Morquio Research Articles

Intracerebroventricular cerliponase alfa for CLN2 disease: Clinical practice considerations from US clinics

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.

“Little people, big world”: Morquio syndrome type A (MPS IVA) in adult life

“Little people, big world”: Morquio syndrome type A (MPS IVA) in adult life

Adherence to international and local guidelines in Irish Morquio syndrome type A patients

Previous investigations have identified patient demographics and procedural characteristics, including operative time, as risk factors for adverse events following total shoulder arthroplasty (TSA). However, many of these risk factors are unmodifiable by physicians. Extended operative time is a partially modifiable variable that has not been fully investigated in its contribution to the incidence of postoperative complications after TSA. The purpose of this study was to investigate whether a 15-min increase in operative time is an independent predictor of adverse events occurring within 30 days following TSA.10,424 TSAs from 2015 to 2017 were queried from the National Surgical Quality Improvement Program database. Bivariate and multivariate binomial logistic regression was performed to investigate the association between a 15-min increase in operative time and the likelihood of developing short-term postoperative adverse events. The statistical analyses were conducted using SPSS Software version 26.0 (IBM Corp., Armonk, NY, USA). The level of significance was set at p<0.05.Multivariate analysis, adjusting for all significantly associated demographics, comorbidities, and procedural characteristics, revealed that a 15-min increase in operative time was associated with an increased likelihood of anemia requiring transfusion, pulmonary embolism, acute renal failure, unplanned reoperation, extended length of stay (≥3 days), and any adverse event within 30 days of TSA (all p<0.05). Higher BMI, younger age, male sex, general anesthesia, and preoperative anemic status predicted longer operative duration.A 15-min increase in operative time is a significant risk factor for postoperative complications, unplanned reoperation, and extended length of stay within 30 days of TSA.Level III; Retrospective Cohort Design using Large Database; Treatment Study

Disability experience of a women with Morquio syndrome type IVA

Disability experience of a women with Morquio syndrome type IVA

Long-term clinical outcomes of patients with Morquio syndrome type A treated with elosulfase alfa: Results from a managed access agreement in England

Long-term clinical outcomes of patients with Morquio syndrome type A treated with elosulfase alfa: Results from a managed access agreement in England

Morquio syndrome type A treatment with non-viral vector

In Gaucher disease, several macrophage-specific biomarkers have been validated for use in the clinic. However, Gaucher disease is more complex involving system-wide pathophysiology beyond the macrophage, and based on gene array analysis in our Gaucher disease mouse model and other emerging pathophysiologic insights, we evaluated serum levels of cathepsins D and S, YKL-40 and progranulin in Gaucher disease patients. We assessed their biomarker potential in Gaucher disease and compared them to established Gaucher disease biomarkers, chitotriosidase, chemokine ligand 18 (CCL18), and other indicators of disease severity and response to therapy. Mean YKL-40 and cathepsin D and S levels were significantly higher in Gaucher disease patients compared to healthy controls; in contrast, mean progranulin levels were lower in Gaucher disease patients compared to healthy controls. Enzyme replacement therapy resulted in a significant reversal of elevated cathepsin D and S but there was no change in progranulin and YKL-40 levels. Patients with persistent splenomegaly after long-term enzyme replacement therapy had significantly higher serum YKL-40 than patients with smaller spleens (63.0 ± 6.4 ng/ml vs. 46.4 ± 4.3 ng/ml, p = .03). Serum YKL-40 levels were higher in subjects with severe bone involvement (Hermann Score 3 to 5) compared to those with milder bone involvement (Hermann Score 1 to 2) (70.1 ± 4.3 ng/ml vs. 48.1 ± 3.7 ng/ml, p = .0002). YKL-40 was only weakly associated with chitotriosidase (r = 0.2, p = .008) and CCL18 (r = 0.3, p = .0004), and cathepsin S was moderately associated with chitotriosidase (r = 0.4, p = .01) and CCL18 (r = 0.6, p < .0001). Receiver operating curves for progranulin and YKL-40 demonstrated areas under the curves of 0.80 and 0.70, respectively. In conclusion, while these biomarkers do not meet robust properties of established macrophage-specific biomarkers, they may inform severity of skeletal disease, contribution of fibrosis to residual splenomegaly, and other disease manifestations. These findings, including markedly low progranulin levels that do not change upon enzyme replacement therapy, are intriguing to prompt further investigations to decipher their role in pathophysiology and relevance to diverse phenotypes of Gaucher disease.

Psychological health in adults with Morquio syndrome type A after six months of enzyme replacement therapy

Vaccination is the primary strategy to prevent hepatitis B virus (HBV) infection in the United States. Prior to 2017, most standard hepatitis B vaccine schedules required 3 doses over 6 months. Heplisav-B, approved in 2017, is administered in 2 doses over a 1 month time period but has a higher per-dose cost ($115.75 per dose compared to $57.25 per Engerix-B dose, costs as of June 1, 2019). We aimed to assess the cost-utility of providing the two-dose Heplisav-B vaccine compared to a three-dose Engerix-B vaccine among adult populations currently recommended for vaccination against hepatitis B. We used a decision-tree model with microsimulation and a Markov disease progression process to assess the cost-utility separately for the following populations: adults with diabetes, obesity, chronic kidney disease, HIV; non-responders to previous hepatitis B vaccination; older adults; and persons who inject drugs (PWID). We modeled epidemiologic outcomes (incident HBV infections, sequelae and related deaths), costs (2019 USD) and benefits (quality-adjusted life years, QALYs) and compared them across strategies. Sensitivity analyses assessed the cost-utility at varying estimates of Heplisav-B efficacy. In the base case scenario for each population, vaccination with Heplisav-B resulted in fewer HBV infections (37.5–59.8% averted), sequelae, and HBV-related deaths (36.3–71.4% averted). Heplisav-B resulted in decreased costs and increased benefits compared to Engerix-B for all populations except non-responders. Incremental costs from the baseline strategy ranged from $4746.78 saved (PWID) to $14.15 added cost (non-responders). Incremental benefits per person ranged from 0.00005 QALYs (older adults) to 0.7 QALYs (PWID). For persons with HIV and PWID, Heplisav-B resulted in lower costs and increased benefits in all scenarios in which Heplisav-B series efficacy was at least 80%. Vaccination using Heplisav-B is a cost-saving strategy compared to Engerix-B for adults with diabetes, chronic kidney disease, obesity, and HIV; older adults; and PWID.

Newborn screening for Morquio syndrome: Results from the 8-plex assay for 70,000 newborns

Cu-Ni-Al ternary spinel solid solution catalysts with different Al content are prepared by the solid-phase ball milling method. The characterizations with XRD, H2-TPR, BET and XPS, and catalytic performance testing are carried out to study the effects of Al content on the physicochemical properties of the Cu-Ni-Al spinels and their sustained release catalytic performances in methanol steam reforming for hydrogen production. Characterization results show a significant increase in the specific surface area and pore volume of the catalysts with increasing the Al content (Al = 2, 3, 4) at a constant Cu/Ni molar ratio of 0.95:0.05. At the same time, both the cell parameters and crystallite sizes of Cu-Ni-Al spinel solid solutions decrease, and the catalysts become difficult to be reduced. Furthermore, the content of spinel Ni2+ increases slightly while the spinel Cu2+ decreases significantly, leading to a declined total content of spinel Cu2+ plus Ni2+. The results also indicate that the presence of Ni2+ inhibits the formation of spinel Cu2+. Surface analysis results show that the increase of Al content transforms the catalyst surface composition from Cu-rich to Al-rich, and the surface spinel Cu2+ decreases, but it is still higher than the spinel bulk. The catalyst testing results show that as the Al content in the catalysts increases, the initial activity increases notably, and the CO selectivity decreases, but too much Al results in an inferior catalytic stability. In general, the catalyst with an Al = 3 shows a better catalytic performance in terms of activity and stability. The results of this paper demonstrate that there is an optimal Al content for the Cu-Ni-Al spinel solid solutions used as the sustained release catalysts, playing a crucial role in obtaining high catalytic stability.

Long-term treatment with elosulfase alfa has an acceptable safety profile for patients with Morquio syndrome type A: Real-world results from the Morquio A Registry Study (MARS)

Childhood central nervous system (CNS) tumour registration and control programs in Southern and Eastern Europe remain thin, despite the lethal nature of the disease. Mortality/survival data were assembled to estimate the burden of malignant CNS tumours, as well as the potential role of sociodemographic survival determinants across 14 cancer registries of this region.Average age-adjusted mortality rates were calculated, whereas time trends were quantified through Poisson and Joinpoint regressions. Kaplan–Meier curves were derived for the maximum and the more recent (10 and 5 year) registration periods. Multivariate Cox regression models were used to assess demographic and disease-related determinants.Variations in mortality (8–16 per million) and survival (5-year: 35–69%) were substantial among the participating registries; in most registries mortality trend was stable, whereas Bulgaria, having the highest starting rate, experienced decreasing annual mortality (−2.4%, p = 0.001). A steep decrease in survival rates was evident before the second year of follow-up. After controlling for diagnostic subgroup, age, gender and diagnostic year, Greece seemed to present higher survival compared with the other contributing registries, although the follow-up period was short. Irrespective of country, however, rural residence was found to impose substantial adverse repercussions on survival (hazard ratio (HR): 1.2, 95% confidence interval (CI): 1.1–1.4).Cross-country mortality and survival variations possibly reflect suboptimal levels of health care delivery and cancer control in some regions of Southern and Eastern Europe, notwithstanding questionable death certification patterns or follow-up procedures. Continuous childhood cancer registration and linkage with clinical data are prerequisite for the reduction of survival inequalities across Europe.

Characterization of disease-specific chondroitin sulfate nonreducing end accumulation in mucopolysaccharidosis IVA.

Morquio syndrome type A, also known as MPS IVA, is a rare autosomal recessive disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase, a lysosomal hydrolase critical in the degradation of keratan sulfate (KS) and chondroitin sulfate (CS). The CS that accumulates in MPS IVA patients has a disease-specific nonreducing end (NRE) terminating with N-acetyl-D-galactosamine 6-sulfate, which can be specifically quantified after enzymatic depolymerization of CS polysaccharide chains. The abundance of N-acetyl-D-galactosamine 6-sulfate over other possible NRE structures is diagnostic for MPS IVA. Here, we describe an assay for the liberation and measurement of N-acetyl-D-galactosamine 6-sulfate and explore its application to MPS IVA patient samples in pilot studies examining disease detection, effects of age and treatment with enzyme-replacement therapy. This assay complements the existing urinary KS assay by quantifying CS-derived substrates, which represent a distinct biochemical aspect of MPS IVA. A more complete understanding of the disease could help to more definitively detect disease across age ranges and more completely measure the pharmacodynamic efficacy of therapies. Larger studies will be needed to clarify the potential value of this CS-derived substrate to manage disease in MPS IVA patients.

Identification of a novel variant in exon 5 of galactosamine (N-acetyl)-6-sulfatase gene in mucopolysaccharidosis IVA patients in Indonesia

Objective: Mucopolysaccharidosis IVA (MPS IVA), or Morquio A syndrome, is a lysosomal storage disorder caused by a deficiency of galactosamine (N-acetyl)-6-sulfatase (GALNS) enzyme that leads to the accumulation of keratan sulfate and chondroitin-6-sulfate in the lysosome and eventually in the tissue or organ damaged. This enzyme deficiency occurs because of mutations in the galactosamine (N-acetyl)-6-sulfatase (GALNS) gene located at locus 16q24.3. GALNS comprises 14 exons, has a size of ~43 kb, and encodes 522 amino acids. Currently, 47 of 368 mutations have been detected in exon 5, indicating that this region is a hotspot of mutations. The objective of this study was to analyze the mutations in exon 5 of GALNS in MPS IVA patients in Indonesia. Materials and Methods: Genomic DNA was isolated from fresh blood samples obtained from patients with MPS IVA and normal individuals at Cipto Mangunkusumo Hospital. Exon 5 of GALNS was amplified using a pair of specific primers, and polymerase chain reaction products were sequenced using an automated sequencing technique. Results: We found a novel missense mutation c.503G>T that alters the amino acid at position 168 from glycine to valine (G168V). Three previously reported variations identified in this study are c.510T>C (Y170), c.566 + 5T>C, and IVS5 + 134G>A. Conclusion: This finding provides new data about variants in exon 5 of GALNS. Further, research is needed to identify variations in other exons and to map the mutation profile in MPS IVA patients in Indonesia.

Proteomic Analysis in Morquio A Cells Treated with Immobilized Enzymatic Replacement Therapy on Nanostructured Lipid Systems.

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 effect 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.

Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model.

Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage leads to minimal impact on the bone lesion. Moreover, short half-life, high cost, instability, and narrow optimal pH range remain unmet challenges in ERT. Thermostable keratanase, endo-β-N-acetylglucosaminidase, has a unique character of a wide optimal pH range of pH 5.0–7.0. We hypothesized that this endoglycosidase degrades keratan sulfate (KS) polymer in circulating blood and, therefore, ameliorates the accumulation of KS in multiple tissues. We propose a novel approach, Substrate Degradation Enzyme Therapy (SDET), to treat bone lesion of MPS IVA. We assessed the effect of thermostable keratanase on blood KS level and bone pathology using Galns knock-out MPS IVA mice. After a single administration of 2 U/kg (= 0.2 mg/kg) of the enzyme at 8 weeks of age via intravenous injection, the level of serum KS was significantly decreased to normal range level, and this suppression was maintained for at least 4 weeks. We administered 2 U/kg of the enzyme to MPS IVA mice every fourth week for 12 weeks (total of 3 times) at newborns or 8 weeks of age. After a third injection, serum mono-sulfated KS levels were kept low for 4 weeks, similar to that in control mice, and at 12 weeks, bone pathology was markedly improved when SDET started at newborns, compared with untreated MPS IVA mice. Overall, thermostable keratanase reduces the level of KS in blood and provides a positive impact on cartilage lesions, demonstrating that SDET is a novel therapeutic approach to MPS IVA.

An ultra-rare mutation (C.181C>T) in GALNS gene associated with Morquio syndrome: A case report

MotivationOne of the rare inherited diseases is the mucopolysaccharidoses disorders (MPS) associated with accumulation of glycosaminoglycan in several organs, leading to abnormalities in musculoskeletal, respiratory, cardiac, neurological, ophthalmological, otolaryngological, and gastrointestinal. Nowadays, an increasing number of patients with MPS are reaching adulthood and are involved in family planning due to improvements in diagnosis, multi-disciplinary care, and therapies such as enzyme replacement therapy and hematopoietic stem cell transplantation. Knowledge on skeletal deformity in MPS remains relatively uncommon and includes a few case reports. To assess more, we present a case report on musculoskeletal deformity in one subject with MPS. CaseThis case revealed that subject with MPS has generalized osteoporosis, Degenerative Joint Disease (DJD) of both hips, general skeletal deformity alongside normal mental status. On physical examination, disproportionate short stature, skeletal dysplasia, osteoporosis, prognathism, negative ulnar variance, angle blunting and ulnar styloid were detected. In the present research work, C.181C>T (p.Arg61Trp) variant of GALNS gene was found through whole exome sequencing and the mutation was confirmed using Sanger sequencing method, which is associated with MPS4A phenotype. ConclusionsPathogenic variant in the GALNS gene associated with hereditary Mucopolysaccharidosis IVA, (MPS4A, Morquio syndrome A) which encodes N-acetylgalactosamin-sulfate sulfatase, may be useful as a biomarker to early diagnosis and treatment.

The characterisation of pulmonary function in patients with mucopolysaccharidoses IVA: A longitudinal analysis

IntroductionMucopolysaccharidosis (MPS) type IVA is a rare, autosomal recessive lysosomal storage disease causing substrate accumulation in various organs and tissues. MPS IVA is associated with both obstructive and restrictive airway disease, with the former often resulting in sleep disordered breathing (SDB). Respiratory failure is a primary cause of death in this condition. The aim of this study was to characterise and catalogue the long-term respiratory changes in patients with MPS IVA treated with, or without, enzyme replacement therapy (ERT). MethodsIn this retrospective, longitudinal, repeated-measures cohort study, descriptive statistics and non-parametric correlation were performed for demographic, respiratory function and oximetry variables over a study period from January 2009 to December 2018. Composite clinical endpoints used in this study for evaluating pulmonary function included spirometry variables (FEV1, FEV1 [%Pred] FVC, FVC [%Pred] and FEV1/FVC), oximetry variables (median %Spo2, ODI 3%, mean nadir 3%, ODI 4%, mean nadir 4% and min dip SpO2 [%]) and 6MWT to assess functional exercise capacity and thus integrated cardiopulmonary function. ResultsSequential spirometry and oximetry values were collected from 16 patients, of which 13/16 were ERT treated. In general, during the study period there was a global reduction in static spirometry values in all subjects, as well as cardiorespiratory function as assessed by the 6MWT, with the decline being delayed in the ERT group. Oximetry changed to a minor degree over time in the ERT group, whereas it declined in the non-ERT group. FEV1, FVC [%predicted] and ODI 3% exhibited a strong, combined positive correlation (r 0.74–95% CI 0.61 to 0.83; p < .0001). Non-invasive ventilation (NIV) and adenotonsillectomy appeared more effective in the ERT group, either improving pulmonary function or attenuating deterioration. ConclusionsWhilst spirometry values showed a gradual decline across all groups, oximetry showed modest improvement in respiratory function. The amalgamation of FEV1, FVC [%predicted] and ODI 3% appeared predictive of changes in respiratory function in this study, suggestive as being composite endpoints for monitoring disease progression as well as guiding response to ERT in MPS IVA patients.

Clinical, biochemical and genetic profiles of patients with mucopolysaccharidosis type IVA (Morquio A syndrome) in Malaysia: the first national natural history cohort study

BackgroundMucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disease due to N-acetylgalactosamine-6-sulfatase (GALNS) deficiency. It results in accumulation of the glycosaminoglycans, keratan sulfate and chondroitin-6-sulfate, leading to skeletal and other systemic impairments. Data on MPS IVA in Asian populations are scarce.MethodsThis is a multicentre descriptive case series of 21 patients comprising all MPS IVA patients in Malaysia. Mutational analysis was performed by PCR and Sanger sequencing of the GALNS gene in 17 patients.ResultsThe patients (15 females and 6 males) had a mean age (± SD) of 15.5 (± 8.1) years. Mean age at symptom onset was 2.6 (± 2.1) years and at confirmed diagnosis was 6.9 (± 4.5) years. The study cohort included patients from all the main ethnic groups in Malaysia – 57% Malay, 29% Chinese and 14% Indian. Common presenting symptoms included pectus carinatum (57%) and genu valgum (43%). Eight patients (38%) had undergone surgery, most commonly knee surgeries (29%) and cervical spine decompression (24%). Patients had limited endurance with lower mean walking distances with increasing age. GALNS gene analysis identified 18 distinct mutations comprising 13 missense, three nonsense, one small deletion and one splice site mutation. Of these, eight were novel mutations (Tyr133Ser, Glu158Valfs*12, Gly168*, Gly168Val, Trp184*, Leu271Pro, Glu320Lys, Leu508Pro). Mutations in exons 1, 5 and 9 accounted for 51% of the mutant alleles identified.ConclusionsAll the MPS IVA patients in this study had clinical impairments. A better understanding of the natural history and the clinical and genetic spectrum of MPS IVA in this population may assist early diagnosis, improve management and permit timely genetic counselling and prenatal diagnosis.

Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance

IntroductionMucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA.MethodsTwenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.ResultsA total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).ConclusionThis manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.

Identification of Ezetimibe and Pranlukast as Pharmacological Chaperones for the Treatment of the Rare Disease Mucopolysaccharidosis Type IVA.

Mucopolysaccharidosis type IVA (MPS IVA) is a rare disease caused by mutations in the gene encoding the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). We report here two GALNS pharmacological chaperones, ezetimibe and pranlukast, identified by molecular docking-based virtual screening. These compounds bound to the active cavity of GALNS and increased its thermal stability as well as the production of recombinant GALNS in bacteria, yeast, and HEK293 cells. MPS IVA fibroblasts treated with these chaperones exhibited increases in GALNS protein and enzyme activity and reduced the size of enlarged lysosomes. Abnormalities in autophagy markers p62 and LC3B-II were alleviated by ezetimibe and pranlukast. Combined treatment of recombinant GALNS with ezetimibe or pranlukast produced an additive effect. Altogether, the results demonstrate that ezetimibe and pranlukast can increase the yield of recombinant GALNS and be used as a monotherapy or combination therapy to improve the therapeutic efficacy of MPS IVA enzyme replacement therapy.

Effect of enzyme replacement therapy on the growth of patients with Morquio A.

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.

Mutation spectrum and pivotal features for differential diagnosis of Mucopolysaccharidosis IVA patients with severe and attenuated phenotype

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by biallelic mutations in GALNS gene and characterized by progressive skeletal deformities with short stature. The aim of this study was to evaluate the genotype, longitudinal height measurement and clinical features of MPS IVA patients. Thirty-two patients from 22 families were enrolled. The ages of patients at diagnosis ranged from two months to 18 years of age, and followed up for three to twenty years. They were classified as severe and attenuated form (intermediate and mild) according to their height measurements. The mean height standard deviation scores (SDS) for Turkish standards at 0–3, 5 and 10 years of ages were found to be −1.1, −4.2 and −7.3 respectively in patients with severe phenotype, while they were +0.4, −1.5 and −3 for intermediate phenotype. Patients with severe form reached a mean final height of −8.5 SDS, and mild phenotype −3.6 SDS. The most common initial and current symptoms in the patients with the severe phenotype were pectus carinatus and/or kyphosis deformities which occurred between 5 months and 3 years of age, and genu valgum deformity which developed after 3 years of age. However, kyphoscoliosis was the most common initial and current findings in the attenuated phenotype. Although, initial symptoms appeared in early childhood in the intermediate phenotype, similar to the severe phenotype, the clinical findings progressed slowly and genu valgum deformity did not develop. In patients with mild phenotype, the onset of symptoms was after 5 years of age. In conclusion, this study provides significant insights into the initial and follow-up clinical features and height values that contribute to the differential diagnosis of the severe and intermediate phenotypes in early childhood. Eleven mutations in GALNS gene in which one of them is novel (c.416G>A) were associated with the severe phenotype and three mutations (c.1038C>A, c.850T>G, c.752G>A) lead to the attenuated phenotype.