RARE DISEASE
Mucopolysaccharidosis type 4A
Mucopolysaccharidosis type 4A
Mucopolysaccharidosis type 4A
Synonyms: GALNS deficiency, Galactosamine-6-sulfatase deficiency, MPS4A, MPSIVA, Morquio disease type A, Mucopolysaccharidosis type IVA, N-acetylgalactosamine-6-sulfate sulfatase deficiency
Synonyms: GALNS deficiency, Galactosamine-6-sulfatase deficiency, MPS4A, MPSIVA, Morquio disease type A, Mucopolysaccharidosis type IVA, N-acetylgalactosamine-6-sulfate sulfatase deficiency
Synonyms: GALNS deficiency, Galactosamine-6-sulfatase deficiency, MPS4A, MPSIVA, Morquio disease type A, Mucopolysaccharidosis type IVA, N-acetylgalactosamine-6-sulfate sulfatase deficiency
Drug discovery
7
drugs
With orphan designations
Overview
Mucopolysaccharidosis type 4A (MPS IVA/Morquio A syndrome) is an autosomal recessive lysosomal storage disorder caused by GALNS gene mutations, leading to deficient N-acetylgalactosamine-6-sulfatase activity. This results in systemic accumulation of keratan sulfate and chondroitin-6-sulfate, causing severe skeletal dysplasia, short stature, spinal instability, respiratory compromise, and corneal clouding. Cognitive function is typically preserved. Disease progression varies, with life expectancy ranging from childhood to >50 years depending on severity and care [1][4][7][10].
Burden
Progressive skeletal deformities cause wheelchair dependency by adolescence in severe cases [1][15]
Major mortality risks: spinal cord compression (odontoid hypoplasia) and respiratory failure [4][10]
High healthcare utilization due to multisystem complications (orthopedic, cardiac, pulmonary) and frequent surgical interventions [1][7]
Therapies
Enzyme replacement therapy: Elosulfase alfa (Vimizim®) improves endurance and reduces keratan sulfate levels but does not reverse skeletal pathology [3][7][15]
Supportive care: Spinal fusion for cervical instability, tracheal reconstruction, joint surgeries, and respiratory support [1][7]
Emerging approaches: Prenatal ERT trials to induce immune tolerance and bone-targeted therapies in preclinical development [7][12]
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
295 drug discovery papers about Mucopolysaccharidosis type 4A, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
295 drug discovery papers about Mucopolysaccharidosis type 4A, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-09-11 | Haematopoietic stem cell transplant in a case of mucopolysaccharidosis IV with Fanconi anaemia and bone marrow failure.
Mucopolysaccharidosis type IV (MPS IV; Morquio syndrome) is a rare lysosomal storage disorder characterised by skeletal dysplasia and multisystem involvement, while Fanconi anaemia (FA) is an inherited bone marrow failure syndrome associated with chromosomal instability and hypersensitivity to conditioning agents. The coexistence of these two disorders poses a unique therapeutic challenge, particularly when haematopoietic stem cell transplantation (HSCT) is indicated. We report a child with MPS IV and FA who underwent HSCT with a non-myeloablative conditioning regimen. The procedure was carefully individualised to balance engraftment success with minimisation of toxicity. This case highlights the complexities of managing overlapping genetic conditions requiring HSCT and demonstrates the value of multidisciplinary planning and personalised transplant strategies in achieving favourable clinical outcomes.
2026-04-28 | Long-Term Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Mucopolysaccharidosis IVA: A 10-Year Follow-Up from a Single-Center Experience in China.
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potential approach for pediatric mucopolysaccharidosis IVA (MPS IVA). However, delayed diagnosis and higher transplant-related complications have limited its broader use. This study investigated treatment-related benefit and up to 10-year outcomes following HSCT in children with MPS IVA. Study Design We retrospectively analyzed 19 pediatric patients with a severe phenotype of MPS IVA who underwent HSCT between January 2015 and July 2025. N-acetylgalactosamine-6-sulfatase (GALNS) enzyme activity, height growth, and organ dysfunction (cardiac, auditory, and visual) was evaluated to analyze the benefit of HSCT. The donor sources include human leukocyte antigen (HLA)-matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT, n = 5), HLA-matched unrelated donor PBSCT (MUD-PBSCT, n = 7), and single-unit unrelated umbilical cord blood transplantation (UD-UCBT, n = 7). The overall survival rate was 94.7% (18/19), apart from 1 mortality due to pulmonary infection. All surviving patients achieved full donor engraftment and durable restoration of GALNS activity. There is no severe graft-versus-host disease (GVHD) was observed. The majority of patients exhibited no deterioration in auditory, visual, respiratory, or cardiac function. During the long-term follow-up period, our cases showed a continued linear growth post-HSCT. Here we demonstrated the data of our HSCT experience in MPS IVA with the safety and efficacy of HSCT. More data with an expanded patient cohort are imperative to delineate the capacity of HSCT to repair severe skeletal manifestations in MPS IVA.
2026-03-05 | Development and characterization of a model of mucopolysaccharidosis type IVA for evaluating therapies targeting bone disease.
Mucopolysaccharidosis type IVA (MPSIVA) is a lysosomal storage disease (LSD) caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which causes the accumulation of keratan sulphate (KS) and chondroitin sulphate (CS). Patients with MPSIVA typically present with severe skeletal and joint disorders, which are not addressed by conventional therapies. Currently, no animal model accurately replicates the human disease, hindering the development of novel therapeutic interventions. To overcome this limitation, we established, by CRISPR-Cas9 technology, a Galns-/- mouse model that expresses a non-functional enzyme and accumulates CS and KS in the urine, plasma and distinct tissues, and glycosaminoglycans in the spleen. The mice exhibit shortened long bones, trabecular bone alterations and skeletal abnormalities in the growth plate. Additionally, we observed increased levels of inflammatory and oxidative markers in visceral organs and plasma. Our newly developed model of MPSIVA demonstrates clear and quantifiable signs of skeletal alterations, providing novel means of assessment of the safety and efficacy of innovative therapies, including hematopoietic stem and progenitor cell gene therapy, which has recently been shown to provide a beneficial effect on skeletal alterations in Hurler syndrome.
2026-01-31 | Allogeneic Hematopoietic Cell Transplantation for Morquio A Syndrome: An International Retrospective Study.
Mucopolysaccharidosis IV A (MPS IVA) or Morquio A syndrome is a lysosomal storage disorder that results from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), causing deposition of glycosaminoglycans, keratan sulfate, and chondroitin-6-sulfate in multiple organs. The main clinical manifestations include severe short stature, severe cervical spine stenosis, and progressive skeletal dysplasia, which leads to severe mobility limitation resulting in patients becoming wheelchair-bound in their second decade of life, and overall shortened life span. The current standard of care for Morquio A is weekly enzyme replacement therapy (ERT). However, ERT is expensive, not widely available worldwide, and offers limited long-term benefits. Allogeneic hematopoietic cell transplantation (HCT) is a way to provide a life-long endogenous enzyme and has the potential to improve outcomes. The main objectives of this study were to investigate the safety and assess the benefits of allogeneic HCT in the treatment of patients with Morquio A. We performed a retrospective study of 41 patients who underwent allogeneic HCT at 9 international centers. Forty-one patients with Morquio A received allogeneic HCT. Three patients experienced graft failure and underwent second transplants. Most (77%) of the transplants were performed using either matched or mismatched unrelated donors, and 71% of the transplants utilized peripheral blood stem cells as the graft source. The overall 3-year survival rate was 90.5%. Graft-versus-host disease (GVHD) was a direct or indirect contributor to mortality in 3 out of 4 patients. The median myeloid engraftment was 100% at the last follow-up, with a median follow-up of 3 years; the median times for neutrophil and platelet engraftment were 12 and 13 days, respectively. The incidence of grade II to IV acute GVHD was 35.5%. Interestingly, in patients who had received pretransplant ERT, the incidence of acute grade II to IV GVHD was 14.9%, compared to 45% in those who had not received pretransplant ERT (P = .075). The incidence of grades III to IV acute and chronic GVHD was 14.2% and 12.7%, respectively. When available, disease-specific outcomes showed complete to near normalization of metabolic biomarkers, as well as improvement in movement scores, stability of heart function, eyes, and cervical spine stenosis. Notably, in patients transplanted below the age of 3 years, growth continued in 6 out of 8 patients, while this effect was less notable in the older cohort. Allogeneic HCT for patients with Morquio A is safe and feasible. This treatment can potentially lead to significantly improved biochemical markers of the disease, preservation of organs, and better clinical manifestations. Additionally, when performed at a young age, ideally before the age of 3 years, allogeneic HCT may result in improved growth. The use of bone marrow as a stem cell source whenever possible, combined with effective GVHD prophylaxis, may enhance transplant success and disease-related outcomes. Long-term benefits and risks require further investigation.
2025-03-19 | Allogeneic hematopoietic stem cell transplantation for mucopolysaccharidosis patients: a single-center experience and assessment of quality of life.
Allogeneic hematopoietic stem cell transplantation (HSCT) has proven to be a viable treatment option for patients with mucopolysaccharidoses (MPS). We investigate the efficacy and improvements in the quality of life of HSCT in pediatric patients with MPS. A retrospective analysis of transplantation data from 46 cases of MPS from a single institution in China was conducted. The cohort of 46 patients included 9 cases of MPS I, 16 cases of MPS II, 15 cases of MPS IVA and 6 cases of MPS VI. The median age at diagnosis was 2.59 years. The median age at transplantation was 3.80 years. The median follow-up time was 3.1 years (range, 0.8-8.1 years) and 43 patients were alive. The incidence of grades II to IV aGVHD was 17.4%, wherein the incidence of grades III and IV aGVHD was 4.3%. The incidence of moderate-to-severe cGVHD was 6.5%. GAGs urinary excretion decreased and enzyme activity levels reached normal. After HSCT, multiple bone dysplasia, upper-airway obstruction and recurrent otitis media were significantly improved; vision, corneal clouding, cardiovascular disease, hepatosplenomegaly and hydrocephalus were improved or remained stable; neurological symptoms were improved or remained stable in most patients but progressed in others; the patients with MPS IH/S and MPS II reached nearly normal growth rate of height and weight. Meanwhile, the patients with MPS IH, MPS IVA and MPS VI remained poor growth after HSCT. The Activities of Daily Living (ADL) scores were improved in most patients with MPS. ADL scores in patients with severe phenotypes were lower than health control subjects and patients with attenuated phenotypes. HSCT is a good therapeutic option for MPS and improves the quality of life of patients. MPS patients with attenuated phenotypes provide a better outcome in ADL after HSCT.
small molecules
2026-03-30 | Ultrasound-guided one-point puncture lumbosacral plexus block combined with laryngeal mask airway general anesthesia for thigh amputation in a patient with mucopolysaccharidosis: a case report.
Mucopolysaccharidosis (MPS) is a group of rare inherited lysosomal storage disorders caused by deficiencies of specific enzymes, leading to abnormal accumulation of glycosaminoglycans in tissues throughout the body. It is often associated with a difficult airway, cervical spine instability, restrictive pulmonary dysfunction, and cardiovascular pathologies, which significantly increase perioperative risks. This manuscript reports a case of a 36-year-old male MPS patient (clinical phenotype highly suggestive of type IV) who underwent right mid-to-upper thigh amputation for a pathological fracture of the right femur. Given his potential difficult airway (Mallampati class III, thyromental distance <6 cm), mild kyphosis, and restrictive pulmonary dysfunction, the anesthetic plan consisted of an ultrasound-guided one-point puncture, dual-target lumbosacral plexus block (35 mL of 0.15% ropivacaine) combined with supraglottic airway (laryngeal mask airway, LMA) under general anesthesia. The block successfully provided an L2-S3 sensory level and served as the basis for postoperative multimodal analgesia. The surgery lasted 2 h with 500 mL blood loss, requiring 2 units of red blood cells. Hemodynamics remained stable, and no additional muscle relaxants were administered. The patient regained consciousness and the LMA was removed 10 min postoperatively. The Numerical Rating Scale (NRS) pain scores at 2, 6, 12, and 24 h postoperatively were 2, 3, 2, and 1, respectively. Functional exercise began on postoperative day 1 without major complications. The patient was discharged 15 days after surgery and was hospitalized for a total of 18 days. With strict patient selection and thorough preparation of emergency airway protocols, combining an LMA with an ultrasound-guided one-point puncture lumbosacral plexus block can be a safe and feasible individualized anesthetic strategy for lower limb proximal surgery in MPS patients. This approach helps avoid intubation risks, reduces opioid consumption, and promotes early recovery. However, due to the considerable difficulty of airway management in patients with MPS, elective surgery requires multidisciplinary consultation and comprehensive airway assessment to ensure perioperative safety.
2026-03-02 | Computational Prediction of Deleterious SNPs in the GALNS Gene Implicated in Morquio A Syndrome (MPS IVA).
Morquio syndrome A, also known as mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disorder resulting from mutations in the gene responsible for N-acetylgalactosamine-6-sulfatase. The deficiency of this enzyme impairs the degradation of glycosaminoglycans, particularly chondroitin 6-sulfate and keratan sulfate. This research uses a variety of computational techniques for analyzing the GALNS variants mainly causing child death and to provide better healthcare. The variants were collected from research sources, such as PubMed, ResearchGate, and ScienceDirect, along with databases like HGMD, ClinVar, and UniProt. The analysis of the conservation, pathogenicity, and stability of the variations was conducted utilizing algorithms such as ConSurf, PredictSNP, and iStable. Structural analysis was carried out using the PDB databank and PyMOL software. Molecular docking was used to study the interaction of native and variant GALNS proteins with Ezetimibe. GROMACS was used to simulate the behavior of the GALNS protein with variants and Ezetimibe binding in docked complexes for over 100 ns. A total of 345 SNP variants were retrieved, of which D40H, C79R, and C79L variants were identified to be highly deleterious after conservation (75 SNPs), pathogenicity (5 SNPs), and biophysical and stability (3 SNPs) analysis. During docking, the native protein demonstrated a strong binding affinity of -8.54 kcal/mol for the drug. The C79R variant displayed a binding affinity of -8.41 kcal/mol, while the C79L and D40H variants showed affinities of -7.07 and -7.92 kcal/mol, respectively. MD simulations of the native and variant structures showed similar ligand binding flexibility and stability, confirmed by RMSD, RMSF, H-bond, and gyration plots. The increased binding affinity and stability of both complexes suggest that Ezetimibe has comparable therapeutic effects for both the native and variant forms. This work provides detailed structural and dynamic insights into the GALNS protein, paving the way for further research and new treatments for Morquio syndrome A.
2025-09-04 | Case report: Successful treatment of a patient presenting with a very rare association of acute lymphoblastic leukemia and mucopolysaccharidosis type IVA
Treating Acute Lymphoblastic Leukemia (ALL) in patients with genetic disorders poses significant challenges for onco-hematologists. Mucopolysaccharidosis type IVA (MPS-IVA) is a lysosomal storage disorder that clinically manifests with progressive and multi-systemic comorbidities, primarily affecting the bone, cartilage, spine, heart and lungs. We report a unique case of B-lineage ALL in a patient with MPS-IVA, who was successfully cured with a personalized chemo-radiotherapy approach. The treatment strategy aimed to balance a curative-intent chemotherapy attempt with the minimization of life-threatening complications. This case highlights the importance of individualized therapy in managing ALL in the context of complex comorbidities.
2025-05-28 | Exploring Multivalent Architectures for Binding and Stabilization of N-Acetylgalactosamine 6-Sulfatase.
Morquio A syndrome is a lysosomal disorder caused by the deficiency of the lysosomal enzyme N-acetylgalactosamine 6-sulfatase (GALNS, EC 3.1.6.4). Currently, enzyme replacement therapy (ERT) is used to treat Morquio A through the infusion of the recombinant enzyme VIMIZIM® (elosulfase alfa, BioMarin). Unfortunately, the recombinant enzyme exhibits low conformational stability in vivo. A promising approach to address this issue is the coadministration of recombinant human GALNS (rhGALNS) with a pharmacological chaperone (PC), a molecule that selectively binds to the misfolded protein, stabilizes its conformation, and assists in the restoration of the impaired function. We report in this work the synthesis of a library of multivalent glycomimetics exploiting the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between several dendrimeric scaffolds armed with terminal alkynes and azido ending iminosugars of different structures (pyrrolidines, piperidines, and pyrrolizidines) or simple azido ending carbohydrates as bioactive units. The biological evaluation identified pyrrolidine-based nonavalent dendrimers 1 and 36 as the most promising compounds, able both to bind the native enzyme with IC50 in the micromolar range and to act as enzyme stabilizers toward rhGALNS in a thermal denaturation study, thus identifying promising compounds for a combined PC/ERT therapy.
2025-05-26 | Heliox in the management of respiratory failure in a Morquio A syndrome patient with trachea narrowing.
Morquio A Syndrome is a mucopolysaccharide deposition disease where patients can develop respiratory failure due to airway narrowing by polysaccharide deposition, anatomical distortion and compression of the airway. Definitive management with surgery is high risk, only performed in the highly specialized centers, and by the time they develop respiratory failure they may not be a candidate for surgery due to difficulty intubation. Consequently, they often end up with long term BiPAP dependent and suffer from side effects of abdominal, facial pain and depression. Heliox is low density gas mixture which can facilitate oxygen delivery in narrowed airway. Here we report a case of Morquio A syndrome patient with 24-h BiPAP dependence and successfully treated with Heliox and weaned off BiPAP for 4 hours a day with improved quality of life.
proteins
2026-09-28 | Differential Diagnosis of Mucopolysaccharidoses Types I, II, III, IVA, and VI Through Analysis of Leukocytic Inclusions.
Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs), which can lead to cytoplasmic alterations in leukocytes. The objective of this study was to characterize leukocyte inclusions in patients with different types of MPS and assess their diagnostic relevance. A total of 69 Brazilian patients diagnosed with five MPS types were evaluated through cytological analysis of peripheral blood smears. Distinct leukocyte inclusion patterns were observed in four subtypes. In MPS Type II, small violet cytoplasmic inclusions were present in lymphocytes. In MPS Type III, larger violet inclusions were identified in lymphocytes. Patients with MPS Type IVA showed large, sparse granulations in neutrophils, while those with MPS Type VI exhibited coarse inclusions in all leukocytes, characteristic of the Alder-Reilly anomaly. No leukocyte inclusions were found in MPS Type I. These observations demonstrate that leukocyte inclusions vary according to MPS subtype and may represent a useful auxiliary cytological finding. Their identification may support diagnostic suspicion and contribute to the differential diagnosis of MPS II, III, IVA, and VI, complementing enzymatic and biochemical testing.
2026-03-05 | P044: First report of GLP-1 agonist use in MCAD deficiency
Case Presentation: A 29-year-old Hispanic female presented with a clinical and biochemical diagnosis of MPSIVA.She has short stature, mild corneal clouding, pectus carinatum, required multiple knee surgeries and her x-ray showed bullet shaped vertebrae.This individual had two affected siblings with MPSIVA who are unavailable for testing.Her mother is mildly affected and presents with corneal clouding and short stature.Diagnostic Workup: This individual initially had an LSD panel which identified one pathogenic variant in the GALNS gene, c.107T>C, which was insufficient to explain the patient's phenotype.ES with RNA-seq was ordered.RNA-seq analysis identified an 11 bp deletion in an alternative transcript (NM_001323544.2), leading to frameshift: p.(Gly43Aspfs*5).This aberrant transcript was a consequence of a single nucleotide change (c.121-210C>T) located in intron 1 and is 210 bp upstream of the splice acceptor site for exon 2 in the MANE transcript (NM_000512.5).As this variant is located at the startproximal nonsense-mediated mRNA decay insensitivity region, re-initiation of translation at the next in-frame start codon (p.47) is possible.This variant was originally classified as likely benign (LB) due to being observed at a frequency of 0.31% (523/166064 alleles) with the highest frequency noted in the African subpopulation at 3.05% in the gnomAD database.However, this variant has also been reported in the compound heterozygous and homozygous state in four individuals with MPSIVA and has been classified as a "Potentially Disease Associated Mutation" in the Human Gene Mutation Database.Based on the RNA-seq analysis and other affected individuals identified with this variant, the lab was able to upgrade the variant from LB to a variant of uncertain significance (VUS) and may represent a hypomorphic allele.Outcome and Follow-Up: The provider was able to provide this individual with a molecular diagnosis of MPSIVA based on the detection of two GALNS variants.Since then, we have tested the mildly affected mother who was found to be homozygous for the c.121-210C>T variant with consistent RNA-seq results to the proband.This strengthens the understanding that this is a hypomorphic allele.Testing the proband's siblings is still recommended. Conclusion:The use of ES with RNA-seq was able to identify a variant that was -210 nucleotides upstream of the splice acceptor site and lead to an upgrade in variant classification from LB to VUS.This highlights the diagnostic advantages of using RNA-seq over standard DNA-only testing methodology.RNAseq can aid in identifying aberrant splicing, mono-allelic expression, and aberrant expression which can increase diagnostic yield.Having a molecular diagnosis can provide individuals with different treatment options, including possible GT enrollment, and family planning options.
2025-05-22 | A Rare Case of Morquio Syndrome in Palestine: Clinical, Radiological, and Genetic Insights.
Morquio A syndrome, also known as mucopolysaccharidosis type IVA (MPS IVA), is a rare lysosomal storage disorder that mostly affects the skeletal system. It spares cognitive function but causes short stature, increasing deformities and anomalies in the joints, as well as respiratory, cardiac, dental, hearing, and vision problems. This report describes a six-year-old boy with growth retardation and skeletal deformities, and highlights the characteristic clinical features, diagnostic approach, and challenges in the management of MPS IVA, emphasizing the importance of early recognition and comprehensive treatment strategies to optimize patient outcomes.
2025-03-01 | A Case Report of Cardiac Ascites in Morquio Syndrome Complicated by Pulmonary Hypertension
Morquio syndrome, or mucopolysaccharidosis type IV (MPS IV), is a rare lysosomal storage disorder characterized by skeletal dysplasia and dysostosis multiplex. While primarily associated with skeletal manifestations, MPS IV can also affect systemic organs. Here, we present a case of a 64-year-old woman with MPS IVC who presented with cardiac ascites. The patient's disease course was characterized by idiopathic pulmonary hypertension to cor pulmonale and subsequent cardiac ascites formation. Utilizing paracentesis with cytology as well as an analysis of the patient's clinical history and disease progression, we provide insights into the interplay between Morquio syndrome and cardiac ascites.
2024-08-26 | Diminished GALNS activity in induced pluripotent stem cells of mucopolysaccharidosis IVA caused by compound p.S162Y and p.C165F mutation.
Mucopolysaccharidosis (MPS) IVA is a lysosomal storage disorder caused by mutations in the gene encoding the galactosamine (N-acetyl)-6-sulfatase (GALNS) enzyme. Children with MPS IVA usually develop pectus carinatum, genu valgum and multiple skeletal abnormalities. To establish a patient-derived induced pluripotent stem cell (iPSC) disease model to investigate the effects of two GALNS missense mutations. The medical history and clinical manifestations of a patient with MPS IVA were first inspected. The effects of the identified GALNS mutations were predicted through bioinformatic analysis. iPSCs were then generated by using Sendai virus to introduce Yamanaka reprogramming factors to urinary cells isolated from the patient. The pluripotency, karyotypic integrity, genetic mutations and differentiation ability of the iPSCs were tested. The effects of the GALNS mutations were further experimentally characterized using patient-derived cells. The patient exhibited a typical MPS IVA phenotype. Enzyme replacement therapy could not correct her skeletal abnormalities. GALNS c.485C>A (p.S162Y) and c.494G>T (p.C165F) mutations, inherited from her father and mother, respectively, were identified in the patient. These two mutations were predicted to disturb the hydrophobic core of the GALNS catalytic domain. Patient-derived iPSCs were successfully generated, and further characterization indicated that the two missense mutations significantly diminished GALNS activity without affecting its amount at both the RNA and protein levels. We established a novel clinically relevant MPS IVA disease model that will be useful not only for investigating the pathogenic mechanisms of MPS IVA variants but also for drug screening and preclinical evaluation of novel therapies.
gene therapies
2026-01-30 | Collagen Type II-Targeting Lentiviral Gene Therapy for Mucopolysaccharidosis IVA.
Mucopolysaccharidosis (MPS IVA) is caused by pathogenic variations in the GALNS gene, leading to the accumulation of glycosaminoglycans in tissues and causing progressive skeletal lesions. While conventional lentiviral vectors (LVs) provide long-term stable expression, they do not deliver therapeutic levels to bone and cartilage. We hypothesized that engineering the LV envelope with a collagen type II-targeting peptide (WYRGRL) increases the binding affinity of the LVs for bone and cartilage. These modified vectors carrying the CBh and COL2A1 promoters delivered the GALNS gene to MPS IVA newborn mice via intravenous (IV) or intraarticular (IA) administration. The peptide-modified LVs exhibited markedly increased uptake in the liver when administered IV, but lower enzyme activity than that of the conventional vector. The modified WYRGRL-LV-COL2A1 vector elevated GALNS activity in other tissues, suggesting systemic benefits. When administered IA, the modified vectors showed potential for local treatment due to the WYRGRL peptide-mediated uptake. Additionally, there was a reduction in keratan sulfate glycosaminoglycan levels in plasma and tissues, indicating that this peptide can be a suitable candidate for disease modification. These findings pave the way for further preclinical and clinical studies, offering new possibilities for the development of targeted therapies for skeletal diseases.
2025-11-26 | Long-Term Liver-Targeted AAV8 Gene Therapy for Mucopolysaccharidosis IVA.
Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease with an autosomal recessive trait caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme, which leads to the accumulation of chondroitin-6-sulfate and keratan sulfate, primarily in cartilage and its extracellular matrix, resulting in a direct impact on cartilage and bone development, as well as subsequent systemic skeletal dysplasia. ERT and HSCT are current treatment options, but they have a limited effect on bone lesions. In this article, we investigated liver-specific AAV8 vectors with a thyroxine-binding globulin promoter in the MPS IVA murine model to evaluate the long-term (24 weeks in males and 48 weeks in females) effects of gene therapy on biochemical markers and bone pathology. Both treated groups showed GALNS enzyme activity at supraphysiological levels in plasma and in various tissues, including the liver, heart, spleen, and bone. Keratan sulfate in both groups was normalized in plasma, liver, and bone (male mice). Pathological analyses revealed a decrease in vacuolated cells in the heart muscle and valves and improvement in bone pathology in treated male mice. However, the therapeutic impact was less pronounced in treated female mice. Overall, male mice indicated a substantial improvement in biochemical parameters and pathology compared to female mice.
2025-11-22 | "Comprehensive Clinical Evaluation And Management Of Congenital Mucopolysacchariodosos type IVA: A Case Report"
This report outlines a brief clinical description of a 2-year-old boy diagnosed with Morquio syndrome (Mucopolysaccharidosis type IVA), a rare autosomal recessive lysosomal storage disorder. The disease results from a deficiency of the N-acetyl-galactosamine-6-sulfatase enzyme, causing the buildup of glycosaminoglycans. This accumulation leads to congenital malformations, disproportionate short stature, significant skeletal deformities, and multisystem involvement, while cognitive function generally remains intact. The case underscores the significance of early recognition, treatment options such as enzyme replacement therapy with Elosulfase alfa, and the necessity of comprehensive multidisciplinary management, genetic counseling, and regular follow-up. It further discusses diagnostic difficulties and explores emerging treatment strategies like gene therapy for managing these progressive hereditary metabolic conditions.
2025-10-15 | Recent advances in mucopolysaccharidosis IVA treatment.
Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is a rare lysosomal storage disorder caused by mutations in the GALNS gene, resulting in N-acetylgalactosamine-6-sulfatase (GALNS) deficiency and accumulation of keratan sulfate and chondroitin-6-sulfate. MPS IVA primarily affects the skeletal system, leading to progressive dysplasia and multi-organ involvement. Although enzyme replacement therapy (ERT) with elosulfase alfa is currently the only approved treatment, its clinical benefit on bone pathology is limited due to rapid clearance and poor penetration into avascular cartilage. Strategies to enhance enzyme stability and targeting, such as PEGylated hydrogels and extracellular vesicles, have shown promise in enhancing the biodistribution and stability of GALNS, while pharmacological chaperones, including ezetimibe, pranlukast, and bromocriptine, seem to stabilize GALNS in vitro. Promisingly, gene therapy (GT) has demonstrated significant preclinical progress using adeno-associated virus (AAV), lentiviral (LV), and CRISPR/Cas9 platforms. For instance, AAV vectors employing bone-targeting peptides and tandem promoters improve skeletal manifestations in murine and rat models. Similarly, recent ex vivo LV-based GT studies have opened new avenues in the treatment of MPS IVA. Furthermore, CRISPR/nCas9-based strategies targeting safe harbor loci have successfully restored GALNS activity in MPS IVA fibroblasts and mouse models supporting the notion that gene editing may represent a potential therapeutic approach. On the other hand, antisense-based therapies using modified U7 small nuclear RNAs and circular RNAs offer novel approaches to correct pseudoexon activation from deep-intronic variants while expanding the therapeutic alternatives in MPS IVA. Importantly, recent evidence revealed that mitochondrial dysfunction in chondrocytes may contribute to the pathology of MPS IVA, uncovering new targets beyond GALNS enzyme activity recovery. This review highlights recent advances in the treatment of MPS IVA and discusses new directions to improve outcomes in MPS IVA treatment.
2025-07-29 | Integrase-Deficient Lentiviral Vector as a Platform for Efficient CRISPR/Cas9-Mediated Gene Editing for Mucopolysaccharidosis IVA.
Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder causing systemic skeletal dysplasia due to a deficiency of N-acetyl-galactosamine-6-sulfate sulfatase (GALNS) enzyme activity, leading to the impaired degradation and accumulation of glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate. While treatments such as enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are available, they have significant limitations regarding efficacy in skeletal tissues and long-term safety, highlighting the need for more effective therapies. We evaluated a novel gene therapy approach using a dual Integrase-deficient lentiviral vector (IDLV) to deliver an expression cassette that includes human GALNS cDNA and Cas9 sgRNA, targeting the upstream region of the mouse Galns initial codon. This approach leverages the endogenous promoter to drive transgene expression. We assessed in vitro transduction, editing, and functional correction in NIH3T3 and MPS IVA mouse fibroblasts. In vivo efficacy was successfully evaluated via the facial vein injection in MPS IVA newborn mice. In vitro, this IDLV platform demonstrated supraphysiological GALNS activity in cell lysate, resulting in the normalization of KS levels. In vivo direct IDLV platform in newborn MPS IVA mice led to sustained plasma GALNS activity, reduced plasma KS, and favorable biodistribution. Partial correction of heart and bone pathology was observed, with no vector toxicity and minimal antibody responses. This dual IDLV-CRISPR/Cas9 approach effectively mediated targeted GALNS knock-in, yielding sustained enzyme activity, reduced KS storage, and partial pathological amelioration in MPS IVA mice. In conclusion, IDLVs represent an efficient, safe platform for delivering the CRISPR/Cas9 gene editing system for MPS IVA.
cell therapies
2026-09-11 | Haematopoietic stem cell transplant in a case of mucopolysaccharidosis IV with Fanconi anaemia and bone marrow failure.
Mucopolysaccharidosis type IV (MPS IV; Morquio syndrome) is a rare lysosomal storage disorder characterised by skeletal dysplasia and multisystem involvement, while Fanconi anaemia (FA) is an inherited bone marrow failure syndrome associated with chromosomal instability and hypersensitivity to conditioning agents. The coexistence of these two disorders poses a unique therapeutic challenge, particularly when haematopoietic stem cell transplantation (HSCT) is indicated. We report a child with MPS IV and FA who underwent HSCT with a non-myeloablative conditioning regimen. The procedure was carefully individualised to balance engraftment success with minimisation of toxicity. This case highlights the complexities of managing overlapping genetic conditions requiring HSCT and demonstrates the value of multidisciplinary planning and personalised transplant strategies in achieving favourable clinical outcomes.
2026-04-28 | Long-Term Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Mucopolysaccharidosis IVA: A 10-Year Follow-Up from a Single-Center Experience in China.
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potential approach for pediatric mucopolysaccharidosis IVA (MPS IVA). However, delayed diagnosis and higher transplant-related complications have limited its broader use. This study investigated treatment-related benefit and up to 10-year outcomes following HSCT in children with MPS IVA. Study Design We retrospectively analyzed 19 pediatric patients with a severe phenotype of MPS IVA who underwent HSCT between January 2015 and July 2025. N-acetylgalactosamine-6-sulfatase (GALNS) enzyme activity, height growth, and organ dysfunction (cardiac, auditory, and visual) was evaluated to analyze the benefit of HSCT. The donor sources include human leukocyte antigen (HLA)-matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT, n = 5), HLA-matched unrelated donor PBSCT (MUD-PBSCT, n = 7), and single-unit unrelated umbilical cord blood transplantation (UD-UCBT, n = 7). The overall survival rate was 94.7% (18/19), apart from 1 mortality due to pulmonary infection. All surviving patients achieved full donor engraftment and durable restoration of GALNS activity. There is no severe graft-versus-host disease (GVHD) was observed. The majority of patients exhibited no deterioration in auditory, visual, respiratory, or cardiac function. During the long-term follow-up period, our cases showed a continued linear growth post-HSCT. Here we demonstrated the data of our HSCT experience in MPS IVA with the safety and efficacy of HSCT. More data with an expanded patient cohort are imperative to delineate the capacity of HSCT to repair severe skeletal manifestations in MPS IVA.
2026-03-05 | Development and characterization of a model of mucopolysaccharidosis type IVA for evaluating therapies targeting bone disease.
Mucopolysaccharidosis type IVA (MPSIVA) is a lysosomal storage disease (LSD) caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which causes the accumulation of keratan sulphate (KS) and chondroitin sulphate (CS). Patients with MPSIVA typically present with severe skeletal and joint disorders, which are not addressed by conventional therapies. Currently, no animal model accurately replicates the human disease, hindering the development of novel therapeutic interventions. To overcome this limitation, we established, by CRISPR-Cas9 technology, a Galns-/- mouse model that expresses a non-functional enzyme and accumulates CS and KS in the urine, plasma and distinct tissues, and glycosaminoglycans in the spleen. The mice exhibit shortened long bones, trabecular bone alterations and skeletal abnormalities in the growth plate. Additionally, we observed increased levels of inflammatory and oxidative markers in visceral organs and plasma. Our newly developed model of MPSIVA demonstrates clear and quantifiable signs of skeletal alterations, providing novel means of assessment of the safety and efficacy of innovative therapies, including hematopoietic stem and progenitor cell gene therapy, which has recently been shown to provide a beneficial effect on skeletal alterations in Hurler syndrome.
2026-01-31 | Allogeneic Hematopoietic Cell Transplantation for Morquio A Syndrome: An International Retrospective Study.
Mucopolysaccharidosis IV A (MPS IVA) or Morquio A syndrome is a lysosomal storage disorder that results from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), causing deposition of glycosaminoglycans, keratan sulfate, and chondroitin-6-sulfate in multiple organs. The main clinical manifestations include severe short stature, severe cervical spine stenosis, and progressive skeletal dysplasia, which leads to severe mobility limitation resulting in patients becoming wheelchair-bound in their second decade of life, and overall shortened life span. The current standard of care for Morquio A is weekly enzyme replacement therapy (ERT). However, ERT is expensive, not widely available worldwide, and offers limited long-term benefits. Allogeneic hematopoietic cell transplantation (HCT) is a way to provide a life-long endogenous enzyme and has the potential to improve outcomes. The main objectives of this study were to investigate the safety and assess the benefits of allogeneic HCT in the treatment of patients with Morquio A. We performed a retrospective study of 41 patients who underwent allogeneic HCT at 9 international centers. Forty-one patients with Morquio A received allogeneic HCT. Three patients experienced graft failure and underwent second transplants. Most (77%) of the transplants were performed using either matched or mismatched unrelated donors, and 71% of the transplants utilized peripheral blood stem cells as the graft source. The overall 3-year survival rate was 90.5%. Graft-versus-host disease (GVHD) was a direct or indirect contributor to mortality in 3 out of 4 patients. The median myeloid engraftment was 100% at the last follow-up, with a median follow-up of 3 years; the median times for neutrophil and platelet engraftment were 12 and 13 days, respectively. The incidence of grade II to IV acute GVHD was 35.5%. Interestingly, in patients who had received pretransplant ERT, the incidence of acute grade II to IV GVHD was 14.9%, compared to 45% in those who had not received pretransplant ERT (P = .075). The incidence of grades III to IV acute and chronic GVHD was 14.2% and 12.7%, respectively. When available, disease-specific outcomes showed complete to near normalization of metabolic biomarkers, as well as improvement in movement scores, stability of heart function, eyes, and cervical spine stenosis. Notably, in patients transplanted below the age of 3 years, growth continued in 6 out of 8 patients, while this effect was less notable in the older cohort. Allogeneic HCT for patients with Morquio A is safe and feasible. This treatment can potentially lead to significantly improved biochemical markers of the disease, preservation of organs, and better clinical manifestations. Additionally, when performed at a young age, ideally before the age of 3 years, allogeneic HCT may result in improved growth. The use of bone marrow as a stem cell source whenever possible, combined with effective GVHD prophylaxis, may enhance transplant success and disease-related outcomes. Long-term benefits and risks require further investigation.
2025-03-19 | Allogeneic hematopoietic stem cell transplantation for mucopolysaccharidosis patients: a single-center experience and assessment of quality of life.
Allogeneic hematopoietic stem cell transplantation (HSCT) has proven to be a viable treatment option for patients with mucopolysaccharidoses (MPS). We investigate the efficacy and improvements in the quality of life of HSCT in pediatric patients with MPS. A retrospective analysis of transplantation data from 46 cases of MPS from a single institution in China was conducted. The cohort of 46 patients included 9 cases of MPS I, 16 cases of MPS II, 15 cases of MPS IVA and 6 cases of MPS VI. The median age at diagnosis was 2.59 years. The median age at transplantation was 3.80 years. The median follow-up time was 3.1 years (range, 0.8-8.1 years) and 43 patients were alive. The incidence of grades II to IV aGVHD was 17.4%, wherein the incidence of grades III and IV aGVHD was 4.3%. The incidence of moderate-to-severe cGVHD was 6.5%. GAGs urinary excretion decreased and enzyme activity levels reached normal. After HSCT, multiple bone dysplasia, upper-airway obstruction and recurrent otitis media were significantly improved; vision, corneal clouding, cardiovascular disease, hepatosplenomegaly and hydrocephalus were improved or remained stable; neurological symptoms were improved or remained stable in most patients but progressed in others; the patients with MPS IH/S and MPS II reached nearly normal growth rate of height and weight. Meanwhile, the patients with MPS IH, MPS IVA and MPS VI remained poor growth after HSCT. The Activities of Daily Living (ADL) scores were improved in most patients with MPS. ADL scores in patients with severe phenotypes were lower than health control subjects and patients with attenuated phenotypes. HSCT is a good therapeutic option for MPS and improves the quality of life of patients. MPS patients with attenuated phenotypes provide a better outcome in ADL after HSCT.
small molecules
2026-03-30 | Ultrasound-guided one-point puncture lumbosacral plexus block combined with laryngeal mask airway general anesthesia for thigh amputation in a patient with mucopolysaccharidosis: a case report.
Mucopolysaccharidosis (MPS) is a group of rare inherited lysosomal storage disorders caused by deficiencies of specific enzymes, leading to abnormal accumulation of glycosaminoglycans in tissues throughout the body. It is often associated with a difficult airway, cervical spine instability, restrictive pulmonary dysfunction, and cardiovascular pathologies, which significantly increase perioperative risks. This manuscript reports a case of a 36-year-old male MPS patient (clinical phenotype highly suggestive of type IV) who underwent right mid-to-upper thigh amputation for a pathological fracture of the right femur. Given his potential difficult airway (Mallampati class III, thyromental distance <6 cm), mild kyphosis, and restrictive pulmonary dysfunction, the anesthetic plan consisted of an ultrasound-guided one-point puncture, dual-target lumbosacral plexus block (35 mL of 0.15% ropivacaine) combined with supraglottic airway (laryngeal mask airway, LMA) under general anesthesia. The block successfully provided an L2-S3 sensory level and served as the basis for postoperative multimodal analgesia. The surgery lasted 2 h with 500 mL blood loss, requiring 2 units of red blood cells. Hemodynamics remained stable, and no additional muscle relaxants were administered. The patient regained consciousness and the LMA was removed 10 min postoperatively. The Numerical Rating Scale (NRS) pain scores at 2, 6, 12, and 24 h postoperatively were 2, 3, 2, and 1, respectively. Functional exercise began on postoperative day 1 without major complications. The patient was discharged 15 days after surgery and was hospitalized for a total of 18 days. With strict patient selection and thorough preparation of emergency airway protocols, combining an LMA with an ultrasound-guided one-point puncture lumbosacral plexus block can be a safe and feasible individualized anesthetic strategy for lower limb proximal surgery in MPS patients. This approach helps avoid intubation risks, reduces opioid consumption, and promotes early recovery. However, due to the considerable difficulty of airway management in patients with MPS, elective surgery requires multidisciplinary consultation and comprehensive airway assessment to ensure perioperative safety.
2026-03-02 | Computational Prediction of Deleterious SNPs in the GALNS Gene Implicated in Morquio A Syndrome (MPS IVA).
Morquio syndrome A, also known as mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disorder resulting from mutations in the gene responsible for N-acetylgalactosamine-6-sulfatase. The deficiency of this enzyme impairs the degradation of glycosaminoglycans, particularly chondroitin 6-sulfate and keratan sulfate. This research uses a variety of computational techniques for analyzing the GALNS variants mainly causing child death and to provide better healthcare. The variants were collected from research sources, such as PubMed, ResearchGate, and ScienceDirect, along with databases like HGMD, ClinVar, and UniProt. The analysis of the conservation, pathogenicity, and stability of the variations was conducted utilizing algorithms such as ConSurf, PredictSNP, and iStable. Structural analysis was carried out using the PDB databank and PyMOL software. Molecular docking was used to study the interaction of native and variant GALNS proteins with Ezetimibe. GROMACS was used to simulate the behavior of the GALNS protein with variants and Ezetimibe binding in docked complexes for over 100 ns. A total of 345 SNP variants were retrieved, of which D40H, C79R, and C79L variants were identified to be highly deleterious after conservation (75 SNPs), pathogenicity (5 SNPs), and biophysical and stability (3 SNPs) analysis. During docking, the native protein demonstrated a strong binding affinity of -8.54 kcal/mol for the drug. The C79R variant displayed a binding affinity of -8.41 kcal/mol, while the C79L and D40H variants showed affinities of -7.07 and -7.92 kcal/mol, respectively. MD simulations of the native and variant structures showed similar ligand binding flexibility and stability, confirmed by RMSD, RMSF, H-bond, and gyration plots. The increased binding affinity and stability of both complexes suggest that Ezetimibe has comparable therapeutic effects for both the native and variant forms. This work provides detailed structural and dynamic insights into the GALNS protein, paving the way for further research and new treatments for Morquio syndrome A.
2025-09-04 | Case report: Successful treatment of a patient presenting with a very rare association of acute lymphoblastic leukemia and mucopolysaccharidosis type IVA
Treating Acute Lymphoblastic Leukemia (ALL) in patients with genetic disorders poses significant challenges for onco-hematologists. Mucopolysaccharidosis type IVA (MPS-IVA) is a lysosomal storage disorder that clinically manifests with progressive and multi-systemic comorbidities, primarily affecting the bone, cartilage, spine, heart and lungs. We report a unique case of B-lineage ALL in a patient with MPS-IVA, who was successfully cured with a personalized chemo-radiotherapy approach. The treatment strategy aimed to balance a curative-intent chemotherapy attempt with the minimization of life-threatening complications. This case highlights the importance of individualized therapy in managing ALL in the context of complex comorbidities.
2025-05-28 | Exploring Multivalent Architectures for Binding and Stabilization of N-Acetylgalactosamine 6-Sulfatase.
Morquio A syndrome is a lysosomal disorder caused by the deficiency of the lysosomal enzyme N-acetylgalactosamine 6-sulfatase (GALNS, EC 3.1.6.4). Currently, enzyme replacement therapy (ERT) is used to treat Morquio A through the infusion of the recombinant enzyme VIMIZIM® (elosulfase alfa, BioMarin). Unfortunately, the recombinant enzyme exhibits low conformational stability in vivo. A promising approach to address this issue is the coadministration of recombinant human GALNS (rhGALNS) with a pharmacological chaperone (PC), a molecule that selectively binds to the misfolded protein, stabilizes its conformation, and assists in the restoration of the impaired function. We report in this work the synthesis of a library of multivalent glycomimetics exploiting the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between several dendrimeric scaffolds armed with terminal alkynes and azido ending iminosugars of different structures (pyrrolidines, piperidines, and pyrrolizidines) or simple azido ending carbohydrates as bioactive units. The biological evaluation identified pyrrolidine-based nonavalent dendrimers 1 and 36 as the most promising compounds, able both to bind the native enzyme with IC50 in the micromolar range and to act as enzyme stabilizers toward rhGALNS in a thermal denaturation study, thus identifying promising compounds for a combined PC/ERT therapy.
2025-05-26 | Heliox in the management of respiratory failure in a Morquio A syndrome patient with trachea narrowing.
Morquio A Syndrome is a mucopolysaccharide deposition disease where patients can develop respiratory failure due to airway narrowing by polysaccharide deposition, anatomical distortion and compression of the airway. Definitive management with surgery is high risk, only performed in the highly specialized centers, and by the time they develop respiratory failure they may not be a candidate for surgery due to difficulty intubation. Consequently, they often end up with long term BiPAP dependent and suffer from side effects of abdominal, facial pain and depression. Heliox is low density gas mixture which can facilitate oxygen delivery in narrowed airway. Here we report a case of Morquio A syndrome patient with 24-h BiPAP dependence and successfully treated with Heliox and weaned off BiPAP for 4 hours a day with improved quality of life.
proteins
2026-09-28 | Differential Diagnosis of Mucopolysaccharidoses Types I, II, III, IVA, and VI Through Analysis of Leukocytic Inclusions.
Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs), which can lead to cytoplasmic alterations in leukocytes. The objective of this study was to characterize leukocyte inclusions in patients with different types of MPS and assess their diagnostic relevance. A total of 69 Brazilian patients diagnosed with five MPS types were evaluated through cytological analysis of peripheral blood smears. Distinct leukocyte inclusion patterns were observed in four subtypes. In MPS Type II, small violet cytoplasmic inclusions were present in lymphocytes. In MPS Type III, larger violet inclusions were identified in lymphocytes. Patients with MPS Type IVA showed large, sparse granulations in neutrophils, while those with MPS Type VI exhibited coarse inclusions in all leukocytes, characteristic of the Alder-Reilly anomaly. No leukocyte inclusions were found in MPS Type I. These observations demonstrate that leukocyte inclusions vary according to MPS subtype and may represent a useful auxiliary cytological finding. Their identification may support diagnostic suspicion and contribute to the differential diagnosis of MPS II, III, IVA, and VI, complementing enzymatic and biochemical testing.
2026-03-05 | P044: First report of GLP-1 agonist use in MCAD deficiency
Case Presentation: A 29-year-old Hispanic female presented with a clinical and biochemical diagnosis of MPSIVA.She has short stature, mild corneal clouding, pectus carinatum, required multiple knee surgeries and her x-ray showed bullet shaped vertebrae.This individual had two affected siblings with MPSIVA who are unavailable for testing.Her mother is mildly affected and presents with corneal clouding and short stature.Diagnostic Workup: This individual initially had an LSD panel which identified one pathogenic variant in the GALNS gene, c.107T>C, which was insufficient to explain the patient's phenotype.ES with RNA-seq was ordered.RNA-seq analysis identified an 11 bp deletion in an alternative transcript (NM_001323544.2), leading to frameshift: p.(Gly43Aspfs*5).This aberrant transcript was a consequence of a single nucleotide change (c.121-210C>T) located in intron 1 and is 210 bp upstream of the splice acceptor site for exon 2 in the MANE transcript (NM_000512.5).As this variant is located at the startproximal nonsense-mediated mRNA decay insensitivity region, re-initiation of translation at the next in-frame start codon (p.47) is possible.This variant was originally classified as likely benign (LB) due to being observed at a frequency of 0.31% (523/166064 alleles) with the highest frequency noted in the African subpopulation at 3.05% in the gnomAD database.However, this variant has also been reported in the compound heterozygous and homozygous state in four individuals with MPSIVA and has been classified as a "Potentially Disease Associated Mutation" in the Human Gene Mutation Database.Based on the RNA-seq analysis and other affected individuals identified with this variant, the lab was able to upgrade the variant from LB to a variant of uncertain significance (VUS) and may represent a hypomorphic allele.Outcome and Follow-Up: The provider was able to provide this individual with a molecular diagnosis of MPSIVA based on the detection of two GALNS variants.Since then, we have tested the mildly affected mother who was found to be homozygous for the c.121-210C>T variant with consistent RNA-seq results to the proband.This strengthens the understanding that this is a hypomorphic allele.Testing the proband's siblings is still recommended. Conclusion:The use of ES with RNA-seq was able to identify a variant that was -210 nucleotides upstream of the splice acceptor site and lead to an upgrade in variant classification from LB to VUS.This highlights the diagnostic advantages of using RNA-seq over standard DNA-only testing methodology.RNAseq can aid in identifying aberrant splicing, mono-allelic expression, and aberrant expression which can increase diagnostic yield.Having a molecular diagnosis can provide individuals with different treatment options, including possible GT enrollment, and family planning options.
2025-05-22 | A Rare Case of Morquio Syndrome in Palestine: Clinical, Radiological, and Genetic Insights.
Morquio A syndrome, also known as mucopolysaccharidosis type IVA (MPS IVA), is a rare lysosomal storage disorder that mostly affects the skeletal system. It spares cognitive function but causes short stature, increasing deformities and anomalies in the joints, as well as respiratory, cardiac, dental, hearing, and vision problems. This report describes a six-year-old boy with growth retardation and skeletal deformities, and highlights the characteristic clinical features, diagnostic approach, and challenges in the management of MPS IVA, emphasizing the importance of early recognition and comprehensive treatment strategies to optimize patient outcomes.
2025-03-01 | A Case Report of Cardiac Ascites in Morquio Syndrome Complicated by Pulmonary Hypertension
Morquio syndrome, or mucopolysaccharidosis type IV (MPS IV), is a rare lysosomal storage disorder characterized by skeletal dysplasia and dysostosis multiplex. While primarily associated with skeletal manifestations, MPS IV can also affect systemic organs. Here, we present a case of a 64-year-old woman with MPS IVC who presented with cardiac ascites. The patient's disease course was characterized by idiopathic pulmonary hypertension to cor pulmonale and subsequent cardiac ascites formation. Utilizing paracentesis with cytology as well as an analysis of the patient's clinical history and disease progression, we provide insights into the interplay between Morquio syndrome and cardiac ascites.
2024-08-26 | Diminished GALNS activity in induced pluripotent stem cells of mucopolysaccharidosis IVA caused by compound p.S162Y and p.C165F mutation.
Mucopolysaccharidosis (MPS) IVA is a lysosomal storage disorder caused by mutations in the gene encoding the galactosamine (N-acetyl)-6-sulfatase (GALNS) enzyme. Children with MPS IVA usually develop pectus carinatum, genu valgum and multiple skeletal abnormalities. To establish a patient-derived induced pluripotent stem cell (iPSC) disease model to investigate the effects of two GALNS missense mutations. The medical history and clinical manifestations of a patient with MPS IVA were first inspected. The effects of the identified GALNS mutations were predicted through bioinformatic analysis. iPSCs were then generated by using Sendai virus to introduce Yamanaka reprogramming factors to urinary cells isolated from the patient. The pluripotency, karyotypic integrity, genetic mutations and differentiation ability of the iPSCs were tested. The effects of the GALNS mutations were further experimentally characterized using patient-derived cells. The patient exhibited a typical MPS IVA phenotype. Enzyme replacement therapy could not correct her skeletal abnormalities. GALNS c.485C>A (p.S162Y) and c.494G>T (p.C165F) mutations, inherited from her father and mother, respectively, were identified in the patient. These two mutations were predicted to disturb the hydrophobic core of the GALNS catalytic domain. Patient-derived iPSCs were successfully generated, and further characterization indicated that the two missense mutations significantly diminished GALNS activity without affecting its amount at both the RNA and protein levels. We established a novel clinically relevant MPS IVA disease model that will be useful not only for investigating the pathogenic mechanisms of MPS IVA variants but also for drug screening and preclinical evaluation of novel therapies.
gene therapies
2026-01-30 | Collagen Type II-Targeting Lentiviral Gene Therapy for Mucopolysaccharidosis IVA.
Mucopolysaccharidosis (MPS IVA) is caused by pathogenic variations in the GALNS gene, leading to the accumulation of glycosaminoglycans in tissues and causing progressive skeletal lesions. While conventional lentiviral vectors (LVs) provide long-term stable expression, they do not deliver therapeutic levels to bone and cartilage. We hypothesized that engineering the LV envelope with a collagen type II-targeting peptide (WYRGRL) increases the binding affinity of the LVs for bone and cartilage. These modified vectors carrying the CBh and COL2A1 promoters delivered the GALNS gene to MPS IVA newborn mice via intravenous (IV) or intraarticular (IA) administration. The peptide-modified LVs exhibited markedly increased uptake in the liver when administered IV, but lower enzyme activity than that of the conventional vector. The modified WYRGRL-LV-COL2A1 vector elevated GALNS activity in other tissues, suggesting systemic benefits. When administered IA, the modified vectors showed potential for local treatment due to the WYRGRL peptide-mediated uptake. Additionally, there was a reduction in keratan sulfate glycosaminoglycan levels in plasma and tissues, indicating that this peptide can be a suitable candidate for disease modification. These findings pave the way for further preclinical and clinical studies, offering new possibilities for the development of targeted therapies for skeletal diseases.
2025-11-26 | Long-Term Liver-Targeted AAV8 Gene Therapy for Mucopolysaccharidosis IVA.
Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease with an autosomal recessive trait caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme, which leads to the accumulation of chondroitin-6-sulfate and keratan sulfate, primarily in cartilage and its extracellular matrix, resulting in a direct impact on cartilage and bone development, as well as subsequent systemic skeletal dysplasia. ERT and HSCT are current treatment options, but they have a limited effect on bone lesions. In this article, we investigated liver-specific AAV8 vectors with a thyroxine-binding globulin promoter in the MPS IVA murine model to evaluate the long-term (24 weeks in males and 48 weeks in females) effects of gene therapy on biochemical markers and bone pathology. Both treated groups showed GALNS enzyme activity at supraphysiological levels in plasma and in various tissues, including the liver, heart, spleen, and bone. Keratan sulfate in both groups was normalized in plasma, liver, and bone (male mice). Pathological analyses revealed a decrease in vacuolated cells in the heart muscle and valves and improvement in bone pathology in treated male mice. However, the therapeutic impact was less pronounced in treated female mice. Overall, male mice indicated a substantial improvement in biochemical parameters and pathology compared to female mice.
2025-11-22 | "Comprehensive Clinical Evaluation And Management Of Congenital Mucopolysacchariodosos type IVA: A Case Report"
This report outlines a brief clinical description of a 2-year-old boy diagnosed with Morquio syndrome (Mucopolysaccharidosis type IVA), a rare autosomal recessive lysosomal storage disorder. The disease results from a deficiency of the N-acetyl-galactosamine-6-sulfatase enzyme, causing the buildup of glycosaminoglycans. This accumulation leads to congenital malformations, disproportionate short stature, significant skeletal deformities, and multisystem involvement, while cognitive function generally remains intact. The case underscores the significance of early recognition, treatment options such as enzyme replacement therapy with Elosulfase alfa, and the necessity of comprehensive multidisciplinary management, genetic counseling, and regular follow-up. It further discusses diagnostic difficulties and explores emerging treatment strategies like gene therapy for managing these progressive hereditary metabolic conditions.
2025-10-15 | Recent advances in mucopolysaccharidosis IVA treatment.
Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is a rare lysosomal storage disorder caused by mutations in the GALNS gene, resulting in N-acetylgalactosamine-6-sulfatase (GALNS) deficiency and accumulation of keratan sulfate and chondroitin-6-sulfate. MPS IVA primarily affects the skeletal system, leading to progressive dysplasia and multi-organ involvement. Although enzyme replacement therapy (ERT) with elosulfase alfa is currently the only approved treatment, its clinical benefit on bone pathology is limited due to rapid clearance and poor penetration into avascular cartilage. Strategies to enhance enzyme stability and targeting, such as PEGylated hydrogels and extracellular vesicles, have shown promise in enhancing the biodistribution and stability of GALNS, while pharmacological chaperones, including ezetimibe, pranlukast, and bromocriptine, seem to stabilize GALNS in vitro. Promisingly, gene therapy (GT) has demonstrated significant preclinical progress using adeno-associated virus (AAV), lentiviral (LV), and CRISPR/Cas9 platforms. For instance, AAV vectors employing bone-targeting peptides and tandem promoters improve skeletal manifestations in murine and rat models. Similarly, recent ex vivo LV-based GT studies have opened new avenues in the treatment of MPS IVA. Furthermore, CRISPR/nCas9-based strategies targeting safe harbor loci have successfully restored GALNS activity in MPS IVA fibroblasts and mouse models supporting the notion that gene editing may represent a potential therapeutic approach. On the other hand, antisense-based therapies using modified U7 small nuclear RNAs and circular RNAs offer novel approaches to correct pseudoexon activation from deep-intronic variants while expanding the therapeutic alternatives in MPS IVA. Importantly, recent evidence revealed that mitochondrial dysfunction in chondrocytes may contribute to the pathology of MPS IVA, uncovering new targets beyond GALNS enzyme activity recovery. This review highlights recent advances in the treatment of MPS IVA and discusses new directions to improve outcomes in MPS IVA treatment.
2025-07-29 | Integrase-Deficient Lentiviral Vector as a Platform for Efficient CRISPR/Cas9-Mediated Gene Editing for Mucopolysaccharidosis IVA.
Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder causing systemic skeletal dysplasia due to a deficiency of N-acetyl-galactosamine-6-sulfate sulfatase (GALNS) enzyme activity, leading to the impaired degradation and accumulation of glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate. While treatments such as enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are available, they have significant limitations regarding efficacy in skeletal tissues and long-term safety, highlighting the need for more effective therapies. We evaluated a novel gene therapy approach using a dual Integrase-deficient lentiviral vector (IDLV) to deliver an expression cassette that includes human GALNS cDNA and Cas9 sgRNA, targeting the upstream region of the mouse Galns initial codon. This approach leverages the endogenous promoter to drive transgene expression. We assessed in vitro transduction, editing, and functional correction in NIH3T3 and MPS IVA mouse fibroblasts. In vivo efficacy was successfully evaluated via the facial vein injection in MPS IVA newborn mice. In vitro, this IDLV platform demonstrated supraphysiological GALNS activity in cell lysate, resulting in the normalization of KS levels. In vivo direct IDLV platform in newborn MPS IVA mice led to sustained plasma GALNS activity, reduced plasma KS, and favorable biodistribution. Partial correction of heart and bone pathology was observed, with no vector toxicity and minimal antibody responses. This dual IDLV-CRISPR/Cas9 approach effectively mediated targeted GALNS knock-in, yielding sustained enzyme activity, reduced KS storage, and partial pathological amelioration in MPS IVA mice. In conclusion, IDLVs represent an efficient, safe platform for delivering the CRISPR/Cas9 gene editing system for MPS IVA.
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Drug Discovery Landscape
7 orphan drug designations for Mucopolysaccharidosis type 4A, including 2 approved therapies.
7 orphan drug designations for Mucopolysaccharidosis type 4A, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
adeno-associated virus 8 vector expressing functional human cDNA encoding the N-acetylgalactosamine-6-sulfate sulfatase | gene therapies | FDA | — | National Center for Advancing Translational Sciences, National Institutes of Health |
Autologous CD34+ haematopoietic stem and progenitor cells genetically modified with a lentiviral vector encoding for the N-acetylgalactosamine 6-sulfatase cDNA | gene therapies | EMA | — | Fondazione Telethon Ets |
Adeno-associated virus serotype 9 vector containing human Nacetylgalactosamine-6-sulfate sulfatase gene | gene therapies | FDA | — | Esteve Pharmaceuticals, S.A. |
Adeno-associated virus serotype 9 vector containing human N-acetylgalactosamine-6-sulfate sulfatase gene | gene therapies | EMA | — | Esteve Pharmaceuticals S.A. |
Elosulfase alfa [Vimizim] | proteins | EMA | Approved | Biomarin International Limited |
elosulfase alfa [Vimizim] | proteins | FDA | Approved | BioMarin Pharmaceutical Inc. |
N-terminal hexaglutamine-tagged recombinant human N-acetylgalactosamine-6-sulfate sulfatase | proteins | EMA | — | Granzer Regulatory Consulting & Services GmbH |
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