Natural history of hearing loss in adults with mucopolysaccharidoses across phenotype and genotype.

Almost all patients with mucopolysaccharidosis (MPS) develop respiratory dysfunction of varying severity during disease progression. While respiratory disease in MPS has traditionally been attributed to upper airway obstruction caused by glycosaminoglycan (GAG) accumulation in the trachea and bronchi, involvement of the intrapulmonary conducting airways and lung parenchyma remains poorly defined. Here, we characterised lung disease in a mouse model of MPS I using a combination of non-invasive X-ray Velocimetry (XV) functional lung imaging and gold-standard flexiVent respiratory mechanics testing, complemented by lung volume measurements and histological analysis. XV provides regional ventilation information across the entire lung during tidal breathing. MPS I mice demonstrated reduced mean specific ventilation (the average regional expansion of lung tissue across the respiratory cycle), driven predominantly by reduced ventilation in the inner (mediastinal-adjacent) lung regions, with evidence of spatially heterogeneous ventilation distribution. Lung mechanics testing showed increased conducting airway resistance, increased respiratory system compliance and reduced tissue elastance, consistent with impaired elastic recoil and expiratory flow limitation. Lung volume analysis revealed reduced opening pressure following degassing together with increased residual volume, functional residual capacity and vital capacity. Histological analysis demonstrated heterogeneous parenchymal architecture with regions of enlarged airspaces. Together, these findings demonstrate that respiratory dysfunction in MPS I is not limited to upper airway obstruction but also involves intrinsic abnormalities of the intrapulmonary conducting airways and lung parenchyma. This intrinsic pulmonary pathology likely contributes to obstructive lung disease and may underlie the susceptibility to respiratory failure observed in patients with MPS I.

The LYSET gene encodes the LYSET transmembrane protein, which regulates lysosome biogenesis by activating the mannose-6-phosphate (M6P) pathway. This is an autosomal recessive, ultrarare, and severe progressive skeletal dysplasia with coarse facies, distended abdomen, short stature, and severe physical disability. In a diagnostic odyssey, we report a female patient, born in 2008, daughter of consanguineous parents, with hand contractures and a typical facial appearance since 5 months old. She was clinically diagnosed at 2 years old with contractures and severe dysplasia. Systolic murmur, thickening of mitral and aortic valves, and tricuspid regurgitation were observed. Nine enzymes showed increased levels in plasma, and seven showed decreased levels in fibroblasts. Abnormal sialic acid profile and GAGs (glycosaminoglycans) were detected in urine. No variants were identified during more than a decade of investigation. A whole-genome analysis identified the homozygous nonsense variant NM_001098621.4:c.112C>T (p.Gln38Ter) in the LYSET gene. The patient had not been diagnosed before due to the recent association of the gene with the lysosomal hydrolase labeling pathway. She died in 2018 from respiratory causes. The discovery of the relationship between the LYSET gene and lysosomal biogenesis was determinative of the diagnostic conclusion. Cases of dysostosis multiplex can be highly challenging due to the rarity of the disease and its clinical similarity to mucopolysaccharidosis (MPS) and mucolipidosis II/III (MLII/III). This is the first western report of a challenging case of an extensive diagnostic odyssey and demonstrates that the LYSET gene must be considered in the differential diagnosis when M6P-labeled lysosomal enzymes are altered.

Mucopolysaccharidoses (MPS) are severe, inherited metabolic diseases, classified among lysosomal storage diseases (LSDs). The presence of pathological variants of genes coding for enzymes involved in the degradation of glycosaminoglycans (GAGs) is a primary cause of each MPS type, and accumulation of these compounds is a characteristic feature of MPS. Depending on the kind of defective enzyme and the type of stored GAG(s), 12 classical types are distinguished, and a few other related diseases, whose classification is unclear. Although there is no fully effective cure for MPS, several kinds of therapeutic approaches have been proposed to treat these diseases, and some of them have been introduced into clinical practice. In this review article, we present and discuss very recent advances in developing various therapies for MPS, also indicating problems and limitations. This paper focuses on enzyme replacement therapy (ERT), cell- and gene-based therapies (including hematopoietic stem cell transplantation and gene therapy), inhibition of GAG synthesis, and some other newly developed therapeutic approaches. Perspectives on MPS therapies are also discussed.

Musculoskeletal abnormalities are common to mucopolysaccharidoses (MPS) and can negatively affect the patient's quality of life. Data on course of musculoskeletal findings of MPS type IVA and VI are very insufficient. This study aimed to document the effect of regular enzyme replacement therapy (ERT) on musculoskeletal system and quality oflife. Patients diagnosed with MPS type IVA and VI aged≥5years who were observed in the paediatric metabolic diseases' outpatient clinic and physical medicine and rehabilitation clinic of our centre were evaluated. The musculoskeletal examination was performed with paediatric walking arms, legs and spine system (pGALS) and quality of life was evaluated using the Paediatric Outcome Data Collection Instrument (PODCI)scale. A total of 14 patients were followed in 24months. Six of them were diagnosed with MPS type IVA while eight of them were diagnosed with MPS type VI. Mean current age was 11.57±4.91 years, mean age at diagnosis was 2.83±2.71years and the mean age at ERT initiation was 4.33±3.49years for all patients. There were no significant differences between the initial and final PODCI scores. The pGALS examination showed that there has been a significant decrease in lower extremity pathology scores from 3.53±2.10 to 1.76±1.23 (p=0.03) and a decrease in total pGALS scores from 12.30±5.02 to 9.92±4.55 (p=0.00) while there were no significant changes in upper extremity and spine pathology scores. Current treatment regimens provide partial stabilization of musculoskeletal pathologies in patients with MPS, but do not lead to an improvement in quality of life in this aspect.

Mucopolysaccharidosis (MPS) are a group of inherited lysosomal storage genetic disorders that affect the body's ability to break down glycosaminoglycans (GAGs) due to the deficiency of required enzymes. This leads to depositions of these GAGs in various tissues and organs resulting in multi-systemic manifestations including pulmonary and sleep related issues. In recent years, there have been significant advancements in therapeutic options and supportive management which have led to the overall improvement in respiratory care, culminating in improved quality of life for MPS patients. Management of pulmonary and sleep disorders in mucopolysaccharidosis requires a multidisciplinary approach due to the multi-systemic affectation of the genetic disorders. Therapeutic options such as enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) have yielded varying success in mitigating respiratory complications. Emerging treatments such as gene therapies have shown exciting and promising results thus far. Supportive therapies such as airway clearance, regular vaccination and use of positive airway pressure devices are also essential. Pre-operative airway and anesthesia planning is critical to mitigate peri-operative and post-operative complications. Early diagnosis, close monitoring and a patient focused individualized approach are essential for respiratory optimization and overall improvement in clinical outcomes. This review article aims to discuss these advancements in a comprehensive format, making it accessible to medical providers who care for this subset of patients.

Mucopolysaccharidoses (MPS) are disease characterized by the accumulation of glycosaminoglycans, which leads to involvement of multiple systems. Respiratory involvement can lead to obstructions, causing difficulties with daily vital functions and sleep problems. This study aims to assess the sleep quality and disorders of patients with MPS using questionnaires. The study comprised 24 patients diagnosed with MPS and 44 healthy children aged between 6 and 18years. Patients' age, gender, height, weight, MPS subtype, age at diagnosis, enzyme replacement therapy status, and respiratory system findings (recurrent infections, snoring, adenotonsillar hypertrophy) were recorded. The Sleep Disturbance Scale for Children (SDSC) and the Pittsburgh Sleep Quality Index (PSQI) questionnaires were administered to both groups in order to assess sleep quality and disorders. According to the SDSC, sleep onset and maintenance disorders, sleep breathing disorders, sleep-wake transition disorders, excessive sleepiness disorders, sleep hyperhidrosis, and the total SDSC scores were higher in the patient group. According to the PSQI, sleep quality, sleep disturbance, daytime dysfunction, and the total PSQI scores were higher in the patient group. No significant differences were found in SDSC and PSQI total scores according to MPS subtypes. Sleep problems are frequently unnoticed, yet they can have a considerable impact on the quality of life of patients with MPS. In this context, the SDSC and PSQI questionnaires can be utilized to swiftly and cost-effectively screen for sleep problems in patients with MPS. This facilitates the timely identification of sleep disorders, thus enabling the implementation of appropriate preventative measures.

This study compares the outcomes of tension-band plates (TBP) correction of angular deformities in patients with Hurler and Morquoio syndromes mucopolysaccharidoses (MPS) to those with idiopathic etiologies. A retrospective analysis of patients aged less than 18 at a single institution who received TBP between 2005 and 2017 for valgus angular deformities was conducted. Inclusion criteria were patients with complete data and MPS or idiopathic etiology. Femoral and tibial deformities were evaluated independently. Postsurgical X-rays were reported at 6-month intervals. Statistical significance was determined by Mann-Whitney and χ2 tests. Twenty-nine patients were included: Hurler syndrome (8), Morquio syndrome (1), and idiopathic (20). Femoral TBP corrections at 1 year were 4.9° (MPS) and 11.2° (idiopathic); total degrees of correction were 7.3° (MPS) and 8.9° (idiopathic). Tibial TBP corrections at 1 year were 5.8° (MPS) and 5.4° (idiopathic); total degrees of correction were 9.1° (MPS) and 6.0° (idiopathic). The average correction rates for femoral TBPs were 4.3°/year (MPS) and 7.3°/year (idiopathic), and tibial TBPs were 4.5°/year (MPS) and 4.6°/year (idiopathic). Full correction was achieved in four of nine (44.4%) MPS patients and 14 of 20 (70%) idiopathic patients, as well as 9 of 22 (40.9%) MPS limbs and 20 of 38 (52.6%) idiopathic limbs. There were no statistically significant differences between groups or by gender. MPS patients with femoral and tibial TBPs experienced comparable correction rates to idiopathic patients, although idiopathic patients corrected slightly faster, consistent with prior literature. This demonstrates that TBP is an effective growth modulation technique for MPS patients despite morphological differences.

Cerebrospinal fluid heparan sulfate as a biomarker for neuronopathic mucopolysaccharidoses: Rationale and regulatory challenges.

Quantification of glycosaminoglycans in dried blood spots, and evaluation of its usefulness as a secondary newborn screening test for mucopolysaccharidoses.

Background/Objectives: Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by impaired glycosaminoglycan degradation, leading to multisystem involvement and progressive growth impairment. Longitudinal growth data in MPS IVA and MPS IIIA, including the association of ERT with growth outcomes, remain limited. This study aimed to characterize growth trajectories in MPS IVA and MPS IIIA and to assess the association of ERT with Elosulfase alfa on growth outcomes in MPS IVA patients. Methods: We retrospectively analyzed growth data from 39 patients with MPS subtypes IIIA and IVA followed at a single center between 2004 and 2024. Height and weight standard deviation scores (SDS) were calculated relative to CDC growth references and modeled using linear mixed-effects models (LMM). In the MPS IVA subgroup, the effect of ERT with Elosulfase alfa was assessed using LMM and paired SDS comparisons. Results: Growth impairment was evident across both subtypes with distinct trajectories. MPS IIIA patients showed significant height decline after age six with progressive weight loss in later childhood. MPS IVA patients exhibited persistently severe short stature and a tendency toward overweight with advancing age. Among the 16 MPS IVA patients treated with Elosulfase alfa who were included in the analysis, height SDS declined significantly during treatment (−0.127 SDS/year [95% CI: −0.194, −0.061], p < 0.001), and the rate of decline was not significantly affected by age at ERT initiation (interaction p = 0.53). Conclusions: ERT with Elosulfase alfa did not prevent progressive height loss relative to population norms. The rate of height SDS decline was not significantly influenced by the timing of ERT initiation (interaction p = 0.53), and causal conclusions cannot be drawn from this observational data.

Voice Characteristics and Parent-Reported Voice Handicap in Children With Mucopolysaccharidosis: A Pilot Case-Control Study.

Treosulfan (Treo), a prodrug of a bifunctional alkylating agent, has been used in conditioning regimens to reduce the risk of hepatic sinusoidal obstruction syndrome. We aimed to establish a Treo-based conditioning regimen for mucopolysaccharidosis (MPS) as a phase 1 study. The regimen included thoracoabdominal irradiation, Treo, fludarabine, and antithymocyte globulin. Antithymocyte globulin was omitted in cord blood transplantation. Five patients with MPS II, aged 8months to 21years, were enrolled. Stem cell sources were HLA-C-mismatched unrelated bone marrow in one patient and HLA 1 to 3 allele-mismatched cord blood in four. No patients experienced grade 4 toxicities. Absolute neutrophil count > 500/µL was achieved at a median of 16days. A pharmacokinetic study showed that AUC0-12h was 50% higher in children than in adults. Bone marrow donor chimerism at 4weeks post-transplant was 100% in two patients and 96.7% to 98.1% in three; at 8weeks, it was 100% in four patients and 77.1% in one who received a reduced dose of Treo. Three patients are alive, but two died at 415 and 767days post-transplant due to factors unrelated to the conditioning regimen. Treo remains a valuable agent for conditioning regimens in MPS.

Most patients with mucopolysaccharidosis (MPS) experience skeletal involvement due to impaired bone remodeling, glycosaminoglycan (GAG) accumulation, reduced mobility, and nutritional deficiencies. These factors may predispose to low bone mass and increased fracture risk. This study assessed bone mineral density (BMD) using height-adjusted dual-energy X-ray absorptiometry (DXA) in pediatric MPS patients receiving enzyme replacement therapy (ERT) and examined its associations with clinical, functional, and biochemical parameters. This cross-sectional study included 29 children with biochemically and/or genetically confirmed MPS receiving ERT at Tanta University Hospital. Children under 5 years and ERT-naïve patients were excluded. BMD was measured at the lumbar spine (L1-L4) and femoral neck using DXA and adjusted for height-for-age z-score (HAZ). Clinical data, Katz Activities of Daily Living (ADL) score, anthropometry, and biochemical markers of bone metabolism were recorded. Statistical analyses included the Shapiro-Wilk test, Pearson correlation, and two-tailed t-test (p < 0.05). The cohort included 29 patients (19 males, 10 females; mean age 9.79 ± 3.85 years): 13 with MPS IVA, 11 with MPS I, 3 with MPS II, and 2 with MPS VI. Mean HAZ-adjusted BMD z-scores were - 1.84 ± 1.38 (right femur), - 2.07 ± 1.22 (left femur), and - 3.00 ± 1.49 (lumbar spine). Low bone mass for age (HAZ-adjusted z ≤ - 2) was present in 20/29 (68.9%) patients, predominantly affecting the spine. Vitamin D insufficiency/deficiency was observed in 75.9% of patients. Katz ADL score correlated strongly with BMD at all sites, particularly the lumbar spine (r = 0.88, p < 0.001). Total calcium and vitamin D levels showed positive correlations with BMD. Patients with cardiac involvement had significantly lower BMI than those without cardiac disease (p < 0.001). Pediatric patients with MPS receiving ERT show a high prevalence of low bone mass for age, driven by a multifactorial interaction between impaired mobility, nutritional deficiencies, and intrinsic skeletal pathology. Routine height-adjusted DXA monitoring, early physiotherapy, and proactive vitamin D and calcium supplementation should be integrated into comprehensive MPS care.

Nationwide Newborn Screening for Mucopolysaccharidoses in Taiwan: Impact, Early Diagnosis, and Clinical Advances over the Past Decade.

Patients with mucopolysaccharidosis (MPS) appear to have an increased risk of developing dental disease. This study aimed to evaluate the status of dental caries and dental anomalies among Chinese patients with different types of MPS. This retrospective study analyzed a consecutive cohort of 102 pediatric patients with MPS who visited the Department of Stomatology at the Capital Center for Children's Health between August 2010 and August 2025. Eligible patients were defined as those with a confirmed diagnosis of MPS who were aged ≤14 years at the time of their dental visit and had complete dental examination records available. Dental caries and anomalies were assessed through clinical records and radiographic data. Dental caries were observed in 55.9% (57/102) of patients, and no statistically significant difference was observed across the MPS subtypes (P=.72). Deep dentinal caries (d4-6mft) were observed in 40.2% (41/102) of the participants and contributed most to the total decayed, missing, and filled teeth index score. The overall prevalence of dental anomalies was 32.4% (33/102), with a statistically significant difference among MPS subtypes (P=.005). Patients with MPS type IV had a significantly higher risk of dental anomalies compared to those with MPS type II (odds ratio 6.32, 95% CI 1.55-28.28; P=.01), after adjusting for age and gender. The prevalence of dental anomalies differed significantly across MPS subtypes, while that of dental caries did not. These findings emphasize the need for early, targeted preventive care and tailored dental interventions to improve oral health outcomes in this population.

Mucopolysaccharidosis Type IV is a multisystem lysosomal storage disease characterized by severe skeletal dysplasia resulting from impaired degradation of the glycosaminoglycans keratan sulfate and chondroitin-6-sulfate. The condition is classified into Types A and B based on the underlying enzyme deficiency. Low bone mineral density (BMD) is a feature of the skeletal phenotype, contributing to increased fracture risk. Extraskeletal manifestations include, among others, cardiovascular disease due to valvular stenosis and regurgitation, myocardial remodeling, coronary artery disease, and vascular stiffness, all associated with glycosaminoglycan accumulation. We report two adult patients with mucopolysaccharidosis Type IVB treated with the osteoanabolic agent teriparatide for an apparently low BMD. The first patient presented with a non-healing femoral fracture requiring BMD improvement prior to surgical fixation. This patient was treated with teriparatide for 2 years, which resulted in significant BMD gain, enabling successful surgical fixation. The second patient received teriparatide for only 6 months and showed stable BMD. Notably, both patients developed serious cardiac problems during teriparatide treatment: the first patient experienced rapidly progressive aortic stenosis, while the second patient developed dyspnea and polyuria due to worsening dynamic left ventricular outflow tract obstruction, which had previously been asymptomatic. Both patients required invasive cardiac interventions, which carry high risk in mucopolysaccharidosis due to unique anatomical and anesthetic challenges. The temporal association between teriparatide treatment and the onset of cardiac problems in both patients is noteworthy and raises the possibility of a treatment-related effect. Therefore, we recommend cautious use of teriparatide in patients with mucopolysaccharidosis Type IV.

Cervical spine atlantoaxial instability (AAI) is frequently encountered in patients with mucopolysaccharidoses (MPS). The value of clinical examination, radiographic measurements, and MRI findings in determining the management of MPS AAI is unknown. The goal of this study is to compare these tools and report the utility and significance of each in surgical decision-making. Retrospective case-control series from a single center's skeletal dysplasia (SD) division, 2007-2023, included MPS patients who had documented history, examination, and flexion-extension (F-E) cervical spine radiographs and MRI. Radiographic measurements included dens morphology, anterior atlanto-dens interval (AADI), and posterior atlanto-dens interval (PADI). MRI measurements included cervical stenosis, C1 SAC, and the presence of myelomalacia. Factors important were quantified by sensitivity, specificity, and odds ratio (OR). Criteria cutoffs were defined by receiver operating characteristic (ROC) curve analysis, and a scoring rubric was generated by internal validation. Of all SD patients, 35 had MPS and met all inclusion criteria. The most common diagnosis was Morquio syndrome (77%, 27/35). Patients were majority 54% female and 80% white. About half (18, 51%) underwent surgery at an average age of 10.6-years-old. Measurement analysis followed by ROC evaluation defined 7 surgical cutoffs as follows: (1) paresthesias in the history, (2 and 3) weakness and/or positive Babinski on exam, (4) os or aplastic odontoid morphology, (5) ≥3mm AADI instability, (6) myelomalacia on MRI, and (7) ≥115% C1-C2 stenosis. Stenosis and myelomalacia were the most impactful by OR. Os/aplastic odontoid morphology and positive Babinski were both 100% specific. Validation found that 100% of patients with 0 criteria were able to be managed nonoperatively. Conversely, patients with 3 or more criteria present were overwhelmingly indicated for surgery in 93% of cases. This is the largest case series describing AAI in MPS patients. This study identified the above 7 criteria utilizing MPS-specific thresholds. These thresholds allow for the qualification of pathologic findings against other MPS patients, weight factor importance, and provide guidance for how many factors should be present to indicate MPS AAI for surgical intervention.

Mucopolysaccharidoses (MPSs) are characterized by deficient activity of lysosomal hydrolase enzymes, leading to progressive accumulation of glycosaminoglycans. These glycosaminoglycans can be assayed in biofluids as potential markers of disease severity and response to disease-modifying therapies. This study sought to calculate control reference intervals in a largely pediatric population for key MPS biomarkers: heparan sulfate (HS) and dermatan sulfate (DS) in cerebrospinal fluid (CSF) and urine, and CSF monosialic gangliosides GM2 and GM3. We also explored the effect of age on biomarker levels. Biomarker levels were measured using liquid chromatography-tandem mass spectrometry in CSF and urine samples from pediatric and young adult donors and were compared with baseline CSF and urine biomarker levels from an ongoing Phase 1/2 study of children with MPS II. Age-specific reference intervals were estimated for CSF HS, DS, and GM2, and for urine HS, DS, and the sum of HS and DS, after observing that levels of these markers decreased with age. CSF GM3 levels were not found to be age dependent, therefore a single reference interval was estimated for the reference population. In patients with MPS II, levels of HS and DS, respectively, were 6- and 7-fold higher in CSF, and 13- and 30-fold higher in urine than the upper reference interval limits. Establishing age-specific reference intervals will help to optimize biomarker use in clinical studies.

Background: Mucopolysaccharidoses (MPS) are rare lysosomal storage disorders caused by deficiencies in glycosaminoglycan (GAG)-degrading enzymes, leading to progressive multisystem involvement. Methods: We evaluated two unrelated consanguineous Pakistani families, each with three individuals showing features consistent with MPS. Affected individuals in Family 1 presented with developmental regression, severe cognitive impairment, behavioral abnormalities and facial dysmorphisms. The affected individuals in Family 2 showed classical skeletal dysplasia consistent with Morquio syndrome. Whole-exome sequencing (WES), segregation analysis, and in silico protein modeling were performed to identify and characterize pathogenic gene variants. Results: Analysis of WES data revealed a homozygous missense variant in the SGSH gene [c.548G>A (p.Cys183Tyr)] in the three cases of Family 1 and a homozygous splice-site variant in the GALNS gene (c.423-1G>A) in the cases of Family 2. The SGSH variant, located within the sulfatase catalytic domain and classified as likely pathogenic (ACMG), is consistent with the Sanfilippo A phenotype and represents the first clinical characterization of this allele. Regarding Family 2, we identified the GALNS mutation as a recurrent pathogenic founder allele previously reported in individuals of South Asian descent. Structural modeling of SGSH p.Cys183Tyr predicted disruption of a conserved cysteine residue and altered protein stability, likely supporting its deleterious effect. Conclusions: This study expands the spectrum of MPS-associated variants in Pakistan. The findings underscore the importance of genomic diagnostics for enabling early detection, accurate classification, and genetic counseling in populations with high consanguinity.