Studies
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There are 34 articles listed below.
Liver-Targeted AAV8 Gene Therapy Ameliorates Skeletal and Cardiovascular Pathology in a Mucopolysaccharidosis IVA Murine Model (2020)
Mucopolysaccharidosis type IVA (MPS IVA) is due to the deficiency
of GALNS (N-acetylgalactosamine 6-sulfate sulfatase)
and is characterized by systemic skeletal dysplasia. We have
evaluated adeno-associated virus 8 (AAV8) vectors expressing
different forms of human GALNS under a liver-specific promoter.
The vectors were delivered intravenously into 4-weekold
MPS IVA knockout (KO) and immune tolerant (MTOL)
mice at a dose of 5 1013 genome copies (GC)/kg. These
mice were monitored for 12 weeks post-injection. GALNS
enzyme activity was elevated significantly in plasma of all
treated mice at 2 weeks post-injection. The activity observed
was 4- to 19-fold higher than that in wild-type mice and was
maintained throughout the monitoring period. Treatment
with AAV vectors resulted in a reduction of keratan sulfate
(KS) levels in plasma to normal levels 2 weeks post-injection,
which were maintained until necropsy. Both vectors reduced
the storage in articular cartilage, ligaments, and meniscus surrounding
articular cartilage and growth plate region as well as
heart muscle and valves. Our results suggest that the continuous
presence of high levels of circulating enzyme increases
the penetration into bone and heart and reduces the KS level,
thereby improving storage in these regions. The current
data support a strategy for developing a novel treatment to
address the bone and heart disease in MPS IVA using AAV
gene therapy.
Advances in glycosaminoglycan detection (2020)
Glycosaminoglycans (GAGs) are negatively charged long linear (highly sulfated) polysaccharides
consisting of repeating disaccharide units that are expressed on the surfaces of all nucleated cells. The expression
of GAGs is required for embryogenesis, regulation of cell growth and proliferation, maintenance of tissue hydration,
and interactions of the cells via receptors. Mucopolysaccharidoses (MPS) are caused by deficiency of
specific lysosomal enzymes that result in the accumulation of GAGs in multiple tissues leading to organ dysfunction.
Therefore, GAGs are important biomarkers for MPS. Without any treatment, patients with severe forms
of MPS die within the first two decades of life.
Scope of review: Accurate measurement of GAGs is important to understand the diagnosis and pathogenesis of
MPS and to monitor therapeutic efficacy before, during, and after treatment of the disease. This review covers
various qualitative and quantitative methods for measurement of GAGs, including dye specific, thin layer
chromatography (TLC), capillary electrophoresis, high-performance liquid chromatography (HPLC), liquid
chromatography-tandem mass spectrometry (LC-MS/MS), gas chromatography, ELISA, and automated highthroughput
mass spectrometry. Major conclusion: There are several methods for GAG detection however, specific
GAG detection in the various biological systems requires rapid, sensitive, specific, and cost-effective
methods such as LC-MS/MS.
Pathophysiology of Hip Disorders in Patients with Mucopolysaccharidosis IVA (2020)
Patients with mucopolysaccharidoses IVA (MPS IVA) have a progressive accumulation of
the specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS),
leading to the degeneration of the cartilage matrix and its connective tissue perturbing the
regular microarchitecture of cartilage and successively distorting bone ossification and growth.
Impaired cartilage quality and poor bone mineralization lead to serious hip disorders in MPS IVA
patients. Although hip dysplasia is seen widely in musculoskeletal abnormality of this disorder,
the pathophysiology of the hip bone and cartilage morphology in these patients remains unclear.
Until now, no systemic study of the hip joints in MPS IVA has been reported by using the combined
images of plain film radiographs (PFR) and Magnetic Resonance Imaging (MRI). This study aimed to
assess the bony and cartilaginous features of hip joints and to explore the potentially related factors
of femoral head osteonecrosis (FHN) and hip subluxation/dislocation in patients with MPS IVA.
Hip joints in MPS IVA patients were retrospectively reviewed, based on the findings of PFR and MRI
data from 2014 to 2019. Demographic information was also collected and analyzed with imaging
measurements. A total of 19 patients (eight boys and 11 girls) were recruited, and 38 hip joints in these
patients were examined. Eleven patients (57.9%) had FHN. FHN patients were statistically compared
with those without FHN. Correlations between cartilaginous femoral head coverage (CFHC) and
acetabular index (AI), cartilaginous AI (CAI), or neck-shaft angle (NSA) were investigated in patients
with hip subluxation or dislocation. The greater cartilaginous coverage of the hips than their osseous
inherency was observed. Significant correlation was observed between CFHC and AI (r =0.351,
p = 0.049) or CAI (r =0.381, p = 0.032). Severe subluxations or dislocations were more likely to be
present in those with more dysplastic bony and cartilaginous hips. In conclusion, our study provides
the first systemic description of bony and cartilaginous characteristics in the hip morphology of MPS
IVA patients. We have demonstrated that plain radiography alone leads to a misunderstanding of
hip morphology and that MRI measurements with PFR are an essential tool to evaluate the ‘true’
characterization of hips for MPS IVA patients.
Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management (2020)
Mucopolysaccharidosis type IVA (MPS IVA, or Morquio syndrome type A) is an inherited
metabolic lysosomal disease caused by the deficiency of the N-acetylglucosamine-6-sulfate sulfatase
enzyme. The deficiency of this enzyme accumulates the specific glycosaminoglycans (GAG),
keratan sulfate, and chondroitin-6-sulfate mainly in bone, cartilage, and its extracellular matrix.
GAG accumulation in these lesions leads to unique skeletal dysplasia in MPS IVA patients. Clinical,
radiographic, and biochemical tests are needed to complete the diagnosis of MPS IVA since some
clinical characteristics in MPS IVA are overlapped with other disorders. Early and accurate diagnosis
is vital to optimizing patient management, which provides a better quality of life and prolonged
life-time in MPS IVA patients. Currently, enzyme replacement therapy (ERT) and hematopoietic stem
cell transplantation (HSCT) are available for patients with MPS IVA. However, ERT and HSCT do not
have enough impact on bone and cartilage lesions in patients with MPS IVA. Penetrating the deficient
enzyme into an avascular lesion remains an unmet challenge, and several innovative therapies are
under development in a preclinical study. In this review article, we comprehensively describe the
current diagnosis, treatment, and management for MPS IVA. We also illustrate developing future
therapies focused on the improvement of skeletal dysplasia in MPS IVA.
Validation of Liquid Chromatography-Tandem Mass Spectrometry-Based 5-Plex Assay for Mucopolysaccharidoses (2020)
Mucopolysaccharidoses (MPSs) are rare lysosomal storage diseases caused by the
accumulation of undegraded glycosaminoglycans in cells and tissues. The eectiveness of early
intervention for MPS has been reported. Multiple-assay formats using tandem mass spectrometry have
been developed. Here, we developed a method for simultaneous preparation and better measurement
of the activities of five enzymes involved in MPSs, i.e., MPS I, MPS II, MPS IIIB, MPS IVA, and MPS
VI, which were validated using 672 dried blood spot samples obtained from healthy newborns and
23 patients with MPS. The mean values of the enzyme activities and standard deviations in controls
were as follows: -iduronidase (IDUA), 4.19 1.53 M/h; iduronate-2-sulfatase (I2S), 8.39 2.82 M/h;
N-acetyl--glucosaminidase (NAGLU), 1.96 0.57 M/h; N-acetylgalactosamine-6-sulfatase (GALNS),
0.50 0.20 M/h; and N-acetylgalactosamine-4-sulfatase (ARSB), 2.64 1.01 M/h. All patients
displayed absent or low enzyme activity. In MPS I, IIIB, and VI, each patient group was clearly
separated from controls, whereas there was some overlap between the control and patient groups in
MPS II and IVA, suggesting the occurrence of pseudo-deficiencies. Thus, we established a multiplex
assay for newborn screening using liquid chromatography tandem mass spectrometry, allowing
simultaneous pretreatment and measurement of five enzymes relevant to MPSs.
Oral immunotherapy tolerizes mice to enzyme replacement therapy for Morquio A syndrome (2020)
Immune response to therapeutic enzymes poses a detriment to patient safety and treatment outcome. Enzyme replacement therapy (ERT) is a standard therapeutic option for some types of mucopolysaccharidoses, including Morquio A syndrome caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency. Current protocols tolerize patients using cytotoxic immunosuppressives, which can cause adverse effects. Here we show development of tolerance in Morquio A mice via oral delivery of peptide or GALNS for 10 days prior to ERT. Our results show that using an immunodominant peptide (I10) or the complete GALNS enzyme to orally induce tolerance to GALNS prior to ERT resulted in several improvements to ERT in mice: (a) decreased splenocyte proliferation after in vitro GALNS stimulation, (b) modulation of the cytokine secretion profile, (c) decrease in GALNS-specific IgG or IgE in plasma, (d) decreased GAG storage in liver, and (e) fewer circulating immune complexes in plasma. This model could be extrapolated to other lysosomal storage disorders in which immune response hinders ERT.
Enzyme-Loaded Gel Core Nanostructured Lipid Carriers to Improve Treatment of Lysosomal Storage Diseases: Formulation and In Vitro Cellular Studies of Elosulfase Alfa-Loaded Systems (2019)
Mucopolysaccharidosis IVA (Morquio A) is a rare inherited metabolic disease caused by deficiency of the lysosomal enzyme N-acetylgalatosamine-6-sulfate-sulfatase (GALNS). Until now, treatments employed included hematopoietic stem cell transplantation and enzyme replacement therapy (ERT); the latter being the most commonly used to treat mucopolysaccharidoses, but with serious disadvantages due to rapid degradation and clearance. The purpose of this study was to develop and evaluate the potential of nanostructured lipid carriers (NLCs) by encapsulating elosulfase alfa and preserving its enzyme activity, leading to enhancement of its biological eect in chondrocyte cells. A pegylated elosulfase alfa-loaded NLC was characterized in terms of size, potential, structural lipid composition (DSC and XRD), morphology (TEM microscopy), and stability in human plasma. The final formulation was freeze-dried by selecting the appropriate cryoprotective agent. Viability assays confirmed that NLCs were non-cytotoxic to human fibroblasts. Imaging techniques (confocal and TEM) were used to assess the cellular uptake of NLCs loaded with elosulfase alfa. This study provides evidence that the encapsulated drug exhibits enzyme activity inside the cells. Overall, this study provides a new approach regarding NLCs as a promising delivery system for the encapsulation of elosulfase alfa or other enzymes and the preservation of its activity and stability to be used in enzymatic replacement therapy (ERT).
Proteomic Analysis in Morquio A Cells Treated with Immobilized Enzymatic Replacement Therapy on Nanostructured Lipid Systems (2019)
Morquio A syndrome, or mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disease due to mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. Systemic skeletal dysplasia and the related clinical features of MPS IVA are due to disruption of cartilage and its extracellular matrix, leading to an imbalance of growth. Enzyme replacement therapy (ERT) with recombinant human GALNS, alpha elosulfase, provides a systemic treatment. However, this therapy has a limited impact on skeletal dysplasia because the infused enzyme cannot penetrate cartilage and bone. Therefore, an alternative therapeutic approach to reach the cartilage is an unmet challenge. We have developed a new drug delivery system based on a nanostructure lipid carrier with the capacity to immobilize enzymes used for ERT and to target the lysosomes. This study aimed to assess the eect of the encapsulated enzyme in this new delivery system, using in vitro proteomic technology. We found a greater internalization of the enzyme carried by nanoparticles inside the cells and an improvement of cellular protein routes previously impaired by the disease, compared with conventional ERT. This is the first qualitative and quantitative proteomic assay that demonstrates the advantages of a new delivery system to improve the MPS IVA ERT.
Effect of enzyme replacement therapy on the growth of patients with Morquio A (2019)
Mucopolysaccharidosis IVA (MPS IVA) is a degenerative systemic skeletal dysplasia, in which children exhibit marked short stature and become physically handicapped. This study evaluated the growth patterns of patients treated with enzyme replacement therapy (ERT), compared with those of untreated patients. Cross-sectional and longitudinal data of heights and weights were collected from 128 MPS IVA patients and compared with the growth charts of MPS IVA. Twelve patients (six males, six females) starting ERT before 5 years old were treated for at least 2 years. Six out of 12 patients (50%) with ERT over 2 years stopped growing between 94 and 98 cm (mean height of 95.1 ± 2.2 cm) from 5.0 years to 9.0 years of age (mean age of 6.2 ± 1.6 years). The other patients, except one attenuated case, exhibited a marked slow growth velocity from 3.6 years to 7.7 years. Treated and untreated patients with severe phenotype reached their final heights by ~10 years of age.
Patients treated with ERT exhibited a reduced pubertal growth spurt analogous to their untreated counterparts, which contributes to the marked short stature associated with MPS IVA. Compared with the growth charts for untreated patients,
patients treated with ERT did not show any significant increase in growth in any age group. Overall, ERT-treated patients do
not experience growth improvement and continue to exhibit poor growth despite early ERT intervention before 5 years of
age. These findings indicate that current intravenous ERT is ineffective at correcting abnormal growth in MPS IVA.
Biomarkers in patients with mucopolysaccharidosis type II and IV (2019)
Glycosaminoglycans (GAGs), dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS), are the
primary biomarkers in patients with mucopolysaccharidoses (MPS); however, little is known about other biomarkers.
To explore potential biomarkers and their correlation with GAGs, blood samples were collected from 46
MPS II patients, 34 MPS IVA patients, and 5 MPS IVB patients. We evaluated the levels of 8 pro-inflammatory
factors (EGF, IL-1β, IL-6, MIP-1α, TNF-α, MMP-1, MMP-2, and MMP-9), collagen type II, and DS, HS (HS0S,
HSNS), and KS (mono-sulfated, di-sulfated) in blood.
Eight biomarkers measured were significantly elevated in untreated MPS II patients, compared with those in
normal controls: EGF, IL-1β, IL-6, HS0S, HSNS, DS, mono-sulfated KS, and di-sulfated KS. The same eight biomarkers
remained elevated in ERT-treated patients. However, only three biomarkers remained elevated in post-
HSCT MPS II patients: EGF, mono-sulfated KS, and di-sulfated KS. Post-HSCT patients with MPS II showed that
IL-1β and IL-6 were normalized as HS and DS levels decreased. Eight biomarkers were significantly elevated in
untreated MPS IVA patients: EGF, IL-1β, IL-6, MIP-1α, MMP-9, HSNS, mono-sulfated KS, and di-sulfated KS, and
four biomarkers were elevated in MPS IVA patients under ERT: IL-6, TNF-α, mono-sulfated KS, and di-sulfated
KS. There was no reduction of KS in the ERT-treated MPS IVA patient, compared with untreated patients. Two
biomarkers were significantly elevated in untreated MPS IVB patients: IL-6 and TNF-α.
Reversely, collagen type II level was significantly decreased in untreated and ERT-treated MPS II patients and
untreated MPS IVA patients.
In conclusion, selected pro-inflammatory factors can be potential biomarkers in patients with MPS II and IV as
well as GAGs levels.
Hematopoietic Stem Cell Transplantation for Mucopolysaccharidoses: Past, Present, and Future (2019)
Allogenic hematopoietic stem cell transplantation (HSCT) has proven to be a viable treatment option for a selected
group of patients with mucopolysaccharidoses (MPS), including those with MPS types I, II, IVA, VI, and VII. Early
diagnosis and timely referral to an expert in MPS are critical, followed by a complete examination and evaluation
by a multidisciplinary team, including a transplantation physician. Treatment recommendations for MPS are
based on multiple biological, sociological, and financial factors, including type of MPS, clinical severity, prognosis,
present clinical signs and symptoms (disease stage), age at onset, rate of progression, family factors and expectations,
financial burden, feasibility, availability, risks and benefits of available therapies such as HSCT, enzyme
replacement therapy (ERT), surgical interventions, and other supportive care. International collaboration and data
review are critical to evaluating the therapeutic efficacy and adverse effects of HSCT for MPS. Collaborative efforts
to assess HSCT for MPS have been ongoing since the first attempt at HSCT in a patient with MPS reported in 1981.
The accumulation of data since then has made it possible to identify early outcomes (ie, transplantation outcomes)
and long-term disease-specific outcomes resulting from HSCT. The recent identification of predictive factors and
the development of innovative regimens have significantly improved the outcomes of both engraftment failure
and transplantation-related mortality. Assessment of long-term outcomes has considered a variety of factors,
including type of MPS, type of graft, age at transplantation, and stage of disease progression, among others. Studies
on long-term outcomes are considered a key factor in the use of HSCT in patients with MPS. These studies
have shown the effects and limitations of HSCT on improving disease manifestations and quality of life. In this
review, we summarize the efficacy, side effects, risks, and cost of HSCT for each type of MPS.
Enzyme replacement therapy for mucopolysaccharidoses; past, present, and future (2019)
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, which lack an enzyme corresponding to the
specific type of MPS. Enzyme replacement therapy (ERT) has been the standard therapeutic option for some types of MPS
because of the ability to start immediate treatment with feasibility and safety and to improve prognosis. There are several
disadvantages for current ERT, such as limited impact to the brain and avascular cartilage, weekly or biweekly infusions
lasting 4–5 h, the immune response against the infused enzyme, a short half-life, and the high cost. Clinical studies of ERT
have shown limited efficacy in preventing or resolving progression in neurological, cardiovascular, and skeletal diseases.
One focus is to penetrate the avascular cartilage area to at least stabilize, if not reverse, musculoskeletal diseases. Although
early intervention in some types of MPS has shown improvements in the severity of skeletal dysplasia and stunted growth,
this limits the desired effect of ameliorating musculoskeletal disease progression to young MPS patients. Novel ERT
strategies are under development to reach the brain: (1) utilizing a fusion protein with monoclonal antibody to target a
receptor on the BBB, (2) using a protein complex from plant lectin, glycan, or insulin-like growth factor 2, and (3) direct
infusion across the BBB. As for MPS IVA and VI, bone-targeting ERT will be an alternative to improve therapeutic efficacy
in bone and cartilage. This review summarizes the effect and limitations on current ERT for MPS and describes the new
technology to overcome the obstacles of conventional ERT.
Cochlear implantation in a patient with mucopolysaccharidosis IVA (2019)
Mucopolysaccharidosis IVA (OMIM 253000; also known as Morquio A syndrome) is associated with skeletal, airway, and hearing
abnormalities. Cochlear implantation is an effective intervention for patients with severe-to-profound hearing loss. Patients can
gain substantial improvement in auditory performance, speech perception, and their quality of life from cochlear implantation.
Although severe progressive sensorineural hearing loss is a common feature of mucopolysaccharidosis IVA, no detailed
description of cochlear implantation for mucopolysaccharidosis IVA has been reported. To review the effectiveness and special
considerations associated with cochlear implantation in patients with mucopolysaccharidosis IVA, we here report the case of
cochlear implantation in mucopolysaccharidosis IVA by a multidisciplinary team. A retrospective chart review was conducted
on a 34-year-old female with mucopolysaccharidosis IVA, who received a cochlear implant. Audiometric thresholds, speech
perception scores, and cochlear implant processor mapping information were reviewed during the first 12 months following
cochlear implantation. The results of audiological tests indicate improved hearing thresholds as well as remarkable enhancement
of speech perception skills over 12 months of cochlear implant use. Cochlear implantation improved auditory performance in
a mucopolysaccharidosis IVA patient with postlingually severe-to-profound sensorineural hearing loss. The benefits of cochlear
implantation could be meaningful for other Morquio patients with progressive hearing loss, although the risks of surgery and
anesthesia should be carefully considered by a multidisciplinary team of experts during the cochlear implant candidacy process.
Citation:
Tailoring the AAV2 capsid vector for bone-targeting (2018)
Targeting specific tissues remains a major challenge to the promise of gene therapy. For example, several
strategies have failed to target adeno-associated virus 2 (AAV2) vectors, to bone. We have evaluated in vitro and in vivo the affinity
of an AAV2 vector to bone matrix, hydroxyapatite (HA) to treat Mucopolysacccharidosis IVA.
METHODS: To increase vector affinity to HA, an aspartic acid octapeptide (D8) was inserted immediately after the N-terminal region
of the VP2 capsid protein. The modified vector had physical titers and transduction efficiencies comparable to the unmodified
vector.
RESULTS: The bone-targeting vector had significantly higher HA affinity and vector genome copies in bone than the unmodified
vector. The modified vector was also released from HA, and its enzyme activity in bone, 3 months post infusion, was 4.7-fold higher
than the unmodified vector.
CONCLUSION: Inserting a bone-targeting peptide into the vector capsid increases gene delivery and expression in the bone
without decreasing enzyme expression. This approach could be a novel strategy to treat systemic bone diseases.
Molecular genetics and metabolism, special edition: Diagnosis, diagnosis and prognosis of Mucopolysaccharidosis IVA (2018)
Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is an autosomal recessive disorder caused by the
deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to the accumulation of
specific glycosaminoglycans (GAGs), chondroitin-6-sulfate (C6S) and keratan sulfate (KS), which are mainly synthesized
in the cartilage. Therefore, the substrates are stored primarily in the cartilage and its extracellular matrix
(ECM), leading to a direct impact on bone development and successive systemic skeletal spondylepiphyseal
dysplasia. The skeletal-related symptoms for MPS IVA include short stature with short neck and trunk, odontoid
hypoplasia, spinal cord compression, tracheal obstruction, obstructive airway, pectus carinatum, restrictive
lung, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity of joints. The degree of
imbalance of growth in bone and other organs and tissues largely contributes to unique skeletal dysplasia and
clinical severity. Diagnosis of MPS IVA needs clinical, radiographic, and laboratory testing to make a complete
conclusion. To diagnose MPS IVA, total urinary GAG analysis which has been used is problematic since the values
overlap with those in age-matched controls. Currently, urinary and blood KS and C6S, the enzyme activity of
GALNS, and GALNS molecular analysis are used for diagnosis and prognosis of clinical phenotype in MPS IVA.
MPS IVA can be diagnosed with unique characters although this disorder relates closely to other disorders in
some characteristics.
In this review article, we comprehensively describe clinical, radiographic, biochemical, and molecular diagnosis
and clinical assessment tests for MPS IVA. We also compare MPS IVA to other closely related disorders to
differentiate MPS IVA. Overall, imbalance of growth in MPS IVA patients underlies unique skeletal manifestations
leading to a critical indicator for diagnosis.
Development of Bone Targeting Drugs (2017)
The skeletal system, comprising bones, ligaments, cartilage and their connective tissues,
is critical for the structure and support of the body. Diseases that affect the skeletal system can be
difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of
action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with
either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type.
Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix
that includes a high concentration of positively-charged Ca2+. The strategies for designing such
targeting moieties can involve synthetic and/or biological components including negatively-charged
amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant
impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis,
osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however,
both delivering the drug to its target without losing activity and avoiding adverse local effects remain
a challenge. In this review, we investigate the current development of bone-targeting moieties,
their efficacy and limitations, and discuss future directions for the development of these specific
targeted treatments.
Introduction of Mucopolysaccharidosis type IV (2005)
These educational slides were kindly co-produced by Morquio families, International
Morquio Organization (IMO), Morquio Conference, and Dr. Shunji Tomatsu
(Department of Pediatrics, Saint Louis University) to increase the awareness of
mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome). It provides a short
introduction about lysosomal storage disorders (LSD) and MPS in general, before going
into more detail about MPS IVA. We have tried to cover the whole spectrum of disease,
ranging from the most severe MPS IVA patients to the attenuated form of the disease.
The slides included the update basic research and clinical research. The slides can be
used for education to physicians, families, patients, and local communities.
We would like to thank individual
Morquio families for providing the pictures and
acknowledge Dr. Tadao Orii (Department of Pediatrics, Gifu University) and Dr. William
Mackenzie (Department of Pediatric Orthopedics, Alfred I. duPont Hospital for
Children) for contributing the slides and proofreading the slides.
Please contact
Maria McClellan and Jocelyn Wong ( Morquio Conference;
https:// morquioconference.wixsite.com/morquio ) if you have any question on this
educational CD. This educational CD is translated or under translation into the following
languages: Arabic, French, German, Italian, Japanese, Polish, Portuguese, and Spanish.
If you need educational CD for one of those languages, please ask IMO office.
© 2005 International
Morquio Organization & Morquio Conference
Older articles
Mucopolysaccharidoses Update (2 Volume Set) Books (2018)
Book Description:
Mucopolysaccharidoses (MPS) are caused by a deficiency of lysosomal enzyme activities needed to degrade glycosaminoglycans (GAGs), which are long unbranched polysaccharides consisting of repeating disaccharides. GAGs include: Chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS), and hyaluronan. Their catabolism may be blocked singly or in combination depending on the specific enzyme deficiency. There are eleven known enzyme deficiencies, resulting in seven distinct forms of MPS with a collective incidence higher than 1 in 25,000 live births. Accumulation of undegraded metabolites in lysosomes gives rise to distinct clinical syndromes. Generally, the clinical conditions progress if untreated, leading to developmental delay, systemic skeletal deformities, and early death.
Other clinical features include coarse facial features, corneal clouding, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, heart valvular disease and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis. Patients may need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy throughout their lifetime. Current measures to intervene in bone disease progression and CNS involvement are not perfect and palliative, and improved therapies are urgently required and are being proposed.
Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzymes to the brain and bones, especially avascular cartilage, to prevent or ameliorate the devastating neurological defects and skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion and damage, since the severity of CNS involvement and skeletal dysplasia is associated with the level of activity in a patient’s daily life.
For the maximum benefit of available therapies, early detection and intervention are critical. Newborn screening and diagnostic systems have been developed by using tandem mass spectrometry. We review the history of diagnosis and newborn screening as well. Overall, this book illustrates a to-date overview of the pathogenesis, diagnosis, biomarkers, screening, and updated therapies as well as their impact on MPS, including ERT, HSCT, gene therapy, and anti-inflammatory drugs. History and activities of MPS societies are also described. It is a comprehensive textbook meant to cover many areas in the field of MPS and appeals to a broad spectrum of readers including physicians, scientists, students, pharmaceutical companies, and MPS communities. (Nova Medicine and Health)
Editors:
Shunji Tomatsu, MD, PhD, Roberto Giugliani Tadao Orii, MD, Maurizio Scarpa, MD, PhD, Paul Harmatz, Christine Lavery and Grzegorz Wegrzyn, PhD
Growth Impairment in Mucopolysaccharidoses (2018)
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders that affect regulation of glycosaminoglycan (GAG) processing. In MPS, the lysosomes cannot efficiently break down GAGs, and the specific GAGs accumulated depend on the type of MPS. The level of impairment of breakdown varies between patients, making this one of the many factors that lead to a range of clinical presentations even in the same type of MPS. These clinical presentations usually involve skeletal dysplasia, in which the most common feature is bone growth impairment and successive short stature. Growth impairment occurs due to the deposition and retention of GAGs in bone and cartilage. The accumulation of GAGs in these tissues leads to progressive damage in cartilage that in turn reduces bone growth by destruction of the growth plate, incomplete ossification, and imbalance of growth. Imbalance of growth leads to various skeletal abnormalities including disproportionate dwarfism with short neck and trunk, prominent forehead, rigidity of joints, tracheal obstruction, kyphoscoliosis, pectus carinatum, pla- tyspondyly, round-shaped vertebral bodies or beaking sign, underdeveloped acetabula, wide flared iliac, coxa valgus, flattered capital femoral epiphyses, and genu valgum. If left untreated, skeletal abnormalities including growth impairment result in a significant impact on these patients' quality of life and activity of daily living, leading to high morbidity and severe handicap.
This review focuses on growth impairment in untreated patients with MPS. We comprehensively describe the growth abnormalities through height, weight, growth velocity, and BMI in each type of MPS and compare the status of growth with healthy age-matched controls. The timing, the degree, and the difference in growth impairment of each MPS are highlighted to understand the natural course of growth and to evaluate future therapeutic efficacy.
Citation:
Melbouci, M., Molecular Genetics and Metabolism (2018), https://doi.org/10.1016/j.ymgme.2018.03.004
Clinical Presentation & Diagnosis of Mucopolysaccharidoses (2018)
Mucopolysaccharidoses (MPS) are estimated to affect1 in 25,000 live births although specific rates vary be- tween the ethnic origin and country. MPS are a group of lysosomal storage disorders, which cause the buildup of GAG(s) due to insufficient or absent GAG-degrading enzymes. With seven types of MPS disorders and eleven subtypes, the MPS family presents unique challenges for early clinical diagnosis due to the molecular and clinical heterogeneity between groups and patients. Novel methods of early identification, particularly newborn screen- ing through mass spectrometry, can change the flow of diagnosis, allowing enzyme and GAG quantification before the presentation of clinical symptoms improving outcomes. Genetic testing of patients and their families can also be conducted preemptively. This testing enables families to make informed decisions about family planning, leading to prenatal diagnosis.
In this review, we discuss the clinical symptoms of each MPS type as they initially appear in patients, bio- chemical and molecular diagnostic methods, and the future of newborn screening for this group of disorders.
Neurophysiology of Hearing in Patients with Mucopolysaccharidosis type IV (2018)
Background: Hearing impairment is a common problem in patients with mucopolysaccharidosis IV (MPS IV) throughout their life. Many of the adult patients with MPS IV exhibit permanent or severe hearing loss. However, there has been no systematic review of detailed audiological test results in MPS IV.
Materials and methods: Fourteen individuals with MPS IV (13 MPS IVA and 1 MPS IVB; aged between 12 and 38years old) participated in the current study. We obtained auditory neurophysiological responses (auditory brainstem responses and otoacoustic emissions test) in addition to pure-tone audiometry and middle ear function tests (tympanometry and acoustic reflexes).
Results: The results indicated various levels and types of hearing loss with abnormal neurophysiological responses even in those patients with MPS IVA with normal pure tone thresholds. We also found a strong relationship between height (short stature is an indicator of skeletal severity) and hearing sensitivity as well as a strong relationship between height and outer hair cell function in the inner ear (measured by otoacoustic emissions) among MPS IVA patients.
Conclusion: The strong correlation between reduced height and hearing loss indicates that patients with severe skeletal dysplasia may be at higher risk of developing more severe hearing loss. More importantly, the spectrum of hearing disorders indicates that MPS IV patients should have annual neurophysiological hearing tests in addition to audiometric testing from an early age regardless of their skeletal severity to more carefully monitor disease progression.
Glycosaminoglycans Analysis in Blood & Urine of Patients with Mucopolysaccharidosis (2018)
To explore the correlation between glycosaminoglycan (GAG) levels and mucopolysaccharidosis (MPS) type, we have evaluated the GAG levels in blood of MPS II, III, IVA, and IVB and urine of MPS IVA, IVB, and VI by tandem mass spectrometry. Dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS; mono-sulfated KS, di-sul- fated KS), and the ratio of di-sulfated KS in total KS were measured.
Patients with untreated MPS II had higher levels of DS and HS in blood while untreated MPS III had higher levels of HS in blood than age-matched controls. Untreated MPS IVA had higher levels of KS in blood and urine than age-matched controls. The ratio of blood di-sulfated KS/total KS in untreated MPS IVA was constant and higher than that in controls for children up to 10years of age. The ratio of urine di-sulfated KS/total KS in un- treated MPS IVA was also higher than that in age-matched controls, but the ratio in untreated MPS IVB was lower than controls. ERT reduced blood DS and HS in MPS II, and urine KS in MPS IVA patients, although GAGs levels remained higher than the observed in age-matched controls. ERT did not change blood KS levels in MPS IVA. MPS VI under ERT still had an elevation of urine DS level compared to age-matched controls. There was a positive correlation between blood and urine KS in untreated MPS IVA patients but not in MPS IVA patients treated with ERT. Blood and urine KS levels were secondarily elevated in MPS II and VI, respectively.
Overall, measurement of GAG levels in blood and urine is useful for diagnosis of MPS, while urine KS is not a useful biomarker for monitoring therapeutic efficacy in MPS IVA.
Non-invasive Pulmonary Function Test on Morquio patients (2017)
Morquio patients, in many cases, present with severe tracheal narrowing and restrictive lung problems making them susceptible to high mortality arising from sleep apnea and related complications. Tracheal obstruction with growth imbalance, short neck, adeno and tonsillar hypertrophy, large mandible, and/or pectus carinatum also contributes to the challenges in managing the airway with intubation and extubation due to factors intrinsic to Morquio syndrome. Taken together, these issues lead to serious respiratory distress and life-threatening complications during anesthetic procedures. Furthermore, patients with Morquio syndrome frequently cannot perform standard pulmonary function tests as a result of their distinctive skeletal dysplasia and chest deformity, thus making diagnosis of incipient pulmonary disease difficult. In many cases, conventional spirometry is too difficult for patients to complete, deriving from issues with cooperation or clinical circumstance. Therefore, it is an unmet challenge to assess pulmonary insufficiency with standard pulmonary function test (PFT) with minimal effort. Non-invasive PFT such as respiratory inductance plethysmography, impulse oscillometry system, and pneumotachography were described in Morquio patients as compared with spirometry. Findings from our previous study indicate that these non-invasive tests are a reliable approach to evaluate lung function in a larger range of patients, and provide valuable clinical information otherwise unobtainable from invasive tests. In conclusion, the present study describes the utility of non-invasive (PFT) to accommodate a broad range of patients including intolerance to effort-dependent PFT.
Natural History of Morquio A Patient with Tracheal Obstruction from Birth to Death (2017)
Morquio A syndrome (mucopolysaccharidosis IVA, MPS IVA) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase, resulting in systemic accumulation of the partially degraded glycosaminoglycans (GAGs), keratan sulfate and chondroitin-6-sulfate. The accumulation of these GAGs leads to distinguishing features as skeletal dysplasia with disproportionate dwarfism, short neck, kyphoscoliosis, pectus carinatum, tracheal obstruction, coxa valga, genu valgum, and joint laxity. In the absence of autopsied cases and systemic analysis of multiple tissues, the pathological mechanism of the characteristic skeletal dysplasia associated with the disease largely remains a question. Here we report an autopsied case of a 23-year-old male with MPS IVA, who developed characteristic skeletal abnormalities by 4 months of age and died of severe tracheal obstruction and hypoventilation originating from respiratory muscle weakness from neurological cord deficit due to cord myelopathy at the age of 23. We analyzed postmortem tissues pathohistologically, including the thyroid, lung, lung bronchus, trachea, heart, aorta, liver, spleen, kidney, testes, humerus, knee cartilage, and knee ligament.
Examination of the tissues demonstrated systemic storage materials in multiple tissues, as well as severely ballooned and vacuolated chondrocytes in the trachea, humerus, knee cartilage, and lung bronchus.
This autopsied case with MPS IVA addresses the importance of tracheal obstruction for morbidity and mortality of the disease, and the pathological findings contribute to a further understanding of the pathogenesis of MPS IVA and the development of novel therapies.
Gene Therapy for Mucopolysaccharidoses (2017)
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders (LSDs) caused by a deficiency of lysosomal enzymes, leading to a wide range of various clinical symptoms depending upon the type of MPS or its severity. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), substrate reduction therapy (SRT), and various surgical procedures are currently available for patients with MPS. However, there is no curative treatment for this group of disorders. Gene therapy should be a one-time permanent therapy, repairing the cause of enzyme deficiency. Preclinical studies of gene therapy for MPS have been developed over the past three decades. Currently, clinical trials of gene therapy for some types of MPS are ongoing in the United States, some European countries, and Australia.
Here, in this review, we summarize the development of gene therapy for MPS in preclinical and clinical trials.
Sawamoto, K., Molecular Genetics and Metabolism (2017), https://doi.org/10.1016/j.ymgme.2017.12.434
Epidemiology of mucopolysaccharidoses (2017)
The aim of this study was to obtain data about the epidemiology of the different types of mucopolysaccharidoses in Japan and Switzerland and to compare with similar data from other countries.
Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II, accounting for 55% of all MPS. MPS I, III, and IV accounted for 15, 16, and 10%, respectively. MPS VI and VII were more rare and accounted for 1.7 and 1.3%, respectively.
A retrospective epidemiological data collection was performed in Switzerland between 1975 and 2008 (34 years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12, 24, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3 and 2.4%, respectively.
The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms.
Citation:
S.A. Khan, et al., Epidemiology of mucopolysaccharidoses, Mol. Genet. Metab. (2017), http://dx.doi.org/10.1016/ j.ymgme.2017.05.016
Bone Mineral Density in MPS IV A (Morquio Syndrome Type A) (2016)
Mucopolysaccharidosis IV A (MPS IV A), Morquio A, is caused by deficiency in lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which is responsible for the catabolism of the glycosaminoglycans (GAGs) keratan sulfate (KS) and chondroitin 6-sulfate (C6S). Accumulation of GAGs results in disrupted cartilage formation and skeletal dysplasia. In this prospective cross-sectional study, bone mineral density (BMD) of the whole body (WB),
lumbar spine (LS), and lateral distal femur (LDF) was acquired by dual-energy X-ray absorptiometry (DXA) on patients with MPS IV A. Functional abilities, medical history, Tanner score, and laboratory results were reviewed. Age and sex-matched norms were used to calculate Z-scores. Participants included 18 patients (13 females; 16 were unrelated) with a mean age of 21.4 years (3.3 to 40.8 years). While every patient was able to bear weight, 9 were full-time ambulators. Whole-body DXA could be obtained on only 6 patients (5 full-time ambulators) because of respiratory compromise caused by the position, presence of hardware, or positioning difficulties. Mean WB Z-score was -2.0 (range -0.3 to -4.1). Technical issues invalidating LS DXA in 8 patients included kyphosis at the thoracolumbar junction resulting in overlap of vertebrae in the posterior-anterior view. Mean LS BMD Z-score in full-time ambulators was -3.4 (range -1.6 to -5.0) and in the non-/partial ambulator was -4.0 (-3.7 to -4.2). Lateral distal femur BMD was acquired on every patient, and average Z-scores were -2 or less at all sites; full-time ambulators exhibited higher BMD. In conclusion, the LDF proved to be the most feasible site to
measure in patients with MPS IV A. The higher LDF values in ambulators suggest this should be a consideration in promoting bone health for this group.
Current Therapies for Morquio A Syndrome and Their Clinical Outcomes (2016)
Introduction: Morquio A syndrome is characterized by a unique skeletal dysplasia, leading to short neck and trunk, pectus carinatum, laxity of joints, kyphoscoliosis, and tracheal obstruction. Cervical spinal cord compression/inability, a restrictive and obstructive airway, and/or bone deformity and imbalance of growth, are life-threatening to Morquio A patients, leading to a high morbidity and mortality. It is critical to review the current therapeutic approaches with respect to their efficacy and limitations.
Areas covered: Patients with progressive skeletal dysplasia often need to undergo orthopedic surgical interventions in the first two decades of life. Recently, we have treated four patients with a new surgery to correct progressive tracheal obstruction. Enzyme replacement therapy (ERT) has been approved clinically. Cell-based therapies such as hematopoietic stem cell therapy (HSCT) and gene therapy are typically one-time, permanent treatments for enzyme deficiencies. We report here on four Morquio A patients treated with HSCT approved in Japan and followed for at least ten years after treatment. Gene therapy is under investigation on mouse models but not yet available as a therapeutic option.
Expert opinion: ERT and HSCT in combination with surgical intervention(s) are a therapeutic option for Morquio A; however, the approach for bone and cartilage lesion remains an unmet challenge.
Kazuki Sawamoto, Yasuyuki Suzuki, William G. Mackenzie, Mary C. Theroux, Christian Pizarro, Hiromasa Yabe, Kenji E. Orii, Robert W. Mason, Tadao Orii & Shunji Tomatsu (2016): Current therapies for Morquio A syndrome and their clinical outcomes, Expert Opinion on Orphan Drugs, DOI: 10.1080/21678707.2016.1214572
Mucopolysaccharidosis IVA and glycosaminoglycans (2016)
Mucopolysaccharidosis IVA (MPS IVA; Morquio A: OMIM 253000) is a lysosomal storage disease with an autosomal recessive trait caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to accumulation of specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS). C6S and KS are mainly produced in the cartilage. Therefore, the undegraded substrates are stored primarily in cartilage and in its extracellular matrix (ECM), leading to a direct impact on cartilage and bone development, and successive systemic skeletal dysplasia. Chondrogenesis, the earliest phase of skeletal formation, is maintained by cellular interactions with the ECM, growth and differentiation factors, signaling pathways, and transcription factors in a temporal-spatial manner. In patients with MPS IVA, the cartilage is disrupted at birth as a consequence of abnormal chondrogenesis and/or endochondral ossification. The unique skeletal features are distinguished by a disproportional short stature, odontoid hypoplasia, spinal cord compression, tracheal obstruction, pectus carinatum, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity of joints. In spite of many descriptions of these unique clinical features, delay of diagnosis still happens. The pathogenesis and treatment of systemic skeletal dysplasia in MPS IVA remains an unmet challenge.
In this review article, we comprehensively describe historical aspect, property of GAGs, diagnosis, screening, pathogenesis, and current and future therapies of MPS IVA.
Activity of Daily Living for Morquio A syndrome (2016)
The aim of this study was to evaluate the activity of daily living (ADL) and surgical interventions in patients with mucopolysaccharidosis IVA (MPS IVA).
The factor(s) that affect ADL are age, clinical phenotypes, surgical interventions, therapeutic effect, and body mass index.
The ADL questionnaire comprises three domains: “Movement,” “Movement with cognition,” and “Cognition.” Each domain has four subcategories rated on a 5-point scale based on the level of assistance. The questionnaire was collected from 145 healthy controls and 82 patients with MPS IVA. The patient cohort consisted of 63 severe and 17 attenuated phenotypes (2 were undefined); 4 patients treated with hematopoietic stem cell transplantation (HSCT), 33 patients treated with enzyme replacement therapy (ERT) for more than a year, and 45 untreated patients.
MPS IVA patients show a decline in ADL scores after 10 years of age. Patients with a severe phenotype have a lower ADL score than healthy control subjects, and lower scores than patients with an attenuated phenotype in domains of “Movement” and “Movement with cognition.” Patients, who underwent HSCT and were followed up for over 10 years, had higher ADL scores and fewer surgical interventions than untreated patients. ADL scores for ERT patients (2.5 years follow-up on average) were similar with the-age-matched controls below 10 years of age, but declined in older patients. Surgical frequency was higher for severe phenotypic patients than attenuated ones. Surgical frequency for patients treated with ERT was not decreased compared to untreated patients.
In conclusion, we have shown the utility of the proposed ADL questionnaire and frequency of surgical interventions in patients with MPS IVA to evaluate the clinical severity and therapeutic efficacy compared with age-matched controls.
Citation:
Tomatsu, S., Yasuyuki, S., Yasuda, E., Orii, T., & Sawamoto, K. (2016). Activity of daily living for Morquio syndrome type A. Molecular Genetics and Metabolism, 117(2). doi:10.1016/j.ymgme.2015.12.462
Surgical Reconstruction for Severe Tracheal Obstruction in Morquio A Syndrome (2016)
Progressive tracheal obstruction is commonly seen in Morquio A syndrome and can lead to life-threatening complications. Although tracheostomy can address severe upper airway obstruction, lower airway obstruction, commonly associated with a narrow thoracic inlet and vascular compression, requires an alternative approach. We describe the case of a 16-year-old patient with Morquio A syndrome whose near-fatal tracheal obstruction was relieved by timely surgical tracheal vascular reconstruction with dramatic resolution of his respiratory symptoms.
Enzyme Replacement Therapy for Treating Mucopolysaccharidosis type IVA (Morquio A syndrome): Effect and Limitations (2015)
Introduction: Following a Phase III, randomized, double-blind, placebo (PBO)- controlled, multinational study in subjects with mucopolysaccharidosis IVA (MPS IVA), enzyme replacement therapy (ERT) of elosulfase alfa has been approved in several countries. The study was designed to evaluate safety and efficacy of elosulfase alfa in patients with MPS IVA aged 5 years and older. Areas covered: Outcomes of clinical trials for MPS IVA have been described. Subjects received either 2.0 mg/kg/week, 2.0 mg/kg/every other week, or PBO, for 24 weeks. The primary endpoint was the change from baseline 6-min walk test (6MWT) distance compared to PBO. The 6MWT results improved in patients receiving 2 mg/kg weekly compared to PBO. The every other week regimen resulted in walk distances comparable to PBO. There was no change from baseline in the 3 Min Stair Climb Test in both treatment groups. Following completion of the initial study, patients, who continued to receive elosulfase alfa 2 mg/kg weekly (QW) for another 48 weeks (for a total of up to 72-week exposure), did not show additional improvement on 6MWT. Expert opinion: We suggest that ERT is a therapeutic option for MPS IVA, providing a modest effect and the majority of the effects are seen in the soft tissues.
Shunji Tomatsu MD PhD , Kazuki Sawamoto, Tsutomu Shimada, Michael B Bober, Francyne Kubaski, Eriko Yasuda, Robert W Mason, Shaukat Khan, Carlos J Alméciga- Díaz, Luis A Barrera, William G Mackenzie & Tadao Orii (2015): Enzyme replacement therapy for treating mucopolysaccharidosis type IVA (Morquio A syndrome): effect and limitations, Expert Opinion on Orphan Drugs, DOI: 10.1517/21678707.2015.1086640
Hematopoietic Stem Cell Transplantation for Morquio A syndrome (2015)
Morquio A syndrome features systemic skeletal dysplasia. To date, there has been no curative therapy for this skeletal dysplasia. No systemic report on a long-term effect of hematopoietic stem cell transplantation (HSCT) for Morquio A has been described.
We conducted HSCT for 4 cases with Morquio A (age at HSCT: 4–15 years, mean 10.5 years) and followed them at least 10 years (range 11–28 years; mean 19 years). Current age ranged between 25 and 36 years of age (mean 29.5 years). All cases had a successful full engraftment of allogeneic bone marrow transplantation without serious GVHD. Transplanted bone marrow derived from HLA-identical siblings (three cases) or HLA-identical unrelated donor. The levels of the enzyme activity in the recipient's lymphocytes reached the levels of donors' enzyme activities within two years after HSCT.
For the successive over 10 years post-BMT, GALNS activity in lymphocytes was maintained at the same level as the donors. Except one case who had osteotomy in both legs one year later post BMT, other three cases had no orthopedic surgical intervention. All cases remained ambulatory, and three of them could walk over 400 m. Activity of daily living (ADL) in patients with HSCT was better than untreated patients. The patient who underwent HSCT at four years of age showed the best ADL score.
In conclusion, the long-term study of HSCT has demonstrated therapeutic effect in amelioration of progression of the disease in respiratory function, ADL, and biochemical findings, suggesting that HSCT is a therapeutic option for patients with Morquio A.
Impact of Enzyme Replacement Therapy and Hematopoietic Stem Cell Transplantation in Patients with Morquio A Syndrome (2015)
Abstract:
Patients with mucopolysaccharidosis IVA (MPS IVA) can present with systemic skeletal dysplasia, leading to a need for multiple orthopedic surgical procedures, and often become wheelchair bound in their teenage years. Studies on patients with MPS IVA treated by enzyme replacement therapy (ERT) showed a sharp reduction on urinary keratan sulfate, but only modest improvement based on a 6-minute walk test and no significant improvement on a 3-minute climb-up test and lung function test compared with the placebo group, at least in the short-term. Surgical remnants from ERT-treated patients did not show reduction of stor- age materials in chondrocytes. The impact of ERT on bone lesions in patients with MPS IVA remains limited. ERT seems to be enhanced in a mouse model of MPS IVA by a novel form of the enzyme tagged with a bone-targeting moiety. The tagged enzyme remained in the circulation much longer than untagged native enzyme and was delivered to and retained in bone. Three- month-old MPS IVA mice treated with 23 weekly infusions of tagged enzyme showed marked clearance of the storage materials in bone, bone marrow, and heart valves. When treatment was initiated at birth, reduction of storage materials in tissues was even greater. These findings indicate that specific targeting of the enzyme to bone at an early stage may improve efficacy of ERT for MPS IVA. Recombinant N-acetylgalactosamine-6-sulfate sulfatase (GALNS) in Escherichia coli BL21 (DE3) (erGALNS) and in the methylotrophic yeast Pichia pastoris (prGALNS) has been produced as an alternative to the conventional production in Chinese hamster ovary cells. Recombinant GALNS produced in microorganisms may help to reduce the high cost of ERT and the introduction of modifications to enhance target- ing. Although only a limited number of patients with MPS IVA have been treated with hematopoietic stem cell transplantation (HSCT), beneficial effects have been reported. A wheelchair-bound patient with a severe form of MPS IVA was treated with HSCT at 15 years of age and followed up for 10 years. Radiographs showed that the figures of major and minor trochanter appeared. Loud snoring and apnea disappeared. In all, 1 year after bone marrow transplantation, bone mineral density at L2–L4 was increased from 0.372 g/cm2 to 0.548 g/cm2 and was maintained at a level of 0.48±0.054 for the following 9 years. Pulmonary vital capacity increased approximately 20% from a baseline of 1.08 L to around 1.31 L over the first 2 years and was maintained thereafter. Activity of daily living was improved similar to the normal control group. After bilateral osteotomies, a patient can walk over 400 m using hip–knee–ankle–foot orthoses. This long-term observation of a patient shows that this treatment can produce clinical improvements although bone deformity remained unchanged. In conclusion, ERT is a therapeutic option for MPS IVA patients, and there are some indications that HSCT may be an alternative to treat this disease. However, as neither seems to be a curative therapy, at least for the skeletal dysplasia in MPS IVA patients, new approaches are investigated to enhance efficacy and reduce costs to benefit MPS IVA patients.
Citation:
Tomatsu, S., Giugliani, R., Kubaski, F., Kazuki, S., Alméciga-Díaz, C. J., Barrera, L., . . . Sanchez, O. (2015). Impact of enzyme replacement therapy and hematopoietic stem cell transplantation in patients with Morquio A syndrome. Drug Design, Development and Therapy, 1937. doi:10.2147/dddt.s68562
Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB (2015)
Abstract:
Keratan sulfate (KS) is a storage material in mucopolysaccharidosis IV (MPS IV). However, no detailed analysis has been reported on subclasses of KS: mono- sulfated KS and di-sulfated KS. We established a novel method to distinguish and quantify mono- and di-sulfated KS using liquid chromatography–tandem mass spectrometry and measured both KS levels in various specimens.
Di-sulfated KS was dominant in shark cartilage and rat serum, while mono-sulfated KS was dominant in bovine cornea and human serum. Levels of both mono- and di-sulfated KS varied with age in the blood and urine from control subjects and patients with MPS II and IVA. The mean levels of both forms of KS in the plasma/serum from patients with MPS II, IVA, and IVB were elevated compared with that in age-matched controls. Di-sulfated KS provided more significant difference between MPS IVA and the age-matched controls than mono-sulfated KS. The ratio of di-sulfated KS to total KS in plasma/serum increased with age in control subjects and patients with MPS II but was age independent in MPS IVA patients. Consequently, this ratio can discriminate younger MPS IVA patients from controls. Levels of mono- and di-sulfated KS in urine of MPS IVA and IVB patients were all higher than age-matched controls for all ages studied.
In conclusion, the level of di-sulfated KS and its ratio to total KS can distinguish control subjects from patients with MPS II, IVA, and IVB, indicating that di-sulfated KS may be a novel biomarker for these disorders.
Citation:
Shimada, T., Tomatsu, S., Mason, R. W., Yasuda, E., Mackenzie, W. G., Hossain, J., . . . Orii, T. (2014). Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB. JIMD Reports JIMD Reports, Volume 21, 1-13. doi:10.1007/8904_2014_330
Non-invasive Pulmonary Function Test on Morquio Patients (2015)
In clinical practice, respiratory function tests are difficult to perform in Morquio syndrome patients due to their characteristic skeletal dysplasia, small body size and lack of cooperation of young patients, where in some cases, conventional spirometry for pulmonary function is too challenging. To establish feasible clinical pulmonary end- points and determine whether age impacts lung function in Morquio patients non-invasive pulmonary tests and conventional spirometry were evaluated.
The non-invasive pulmonary tests: impulse oscillometry system, pneumotachography, and respiratory inductance plethysmography in conjunction with conventional spirometry were evaluated in twenty-two Morquio patients (18 Morquio A and 4 Morquio B) (7 males), ranging from 3 to 40 years of age.
Twenty-two patients were compliant with non-invasive tests (100%) with the exception of IOS (81.8%–18 patients). Seventeen patients (77.3%) were compliant with spirometry testing. All subjects had normal vital signs at rest including N95% oxygen saturation, end tidal CO2 (38–44 mm Hg), and age-appropriate heart rate (mean = 98.3, standard deviation = 19) (two patients were deviated). All patients preserved normal values in the impulse oscillometry system, pneumotachography, and respiratory inductance plethysmography, al- though predicted forced expiratory total (72.8 ± 6.9 SE%) decreased with age and was below normal; phase angle (35.5 ± 16.5°), %rib cage (41.6 ± 12.7%), resonant frequency, and forced expiratory volume in 1 s/forced expiratory volume total (110.0 ± 3.2 SE%) were normal and not significantly impacted by age.
The proposed non-invasive pulmonary function tests are able to cover a greater number of patients (young pa- tients and/or wheel-chair bound), thus providing a new diagnostic approach for the assessment of lung function in Morquio syndrome which in many cases may be difficult to evaluate. Morquio patients studied herein demonstrated no clinical or functional signs of restrictive and/or obstructive lung disease.
Citation
F. Kubaski, et al., Non-invasive pulmonary function test on Morquio patients, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.06.007
Therapies for The Bone in Mucopolysaccharidoses (2014)
Abstract:
Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to 1) stenosis of the upper cervical region, 2) restrictive small lung, 3) hip dysplasia, 4) restriction of joint movement, and 5) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tib- ial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required.
Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti- inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life. This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs.
Citation:
Tomatsu, S., Barrera, L. A., Alméciga-Díaz, C. J., Montaño, A. M., Yabe, H., Kubaski, F., & Orii, T. (2015). Therapies for the Bone in Mucopolysaccharidoses. Molecular Genetics and Metabolism, 114(2). doi:10.1016/j.ymgme.2014.12.267
Obstructive Airway in Morquio A syndrome, the Past, the Present and the Future (2015)
Abstract:
Patients with severe tracheal obstruction in Morquio A syndrome are at risk of dying of sleep apnea and related complications. Tracheal obstruction also leads to life-threatening complications during anesthesia as a result of the difficulty in managing the upper airway due to factors inherent to the Morquio A syndrome, compounded by the difficulty in intubating the trachea. A detailed description of the obstructive pathology of the trachea is not available in the literature probably due to lack of a homogenous group of Morquio A patients to study at any one particular center. We present a series of cases with significant tracheal obstruction who were unrecognized due to the difficulty in interpreting tracheal narrowing airway symptoms. Our goal is to provide the guide- lines in the management of these patients that allow earlier recognition and intervention of tracheal obstruction. Sagittal MRI images of the cervical spine of 28 Morquio A patients (12 ± 8.14 years) showed that19/28 (67.9%) patients had at least 25% tracheal narrowing and that narrowing worsened with age (all 8 patients over 15 years had greater than 50% narrowing). Eight out of 28 patients were categorized as severe (N 75%) tracheal narrowing when images were evaluated in neutral head and neck position. Of the 19 patients with tracheal narrowing, com- pression by the tortuous brachiocephalic artery was the most common cause (n = 15). Evidence of such tracheal narrowing was evident as early as at 2 years of age.
The etiology of tracheal impingement by the brachiocephalic artery in Morquio A appears to be due to a combination of the narrow thoracic inlet crowding structures and the disproportionate growth of trachea and brachiocephalic artery in relationship to the chest cavity leading to tracheal tortuosity.
In conclusion, tracheal narrowing, often due to impression from the crossing tortuous brachiocephalic artery, increases with age in Morquio A patients. Greater attention to the trachea is needed when evaluating cervical spine MRIs as well as other imaging and clinical investigations, with the goal of establishing a timely treatment protocol to reduce the mortality rate in this patient population.
Citation:
Tomatsu, S., Averill, L. W., Sawamoto, K., Mackenzie, W. G., Bober, M. B., Pizarro, C., . . . Theroux, M. (2016). Obstructive airway in Morquio A syndrome, the past, the present and the future. Molecular Genetics and Metabolism, 117(2), 150-156. doi:10.1016/j.ymgme.2015.09.007
Morquio A Syndrome: Diagnosis and Current and Future Therapies (2014)
Abstract:
Morquio A syndrome is an autosomal recessive disorder, one of 50 lysosomal storage diseases (LSDs), and is caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Deficiency of this enzyme causes specific glycosaminoglycan (GAG) accumulation: keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The majority of KS is produced in the cartilage, therefore, the undegraded substrates accumulate mainly in cartilage and in its extracelluar matrix (ECM), causing direct leads to direct impact on cartilage and bone development and leading to the resultant systemic skeletal spondyloepiphyseal dysplasia. Chondrogenesis ,the earliest phase of skeletal formation that leads to cartilage and bone formation is controlled by cellular interactions with the ECM, growth and differentiation factors and other molecules that affect signaling pathways and transcription factors in a temporal-spatial manner. In Morquio A patients, in early childhood or even at birth, the cartilage is disrupted presumably as a result of abnormal chondrogenesis and/ or endochondral ossification. The unique clinical features are characterized by a marked short stature, odontoid hypoplasia, protrusion of the chest, kyphoscoliosis, platyspondyly, coxa valga, abnormal gait, and laxity of joints.
In spite of many descriptions of the unique clinical manifestations, diagnosis delay still occurs. The pathogenesis of systemic skeletal dysplasia in Morquio A syndrome remains an enigmatic challenge. In this review article, screening, diagnosis, pathogenesis and current and future therapies of Morquio A are discussed.
Therapies of Mucopolysaccharidosis IVA (Morquio A syndrome) (2013)
Introduction: Morquio A syndrome (mucopolysaccharidosis type IVA, MPS IVA) is one of the lysosomal storage diseases and is caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Deficiency of this enzyme leads to accumulation of glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The majority of KS is produced by chondrocytes, and therefore, the undegraded substrates accumulate mainly in cells and extracelluar matrix (ECM) of cartilage. This has a direct impact on carti- lage and bone development, leading to systemic skeletal dysplasia. In patients with Morquio A, cartilage cells are vacuolated, and this results in abnormal chondrogenesis and/or endochondral ossification.
Areas covered: This article describes the advanced therapies of Morquio A, focused on enzyme replacement therapy (ERT) and gene therapy to deliver the drug to avascular bone lesions. ERT and gene therapies for other types of MPS are also discussed, which provide therapeutic efficacy to bone lesions. Expert opinion: ERT, gene therapy and hematopietic stem therapy are clinically and/or experimentally conducted. However, there is no effective curative therapy for bone lesion to date. One of the limitations for Morquio A therapy is that targeting avascular cartilage tissues remains an unmet challenge. ERT or gene therapy with bone-targeting system will improve the bone pathology and skeletal manifestations more efficiently.
Citation:
Tomatsu, S., Alméciga-Díaz, C. J., Barbosa, H., Montaño, A. M., & Orii, T. (2014). Therapies of mucopolysaccharidosis type IV A (Morquio syndrome type A). Molecular Genetics and Metabolism, 111(2). doi:10.1016/j.ymgme.2013.12.259
Review of Clinical Presentation and Diagnosis of Mucopolysaccharidosis IVA (2013)
Abstract:
Mucopolysaccharidosis type IVA (MPS IVA) was described in 1929 by Luis Morquio from Uruguay and James Brailsford from England, and was later found as an autosomal recessive lysosomal storage disease. MPS IVA is caused by mutations in the gene encoding the enzyme, N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Re- duced GALNS activity results in impaired catabolism of two glycosaminoglycans (GAGs), chondroitin-6-sulfate (C6S) and keratan sulfate (KS). Clinical presentations of MPS IVA reflect a spectrum of progression from a severe “classical” phenotype to a mild “attenuated” phenotype. More than 180 different mutations have been identified in the GALNS gene, which likely explains the phenotypic heterogeneity of the disorder.
Accumulation of C6S and KS manifests predominantly as short stature and skeletal dysplasia (dysostosis mul- tiplex), including atlantoaxial instability and cervical cord compression. However, abnormalities in the visual, auditory, cardiovascular, and respiratory systems can also affect individuals with MPS IVA. Diagnosis is typ- ically based on clinical examination, skeletal radiographs, urinary GAG, and enzymatic activity of GALNS in blood cells or fibroblasts. Deficiency of GALNS activity is a common assessment for the laboratory diagnosis of MPS IVA; however, with recently increased availability, gene sequencing for MPS IVA is often used to con- firm enzyme results. As multiple clinical presentations are observed, diagnosis of MPS IVA may require multi-system considerations.
This review provides a history of defining MPS IVA and how the understanding of the disease manifestations has changed over time. A summary of the accumulated knowledge is presented, including information from the International Morquio Registry. The classical phenotype is contrasted with attenuated cases, which are now being recognized and diagnosed more frequently. Laboratory based diagnoses of MPS IVA are also discussed.
Citation:
Tomatsu, S., Hendriksz, C., Harmatz, P., Beck, M., Simon, J., Wood, T., . . . Orii, T. (2013). A review of the clinical presentation and diagnosis of Mucopolysaccharidosis IVA. Molecular Genetics and Metabolism, 108(2). doi:10.1016/j.ymgme.2012.11.246
Pathogenesis of Morquio A syndrome: An Autopsied Case Reveals Systemic Storage Disorder (2013)
Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase, which results in systemic accumulation of glycosaminoglycans (GAGs), keratan sulfate and chondroitin-6-sulfate. Accumulation of these GAGs causes characteristic features as dispropor- tionate dwarfism associated with skeletal deformities, genu valgum, pigeon chest, joint laxity, and kyphoscoliosis. However, the pathological mechanism of systemic skeletal dysplasia and involvement of other tissues remain unan- swered in the paucity of availability of an autopsied case and successive systemic analyses of multiple tissues.
We report here a 20-year-old male autopsied case with MPS IVA, who developed characteristic skeletal features by the age of 1.5 years and died of acute respiratory distress syndrome five days later after occipito-C1–C2 cervical fusion. We pathohistologically analyzed postmortem tissues including trachea, lung, thyroid, humerus, aorta, heart, liver, spleen, kidney, testes, bone marrow, and lumbar vertebrae.
The postmortem tissues relevant with clinical findings demonstrated 1) systemic storage materials in multiple tissues beyond cartilage, 2) severely vacuolated and ballooned chondrocytes in trachea, humerus, vertebrae, and thyroid cartilage with disorganized extracellular matrix and poor ossification, 3) appearance of foam cells and macrophages in lung, aorta, heart valves, heart muscle, trachea, visceral organs, and bone marrow, and 4) storage of chondrotin-6-sulfate in aorta.
This is the first autopsied case with MPS IVA whose multiple tissues have been analyzed pathohistologically and these pathological findings should provide a new insight into pathogenesis of MPS IVA.
Citation:
Yasuda, E., Fushimi, K., Suzuki, Y., Shimizu, K., Takami, T., Zustin, J., . . . Tomatsu, S. (2013). Pathogenesis of Morquio A syndrome: An autopsied case reveals systemic storage disorder. Molecular Genetics and Metabolism,109(3), 301-311. doi:10.1016/j.ymgme.2013.04.009
Current and Emerging Treatments and Surgical Interventions for Morquio A syndrome: a Review (2013)
Abstract:
Patients with mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) have accumulation of the glycosaminoglycans, keratan sulfate, and chondroitin-6-sulfate, in bone and cartilage, causing systemic spondyloepiphyseal dysplasia. Features include lumbar gibbus, pectus carinatum, flaring of the rib cage, marked short stature, cervical instability and stenosis, kyphoscoliosis, genu valgum, and laxity of joints. Generally, MPS IVA patients are wheelchair-bound as teenagers and do not survive beyond the second or third decade of life as a result of severe bone dysplasia, causing restrictive lung disease and airway narrowing, increasing potential for pneumonia and apnea; stenosis and instability of the upper cervical region; high risk during anesthesia administration due to narrowed airway as well as thora- coabdominal dysfunction; and surgical complications. Patients often need multiple surgical procedures, including cervical decompression and fusion, hip reconstruction and replacement, and femoral or tibial osteotomy, throughout their lifetime. Current measures to intervene in disease progression are largely palliative, and improved therapies are urgently needed. A clini- cal trial for enzyme replacement therapy (ERT) and an investigational trial for hematopoietic stem cell transplantation (HSCT) are underway. Whether sufficient enzyme will be delivered effectively to bone, especially cartilage (avascular region) to prevent the devastating skeletal dysplasias remains unclear. This review provides an overview of historical aspects of studies on MPS IVA, including clinical manifestations and pathogenesis of MPS IVA, orthopedic surgical interventions, and anesthetic care. It also describes perspectives on potential ERT, HSCT, and gene therapy.
Citation:
Tomatsu, S., T., S., Almeciga-Diaz, C., Y., S., . . . S. (2012). Current and emerging treatments and surgical interventions for Morquio A syndrome: A review. Research and Reports in Endocrine Disorders, 65. doi:10.2147/rred.s37278
Impairment of Body Growth in Mucopolysaccharidoses (2012)
Abstract:
Children with mucopolysaccharidoses (MPS) grow poorly and become physically handicapped because of systemic bone disease. For children with skeletal dysplasias, such as MPS, it is important to know the natural history of growth. Understanding of the growth pattern provides assessment of current growth and data on efficacy of individualized medicine in growth-promoting treatments. The purpose of this chapter is to review natural history of growth patterns for MPS II, IVA, and VI patients. The cross-sectional and/or longitudinal data were collected to develop growth curves for the following types of MPS. Interestingly, accelerated growth has been observed in the first years of life in any type of MPS reviewed here, followed by slowing growth rate and growth failure. (1) MPS II: We obtained height and weight measurements from 46 Japanese male patients with MPS II. Mean birth length of boys was 50.9 ± 2.1 cm. The mean height for MPS II at 18 years of age or older was 127.2 ± 8.5 cm. These values corresponded to 0.9 SD and −7.5 SD of the height for normal Japanese males. The mean height was kept higher until 5 years and the mean weight was heavier until 8 years of age. After 7 years of age, short stature was commonly observed in spite of clinical severity by CNS involvement. (2) MPS IVA: Height and weight measurements from 193 girls and 195 boys with MPS IVA were collected. Mean birth lengths of boys and girls were 52.4 ± 3.9 and 52.1 ± 2.9 cm, respectively. Mean heights for males and females at 18 years of age were 119.3 ± 22.6 and 113.5 ± 23.1 cm, respectively. These values correspond to −8.0 SD and −7.7 SD of the mean height for normal males and females. Mean birth weights for boys and girls were 3.56 ± 0.5 and 3.5 ± 0.7 kg, respectively. (3) MPS VI: Growth is severely impacted on this type of MPS. In an observational study in 121 untreated MPS VI patients, a mean height was 115.2 cm ± 26.1 cm and median height was 103.7 cm with a range of 80–169 cm. An inverted correlation of height with the excretion of urinary GAGs and an influence of the genotype on the pattern of this excretion were also demonstrated. Thus, the growth pattern in MPS II patients was characterized by impaired growth velocity after 4 years of age, while the growth patterns in MPS IVA and VI patients were characterized by impaired growth velocity after 1 and 2 years of age.
Citation:
Tomatsu, S., Montaño, A. M., Oikawa, H., Giugliani, R., Harmatz, P., Smith, M., . . . Orii, T. (2011). Impairment of Body Growth in Mucopolysaccharidoses. Handbook of Growth and Growth Monitoring in Health and Disease, 2091-2117. doi:10.1007/978-1-4419-1795-9_126
Comparison of Liquid Chromatography–Tandem Mass Spectrometry and Sandwich ELISA for Determination of Keratan Sulfate in Plasma and Urine (2011)
Abstract:
Background and aim: Mucopolysaccharidosis IVA (MPS IVA) leads to skeletal dysplasia through excessive storage of chondroitin-6-sulfate and keratan sulfate (KS). KS is synthesized mainly in cartilage and released into circulation, making it a critical biomarker for MPS IVA to evaluate clinical course and effectiveness of therapies. Therefore, an accurate and sensitive method is required to measure KS levels.
Material and methods: Using sandwich ELISA and liquid chromatography tandem mass spectrometry (LC/MS/MS) assays, we measured KS levels in blood and urine from MPS IVA patients and healthy controls to evaluate comparability of results. Blood (patients, n = 110; controls, n = 364) and urine (patients, n = 103; controls, n = 326) specimens were obtained.
Results: Plasma and urine KS measurements in patients were age-dependent and higher than age-matched controls. We observed a moderate correlation (r = 0.666; P , 0.001) between urine KS measurements and a weak correlation (r = 0.333; P = 0.002) between plasma KS measurements by ELISA and LC/MS/MS methods in patients. No correlation was found between plasma KS measurements in controls. The difference between KS measurements assayed by LC/MS/MS and ELISA was greater in controls than in patients. A moderate correlation between blood and urine KS measurements in the same individual was observed.
Conclusion: These findings indicate that both methods to measure blood and urine KS are suitable for diagnosis, monitoring therapies, and longitudinal assessment of the disease course in MPS IVA, but the LC/MS/MS method measures over 10 times more KS present in body fluids.
Citation:
Hintze, J. P., Tomatsu, S., Fujii, T., Montaño, A. M., Yamaguchi, S., Suzuki, Y., . . . Orii, T. (2011). Comparison of Liquid Chromatography–Tandem Mass Spectrometry and Sandwich ELISA for Determination of Keratan Sulfate in Plasma and Urine. Biomarker Insights, 6. doi:10.4137/bmi.s7451
Mucopolysaccharidosis Type IVA (Morquio A Disease): Clinical Review and Current Treatment: A Special Review (2011)
Abstract:
Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio A, is a rare, autosomal recessive disorder caused by a deficiency of the lysosomal enzyme N-acetylgalatosamine-6-sulfate-sulfatase (GALNS), which catalyzes a step in the catabolism of glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate (C6S). It leads to accumulation of the KS and C6S, mainly in bone and cornea, causing a systemic skeletal chondrodysplasia. MPS IVA has a variable age of onset and variable rate of progression. Common presenting features include elevation of urinary and blood KS, marked short stature, hypoplasia of the odontoid process, pectus carinatum, kyphoscoliosis, genu valgum, laxity of joints and corneal clouding; however there is no central nervous system impairment. Generally, MPS IVA patients with a severe form do not survive beyond the third decade of life whereas those patients with an attenuated form may survive over 70 years. There has been no effective therapy for MPS IVA, and care has been palliative. Enzyme replacement therapy (ERT) and hematopoietic stem cell therapy (HSCT) have emerged as a treatment for mucopolysaccharidoses dis- orders, including Morquio A disease. This review provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS IVA and describes potential perspectives of ERT and HSCT. The issue of treating very young patients is also discussed.
Citation:
Tomatsu, S., Montano, A. M., Oikawa, H., Rowan, D. J., Smith, M., Barrera, L., . . . Orii, T. (2011). Mucopolysaccharidosis Type IVA (Morquio A Disease): Clinical Review and Current Treatment: A Special Review. Current Pharmaceutical Biotechnology,12(6), 931-945. doi:10.2174/138920111795542615
Adeno-associated Virus Gene Transfer in Morquio A Disease – Effect of Promoters and Sulfatase-modifying Factor 1 (2010)
Mucopolysaccharidosis (MPS) IVA is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme N-acetylgalatosamine-6-sulfate sulfatase (GALNS), which leads to the accumulation of keratan sulfate and chondroitin 6-sulfate, mainly in bone. To explore the possibility of gene therapy for Morquio A disease, we transduced the GALNS gene into HEK293 cells, human MPS IVA fibroblasts and murine MPS IVA chondrocytes by using adeno-associated virus (AAV)-based vectors, which carry human GALNS cDNA. The effects of the promoter and the cotransduction with the sulfatase-modifying factor 1 gene (SUMF1) on GALNS activity levels was evaluated. Downregulation of the cytomegalovirus (CMV) immediate early enhancer ⁄ promoter was not observed for 10 days post-transduction. The eukaryotic promoters induced equal or higher levels of GALNS activity than those induced by the CMV promoter in HEK293 cells. Transduction of human MPS IVA fibroblasts induced GALNS activity levels that were 15–54% of those of normal human fibroblasts, whereas in transduced murine MPS IVA chondrocytes, the enzyme activities increased up to 70% of normal levels. Cotransduction with SUMF1 vector yielded an additional four-fold increase in enzyme activity, although the level of elevation depended on the transduced cell type. These findings suggest the potential application of AAV vectors for the treatment of Morquio A disease, depending on the combined choice of transduced cell type, selection of promoter, and cotransduction of SUMF1.
Citation:
Alméciga-Díaz, C. J., Montaño, A. M., Tomatsu, S., & Barrera, L. A. (2010). Adeno-associated virus gene transfer in Morquio A disease -effect of promoters and sulfatase-modifying factor 1. FEBS Journal, 277(17), 3608-3619. doi:10.1111/j.1742-4658.2010.07769.x
Enhancement of Drug Delivery: Enzyme- replacement Therapy for Murine Morquio A Syndrome (2010)
Mucopolysaccharidosis IVA (MPS IVA, Morquio A dis- ease) is an inherited lysosomal storage disorder that features skeletal chondrodysplasia caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Human GALNS was bioengineered with the N-terminus extended by the hexaglutamate sequence (E6) to improve targeting to bone (E6-GALNS). We initially assessed blood clearance and tissue distribution. Next, to assess the effectiveness of storage clearance and reversal of pathological phenotype, a dose of 250 U/g of enzyme was given weekly to Morquio A mice (adults: 12 or 24 weeks, newborn: 8 weeks). Sulfatase modifier factor 1 (SUMF1) was co-transfected to activate the enzyme fully. The E6-GALNS tagged enzyme had markedly pro- longed clearance from circulation, giving over 20 times exposure time in blood, compared to untagged enzyme. The tagged enzyme was retained longer in bone, with residual enzyme activity demonstrable at 48 hours after infusion. The pathological findings in adult mice treated with tagged enzyme showed substantial clearance of the storage materials in bone, bone marrow, and heart valves, especially after 24 weekly infusions. Mice treated from the newborn period showed marked reduction of storage materials in tissues investigated. These findings indicate the feasibility of using tagged enzyme to enhance delivery and pathological effectiveness in Morquio A mice.
Citation:
Tomatsu, S., Montaño, A. M., Dung, V. C., Ohashi, A., Oikawa, H., Oguma, T., . . . Sly, W. S. (2010). Enhancement of Drug Delivery: Enzyme-replacement Therapy for Murine Morquio A Syndrome. Molecular Therapy, 18(6), 1094-1102. doi:10.1038/mt.2010.32
Validation of Keratan Sulfate Level in Mucopolysaccharidosis type IVA by Liquid Chromatography–tandem Mass Spectrometry (2010)
Abstract:
Mucopolysaccharidosis type IVA (MPS IVA, Morquio A disease), a progressive lysosomal storage disease, causes skeletal chondrodysplasia through excessive storage of keratan sulfate (KS). KS is synthesized mainly in cartilage and released to the circulation. The excess storage of KS disrupts cartilage, consequently releasing more KS into circulation, which is a critical biomarker for MPS IVA. Thus, assessment of KS level provides a potential screening strategy and determines clinical course and efficacy of therapies. We have recently developed a tandem mass spectrometry liquid chromatography [LC/MS/MS] method to assay KS levels in blood. Forty-nine blood specimens from patients with MPS IVA [severe (n = 33), attenuated (n = 11) and undefined (n = 5)] were analyzed for comparison of blood KS concentration with that of healthy subjects and for correlation with clinical severity. Plasma samples were digested by keratanase II to obtain disaccharides of KS. Digested samples were assayed by LC/MS/MS. We found that blood KS levels (0.4–26 μg/ml) in MPS IVA patients were significantly higher than those in age-matched controls (0.67–4.6 μg/ml; P < 0.0001). It was found that blood KS level varied with age and clinical severity in the patients. Blood KS levels in MPS IVA peaked between 2 years and 5 years of age (mean 11.4 μg/ml). Blood KS levels in severe MPS IVA (mean 7.3 μg/ml) were higher than in the attenuated form (mean 2.1 μg/ml) (P=0.012). We also found elevated blood KS levels in other types of MPS. These findings indicate that the new KS assay for blood is suitable for early diagnosis and longitudinal assessment of disease severity in MPS IVA.
Citation:
Tomatsu, S., Montaño, A. M., Oguma, T., Dung, V. C., Oikawa, H., Carvalho, T. G., . . . Orii, T. (2010). Validation of keratan sulfate level in mucopolysaccharidosis type IVA by liquid chromatography–tandem mass spectrometry. Journal of Inherited Metabolic Disease, 33(S3), 35-42. doi:10.1007/s10545-009-9013-x
Growth Charts for Patients Affected With Morquio A Disease (2008)
Summary:
Children with Morquio A disease grow poorly and become physically handicapped because of systemic bone disease. The purpose of this study was to describe observed growth patterns and their relationship with the physical condition of patients with Morquio A. In a one-center study, questionnaire-based longitudinal and cross sectional data were used to develop growth curves, to assess physical activity and to determine the incidence of surgical procedures in 354 patients with Morquio A. Mean birth lengths of boys and girls were 52.6 and 52.1 cm, respectively. The mean final heights for males and females at 18 years and older were 122.4 21.5 and 113.1 22.6 cm, respectively. These results corresponded to 7.4 SD for males and 7.7 SD for females compared to the normal healthy controls. Mean birth weights for boys and girls were 3.59 0.58 and 3.5 0.7 kg, respectively. The mean body mass index for males and females at over 18 years of age was 24.7 6.1 and 25.6 5.4 kg/m2, respectively. The growth pattern in Morquio A patients was characterized by impaired growth velocity after 1 year of age. This is the first report providing growth charts for patients with Morquio A, which can help with monitoring the disease and assessing the clinical efficacy of treatments. ß 2008 Wiley-Liss, Inc.
Citation:
Montaño, A. M., Tomatsu, S., Brusius, A., Smith, M., & Orii, T. (2008). Growth charts for patients affected with Morquio A disease. American Journal of Medical Genetics Part A, 146A(10), 1286-1295. doi:10.1002/ajmg.a.32281
International Morquio A Registry: Clinical Manifestation and Natural Course of Morquio A disease (2007)
Summary:
Mucopolysaccharidosis IVA (MPS IVA; Morquio A disease) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfate sulfa- tase. The natural history of this disease is incompletely understood. To study which variables influence the clinical outcome, we conducted a study in which MPS IVA patients were asked to fill out a questionnaire with inquiries regarding family history, diagnosis, signs and symptoms, height, weight, surgical history, physical activity, and general complaints. A total of 326 patients (172 male, 154 female) from 42 countries enrolled in the Morquio A Registry programme. The mean age of patients enrolled was 14.9 years for males and 19.1 years for females, with a wide range of 1–73 years. Sixty-four per cent of the patients were under 18 years. Initial symptoms were recognized between 1 and 3 years of age (mean age 2.1 years) and mean age at diagnosis for the patients was 4.7 years. A progressive skeletal dysplasia was commonly observed among the MPS IVA patients. Fifty per cent of patients underwent surgical operations to improve their quality of life. The most frequent surgical sites include neck (51%), ear (33%), leg (26%) and hip (25%). The birth length for affected males and females was 52.2 ± 4.7 cm and 52.2 ± 4.5 cm, respectively. The final adult height for affected males and females was 122.5 ± 22.5 cm and 116.5 ± 20.5 cm, respectively. The results of this study provide a reference for assessment of efficacy for studies of novel therapies.
Citation: Montaño, A. M., Tomatsu, S., Gottesman, G. S., Smith, M. & Orii, T. International Morquio A Registry: Clinical manifestation and natural course of Morquio A disease. Journal of Inherited Metabolic Disease 30, 165–174 (2007).