for early detection, management and treatment of
this patient population.
Palliative treatments have been implemented for many years for MPS
VII patients to manage their symptoms. Currently there are two treatments
that ameliorate the progression of the disease: Hematopoietic Stem Cell
Transplantation (HSCT) and Enzyme replacement therapy (ERT). Two
decades ago experimental approaches of HSCT in mice showed that this
treatment was more successful in neonates rather than in adult mice,
however there were side effects caused by the radiation exposure in
neonates [6]. MPS VII patients that had HSCT have shown improvements
in motor function and decrease of upper respiratory and ear infections.
Unfortunately, cognitive impairment has been refractory to this treatment
and there is increased mortality and morbidity. ERT for MPS VII patients
has recently been approved by the FDA and EMA. ERT has shown some
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Adriana M. Montano
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improvement in fatigue, motor function, pulmonary function and GAG
reduction in 12 patients [7]. Further study is needed to understand whether
ERT will delay progression of MPS VII disease, and improve
cardiovascular, neurological and skeletal disorder seen in the disease. This
chapter presents recent advances in understanding the MPS VII clinical
phenotype, highlight challenges of treatments, and discusses new
therapeutic approaches.
Figure 1. Tridimensional structure of human β-glucuronidase. PDB ID 3HN3. Image
reconstructed from the RCSB Protein Data Bank. Klei, Ghosh, and Anumula. Human
beta-glucuronidase at 1.7 A resolution. 10.2210/pdb3HN3/pdb.
2. GENE DEFECT CAUSING THE DISEASE
Sly disease is caused by mutations in the GUSB gene, which is located
on chromosome 7q11.21-7q11.22, and contains 12 exons and 11 introns
spanning 21 kb [8, 9]. The mature enzyme, GUSB is a tetramer; each
monomer contains four potential N-linked glycosylation sites at Asn173,
Asn272, Asn402 and Asn631 [10]. Its four chains are held together by non-
covalent interactions [11]. Each monomer is made up of three domains, a
jelly roll-like domain containing the lysosomal targeting residues, a
triosephosphate isomerase (TIM) barrel domain (active site), and an
immunoglobulin region constant domain [11-13]. The loop comprising
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Mucopolysaccharidosis Type VII/Sly Disease
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residues 189 to 199 forms a -hairpin motif which is exposed on the
surface and enables recognition of lysosomal enzymes by a
phosphotransferase [11]. The structure of human β-glucuronidase is shown
in Figure 1.
Figure 2. Location of missense, nonsense and splicing mutations in the GUSB gene.
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Adriana M. Montano
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To date, 63 GUSB mutations have been reported by The Human Gene
Mutation Database (HGMD®) [14], of which 52 (82.5%) are
missense/nonsense, five (7.9%) are splice site-related, four (6.3%) are
small deletions, one is a large deletion, and one mutation reduces GUSB
promoter activity [15]. The most prevalent mutation found in different
populations is p. Leu176Phe (p.L176F) [3, 16-18]. Mutations in the GUSB
gene are shown in Figure 2.
3. BIOCHEMICAL DIAGNOSIS
3.1. GAG Determination
The first step to confirm the clinical suspicion of MPS VII is the
quantitation of GAGs (CS, HS and DS) in urine. Over the years, methods
to quantify GAGs in biological fluids have evolved considerably. For
many years, the quantitative analysis of total urinary GAG has been
performed by spectrophotometric analysis using dimethyl methylene blue
(DMB) [19]. Although this methodology has been helpful as a diagnostic
tool, it has encountered several limitations including poor sensitivity and
the potential of providing false negative results. In a study evaluating
sensitivity and specificity of the DMB method, researchers found false
negative results in 15% of all MPS patients analyzed, and false positive
results in 2.9% of controls samples illustrating its limitations as a first-line
screening method [20].
To improve sensitivity and specificity of GAG analyses, tandem-mass
spectrometry has recently been introduced in lysosomal research and
diagnostics. From LC-MS/MS analyzing disaccharides specific for each
type of GAG (KS, HS-NS, HS-0S, HS-6S, DS, CS) [21-23] to detecting
specific nonreducing ends of GAGs (HS) [24]. Each of these techniques
has shown much better reliability and sensitivity and is used currently in
several diagnostic laboratories. In patients with MPS VII, CS levels in
urine tends to be higher than HS and DS, which amounts could vary [25].
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It is important to note that GAG levels change with age and the results
should be interpreted accordingly. GAG levels are high in newborns up to
five years of age and decrease afterwards reaching a plateau around 18
years of age with levels close to healthy controls [20, 26, 27].
3.2. Enzyme Activity and Molecular Studies
The gold standard to reach a definitive diagnosis of MPS VII is by
demonstrated reduced GUSB enzyme activity in fibroblasts or
lymphocytes. Patients with MPS VII will have reduced levels of GUSB
enzyme to below-10% of normal values. Although precise
phenotype/genotype correlation has not been achieved by looking at
mutations in such a heterogenous patient population, patients with GUSB
enzyme activity close to zero tend to exhibit a more severe phenotype than
patients with a residual activity closer to the 10% threshold [3, 28].
3.3. Prenatal Diagnosis
Prenatal screening of MPS VII usually follows an abnormal
ultrasound, suspicion due to non-immune hydrops fetalis (NIHF) or a
history of a sibling affected by the disease. GUSB enzyme activity can be
measured in cultured chorionic villus cells by 11-14 weeks of pregnancy or
in amniotic fluid after 15 weeks of gestation [29, 30]. There have been
reports of diagnosis of MPS VII as early as twelve weeks of gestation
based on a previous pregnancy and presence of NIHF with a confirmatory
enzymatic diagnosis [31, 32].
4. PATHOLOGY
Glycosaminoglycans (GAGs) are repeating disaccharide units
covalently attached to the core proteins forming proteoglycans (PGs) [33].
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Adriana M. Montano
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PGs are ubiquitously distributed in extracellular matrix and on the cell
surface. There are two types of GAGs: non-sulfated GAGs like hyaluronic
acid (HA) and sulfated GAGs including heparan sulfate (HS), dermatan
sulfate (DS), keratan sulfate (KS), and chondroitin sulfate (CS) [34]. The
GAG chains are modified differentially by sulfation generating high
structural diversity, which is an important characteristic linked to their
specific function in cells and tissues. Most of the enzymes involved in the
synthesis of GAGs have been identified. In MPS VII, the GAGs that
accumulate in the lysosomes of the cells are HS, C4S, C6S, and DS; and
the enzyme -glucuronidase is responsible for removing glucuronic acid
residues present in each of these GAGs [1]. Dermatan, heparan and
chondroitin sulfate catabolism is shown in Figure 3.
Post-mortem histological studies have revealed several brain
abnormalities present in patients with MPS VII. GAG accumulation has
been observed in gray matter and neurons. Most neuronal lysosomal
distention was observed in substantia nigra and hippocampus, followed by
cerebral neocortex, glia and cerebellar purkinje cells [35].
Figure 3. Removal of glucuronic acid by action of β-glucuronidase (GUS/GUSB) in
dermatan, heparan and chondroitin sulfate catabolism.
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One of the main causes of mortality in MPS VII patients is
cardiovascular disease. Post-mortem studies have shown enlarged hearts,
fibrosis, thickened heart valves and calcified mitral and aortic valves along
with hypertrophic cardiomyopathy and disrupted elastin laminae [35-37].
Mitral valve disease occurs at early in life in MPS VII patients causing
mitral regurgitation [35]. An autopsy of a 19-year-old patient also revealed
abnormal collagen structure in the mitral valves with neovascularization
and GAG accumulation in fibroblasts [38].
5. CLINICAL PHENOTYPE AND MANIFESTATIONS
Since MPS VII is a highly heterogeneous, and ultra-rare disorder,
precise epidemiological data are hard to obtain. Recently, information on
56 patients from 11 different countries was collected to attempt to
understand the disease severity, its rate of progression and the distribution
of symptoms [3]. In that study, patients with MPS VII were classified
based on their phenotype into three different groups: (i) non-immune
neonatal hydrops fetalis (NIHF), (ii) Infantile or adolescent form with
history of hydrops fetalis, and (iii) Infantile or adolescent form without
known hydrops fetalis [3].
Presence of NIHF is characteristic of the most severe form of MPS VII
disease. NIHF has been reported multiple times in fetuses of different
ethnical backgrounds with MPS VII who had marked ascites,
hepatosplenomegaly, and liver and heart disease, among other findings [39,
40]. NIHF has been reported as early as 10 weeks of gestation with foamy
macrophages in several organs [31]. Recently it was found that about half
of the patients reported with MPS VII phenotype have had NIHF in utero
or at delivery [32]. In addition, it was found that about 20% of the patients
with NIHF had consanguineous parents [32]. The high incidence of NIHF
in patients with MPS VII suggests the importance of adding this lysosomal
disease into the differential diagnosis of NIHF.
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