Long-term Natural History and Elosulfase Alfa Treatment for Mucopolysaccharidosis Type IVA: A Single-Center Study in the Czech Republic

Long-term Natural History and Elosulfase Alfa Treatment for Mucopolysaccharidosis Type IVA: A Single-Center Study in the Czech Republic | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Long-term Natural History and Elosulfase Alfa Treatment for Mucopolysaccharidosis Type IVA: A Single-Center Study in the Czech Republic Robert Šáhó, Lenka Murgašová, Markéta Tesařová, Helena Poupětová, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9023839/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background: Mucopolysaccharidosis type IVA (MPS IVA, Morquio A syndrome) is a rare lysosomal storage disease primarily characterized by severe skeletal dysplasia. Clinical and laboratory data, including treatment responses, are reported for a cohort of Czech patients with MPS IVA. Results: Nineteen patients with MPS IVA from 17 families (13M/6F) were included; only one patient exhibited a mild form. The median age at disease onset was 3.0 ± 1.4 years, whereas the median age at confirmed diagnosis was 5.0 ± 3.5 years. At the time of diagnosis, all patients had skeletal symptoms (pectus carinatum in 58%, short stature in 47%, hip dysplasia in 47%), and 63% had nonskeletal symptoms. Each patient underwent at least one surgical procedure (77% knee, 59% spine, 41% adenotomy). On spinal MRI, 76% of patients presented with cervical stenosis, and 41% presented with cervical myelopathy. Eight patients received ERT for a median duration of 5.5 ± 2.6 years. Compared with non-ERT patients from natural history studies and non-ERT patients within our cohort, beneficial effects were evident in monitored parameters such as changes in the mean FVC and FEV1 volumes and the mean 6MWT distance. Additionally, the hidradenitis suppurativa observed in three patients improved with biologic therapy. We also describe two novel mutations (c.421_422dupTG, c.482G>C). Conclusions: Documenting the natural history of MPS IVA in this population may aid in early diagnosis. Despite the disease's progressive nature, ERT was effective in our MPS IVA patients, demonstrating a consistent impact on endurance across all age groups. mucopolysaccharidosis type IVA enzyme replacement therapy natural history long-term spinal stenosis cervical myelopathy Figures Figure 1 Figure 2 1. Background Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio syndrome type A (OMIM #253000), is a rare but significant lysosomal storage disorder inherited in an autosomal recessive manner. It is caused by mutations in the GALNS gene, resulting in a deficiency of the enzyme N-acetylglucosamine-6-sulfatase (GALNS; EC 3.1.6.4).[ 1 ] This enzyme deficiency results in the progressive accumulation of keratan sulfate (KS) and chondroitin-6-sulfate (CS) within lysosomes, particularly within connective tissues and the cornea,[ 2 ] ultimately driving the hallmark pathophysiology of the disease. Pronounced skeletal abnormalities, including short stature, long-bone deformities, spinal curvature, pectus carinatum, and joint laxity, dominate the clinical presentation of MPS IVA.[ 1 , 3 ] However, its manifestations extend beyond the skeletal system: patients often experience respiratory impairment, valvular heart disease leading to subsequent cardiac hypertrophy, corneal clouding, vision and hearing loss, and characteristic coarse facial features. [ 1 , 4 ] The severity of these clinical features contributes to a highly variable life expectancy. Individuals with milder forms of MPS IVA may live 20–40 years, with some cases reported over 60 years. In contrast, severe phenotypes are often limited to late childhood or adolescence, with mortality typically resulting from spinal cord compression or respiratory failure.[ 5 ] The birth prevalence of MPS IVA is population specific, ranging from 1 in 140,000 in the Czech Republic to 1 in 872,000 in Australia.[ 6 ] Since its approval in 2014, enzyme replacement therapy (ERT) with elosulfase alfa has been recommended as the first-line treatment according to international guidelines.[ 7 ] Clinical trials and registry data have shown that ERT improves quality of life, increases endurance, as evidenced by the 6-minute walk test (6MWT), supports respiratory function, enhances daily activity performance, and reduces urinary KS levels.[ 8 , 9 ] Long-term stabilization of endurance and respiratory function has been reported in the Morquio A Registry Study (MARS).[ 10 ] However, ERT has not demonstrated efficacy in addressing the skeletal dysplasia and bone defects associated with MPS IVA.[ 11 ] While natural history studies have documented the progression of MPS IVA, including a high rate of surgical intervention and a gradual decline in physical endurance,[ 2 , 12 – 16 ] real-world data on the therapeutic impact of ERT remain limited.[ 17 – 21 ] This retrospective observational study reviewed the clinical history, genotypic characteristics, and phenotypic profiles of 19 Czech patients with MPS IVA since 1976. Additionally, we evaluated the effects of ERT in a subset of treated patients, providing valuable insights into the real-world outcomes of ERT in this patient cohort. 2. Patients and methods Nineteen patients who were diagnosed with MPS IVA at the Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic, were included in this study. The diagnosis was confirmed through enzymatic and/or genetic testing. Patients in the cohort were observed longitudinally from 1976–2023, with data analysed at the conclusion of the study. Clinical, laboratory, and genetic data, including data from both outpatient and inpatient visits, were retrospectively collected from patient records. 2.1. Clinical Symptoms Clinical data included the onset of the disease, initial presenting symptoms, age at diagnosis, age at the start of ERT, anthropometric measures, and the presence of hepatomegaly. On the basis of MPS IVA-specific growth charts,[ 22 ] patients were assigned a “classic” designation to classify phenotypes if their height fell below the 75th percentile. Endurance was evaluated via the 6MWT following established guidelines.[ 23 ] Additional clinical evaluations included two-dimensional Doppler echocardiography, spinal MRI, audiometry, ocular examinations of the fundus and anterior segment, spirometry assessments for forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1), and polysomnography. The determination of urinary keratan sulfate quantity was unavailable due to laboratory limitations at our center. 2.2. Enzymology White blood cell enzyme activity was measured in leukocytes isolated via dextran sedimentation and homogenized via ultrasonic disruption (Cole-Parmer CP-130, 30%) on ice. The protein concentration was determined via the Hartree method;[ 24 ] , [ 25 ] GALNS activity was assessed fluorometrically via the use of 4-methylumbelliferyl-β-D-galactopyranoside-6-sulfate (MU-β-Gal-6S) as the substrate.[ 26 ] β-Galactosidase activity was measured using 4-methylumbelliferyl-β-D-galactopyranoside (MU-β-Gal) as the substrate. MU fluorescence (Ex: 365 nm, Em: 448 nm) was detected on a luminiscence spectrometer (Perkin Elmer LS50B, Wellesley, U.S.A.).[ 27 ] 2.3. Molecular Genetic Analyses Genomic DNA was extracted from blood samples, and all exons of the *GALNS* gene (NM_000512.5) were amplified and analysed by Sanger sequencing via the ABI3500xL Genetic Analyser (Applied Biosystems, USA). 2.4. Ethics All data were accessed in compliance with relevant laws and ethical standards for the study period and in accordance with the Declaration of Helsinki, as revised in 2013.[ 28 ] Informed consent for genetic testing was obtained from all participants. Ethical approval for the study was granted by the Institutional Review Board (IRB) of the General University Hospital in Prague (Approval Number: 100/23 S-IV). 3. Results This study involved 19 patients (13 males, 6 females) from 17 unrelated families, all with a confirmed diagnosis of MPS IVA. The cohort's median age was 24.7 ± 13.0 years (range: 3.3–52.0 years), with a mean follow-up period of 18.9 ± 12.7 years (range: 1.3–47.1 years). Notably, patient 17 passed away at 30.5 years of age due to respiratory complications associated with COVID-19 infection. The median age at symptom onset was 3.0 ± 1.4 years (range: 4 months to 5.8 years), whereas the median age at confirmed diagnosis was 5.0 ± 3.5 years (range: 2–16.2 years), with a mean diagnostic delay of 3.1 ± 3.3 years (range: 0–11.2 years). For patient 19, an initial diagnosis of mucopolysaccharidosis was made at age 5 without subtype specification; the patient was later lost to follow-up and re-evaluated at age 48 when MPS IVA was confirmed. Among the 19 patients, 8 (6 males, 2 females) received ERT with elosulfase alfa. The median age at the start of ERT was 6.0 ± 6.0 years (range 2.4–20.5 years). At the time of the study, the median duration of ERT was 5.5 ± 2.6 years (range: 11 months–8.9 years), representing a mean interval of 3.7 ± 5.0 years (range: 0.3–14.4 years) between diagnosis and the commencement of ERT. 3.1. Clinical outcomes 3.1.1. Disease onset The most common initial symptoms observed in the cohort are depicted in Figure 1 and summarized in Table 1. Skeletal symptoms were universal at onset among all 19 patients, with specific findings including pectus carinatum (n=11), short stature (n=9), acetabular dysplasia of the hip (n=9), abnormal gait (n=8), scoliosis (n=7), genu valgum (n=6), and kyphosis (n=6). Additionally, 63% of patients presented initial nonskeletal symptoms, such as acute otitis media (n=6), frequent respiratory infections (n=5), and coarse facial features (n=4). In two patients, the diagnosis was prompted by a family history of MPS IVA. At the time of diagnosis, all patients with available radiographic data (n=17/19) presented classic features of multiplex dysostosis, whereas hepatomegaly was noted in only 19% of patients (3/16). 3.1.2. Anthropometry and growth Among the 18 MPS IVA patients whose birth data were recorded, the mean birth weight was 3,632 ± 534 g (range 2,650–4370 g), with an average gestational age of 38.8 ± 1.2 weeks. The average birth length in this group was 52.6 ± 3.0 cm (range 48–57 cm). On the basis of height assessments, 18 patients exhibited the classic MPS IVA phenotype, whereas one presented with an attenuated phenotype. Short stature was present in 85% (11/13) of patients at the time of diagnosis, with a mean height Z score of -3.2 ± 1.72 (range -5.34--0.56). However, some patients initially grew within the normal percentile range (97th–25th percentile, data not shown) on Czech growth charts during the first 18 months of life. Patient 6, identified with an attenuated phenotype, had a Z score of 0.56 at the age of 5.5 years. At the last recorded visit, the mean Z score for height across the cohort (n=18) was -7.64 ± 2.87 (range -11.33 to -1.54), with patient 6 continuing to have a relatively high Z score of -1.54 (Table 1). When ERT-treated patients were compared with ERT-naïve patients (8 vs 11), the current mean height Z scores were -6.75 ± 3.47 and -8.35 ± 2.23, respectively, although this difference was not statistically significant (p=0.48). The baseline Z score for head circumference was 0.81 ± 1.18 (n=11). 3.1.3. Endurance, spirometry, and assistive devices Spirometric evaluations revealed higher mean values of FVC and FEV1 across all age groups in ERT-treated patients than in untreated patients in natural history studies [14,20,29] and in the untreated patients in our cohort (Table 2, Figure 2a, b). The differences in the FVC between the treated and untreated groups ranged from 1.05 L to 0.25 L, and the FEV1 ranged from 0.89 L to 0.18 L. Unlike the expected decline observed in natural history data, lung function remained stable or improved across age groups in our cohort, regardless of treatment status. Notably, direct statistical analysis was not possible due to the unavailability of source data from natural history studies. 3.1.4. Mobility and Endurance Assessment In the most recent follow-up, 10 patients (53%) were nonambulatory and relied on wheelchairs, with a mean age of 20.3 years when they ceased walking (data available for five patients). Additionally, three patients (16%) used a wheelchair for longer distances, whereas two (11%) required mobility aids such as walkers or crutches. Data for the 6MWT were not available for ERT-naïve patients in this cohort. However, ERT-treated patients demonstrated a greater mean 6MWT distance than did untreated individuals from natural history studies[14,20,29] across all age groups, with differences in distance between the treated and untreated groups ranging from 90.5 m to 315.7 m (Table 3, Figure 2c). Direct statistical analysis was not possible. 3.1.5. Surgical history All patients for whom data were available (n=17) underwent surgery at some point. The average age at first surgical intervention was 6 years. Among these patients, 13 (77%) required at least one knee surgery, whereas 10 (59%) underwent spinal cord surgery. Additional surgeries included adenotomy in 41% (7/17), hip surgery in 29% (5/17), and tympanostomy in 24% (4/17). Hernia repair and strabismus surgeries were performed in 6% of the patients each. The median ages at significant surgical intervention were as follows: knee surgery, 8.8 ± 6.1 years (5.5–35.5 years); spinal cord surgery, 14.0 ± 6.2 years (8.1–31 years); adenotomy, 3.7 ± 2 years (2.9–8.8 years); and hip surgery, 8.1 ± 1.4 years (6.4–9.7 years). Spinal magnetic resonance imaging (MRI) was available for 17 patients, revealing cervical stenosis in 13 (76%), cervical myelopathy in 7 (41%), and thoracic stenosis with odontoid hypoplasia in 5 patients (29%). Patient 4 experienced a significant decline in clinical status at age 15 following spinal cord surgery, which resulted in postoperative paraplegia and sensory impairment distal from the Th12 level. Subsequent complications included the development of a neurogenic bladder and a neurogenic bowel. 3.1.6. Cardiologic evaluation Echocardiographic data from the most recent follow-up were available for 18 patients. The most commonly observed cardiac anomalies were mitral and tricuspid regurgitation (both present in 56% of patients), followed by aortic regurgitation in 44%, aortic and tricuspid valve thickening in 50%, mitral valve thickening in 28%, and pulmonary regurgitation in 22%. The mean age of patients with valvular heart disease was 27.9 ± 11.3 years, whereas the mean age of those without valvular heart disease was 11.2 ± 4.7 years. Mild valvular disease was predominantly observed in patients aged 3.3--18 years, whereas more advanced cases were observed in patients older than 18 years. One patient was identified with hypertrophic cardiomyopathy. The ejection fraction values remained within the normal range (≥55%) for all patients, with mean values of 71% at baseline and 68% at follow-up, indicating preserved systolic function. 3.1.7. ENT Presentation, Vision, and Others Among the 15 patients evaluated for ENT manifestations, 47% (7/15) experienced recurrent upper respiratory tract infections (RURIs), 20% (3/15) had recurrent otitis media (ROMA), and 47% (7/15) had at least one episode of acute otitis media (OMA). Audiometric assessments revealed hearing loss in 67% of the patients (10/15), with conductive hearing loss accounting for 53%, while the remaining cases were attributed to sensorineural and mixed hearing loss. Five patients were already using hearing aids, and the mean age at which hearing loss was documented was 12.4 years (n=8). Four patients had severe obstructive sleep apnea requiring nocturnal noninvasive ventilation (bilevel positive airway pressure (BiPAP)). Surgical interventions for ENT issues are summarized in the surgery history section. Sixteen patients underwent a complete ophthalmologic assessment. Corneal clouding was observed in 75% of the cases, typically without vision impairment. No patients required corneal transplantation. One patient (6%) developed glaucoma. Cycloplegic refraction results revealed that hyperopia was the most common refractive error, affecting 69% of patients, followed by astigmatism at 63% and myopia, strabismus, and amblyopia, each affecting 19% of patients. In addition, three patients had severe forms of hidradenitis suppurativa (HS) and were treated with biologic therapy. This condition is notably uncommon in lysosomal storage disorders. 3.2. Laboratory Data 3.2.1. Enzymatic Analyses All patients exhibited significantly deficient GALNS enzyme activity, with levels below 1% of the long-term control average (34,5 nmol/17 h/mg). In both the classic and attenuated phenotypes, GALNS activity remained below 1% of the control average (Table 1). 3.2.2. Molecular‒Genetic Analyses Nineteen different variants of the GALNS gene were identified among 18 patients (12 males, 6 females) from 16 families. These variants included 13 missense mutations, two large deletions, two null variants (one small in-frame deletion/insertion and one intronic), and one duplication. The most common variants were c.1219A>C p.(Asn407His), which was found in 7 unrelated patients; c.1156C>T p.(Arg386Cys), which was present in 5 patients from 4 families; c.740G>A p.(Gly247Asp), which was found in 3 patients from 2 families; and c.860C>T p.(Ser287Leu), which was found in 3 patients from 2 families (Table 1). Notably, Patient 17 presented with a rare codiagnosis of adenine phosphoribosyltransferase (APRT) deficiency, leading to 2,8-dihydroxyadenine urolithiasis, along with GALNS deficiency. Both the GALNS and APRT genes are located on chromosome 16q24.3, and genetic analysis revealed a deletion involving both genes. Polymerase chain reaction (PCR) confirmed that a novel junction formed by the fusion of sequences distal to GALNS exon 2 and proximal to APRT exon 3, with an estimated deletion size of approximately 100 kb, spanning GALNS intron 2 and APRT intron 2. This case was reported elsewhere.[30] This study identified two unreported variants: a missense variant, c.482G>C (p.Gly161Ala), and a duplication, c.421_422dupTG. Notably, a different substitution at the same nucleotide position, c.482G>A, has been associated with an intermediate phenotype in a Chinese cohort.[31] With respect to duplication, a similar variant located one nucleotide upstream (closer to the intron) has been described previously.[32] Prediction algorithms provide conflicting interpretations of the impact of this duplication. Franklin and Varsome predict normal splicing with effects limited to amino acid substitution and a frameshift leading to p.Trp141Cysfs*13, suggesting that the impact may require reassessment. In contrast, SpliceAI predicts additional effects on splicing, indicating the potential for a more complex pathogenic mechanism. Zygosity analysis revealed that 3 patients were homozygous, 1 was hemizygous, and 15 were compound heterozygous. Sixteen variants associated with the classic phenotype, whereas the variants c.740G>A p.(Gly247Asp) and c.1219A>C p.(Asn407His), were associated with both classic and attenuated phenotypes within this cohort. Two novel variants, the Human Genome Mutation Database and ClinVar, have not been reported in public databases. 4. Discussion This retrospective observational study provides a comprehensive overview of the clinical and laboratory characteristics and evaluates the effectiveness of ERT in a cohort of 19 Czech patients with MPS IVA. Most patients (18/19) exhibited the classic phenotype, with only one presenting an attenuated form. This represents a slightly higher prevalence than previously reported, which indicates the classic phenotype in approximately 75% of cases.[33] The age of onset in toddlerhood and the diagnostic delay observed in this cohort are consistent with other published MPS IVA data. Symptoms often emerge between 1 and 3 years of age, with the mean age of onset reported at approximately 2.0 to 2.6 years. Diagnostic delays are also similar to our findings of 4.7–6.9 years.[2,13,14] As expected, skeletal symptoms, including pectus carinatum, short stature, acetabular dysplasia, and abnormal gait, were universally present. Although infants with MPS IVA are frequently born with average or above-average birth weight and length, growth failure often emerges in the second or third year of life. Recurrent acute otitis media was a prevalent initial symptom in our cohort, underscoring that ENT symptoms, especially hearing loss, are relatively common in MPS IVA. In our cohort, 73% of patients experienced hearing loss, predominantly conductive hearing loss (two-thirds). Hearing loss in MPS IVA is reported in 67% to 94% of cases.[34–36] Consistent with other forms of MPS, younger patients predominantly exhibit conductive hearing loss, whereas sensorineural or mixed hearing loss becomes more prevalent with age.[37] A study by Riedner and Levin revealed that conductive hearing loss was universal in patients under 8 years of age, whereas older patients were more likely to develop sensorineural or mixed hearing loss.[36] Awareness of these ENT symptoms can facilitate earlier detection and long-term management by specialists, who play a crucial role in identifying hearing impairments potentially caused by ossicle deformity, recurrent upper respiratory infections, recurrent otitis media, and glycosaminoglycan accumulation. Although less often discussed, skin conditions such as hidradenitis suppurativa (HS) were observed in three patients (reported elsewhere[38]), although its exact pathophysiology in MPS IVA remains unknown. Orthopedic and spinal surgeries pose significant challenges in managing MPS IVA. All patients underwent surgery, with a mean age of six years at their first procedure. Knee surgeries were the most common (77%), followed by spinal cord surgeries (59%). Cervical spine involvement, especially stenosis and instability, appears nearly universal in MPS IVA, often leading to myelopathy, paralysis, or sudden death. Previous studies reported varying overall surgery rates, ranging from 33% to 71%, underscoring an inconsistent approach to surgical indications. Broomfield et al. reported that 31% (26/82) of MPS IVA patients underwent cervical spine surgery at a median age of 6.1 years, emphasizing the importance of early intervention to preserve long-term neurological function.[39] The sparse literature lacks standardized recommendations for managing these orthopedic and neurosurgical challenges. The timing and indications for surgery are especially critical in spinal procedures, which have shown suboptimal outcomes, as observed in our cohort and other studies.[2] This clinical gap can be addressed through surveillance via spine MRI protocols sensitive to presymptomatic microstructural changes in the spinal cord, similar to those developed by the University of Minnesota group on the basis of their experience in degenerative cervical myelopathy.[40,41] Genetic analysis revealed that missense mutations are the predominant type in the GALNS gene, which is consistent with findings from global databases. The c.1219A>C variant was the most prevalent variant in our cohort, accounting for 22% of all variants. This study also revealed two novel mutations (c.482G>C and c.421_422dupTG). The c.1156C>T variant, identified as the most common variant globally in the literature, was the second most frequent variant in our cohort.[42] Jezela Stanek et al. reported that heterozygotes for the c.121-9T>G variant exhibit less severe growth defects. [43] However, in our cohort, this was observed in only one patient with a mild disease form, whereas five others carrying the same mutation experienced severe growth impairment. This variant appears to be less commonly reported in the literature. In contrast, the c.860C>T variant, which was the fourth most common variant worldwide and the 3rd most common variant in our cohort, is notably the most prevalent variant among the Indian population.[42] Additionally, our findings suggest that combined APRT/GALNS deficiencies, although rare, may be more common than previously recognized, with two cases documented to date, including one in our cohort.[30,44] The administration of elosulfase alfa to patients with MPS IVA in this study resulted in improved walking distances compared with data from age-matched naïve patients reported in the literature.[14,20,29] Data from several sources have also revealed the impact of ERT on the natural history outcomes of mobility issues in MPS, including the pivotal phase 3 randomized, double-blind, placebo-controlled MOR-004 clinical trial, which revealed statistically significant improvement in the 6MWT distance over placebo, which was sustained over 120 weeks.[8,45,46] In their review, Parini et al. reported improvement or stabilization of the 6MWT in MPS IVA patients after 1–3 years of treatment.[47] Pintos-Morel and colleagues reported improved walking distance in all but one cohort of patients after 8 months of ERT.[48] The mean 6MWT distance increased by 30% in four of six patients after ERT for 4.0–6.5 years in the study of Lin et al.[49] Other studies have also examined and reported improvements in walking distance and/or performance on the 3-minute stair climb test after the initiation of ERT.[50,51] With respect to respiratory function, we focused on the characteristics of FVC and FEV1 across all age groups. We observed a general reduction in spirometry values in our patients compared with those in healthy individuals; however, the values remained stable or slightly improved under ERT, and the mean FVC and FEV1 values remained above those recorded in natural history studies.[14,20,29] Numerous studies have conclusively demonstrated that ERT appears to improve pulmonary function.[8,9,45,48,52] MARS, the longest and largest observational study of MPS IVA patients to date, also provided real-world evidence for long-term stabilization of endurance and respiratory function among ERT-treated patients.[10] Mitral and tricuspid regurgitation were the most common symptoms of heart involvement in our cohort, with more advanced cases observed in patients older than 18 years. Only one patient manifested hypertrophic cardiomyopathy. None of our patients had been indicated for valve replacement yet. However, ERT likely has a negligible effect on cardiovascular outcomes, as no significant changes in heart structure or function have been noted.[18,53] ERT had no effect on growth in our patient, whereas the youngest treated patient began therapy at the age of 2.4 years. Unfortunately, the effect of ERT on growth in MPS IV A has never been sufficiently documented.[51,54,55] We emphasize that the anthropometric data of our patients during the first 1.5--2 years were normal. Therefore, normal growth at this age does not rule out the diagnosis of MPS IV A. Our findings should be viewed in light of study limitations such as the limited number of patients, varying frequencies and intervals between clinical examinations, and incomplete data, particularly regarding functional tests from childhood in our adult patients. Furthermore, the absence of specific patient datasets from natural history studies precluded statistical comparisons. However, our study offers valuable real-world data on MPS IVA, which is essential for understanding treatment variability and optimizing clinical decisions. 5. Conclusions Real-world data from Czech patients illustrate the effectiveness of enzyme replacement therapy in enhancing respiratory and endurance functions, although it has no observable impact on growth or skeletal structure. There is a pressing need for international guidelines concerning indications for skeletal and, in particular, spinal surgeries. Concurrent conditions, such as HS or APRT deficiency, are not uncommon in patients with MPS IVA. Abbreviations 6MWT – 6-minute walk test APRT – Adenine phosphoribosyltransferase BiPAP – Bilevel positive airway pressure CS – Chondroitin-6-sulfateENT – Ear, nose, and throat ERT – Enzyme replacement therapy FEV1 – Forced expiratory volume in 1 second FVC – Forced vital capacity GALNS – N -acetylglucosamine-6-sulfatase HS – Hidradenitis suppurativa KS – Keratan sulfate MARS – Morquio A Registry Study MRI – Magnetic resonance imaging MPS – Mucopolysaccharidosis MPS IVA – Mucopolysaccharidosis type IVA (Morquio A syndrome) MU-β-Gal-4-methylumbelliferyl-β-D-galactopyranoside MU-β-Gal-6S – 4-methylumbelliferyl-β-D-galactopyranoside-6-sulfate OMIM – Online Mendelian Inheritance in Man PCR – Polymerase chain reaction ROMA – Recurrent otitis media RURI – Recurrent upper respiratory tract infections Declarations Ethics approval and consent to participate: All procedures involving human participants were conducted in accordance with applicable institutional and national ethical standards and with the Declaration of Helsinki, as revised in 2013. Written informed consent for genetic testing was obtained from all participants or their legal guardians. The study was approved by the Institutional Review Board of the General University Hospital in Prague (approval no. 100/23 S-IV). Availability of data and materials: All data generated or analysed during this study are included in this published article. Competing interests: R.Š. has received lecture honoraria and travel support from Chiesi, BioMarin, Takeda, and Amicus. I.N. has received grant support from Sanofi Genzyme and Takeda and lecture honoraria from Sanofi Genzyme. M.M. has received lecture honoraria, travel support and consulting fees for work unrelated to this study from Chiesi, BioMarin and Takeda. L.M., M.T., H.P. and J.Z. have nothing to disclose. Funding: This work was supported by the Czech Ministry of Health, grant No. RVO 64165, COOPERATIO-Pediatrics, First Faculty of Medicine, Charles University, Prague, and the Rare Diseases Clinical Research Network, Lysosomal Disease Network, NIH U54NS065768 (IN). Authors' contributions : R.Š. collected the data, interpreted the results, drafted and reviewed the manuscript with input from all authors. L.M. collected and evaluated data with a focus on ENT manifestations. M.T. performed the molecular-genetic analyses. H.P. performed the enzyme assays. I.N. evaluated data, reviewed the manuscript. J.Z. followed- up the patients, reviewed the manuscript. M.M. designed the study, was responsible for the initial conception, followed up the patients and collected the clinical data, revised the manuscript with input from all authors. All the authors provided critical feedback and approved the final manuscript. Acknowledgements: We thank BioMarin Pharmaceutical Inc. for covering the Open Access fee. This support had no impact on the decision to write this manuscript or its content. References Hendriksz CJ, Harmatz P, Beck M, Jones S, Wood T, Lachman R, et al. Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA. Mol Genet Metab. 2013;110:54–64. Montaño AM, Tomatsu S, Gottesman GS, Smith M, Orii T. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis. 2007;30:165–74. Khan S, Alméciga-Díaz CJ, Sawamoto K, Mackenzie WG, Theroux MC, Pizarro C, et al. Mucopolysaccharidosis IVA and glycosaminoglycans. Mol Genet Metab. 2017;120:78–95. Hendriksz CJ, Al-Jawad M, Berger KI, Hawley SM, Lawrence R, Mc Ardle C, et al. Clinical overview and treatment options for nonskeletal manifestations of mucopolysaccharidosis type IVA. J Inherit Metab Dis. 2013;36:309–22. Lavery C, Hendriksz C. Mortality in patients with morquio syndrome a. JIMD Rep. 2015;15:59–66. Leadley RM, Lang S, Misso K, Bekkering T, Ross J, Akiyama T, et al. A systematic review of the prevalence of Morquio A syndrome: challenges for study reporting in rare diseases. Orphanet J Rare Dis. 2014;9:173. Akyol MU, Alden TD, Amartino H, Ashworth J, Belani K, Berger KI, et al. Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance. Orphanet J Rare Dis. 2019;14:137. Hendriksz CJ, Burton B, Fleming TR, Harmatz P, Hughes D, Jones SA, et al. Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study. J Inherit Metab Dis. 2014;37:979–90. Hendriksz CJ, Giugliani R, Harmatz P, Mengel E, Guffon N, Valayannopoulos V, et al. Multi-domain impact of elosufase alfa in Morquio A syndrome in the pivotal phase III trial. Mol Genet Metab. 2015;114:178–85. Mitchell JJ, Burton BK, Bober MB, Campeau PM, Cohen S, Dosenovic S, et al. Findings from the Morquio A Registry Study (MARS) after 6 years: Long-term outcomes of MPS IVA patients treated with elosulfase alfa. Mol Genet Metab. 2022;137:164–72. Sawamoto K, Álvarez González JV, Piechnik M, Otero FJ, Couce ML, Suzuki Y, et al. Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management. Int J Mol Sci. 2020;21:1517. Harmatz PR, Mengel KE, Giugliani R, Valayannopoulos V, Lin S-P, Parini R, et al. Longitudinal analysis of endurance and respiratory function from a natural history study of Morquio A syndrome. Mol Genet Metab. 2015;114:186–94. Lin H-Y, Chuang C-K, Chen M-R, Chiu PC, Ke Y-Y, Niu D-M, et al. Natural history and clinical assessment of Taiwanese patients with mucopolysaccharidosis IVA. Orphanet J Rare Dis. 2014;9:21. Leong HY, Abdul Azize NA, Chew HB, Keng WT, Thong MK, Mohd Khalid MKN, et al. Clinical, biochemical and genetic profiles of patients with mucopolysaccharidosis type IVA (Morquio A syndrome) in Malaysia: the first national natural history cohort study. Orphanet J Rare Dis. 2019;14:143. Peretz RH, Flora CH, Adams DJ. Natural history of the oldest known females with mucopolysaccharidosis type IVA (Morquio A syndrome). Am J Med Genet A. 2020;182:1491–5. Lee NH, Cho SY, Maeng SH, Jeon TY, Sohn YB, Kim SJ, et al. Clinical, radiologic, and genetic features of Korean patients with Mucopolysaccharidosis IVA. Korean J Pediatr. 2012;55:430–7. Cleary M, Davison J, Gould R, Geberhiwot T, Hughes D, Mercer J, et al. Impact of long-term elosulfase alfa treatment on clinical and patient-reported outcomes in patients with mucopolysaccharidosis type IVA: results from a Managed Access Agreement in England. Orphanet J Rare Dis. 2021;16:38. Lin H-Y, Chen M-R, Lin S-M, Hung C-L, Niu D-M, Chuang C-K, et al. Cardiac features and effects of enzyme replacement therapy in Taiwanese patients with Mucopolysaccharidosis IVA. Orphanet J Rare Dis. 2018;13:148. Barbosa ICDQ, Paula IS, Melo ICP, Nóbrega SMB, Eufrazino CSDS, Medeiros PFV. Echocardiography in Mucopolysaccharidosis Iva: Evaluation of Enzyme Replacement Therapy. Arq Bras Cardiol - IMAGEM Cardiovasc [Internet]. 2017 [cited 2025 May 19];30. Burton BK, Stepien KM, Campeau PM, Sutton J, Hunt A, Reisewitz P, et al. Real-world treatment with elosulfase alfa in patients with MPS IVA is associated with improved endurance over time. Genet Med Open. 2025;103428. Doherty C, Stapleton M, Piechnik M, Mason RW, Mackenzie WG, Yamaguchi S, et al. Effect of enzyme replacement therapy on the growth of patients with Morquio A. J Hum Genet. 2019;64:625–35. Montaño AM, Tomatsu S, Brusius A, Smith M, Orii T. Growth charts for patients affected with Morquio A disease. Am J Med Genet A. 2008;146A:1286–95. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111–7. Skoog WA, Beck WS. Studies on the fibrinogen, dextran and phytohemagglutinin methods of isolating leukocytes. Blood. 1956;11:436–54. Hartree EF. Determination of protein: A modification of the lowry method that gives a linear photometric response. Anal Biochem. 1972;48:422–7. van Diggelen OP, Zhao H, Kleijer WJ, Janse HC, Poorthuis BJ, van Pelt J, et al. A fluorimetric enzyme assay for the diagnosis of Morquio disease type A (MPS IV A). Clin Chim Acta Int J Clin Chem. 1990;187:131–9. Ullrich K. Screening for lysosomal disorders. Eur J Pediatr. 1994;153:S38-43. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013;310:2191. Harmatz P, Mengel KE, Giugliani R, Valayannopoulos V, Lin S-P, Parini R, et al. The Morquio A Clinical Assessment Program: Baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013;109:54–61. Wang L, Ou X, Sebesta I, Vondrak K, Krijt J, Elleder M, et al. Combined adenine phosphoribosyltransferase and N-acetylgalactosamine-6-sulfate sulfatase deficiency. Mol Genet Metab. 1999;68:78–85. Ye J, Lei H, Zhang H, Qiu W, Han L, Wang Y, et al. [Analysis of GALNS gene mutation in thirty-eight Chinese patients with mucopolysaccharidosis type IVA]. Zhonghua Er Ke Za Zhi Chin J Pediatr. 2013;51:414–9. Dũng VC, Tomatsu S, Montaño AM, Gottesman G, Bober MB, Mackenzie W, et al. Mucopolysaccharidosis IVA: correlation between genotype, phenotype and keratan sulfate levels. Mol Genet Metab. 2013;110:129–38. Tomatsu S, Montaño AM, Oikawa H, Smith M, Barrera L, Chinen Y, et al. Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment. Curr Pharm Biotechnol. 2011;12:931–45. Murgasova L, Jurovcik M, Jesina P, Malinova V, Bloomfield M, Zeman J, et al. Otorhinolaryngological manifestations in 61 patients with mucopolysaccharidosis. Int J Pediatr Otorhinolaryngol. 2020;135:110137. Lin H-Y, Shih S-C, Chuang C-K, Lee K-S, Chen M-R, Lin H-C, et al. Assessment of hearing loss by pure-tone audiometry in patients with mucopolysaccharidoses. Mol Genet Metab. 2014;111:533–8. Riedner ED, Levin LS. Hearing patterns in Morquio’s syndrome (mucopolysaccharidosis IV). Arch Otolaryngol Chic Ill 1960. 1977;103:518–20. Wolfberg J, Chintalapati K, Tomatsu S, Nagao K. Hearing Loss in Mucopolysaccharidoses: Current Knowledge and Future Directions. Diagnostics. 2020;10:554. Fialová J, Kojanová M, Šáhó R, Magner M. Mucopolysaccharidosis type IVA and severe hidradenitis suppurativa: A case series. JAAD Case Rep. 2025;62:146–50. Broomfield A, Zuberi K, Mercer J, Moss G, Finnegan N, Hensman P, et al. Outcomes from 18 years of cervical spine surgery in MPS IVA: a single centre’s experience. Childs Nerv Syst. 2018;34:1705–16. Labounek R, Valošek J, Horák T, Svátková A, Bednařík P, Vojtíšek L, et al. HARDI-ZOOMit protocol improves specificity to microstructural changes in presymptomatic myelopathy. Sci Rep. 2020;10:17529. Labounek R, Bondy MT, Paulson AL, Bédard S, Abramovic M, Alonso-Ortiz E, et al. Body size and intracranial volume interact with the structure of the central nervous system: A multi-center in vivo neuroimaging study. Imaging Neurosci. 2025;3:imag_a_00559. Zanetti A, D’Avanzo F, AlSayed M, Brusius‐Facchin AC, Chien Y, Giugliani R, et al. Molecular basis of mucopolysaccharidosis IVA (Morquio A syndrome): A review and classification of GALNS gene variants and reporting of 68 novel variants. Hum Mutat. 2021;42:1384–98. Jezela-Stanek A, Różdżyńska-Świątkowska A, Kulpanovich A, Ciara E, Marucha J, Tylki-Szymańska A. Novel data on growth phenotype and causative genotypes in 29 patients with Morquio (Morquio-Brailsford) syndrome from Central-Eastern Europe. J Appl Genet. 2019;60:163–74. Fukuda S, Tomatsu S, Masuno M, Ogawa T, Yamagishi A, Rezvi GM, et al. Mucopolysaccharidosis IVA: submicroscopic deletion of 16q24.3 and a novel R386C mutation of N-acetylgalactosamine-6-sulfate sulfatase gene in a classical Morquio disease. Hum Mutat. 1996;7:123–34. Hendriksz CJ, Berger KI, Parini R, AlSayed MD, Raiman J, Giugliani R, et al. Impact of long-term elosulfase alfa treatment on respiratory function in patients with Morquio A syndrome. J Inherit Metab Dis. 2016;39:839–47. Hendriksz CJ, Parini R, AlSayed MD, Raiman J, Giugliani R, Solano Villarreal ML, et al. Long-term endurance and safety of elosulfase alfa enzyme replacement therapy in patients with Morquio A syndrome. Mol Genet Metab. 2016;119:131–43. Parini R, Deodato F. Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations. Int J Mol Sci. 2020;21:2975. Pintos-Morell G, Blasco-Alonso J, Couce ML, Gutiérrez-Solana LG, Guillén-Navarro E, O’Callaghan M, et al. Elosulfase alfa for mucopolysaccharidosis type IVA: Real-world experience in 7 patients from the Spanish Morquio-A early access program. Mol Genet Metab Rep. 2018;15:116–20. Lin H-Y, Chuang C-K, Ke Y-Y, Hsu C-C, Chiu PC, Niu D-M, et al. Long-term effects of enzyme replacement therapy for Taiwanese patients with mucopolysaccharidosis IVA. Pediatr Neonatol. 2019;60:342–3. Do Cao J, Wiedemann A, Quinaux T, Battaglia-Hsu SF, Mainard L, Froissart R, et al. 30 months follow-up of an early enzyme replacement therapy in a severe Morquio A patient: About one case. Mol Genet Metab Rep. 2016;9:42–5. Kılavuz S, Basaran S, Kor D, Bulut FD, Erdem S, Ballı HT, et al. Morquio A syndrome and effect of enzyme replacement therapy in different age groups of Turkish patients: a case series. Orphanet J Rare Dis. 2021;16:144. Kenth JJ, Thompson G, Fullwood C, Wilkinson S, Jones S, Bruce IA. The characterisation of pulmonary function in patients with mucopolysaccharidoses IVA: A longitudinal analysis. Mol Genet Metab Rep. 2019;20:100487. Kampmann C, Abu-Tair T, Gökce S, Lampe C, Reinke J, Mengel E, et al. Heart and Cardiovascular Involvement in Patients with Mucopolysaccharidosis Type IVA (Morquio-A Syndrome). Jefferies JL, editor. PLOS ONE. 2016;11:e0162612. Barak S, Anikster Y, Sarouk I, Stern E, Eisenstein E, Yissar T, et al. Long-Term Outcomes of Early Enzyme Replacement Therapy for Mucopolysaccharidosis IV: Clinical Case Studies of Two Siblings. Diagnostics. 2020;10:108. Jones SA, Bialer M, Parini R, Martin K, Wang H, Yang K, et al. Safety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 y. Pediatr Res. 2015;78:717–22. Tables Table 1: Clinical, enzymatic, and molecular characteristics of the Czech MPS IVA cohort Number / sex Age at 1st symptom (y) Age at dg. (y) Current age (y) ERT initiation age (y) Initial symptoms Height Z-score at dg. Height current Z-score GALNS activity (%+) GALNS variants Skeletal Non- skeletal 1st allele 2nd allele 1/M 3 3.8 13 4.1 kyphosis, scoliosis hepatomegaly, corneal clouding -2.33 -5.2 0 c.151G>A (p.Glu51Lys) c.1219A>C (p.Asn407His) 2/M 0.34 2.6 10 3.3 pectus carinatum, kyphosis, scoliosis, genu varum coarse facies -1.08 -4.68 0.2 c.421_422dupTG c.1219A>C (p.Asn407His) 3/M 0.7 4.7 11.2 6.2 abnormal gait, pectus carinatum, acetabular dysplasia, kyphosis, scoliosis recurrent acute otitis media, recurrent respiratory infections -2.62 -4.81 0.5 c.502G>A (p.Gly168Arg) c.1219A>C (p.Asn407His) 4/F 1.5 4.4 17.6 11.3 short growth, pedes plani, genu varum, pectus carinatum - -3.13 -10.6 0 c.1156C>T (p. Arg386Cys) c.1156C>T (p. Arg386Cys) 5/M 2 5.2 11 5.7 pectus excavatum, pedes equinovarus, acetabular dysplasia, short growth recurrent respiratory infections, recurrent acute otitis media -3.28 -5.92 0 c.139G>A (p.Gly47Arg) c.1520G>T (p.Cys507Phe) 6/M# 2 5.5 15.9 10.2 abnormal gait, - lower limb pain - 0.56 -1.54 0.8 c.740G>A (p.Gly247Asp) c.1219A>C (p.Asn407His) 7/F 3 6.1 22.3 20.5 short growth, pectus carinatum, genu varum, pedes plani, ulnar deviation of the wrist - -3.57 -11.33 0 c.482G>C (p.Gly161Ala) c.1219A>C (p.Asn407His) 8/M 1.3 2 3.3 2.4 abnormal gait, pectus carinatum coarse facies, delay of gross motor skills -2,94 -9.94 0 c.1019G>A (p.Gly340Asp) c.1483-15A>G (p.Asn495Phefs*15) 9/F 3.5 3.9 23.8 - short growth, pectus carinatum - -4.84 -6.43 0 c.116A>G (p.Asp39Gly) 39 kb deletion incl. ex1 part - ex 13 10/M* 5.8 5.8 24.7 - abnormal gait, Skeletal changes without further specification family history, recurrent respiratory infections -5.34 -5.45 0.1 c.286G>T (p.Gly96Cys) c.1156C>T (p. Arg386Cys) 11/M* 3 12.3 32 - acetabular dysplasia, genu varum, short growth - NA -9.09 0.3 c.740G>A (p.Gly247Asp) c.860C>T (p.Ser287Leu) 12/M* 5 16.2 35.8 - pectus carinatum, acetabular dysplasia, short growth family history, recurrent respiratory infections NA -9.89 0.6 c.740G>A (p.Gly247Asp) c.860C>T (p.Ser287Leu) 13/F 3 3 48.6 - acetabular dysplasia, short growth - NA -9.24 0 c.463G>A (p.Gly155Arg) c.1219A>C (p.Asn407His) 14/F 3.5 3.9 32.3 - pedes plani, genu varum, pectus carinatum - NA -7.66 0.2 c.1156C>T (p. Arg386Cys) c.1156C>T (p. Arg386Cys) 15/M* 1 9.1 27.9 - Skeletal changes without further specification coarse facies, recurrent acute otitis media -5.27 -1,7 0.2 c.286G>T (p.Gly96Cys) c.1156C>T (p. Arg386Cys) 16/M 3 5 36.3 - short growth, kyphosis, pectus carinatum coarse facies NA -4.56 0 c.1219A>C (p.Asn407His) c.1219A>C (p.Asn407His) 17/M NA NA † 30.5 - acetabular dysplasia, pectus carinatum, kyphosis, scoliosis, genu varum, pedes plani coarse facies NA -9.24 0 del (100 kb, GALNS in.2 to APRT in. 2) 18/M 3 5 26 - short growth recurrent respiratory infections -4.31 -11.05 0 c.482G>C (p.Gly161Ala) c.1156C>T (p. Arg386Cys) 19/M 3 5 52.1 - acetabular dysplasia, pectus carinatum, kyphosis, scoliosis, ulnar deviation of the wrist hernia, recurrent acute otitis media -3.41 -10.84 0 c.853_855delTTC (p.Phe285del) c.860C>T (p.Ser287Leu) *Patients 10 and 15 are brothers, patients 11 and 12 are brothers, #only patient 6 had attenuated phenotype, + residual activity in leukocytes, percentage of long-term average of controls (34,5 nmol/17h/mg) ERT – enzyme replacement therapy, F- female, GALNS - galactosamine (N-acetyl)-6-sulfatase M – male, NA – not available, , y – years, † death, Table 2: Spirometry results in the Czech MPS IVA cohort compared with those of natural history studies* Age range (years) ERT-treated patients from our study NATURAL HISTORY STUDIES ERT-naïve patients from our study Burton et al. 20 ERT-naïve Leong HY et al. 14 ERT-naïve Harmatz et al. 29 ERT-naïve FVC ± SD (L) FEV1 ± SD (L) FVC ± SD (L) FEV1 ± SD (L) FVC ± SD (L) FVC ± SD (L) FVC ± SD (L) FEV1 ± SD (L) 5-7 1.0 ± 0.2 (25 tests, 5 pt) 0.9± 0.2 (25 tests, 5 pt) 0.75 ± 0.21 (n=31) 0.71 ± 0.19 (n=31) - - - - 9-11 1.77 ± 0.87 (21 tests, 6 pt) 1.51 ± 0.69 (21 tests, 6 pt) 1.11± 0.58 (n=35) 0.95 ± 0.45 (n=35) - - 0.77 (1 test, 1 pt) - 14-16 2.53 ± 2.1 (7 tests, 2 pt) 2.15 ± 1.77 (7 tests, 2 pt) 1.48 ± 1.09 (n=32) 1.26 ± 0.92 (n=32) - - 1.05 ± 0.51 (6 tests, 3 pt) 1.02 ± 0.52 (6 tests, 3 pt) ≤ 18 1.52±1.07 (74 tests, 6 pt) 1.51 ± 0.92 (74 tests, 6 pt) 1.11 ± 0.62 (n=98) 0.97 ± 0.52 (n=98) 0.6 ± 0.1 (n=5) 1.1 ± 0.7 (n=256) 0.97 ± 0.38 (11 tests, 4 pt) 1.07 ± 0.67 (13 test, 4 pt) > 18 - - 1.49 ± 1.27 (n=37) 1.26 ± 1.03 (n=37) 0.9 ± 0.2 L (n=3) 1.5 ± 1.1 L (n=69) 1.59 ± 0.94 (5 test, 5 pt 1.42 ± 1.07 (5 tests, 5 pt) *including 90 evaluations presented as volumes with means ± SD across age groups for ERT-treated and ERT-naïve patients relative to published natural history data. Forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) are shown in litres (L). Results are presented as means and standard deviations. ERT- enzyme replacement therapy, pt - patients Table 3: Results of the 6MWT in the Czech MPS IVA cohort compared with those of natural history studies * Age range (years) ERT-treated patients from our study NATURAL HISTORY STUDIES Leong HY et al. 14 ERT-naïve Harmatz et al. 29 ERT-naïve Burton et al. 20 ERT-naïve 6MWT average + SD (m) 0-4 347.8 ± 98.5 (4 pt, 12 tests) 246.9 ± 87.4 (n=1) 251.6 ± 121.5 (n=37) - 5-11 387.1 ± 94.7 (6 pt, 64 tests) 218.8 ± 98.2 (n=4) 232.5 ± 140.1 (n=127) 259.2 ± 102.1 (n=154) 12-18 347.8 ± 33 (3 pt, 14 tests) 123.7 ± 116.4 (n=5) 181.2 ± 177.3 (n=84) 167.2 ± 168.7 # (n=65) > 18 436.3 ± 62.9 (1 pt, 4 exams) 119.3 ± 121.2 (n=3) 193.1 ± 148.5 (n=68) 157 ± 158.1 (n=76) *displaying mean distances ± SD across different age groups for ERT-treated and ERT-naïve patients, # data from patients aged 14-16 years, 6MWT - 6-minute walking test , ERT – enzyme replacement therapy Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 17 Apr, 2026 Reviewers agreed at journal 27 Mar, 2026 Reviewers invited by journal 24 Mar, 2026 Editor invited by journal 15 Mar, 2026 Editor assigned by journal 05 Mar, 2026 First submitted to journal 04 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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21:41:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9023839/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9023839/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105477046,"identity":"4970db24-74d6-4420-9d34-c91a3bc4ad04","added_by":"auto","created_at":"2026-03-26 13:05:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":214892,"visible":true,"origin":"","legend":"\u003cp\u003eInitial symptoms in the cohort of 19 MPS IVA Czech patients\u003c/p\u003e","description":"","filename":"SahoMPSIVAfig1260130.png","url":"https://assets-eu.researchsquare.com/files/rs-9023839/v1/7296c287826a89b7ec3b2147.png"},{"id":105477049,"identity":"4365cba0-679b-4d5e-86ea-4a287c3a0d68","added_by":"auto","created_at":"2026-03-26 13:05:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":297645,"visible":true,"origin":"","legend":"\u003cp\u003eSpirometry and 6MWT results in the Czech MPS IVA cohort compared with published data (A- FVC, B- FEV 1, C- 6MWT)\u003c/p\u003e","description":"","filename":"SahoMPSIVAfig2260130.png","url":"https://assets-eu.researchsquare.com/files/rs-9023839/v1/6266f495f27112fe81a53a66.png"},{"id":105566209,"identity":"89135323-7e6d-4708-b752-afba2de103d4","added_by":"auto","created_at":"2026-03-27 12:55:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1454351,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9023839/v1/146d4a89-b046-4746-9a45-1422f220447a.pdf"}],"financialInterests":"","formattedTitle":"Long-term Natural History and Elosulfase Alfa Treatment for Mucopolysaccharidosis Type IVA: A Single-Center Study in the Czech Republic","fulltext":[{"header":"1. Background","content":"\u003cp\u003eMucopolysaccharidosis type IVA (MPS IVA), also known as Morquio syndrome type A (OMIM #253000), is a rare but significant lysosomal storage disorder inherited in an autosomal recessive manner. It is caused by mutations in the \u003cem\u003eGALNS\u003c/em\u003e gene, resulting in a deficiency of the enzyme N-acetylglucosamine-6-sulfatase (GALNS; EC 3.1.6.4).[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] This enzyme deficiency results in the progressive accumulation of keratan sulfate (KS) and chondroitin-6-sulfate (CS) within lysosomes, particularly within connective tissues and the cornea,[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] ultimately driving the hallmark pathophysiology of the disease.\u003c/p\u003e \u003cp\u003ePronounced skeletal abnormalities, including short stature, long-bone deformities, spinal curvature, pectus carinatum, and joint laxity, dominate the clinical presentation of MPS IVA.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] However, its manifestations extend beyond the skeletal system: patients often experience respiratory impairment, valvular heart disease leading to subsequent cardiac hypertrophy, corneal clouding, vision and hearing loss, and characteristic coarse facial features. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] The severity of these clinical features contributes to a highly variable life expectancy. Individuals with milder forms of MPS IVA may live 20\u0026ndash;40 years, with some cases reported over 60 years. In contrast, severe phenotypes are often limited to late childhood or adolescence, with mortality typically resulting from spinal cord compression or respiratory failure.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] The birth prevalence of MPS IVA is population specific, ranging from 1 in 140,000 in the Czech Republic to 1 in 872,000 in Australia.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e Since its approval in 2014, enzyme replacement therapy (ERT) with elosulfase alfa has been recommended as the first-line treatment according to international guidelines.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Clinical trials and registry data have shown that ERT improves quality of life, increases endurance, as evidenced by the 6-minute walk test (6MWT), supports respiratory function, enhances daily activity performance, and reduces urinary KS levels.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Long-term stabilization of endurance and respiratory function has been reported in the Morquio A Registry Study (MARS).[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] However, ERT has not demonstrated efficacy in addressing the skeletal dysplasia and bone defects associated with MPS IVA.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eWhile natural history studies have documented the progression of MPS IVA, including a high rate of surgical intervention and a gradual decline in physical endurance,[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] real-world data on the therapeutic impact of ERT remain limited.[\u003cspan additionalcitationids=\"CR18 CR19 CR20\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] This retrospective observational study reviewed the clinical history, genotypic characteristics, and phenotypic profiles of 19 Czech patients with MPS IVA since 1976. Additionally, we evaluated the effects of ERT in a subset of treated patients, providing valuable insights into the real-world outcomes of ERT in this patient cohort.\u003c/p\u003e"},{"header":"2. Patients and methods","content":"\u003cp\u003eNineteen patients who were diagnosed with MPS IVA at the Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic, were included in this study. The diagnosis was confirmed through enzymatic and/or genetic testing. Patients in the cohort were observed longitudinally from 1976\u0026ndash;2023, with data analysed at the conclusion of the study. Clinical, laboratory, and genetic data, including data from both outpatient and inpatient visits, were retrospectively collected from patient records.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Clinical Symptoms\u003c/h2\u003e \u003cp\u003eClinical data included the onset of the disease, initial presenting symptoms, age at diagnosis, age at the start of ERT, anthropometric measures, and the presence of hepatomegaly.\u003c/p\u003e \u003cp\u003eOn the basis of MPS IVA-specific growth charts,[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] patients were assigned a \u0026ldquo;classic\u0026rdquo; designation to classify phenotypes if their height fell below the 75th percentile. Endurance was evaluated via the 6MWT following established guidelines.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] Additional clinical evaluations included two-dimensional Doppler echocardiography, spinal MRI, audiometry, ocular examinations of the fundus and anterior segment, spirometry assessments for forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1), and polysomnography. The determination of urinary keratan sulfate quantity was unavailable due to laboratory limitations at our center.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Enzymology\u003c/h2\u003e \u003cp\u003eWhite blood cell enzyme activity was measured in leukocytes isolated via dextran sedimentation and homogenized via ultrasonic disruption (Cole-Parmer CP-130, 30%) on ice. The protein concentration was determined via the Hartree method;[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] GALNS activity was assessed fluorometrically via the use of 4-methylumbelliferyl-β-D-galactopyranoside-6-sulfate (MU-β-Gal-6S) as the substrate.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] β-Galactosidase activity was measured using 4-methylumbelliferyl-β-D-galactopyranoside (MU-β-Gal) as the substrate. MU fluorescence (Ex: 365 nm, Em: 448 nm) was detected on a luminiscence spectrometer (Perkin Elmer LS50B, Wellesley, U.S.A.).[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Molecular Genetic Analyses\u003c/h2\u003e \u003cp\u003eGenomic DNA was extracted from blood samples, and all exons of the *GALNS* gene (NM_000512.5) were amplified and analysed by Sanger sequencing via the ABI3500xL Genetic Analyser (Applied Biosystems, USA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Ethics\u003c/h2\u003e \u003cp\u003e All data were accessed in compliance with relevant laws and ethical standards for the study period and in accordance with the Declaration of Helsinki, as revised in 2013.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] Informed consent for genetic testing was obtained from all participants. Ethical approval for the study was granted by the Institutional Review Board (IRB) of the General University Hospital in Prague (Approval Number: 100/23 S-IV).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eThis study involved 19 patients (13 males, 6 females) from 17 unrelated families, all with a confirmed diagnosis of MPS IVA. The cohort\u0026apos;s median age was 24.7 \u0026plusmn; 13.0 years (range: 3.3\u0026ndash;52.0 years), with a mean follow-up period of 18.9 \u0026plusmn; 12.7 years (range: 1.3\u0026ndash;47.1 years). Notably, patient 17 passed away at 30.5 years of age due to respiratory complications associated with COVID-19 infection. The median age at symptom onset was 3.0 \u0026plusmn; 1.4 years (range: 4 months to 5.8 years), whereas the median age at confirmed diagnosis was 5.0 \u0026plusmn; 3.5 years (range: 2\u0026ndash;16.2 years), with a mean diagnostic delay of 3.1 \u0026plusmn; 3.3 years (range: 0\u0026ndash;11.2 years). For patient 19, an initial diagnosis of mucopolysaccharidosis was made at age 5 without subtype specification; the patient was later lost to follow-up and re-evaluated at age 48 when MPS IVA was confirmed.\u003c/p\u003e\n\u003cp\u003eAmong the 19 patients, 8 (6 males, 2 females) received ERT with elosulfase alfa. The median age at the start of ERT was 6.0 \u0026plusmn; 6.0 years (range 2.4\u0026ndash;20.5 years). At the time of the study, the median duration of ERT was 5.5 \u0026plusmn; 2.6 years (range: 11 months\u0026ndash;8.9 years), representing a mean interval of 3.7 \u0026plusmn; 5.0 years (range: 0.3\u0026ndash;14.4 years) between diagnosis and the commencement of ERT.\u003c/p\u003e\n\u003ch3\u003e3.1. Clinical outcomes\u003c/h3\u003e\n\u003ch3\u003e3.1.1. Disease onset\u003c/h3\u003e\n\u003cp\u003eThe most common initial symptoms observed in the cohort are depicted in Figure 1 and summarized in Table 1. Skeletal symptoms were universal at onset among all 19 patients, with specific findings including pectus carinatum (n=11), short stature (n=9), acetabular dysplasia of the hip (n=9), abnormal gait (n=8), scoliosis (n=7), genu valgum (n=6), and kyphosis (n=6). Additionally, 63% of patients presented initial nonskeletal symptoms, such as acute otitis media (n=6), frequent respiratory infections (n=5), and coarse facial features (n=4). In two patients, the diagnosis was prompted by a family history of MPS IVA. At the time of diagnosis, all patients with available radiographic data (n=17/19) presented classic features of multiplex dysostosis, whereas hepatomegaly was noted in only 19% of patients (3/16).\u003c/p\u003e\n\u003cp\u003e3.1.2. Anthropometry and growth\u003c/p\u003e\n\u003cp\u003eAmong the 18 MPS IVA patients whose birth data were recorded, the mean birth weight was 3,632 \u0026plusmn; 534 g (range 2,650\u0026ndash;4370 g), with an average gestational age of 38.8 \u0026plusmn; 1.2 weeks. The average birth length in this group was 52.6 \u0026plusmn; 3.0 cm (range 48\u0026ndash;57 cm). On the basis of height assessments, 18 patients exhibited the classic MPS IVA phenotype, whereas one presented with an attenuated phenotype. Short stature was present in 85% (11/13) of patients at the time of diagnosis, with a mean height Z score of -3.2 \u0026plusmn; 1.72 (range -5.34--0.56). However, some patients initially grew within the normal percentile range (97th\u0026ndash;25th percentile, data not shown) on Czech growth charts during the first 18 months of life. Patient 6, identified with an attenuated phenotype, had a Z score of 0.56 at the age of 5.5 years. At the last recorded visit, the mean Z score for height across the cohort (n=18) was -7.64 \u0026plusmn; 2.87 (range -11.33 to -1.54), with patient 6 continuing to have a relatively high Z score of -1.54 (Table 1). When ERT-treated patients were compared with ERT-na\u0026iuml;ve patients (8 vs 11), the current mean height Z scores were -6.75 \u0026plusmn; 3.47 and -8.35 \u0026plusmn; 2.23, respectively, although this difference was not statistically significant (p=0.48). The baseline Z score for head circumference was 0.81 \u0026plusmn; 1.18 (n=11).\u003c/p\u003e\n\u003cp\u003e3.1.3. Endurance, spirometry, and assistive devices\u003c/p\u003e\n\u003cp\u003eSpirometric evaluations revealed higher mean values of FVC and FEV1 across all age groups in ERT-treated patients than in untreated patients in natural history studies [14,20,29] and in the untreated patients in our cohort (Table 2, Figure 2a, b). The differences in the FVC between the treated and untreated groups ranged from 1.05 L to 0.25 L, and the FEV1 ranged from 0.89 L to 0.18 L. Unlike the expected decline observed in natural history data, lung function remained stable or improved across age groups in our cohort, regardless of treatment status. Notably, direct statistical analysis was not possible due to the unavailability of source data from natural history studies.\u003c/p\u003e\n\u003cp\u003e3.1.4. Mobility and Endurance Assessment\u003c/p\u003e\n\u003cp\u003eIn the most recent follow-up, 10 patients (53%) were nonambulatory and relied on wheelchairs, with a mean age of 20.3 years when they ceased walking (data available for five patients). Additionally, three patients (16%) used a wheelchair for longer distances, whereas two (11%) required mobility aids such as walkers or crutches. Data for the 6MWT were not available for ERT-na\u0026iuml;ve patients in this cohort. However, ERT-treated patients demonstrated a greater mean 6MWT distance than did untreated individuals from natural history studies[14,20,29] across all age groups, with differences in distance between the treated and untreated groups ranging from 90.5 m to 315.7 m (Table 3, Figure 2c). Direct statistical analysis was not possible.\u003c/p\u003e\n\u003cp\u003e3.1.5. Surgical history\u003c/p\u003e\n\u003cp\u003eAll patients for whom data were available (n=17) underwent surgery at some point. The average age at first surgical intervention was 6 years. Among these patients, 13 (77%) required at least one knee surgery, whereas 10 (59%) underwent spinal cord surgery. Additional surgeries included adenotomy in 41% (7/17), hip surgery in 29% (5/17), and tympanostomy in 24% (4/17). Hernia repair and strabismus surgeries were performed in 6% of the patients each. The median ages at significant surgical intervention were as follows: knee surgery, 8.8 \u0026plusmn; 6.1 years (5.5\u0026ndash;35.5 years); spinal cord surgery, 14.0 \u0026plusmn; 6.2 years (8.1\u0026ndash;31 years); adenotomy, 3.7 \u0026plusmn; 2 years (2.9\u0026ndash;8.8 years); and hip surgery, 8.1 \u0026plusmn; 1.4 years (6.4\u0026ndash;9.7 years). Spinal magnetic resonance imaging (MRI) was available for 17 patients, revealing cervical stenosis in 13 (76%), cervical myelopathy in 7 (41%), and thoracic stenosis with odontoid hypoplasia in 5 patients (29%). Patient 4 experienced a significant decline in clinical status at age 15 following spinal cord surgery, which resulted in postoperative paraplegia and sensory impairment distal from the Th12 level. Subsequent complications included the development of a neurogenic bladder and a neurogenic bowel.\u003c/p\u003e\n\u003cp\u003e3.1.6. Cardiologic evaluation\u003c/p\u003e\n\u003cp\u003eEchocardiographic data from the most recent follow-up were available for 18 patients. The most commonly observed cardiac anomalies were mitral and tricuspid regurgitation (both present in 56% of patients), followed by aortic regurgitation in 44%, aortic and tricuspid valve thickening in 50%, mitral valve thickening in 28%, and pulmonary regurgitation in 22%. The mean age of patients with valvular heart disease was 27.9 \u0026plusmn; 11.3 years, whereas the mean age of those without valvular heart disease was 11.2 \u0026plusmn; 4.7 years. Mild valvular disease was predominantly observed in patients aged 3.3--18 years, whereas more advanced cases were observed in patients older than 18 years. One patient was identified with hypertrophic cardiomyopathy. The ejection fraction values remained within the normal range (\u0026ge;55%) for all patients, with mean values of 71% at baseline and 68% at follow-up, indicating preserved systolic function.\u003c/p\u003e\n\u003cp\u003e3.1.7. ENT Presentation, Vision, and Others\u003c/p\u003e\n\u003cp\u003eAmong the 15 patients evaluated for ENT manifestations, 47% (7/15) experienced recurrent upper respiratory tract infections (RURIs), 20% (3/15) had recurrent otitis media (ROMA), and 47% (7/15) had at least one episode of acute otitis media (OMA). Audiometric assessments revealed hearing loss in 67% of the patients (10/15), with conductive hearing loss accounting for 53%, while the remaining cases were attributed to sensorineural and mixed hearing loss. Five patients were already using hearing aids, and the mean age at which hearing loss was documented was 12.4 years (n=8). Four patients had severe obstructive sleep apnea requiring nocturnal noninvasive ventilation (bilevel positive airway pressure (BiPAP)). Surgical interventions for ENT issues are summarized in the surgery history section.\u003c/p\u003e\n\u003cp\u003eSixteen patients underwent a complete ophthalmologic assessment. Corneal clouding was observed in 75% of the cases, typically without vision impairment. No patients required corneal transplantation. One patient (6%) developed glaucoma. Cycloplegic refraction results revealed that hyperopia was the most common refractive error, affecting 69% of patients, followed by astigmatism at 63% and myopia, strabismus, and amblyopia, each affecting 19% of patients.\u003c/p\u003e\n\u003cp\u003eIn addition, three patients had severe forms of hidradenitis suppurativa (HS) and were treated with biologic therapy. This condition is notably uncommon in lysosomal storage disorders.\u003c/p\u003e\n\u003cp\u003e3.2. Laboratory Data\u003c/p\u003e\n\u003cp\u003e3.2.1. Enzymatic Analyses\u003c/p\u003e\n\u003cp\u003eAll patients exhibited significantly deficient GALNS enzyme activity, with levels below 1% of the long-term control average (34,5 nmol/17 h/mg). In both the classic and attenuated phenotypes, GALNS activity remained below 1% of the control average (Table 1).\u003c/p\u003e\n\u003cp\u003e3.2.2. Molecular‒Genetic Analyses\u003c/p\u003e\n\u003cp\u003eNineteen different variants of the \u003cem\u003eGALNS\u003c/em\u003e gene were identified among 18 patients (12 males, 6 females) from 16 families. These variants included 13 missense mutations, two large deletions, two null variants (one small in-frame deletion/insertion and one intronic), and one duplication. The most common variants were c.1219A\u0026gt;C p.(Asn407His), which was found in 7 unrelated patients; c.1156C\u0026gt;T p.(Arg386Cys), which was present in 5 patients from 4 families; c.740G\u0026gt;A p.(Gly247Asp), which was found in 3 patients from 2 families; and c.860C\u0026gt;T p.(Ser287Leu), which was found in 3 patients from 2 families (Table 1).\u003c/p\u003e\n\u003cp\u003eNotably, Patient 17 presented with a rare codiagnosis of adenine phosphoribosyltransferase (APRT) deficiency, leading to 2,8-dihydroxyadenine urolithiasis, along with GALNS deficiency. Both the \u003cem\u003eGALNS\u003c/em\u003e and \u003cem\u003eAPRT\u003c/em\u003e genes are located on chromosome 16q24.3, and genetic analysis revealed a deletion involving both genes. Polymerase chain reaction (PCR) confirmed that a novel junction formed by the fusion of sequences distal to GALNS exon 2 and proximal to APRT exon 3, with an estimated deletion size of approximately 100 kb, spanning \u003cem\u003eGALNS\u003c/em\u003e intron 2 and \u003cem\u003eAPRT\u003c/em\u003e intron 2. This case was reported elsewhere.[30]\u003c/p\u003e\n\u003cp\u003eThis study identified two unreported variants: a missense variant, c.482G\u0026gt;C (p.Gly161Ala), and a duplication, c.421_422dupTG. Notably, a different substitution at the same nucleotide position, c.482G\u0026gt;A, has been associated with an intermediate phenotype in a Chinese cohort.[31] With respect to duplication, a similar variant located one nucleotide upstream (closer to the intron) has been described previously.[32] Prediction algorithms provide conflicting interpretations of the impact of this duplication. Franklin and Varsome predict normal splicing with effects limited to amino acid substitution and a frameshift leading to p.Trp141Cysfs*13, suggesting that the impact may require reassessment. In contrast, SpliceAI predicts additional effects on splicing, indicating the potential for a more complex pathogenic mechanism.\u003c/p\u003e\n\u003cp\u003eZygosity analysis revealed that 3 patients were homozygous, 1 was hemizygous, and 15 were compound heterozygous. Sixteen variants associated with the classic phenotype, whereas the variants c.740G\u0026gt;A p.(Gly247Asp) and c.1219A\u0026gt;C p.(Asn407His), were associated with both classic and attenuated phenotypes within this cohort.\u003c/p\u003e\n\u003cp\u003eTwo novel variants, the Human Genome Mutation Database and ClinVar, have not been reported in public databases.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis retrospective observational study provides a comprehensive overview of the clinical and laboratory characteristics and evaluates the effectiveness of ERT in a cohort of 19 Czech patients with MPS IVA. Most patients (18/19) exhibited the classic phenotype, with only one presenting an attenuated form. This represents a slightly higher prevalence than previously reported, which indicates the classic phenotype in approximately 75% of cases.[33] The age of onset in toddlerhood and the diagnostic delay observed in this cohort are consistent with other published MPS IVA data. Symptoms often emerge between 1 and 3 years of age, with the mean age of onset reported at approximately 2.0 to 2.6 years. Diagnostic delays are also similar to our findings of 4.7–6.9 years.[2,13,14]\u003c/p\u003e\n\u003cp\u003eAs expected, skeletal symptoms, including pectus carinatum, short stature, acetabular dysplasia, and abnormal gait, were universally present. Although infants with MPS IVA are frequently born with average or above-average birth weight and length, growth failure often emerges in the second or third year of life.\u003c/p\u003e\n\u003cp\u003eRecurrent acute otitis media was a prevalent initial symptom in our cohort, underscoring that ENT symptoms, especially hearing loss, are relatively common in MPS IVA. In our cohort, 73% of patients experienced hearing loss, predominantly conductive hearing loss (two-thirds). Hearing loss in MPS IVA is reported in 67% to 94% of cases.[34–36] Consistent with other forms of MPS, younger patients predominantly exhibit conductive hearing loss, whereas sensorineural or mixed hearing loss becomes more prevalent with age.[37] A study by Riedner and Levin revealed that conductive hearing loss was universal in patients under 8 years of age, whereas older patients were more likely to develop sensorineural or mixed hearing loss.[36] Awareness of these ENT symptoms can facilitate earlier detection and long-term management by specialists, who play a crucial role in identifying hearing impairments potentially caused by ossicle deformity, recurrent upper respiratory infections, recurrent otitis media, and glycosaminoglycan accumulation. Although less often discussed, skin conditions such as hidradenitis suppurativa (HS) were observed in three patients (reported elsewhere[38]), although its exact pathophysiology in MPS IVA remains unknown.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Orthopedic and spinal surgeries pose significant challenges in managing MPS IVA. All patients underwent surgery, with a mean age of six years at their first procedure. Knee surgeries were the most common (77%), followed by spinal cord surgeries (59%). Cervical spine involvement, especially stenosis and instability, appears nearly universal in MPS IVA, often leading to myelopathy, paralysis, or sudden death. Previous studies reported varying overall surgery rates, ranging from 33% to 71%, underscoring an inconsistent approach to surgical indications. Broomfield et al. reported that 31% (26/82) of MPS IVA patients underwent cervical spine surgery at a median age of 6.1 years, emphasizing the importance of early intervention to preserve long-term neurological function.[39] The sparse literature lacks standardized recommendations for managing these orthopedic and neurosurgical challenges. The timing and indications for surgery are especially critical in spinal procedures, which have shown suboptimal outcomes, as observed in our cohort and other studies.[2] This clinical gap can be addressed through surveillance via spine MRI protocols sensitive to presymptomatic microstructural changes in the spinal cord, similar to those developed by the University of Minnesota group on the basis of their experience in degenerative cervical myelopathy.[40,41]\u003c/p\u003e\n\u003cp\u003eGenetic analysis revealed that missense mutations are the predominant type in the \u003cem\u003eGALNS\u003c/em\u003e gene, which is consistent with findings from global databases. The c.1219A\u0026gt;C variant was the most prevalent variant in our cohort, accounting for 22% of all variants. This study also revealed two novel mutations (c.482G\u0026gt;C and c.421_422dupTG). The c.1156C\u0026gt;T variant, identified as the most common variant globally in the literature, was the second most frequent variant in our cohort.[42] Jezela Stanek et al. reported that heterozygotes for the c.121-9T\u0026gt;G variant exhibit less severe growth defects. [43] However, in our cohort, this was observed in only one patient with a mild disease form, whereas five others carrying the same mutation experienced severe growth impairment. This variant appears to be less commonly reported in the literature. In contrast, the c.860C\u0026gt;T variant, which was the fourth most common variant worldwide and the 3rd most common variant in our cohort, is notably the most prevalent variant among the Indian population.[42] Additionally, our findings suggest that combined APRT/GALNS deficiencies, although rare, may be more common than previously recognized, with two cases documented to date, including one in our cohort.[30,44]\u003c/p\u003e\n\u003cp\u003eThe administration of elosulfase alfa to patients with MPS IVA in this study resulted in improved walking distances compared with data from age-matched naïve patients reported in the literature.[14,20,29] Data from several sources have also revealed the impact of ERT on the natural history outcomes of mobility issues in MPS, including the pivotal phase 3 randomized, double-blind, placebo-controlled MOR-004 clinical trial, which revealed statistically significant improvement in the 6MWT distance over placebo, which was sustained over 120 weeks.[8,45,46] In their review, Parini et al. reported improvement or stabilization of the 6MWT in MPS IVA patients after 1–3 years of treatment.[47] Pintos-Morel and colleagues reported improved walking distance in all but one cohort of patients after 8 months of ERT.[48] The mean 6MWT distance increased by 30% in four of six patients after ERT for 4.0–6.5 years in the study of Lin et al.[49] Other studies have also examined and reported improvements in walking distance and/or performance on the 3-minute stair climb test after the initiation of ERT.[50,51]\u003c/p\u003e\n\u003cp\u003eWith respect to respiratory function, we focused on the characteristics of FVC and FEV1 across all age groups. We observed a general reduction in spirometry values in our patients compared with those in healthy individuals; however, the values remained stable or slightly improved under ERT, and the mean FVC and FEV1 values remained above those recorded in natural history studies.[14,20,29] Numerous studies have conclusively demonstrated that ERT appears to improve pulmonary function.[8,9,45,48,52] MARS, the longest and largest observational study of MPS IVA patients to date, also provided real-world evidence for long-term stabilization of endurance and respiratory function among ERT-treated patients.[10]\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Mitral and tricuspid regurgitation were the most common symptoms of heart involvement in our cohort, with more advanced cases observed in patients older than 18 years. Only one patient manifested hypertrophic cardiomyopathy. None of our patients had been indicated for valve replacement yet. However, ERT likely has a negligible effect on cardiovascular outcomes, as no significant changes in heart structure or function have been noted.[18,53]\u003c/p\u003e\n\u003cp\u003eERT had no effect on growth in our patient, whereas the youngest treated patient began therapy at the age of 2.4 years. Unfortunately, the effect of ERT on growth in MPS IV A has never been sufficiently documented.[51,54,55] We emphasize that the anthropometric data of our patients during the first 1.5--2 years were normal. Therefore, normal growth at this age does not rule out the diagnosis of MPS IV A.\u003c/p\u003e\n\u003cp\u003eOur findings should be viewed in light of study limitations such as the limited number of patients, varying frequencies and intervals between clinical examinations, and incomplete data, particularly regarding functional tests from childhood in our adult patients. Furthermore, the absence of specific patient datasets from natural history studies precluded statistical comparisons. However, our study offers valuable real-world data on MPS IVA, which is essential for understanding treatment variability and optimizing clinical decisions.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eReal-world data from Czech patients illustrate the effectiveness of enzyme replacement therapy in enhancing respiratory and endurance functions, although it has no observable impact on growth or skeletal structure. There is a pressing need for international guidelines concerning indications for skeletal and, in particular, spinal surgeries. Concurrent conditions, such as HS or APRT deficiency, are not uncommon in patients with MPS IVA.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e6MWT – 6-minute walk test\u003c/p\u003e\n\u003cp\u003eAPRT – Adenine phosphoribosyltransferase\u003c/p\u003e\n\u003cp\u003eBiPAP – Bilevel positive airway pressure\u003c/p\u003e\n\u003cp\u003eCS – Chondroitin-6-sulfateENT – Ear, nose, and throat\u003c/p\u003e\n\u003cp\u003eERT – Enzyme replacement therapy\u003c/p\u003e\n\u003cp\u003eFEV1 – Forced expiratory volume in 1 second\u003c/p\u003e\n\u003cp\u003eFVC – Forced vital capacity\u003c/p\u003e\n\u003cp\u003eGALNS – \u003cem\u003eN\u003c/em\u003e-acetylglucosamine-6-sulfatase\u003c/p\u003e\n\u003cp\u003eHS – Hidradenitis suppurativa\u003c/p\u003e\n\u003cp\u003eKS – Keratan sulfate\u003c/p\u003e\n\u003cp\u003eMARS – Morquio A Registry Study\u003c/p\u003e\n\u003cp\u003eMRI – Magnetic resonance imaging\u003c/p\u003e\n\u003cp\u003eMPS – Mucopolysaccharidosis\u003c/p\u003e\n\u003cp\u003eMPS IVA – Mucopolysaccharidosis type IVA (Morquio A syndrome)\u003c/p\u003e\n\u003cp\u003eMU-β-Gal-4-methylumbelliferyl-β-D-galactopyranoside\u003c/p\u003e\n\u003cp\u003eMU-β-Gal-6S – 4-methylumbelliferyl-β-D-galactopyranoside-6-sulfate\u003c/p\u003e\n\u003cp\u003eOMIM – Online Mendelian Inheritance in Man\u003c/p\u003e\n\u003cp\u003ePCR – Polymerase chain reaction\u003c/p\u003e\n\u003cp\u003eROMA – Recurrent otitis media\u003c/p\u003e\n\u003cp\u003eRURI – Recurrent upper respiratory tract infections\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eAll procedures involving human participants were conducted in accordance with applicable institutional and national ethical standards and with the Declaration of Helsinki, as revised in 2013. Written informed consent for genetic testing was obtained from all participants or their legal guardians. The study was approved by the Institutional Review Board of the General University Hospital in Prague (approval no. 100/23 S-IV).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eR.Š. has received lecture honoraria and travel support from Chiesi, BioMarin, Takeda, and Amicus.\u003c/p\u003e\n\u003cp\u003eI.N. has received grant support from Sanofi Genzyme and Takeda and lecture honoraria from Sanofi Genzyme.\u003c/p\u003e\n\u003cp\u003eM.M.\u0026nbsp;has received lecture honoraria, travel support and consulting fees for work unrelated to this study from Chiesi, BioMarin and Takeda.\u003c/p\u003e\n\u003cp\u003eL.M., M.T., H.P. and J.Z. have nothing to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This work was supported by the Czech Ministry of Health, grant No. RVO 64165, COOPERATIO-Pediatrics, First Faculty of Medicine, Charles University, Prague, and the Rare Diseases Clinical Research Network, Lysosomal Disease Network, NIH U54NS065768 (IN).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eR.Š. collected the data, interpreted the results, drafted and reviewed the manuscript with input from all authors.\u003c/p\u003e\n\u003cp\u003eL.M. collected and evaluated data with a focus on ENT manifestations.\u003c/p\u003e\n\u003cp\u003eM.T. performed the molecular-genetic analyses.\u003c/p\u003e\n\u003cp\u003eH.P. performed the enzyme assays.\u003c/p\u003e\n\u003cp\u003eI.N. evaluated data, reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003eJ.Z. followed- up the patients, reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003eM.M. designed the study, was responsible for the initial conception, followed up the patients and collected the clinical data, revised the manuscript with input from all authors.\u003c/p\u003e\n\u003cp\u003eAll the authors provided critical feedback and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eWe thank BioMarin Pharmaceutical Inc. for covering the Open Access fee. This support had no impact on the decision to write this manuscript or its content.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHendriksz CJ, Harmatz P, Beck M, Jones S, Wood T, Lachman R, et al. Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA. Mol Genet Metab. 2013;110:54\u0026ndash;64. \u003c/li\u003e\n\u003cli\u003eMonta\u0026ntilde;o AM, Tomatsu S, Gottesman GS, Smith M, Orii T. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis. 2007;30:165\u0026ndash;74. \u003c/li\u003e\n\u003cli\u003eKhan S, Alm\u0026eacute;ciga-D\u0026iacute;az CJ, Sawamoto K, Mackenzie WG, Theroux MC, Pizarro C, et al. Mucopolysaccharidosis IVA and glycosaminoglycans. Mol Genet Metab. 2017;120:78\u0026ndash;95. \u003c/li\u003e\n\u003cli\u003eHendriksz CJ, Al-Jawad M, Berger KI, Hawley SM, Lawrence R, Mc Ardle C, et al. Clinical overview and treatment options for nonskeletal manifestations of mucopolysaccharidosis type IVA. J Inherit Metab Dis. 2013;36:309\u0026ndash;22. \u003c/li\u003e\n\u003cli\u003eLavery C, Hendriksz C. Mortality in patients with morquio syndrome a. JIMD Rep. 2015;15:59\u0026ndash;66. \u003c/li\u003e\n\u003cli\u003eLeadley RM, Lang S, Misso K, Bekkering T, Ross J, Akiyama T, et al. A systematic review of the prevalence of Morquio A syndrome: challenges for study reporting in rare diseases. Orphanet J Rare Dis. 2014;9:173. \u003c/li\u003e\n\u003cli\u003eAkyol MU, Alden TD, Amartino H, Ashworth J, Belani K, Berger KI, et al. Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance. Orphanet J Rare Dis. 2019;14:137. \u003c/li\u003e\n\u003cli\u003eHendriksz CJ, Burton B, Fleming TR, Harmatz P, Hughes D, Jones SA, et al. Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study. J Inherit Metab Dis. 2014;37:979\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eHendriksz CJ, Giugliani R, Harmatz P, Mengel E, Guffon N, Valayannopoulos V, et al. Multi-domain impact of elosufase alfa in Morquio A syndrome in the pivotal phase III trial. Mol Genet Metab. 2015;114:178\u0026ndash;85. \u003c/li\u003e\n\u003cli\u003eMitchell JJ, Burton BK, Bober MB, Campeau PM, Cohen S, Dosenovic S, et al. Findings from the Morquio A Registry Study (MARS) after 6 years: Long-term outcomes of MPS IVA patients treated with elosulfase alfa. Mol Genet Metab. 2022;137:164\u0026ndash;72. \u003c/li\u003e\n\u003cli\u003eSawamoto K, \u0026Aacute;lvarez Gonz\u0026aacute;lez JV, Piechnik M, Otero FJ, Couce ML, Suzuki Y, et al. Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management. Int J Mol Sci. 2020;21:1517. \u003c/li\u003e\n\u003cli\u003eHarmatz PR, Mengel KE, Giugliani R, Valayannopoulos V, Lin S-P, Parini R, et al. Longitudinal analysis of endurance and respiratory function from a natural history study of Morquio A syndrome. Mol Genet Metab. 2015;114:186\u0026ndash;94. \u003c/li\u003e\n\u003cli\u003eLin H-Y, Chuang C-K, Chen M-R, Chiu PC, Ke Y-Y, Niu D-M, et al. Natural history and clinical assessment of Taiwanese patients with mucopolysaccharidosis IVA. Orphanet J Rare Dis. 2014;9:21. \u003c/li\u003e\n\u003cli\u003eLeong HY, Abdul Azize NA, Chew HB, Keng WT, Thong MK, Mohd Khalid MKN, et al. Clinical, biochemical and genetic profiles of patients with mucopolysaccharidosis type IVA (Morquio A syndrome) in Malaysia: the first national natural history cohort study. Orphanet J Rare Dis. 2019;14:143. \u003c/li\u003e\n\u003cli\u003ePeretz RH, Flora CH, Adams DJ. Natural history of the oldest known females with mucopolysaccharidosis type IVA (Morquio A syndrome). Am J Med Genet A. 2020;182:1491\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eLee NH, Cho SY, Maeng SH, Jeon TY, Sohn YB, Kim SJ, et al. Clinical, radiologic, and genetic features of Korean patients with Mucopolysaccharidosis IVA. Korean J Pediatr. 2012;55:430\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eCleary M, Davison J, Gould R, Geberhiwot T, Hughes D, Mercer J, et al. Impact of long-term elosulfase alfa treatment on clinical and patient-reported outcomes in patients with mucopolysaccharidosis type IVA: results from a Managed Access Agreement in England. Orphanet J Rare Dis. 2021;16:38. \u003c/li\u003e\n\u003cli\u003eLin H-Y, Chen M-R, Lin S-M, Hung C-L, Niu D-M, Chuang C-K, et al. Cardiac features and effects of enzyme replacement therapy in Taiwanese patients with Mucopolysaccharidosis IVA. Orphanet J Rare Dis. 2018;13:148. \u003c/li\u003e\n\u003cli\u003eBarbosa ICDQ, Paula IS, Melo ICP, N\u0026oacute;brega SMB, Eufrazino CSDS, Medeiros PFV. Echocardiography in Mucopolysaccharidosis Iva: Evaluation of Enzyme Replacement Therapy. Arq Bras Cardiol - IMAGEM Cardiovasc [Internet]. 2017 [cited 2025 May 19];30. \u003c/li\u003e\n\u003cli\u003eBurton BK, Stepien KM, Campeau PM, Sutton J, Hunt A, Reisewitz P, et al. Real-world treatment with elosulfase alfa in patients with MPS IVA is associated with improved endurance over time. Genet Med Open. 2025;103428. \u003c/li\u003e\n\u003cli\u003eDoherty C, Stapleton M, Piechnik M, Mason RW, Mackenzie WG, Yamaguchi S, et al. Effect of enzyme replacement therapy on the growth of patients with Morquio A. J Hum Genet. 2019;64:625\u0026ndash;35. \u003c/li\u003e\n\u003cli\u003eMonta\u0026ntilde;o AM, Tomatsu S, Brusius A, Smith M, Orii T. Growth charts for patients affected with Morquio A disease. Am J Med Genet A. 2008;146A:1286\u0026ndash;95. \u003c/li\u003e\n\u003cli\u003eATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166:111\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eSkoog WA, Beck WS. Studies on the fibrinogen, dextran and phytohemagglutinin methods of isolating leukocytes. Blood. 1956;11:436\u0026ndash;54.\u003c/li\u003e\n\u003cli\u003eHartree EF. Determination of protein: A modification of the lowry method that gives a linear photometric response. Anal Biochem. 1972;48:422\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003evan Diggelen OP, Zhao H, Kleijer WJ, Janse HC, Poorthuis BJ, van Pelt J, et al. A fluorimetric enzyme assay for the diagnosis of Morquio disease type A (MPS IV A). Clin Chim Acta Int J Clin Chem. 1990;187:131\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eUllrich K. Screening for lysosomal disorders. Eur J Pediatr. 1994;153:S38-43. \u003c/li\u003e\n\u003cli\u003eWorld Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013;310:2191. \u003c/li\u003e\n\u003cli\u003eHarmatz P, Mengel KE, Giugliani R, Valayannopoulos V, Lin S-P, Parini R, et al. The Morquio A Clinical Assessment Program: Baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013;109:54\u0026ndash;61. \u003c/li\u003e\n\u003cli\u003eWang L, Ou X, Sebesta I, Vondrak K, Krijt J, Elleder M, et al. Combined adenine phosphoribosyltransferase and N-acetylgalactosamine-6-sulfate sulfatase deficiency. Mol Genet Metab. 1999;68:78\u0026ndash;85. \u003c/li\u003e\n\u003cli\u003eYe J, Lei H, Zhang H, Qiu W, Han L, Wang Y, et al. [Analysis of GALNS gene mutation in thirty-eight Chinese patients with mucopolysaccharidosis type IVA]. Zhonghua Er Ke Za Zhi Chin J Pediatr. 2013;51:414\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eDũng VC, Tomatsu S, Monta\u0026ntilde;o AM, Gottesman G, Bober MB, Mackenzie W, et al. Mucopolysaccharidosis IVA: correlation between genotype, phenotype and keratan sulfate levels. Mol Genet Metab. 2013;110:129\u0026ndash;38. \u003c/li\u003e\n\u003cli\u003eTomatsu S, Monta\u0026ntilde;o AM, Oikawa H, Smith M, Barrera L, Chinen Y, et al. Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment. Curr Pharm Biotechnol. 2011;12:931\u0026ndash;45. \u003c/li\u003e\n\u003cli\u003eMurgasova L, Jurovcik M, Jesina P, Malinova V, Bloomfield M, Zeman J, et al. Otorhinolaryngological manifestations in 61 patients with mucopolysaccharidosis. Int J Pediatr Otorhinolaryngol. 2020;135:110137. \u003c/li\u003e\n\u003cli\u003eLin H-Y, Shih S-C, Chuang C-K, Lee K-S, Chen M-R, Lin H-C, et al. Assessment of hearing loss by pure-tone audiometry in patients with mucopolysaccharidoses. Mol Genet Metab. 2014;111:533\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eRiedner ED, Levin LS. Hearing patterns in Morquio\u0026rsquo;s syndrome (mucopolysaccharidosis IV). Arch Otolaryngol Chic Ill 1960. 1977;103:518\u0026ndash;20. \u003c/li\u003e\n\u003cli\u003eWolfberg J, Chintalapati K, Tomatsu S, Nagao K. Hearing Loss in Mucopolysaccharidoses: Current Knowledge and Future Directions. Diagnostics. 2020;10:554. \u003c/li\u003e\n\u003cli\u003eFialov\u0026aacute; J, Kojanov\u0026aacute; M, \u0026Scaron;\u0026aacute;h\u0026oacute; R, Magner M. Mucopolysaccharidosis type IVA and severe hidradenitis suppurativa: A case series. JAAD Case Rep. 2025;62:146\u0026ndash;50. \u003c/li\u003e\n\u003cli\u003eBroomfield A, Zuberi K, Mercer J, Moss G, Finnegan N, Hensman P, et al. Outcomes from 18 years of cervical spine surgery in MPS IVA: a single centre\u0026rsquo;s experience. Childs Nerv Syst. 2018;34:1705\u0026ndash;16. \u003c/li\u003e\n\u003cli\u003eLabounek R, Valo\u0026scaron;ek J, Hor\u0026aacute;k T, Sv\u0026aacute;tkov\u0026aacute; A, Bednař\u0026iacute;k P, Vojt\u0026iacute;\u0026scaron;ek L, et al. HARDI-ZOOMit protocol improves specificity to microstructural changes in presymptomatic myelopathy. Sci Rep. 2020;10:17529. \u003c/li\u003e\n\u003cli\u003eLabounek R, Bondy MT, Paulson AL, B\u0026eacute;dard S, Abramovic M, Alonso-Ortiz E, et al. Body size and intracranial volume interact with the structure of the central nervous system: A multi-center in vivo neuroimaging study. Imaging Neurosci. 2025;3:imag_a_00559. \u003c/li\u003e\n\u003cli\u003eZanetti A, D\u0026rsquo;Avanzo F, AlSayed M, Brusius‐Facchin AC, Chien Y, Giugliani R, et al. Molecular basis of mucopolysaccharidosis IVA (Morquio A syndrome): A review and classification of \u003cem\u003eGALNS\u003c/em\u003e gene variants and reporting of 68 novel variants. Hum Mutat. 2021;42:1384\u0026ndash;98. \u003c/li\u003e\n\u003cli\u003eJezela-Stanek A, R\u0026oacute;żdżyńska-Świątkowska A, Kulpanovich A, Ciara E, Marucha J, Tylki-Szymańska A. Novel data on growth phenotype and causative genotypes in 29 patients with Morquio (Morquio-Brailsford) syndrome from Central-Eastern Europe. J Appl Genet. 2019;60:163\u0026ndash;74. \u003c/li\u003e\n\u003cli\u003eFukuda S, Tomatsu S, Masuno M, Ogawa T, Yamagishi A, Rezvi GM, et al. Mucopolysaccharidosis IVA: submicroscopic deletion of 16q24.3 and a novel R386C mutation of N-acetylgalactosamine-6-sulfate sulfatase gene in a classical Morquio disease. Hum Mutat. 1996;7:123\u0026ndash;34. \u003c/li\u003e\n\u003cli\u003eHendriksz CJ, Berger KI, Parini R, AlSayed MD, Raiman J, Giugliani R, et al. Impact of long-term elosulfase alfa treatment on respiratory function in patients with Morquio A syndrome. J Inherit Metab Dis. 2016;39:839\u0026ndash;47. \u003c/li\u003e\n\u003cli\u003eHendriksz CJ, Parini R, AlSayed MD, Raiman J, Giugliani R, Solano Villarreal ML, et al. Long-term endurance and safety of elosulfase alfa enzyme replacement therapy in patients with Morquio A syndrome. Mol Genet Metab. 2016;119:131\u0026ndash;43. \u003c/li\u003e\n\u003cli\u003eParini R, Deodato F. Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations. Int J Mol Sci. 2020;21:2975. \u003c/li\u003e\n\u003cli\u003ePintos-Morell G, Blasco-Alonso J, Couce ML, Guti\u0026eacute;rrez-Solana LG, Guill\u0026eacute;n-Navarro E, O\u0026rsquo;Callaghan M, et al. Elosulfase alfa for mucopolysaccharidosis type IVA: Real-world experience in 7 patients from the Spanish Morquio-A early access program. Mol Genet Metab Rep. 2018;15:116\u0026ndash;20. \u003c/li\u003e\n\u003cli\u003eLin H-Y, Chuang C-K, Ke Y-Y, Hsu C-C, Chiu PC, Niu D-M, et al. Long-term effects of enzyme replacement therapy for Taiwanese patients with mucopolysaccharidosis IVA. Pediatr Neonatol. 2019;60:342\u0026ndash;3. \u003c/li\u003e\n\u003cli\u003eDo Cao J, Wiedemann A, Quinaux T, Battaglia-Hsu SF, Mainard L, Froissart R, et al. 30 months follow-up of an early enzyme replacement therapy in a severe Morquio A patient: About one case. Mol Genet Metab Rep. 2016;9:42\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eKılavuz S, Basaran S, Kor D, Bulut FD, Erdem S, Ballı HT, et al. Morquio A syndrome and effect of enzyme replacement therapy in different age groups of Turkish patients: a case series. Orphanet J Rare Dis. 2021;16:144.\u003c/li\u003e\n\u003cli\u003eKenth JJ, Thompson G, Fullwood C, Wilkinson S, Jones S, Bruce IA. The characterisation of pulmonary function in patients with mucopolysaccharidoses IVA: A longitudinal analysis. Mol Genet Metab Rep. 2019;20:100487.\u003c/li\u003e\n\u003cli\u003eKampmann C, Abu-Tair T, G\u0026ouml;kce S, Lampe C, Reinke J, Mengel E, et al. Heart and Cardiovascular Involvement in Patients with Mucopolysaccharidosis Type IVA (Morquio-A Syndrome). Jefferies JL, editor. PLOS ONE. 2016;11:e0162612. \u003c/li\u003e\n\u003cli\u003eBarak S, Anikster Y, Sarouk I, Stern E, Eisenstein E, Yissar T, et al. Long-Term Outcomes of Early Enzyme Replacement Therapy for Mucopolysaccharidosis IV: Clinical Case Studies of Two Siblings. Diagnostics. 2020;10:108.\u003c/li\u003e\n\u003cli\u003eJones SA, Bialer M, Parini R, Martin K, Wang H, Yang K, et al. Safety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 y. Pediatr Res. 2015;78:717\u0026ndash;22.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1:\u003c/strong\u003e Clinical, enzymatic, and molecular characteristics of the Czech MPS IVA cohort\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"753\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber / sex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at 1st symptom (y)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at dg. (y)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCurrent age (y)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eERT initiation age (y)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eInitial symptoms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeight Z-score at dg.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 53px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeight current Z-score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGALNS activity (%+)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 164px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eGALNS\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;variants\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSkeletal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNon- skeletal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1st allele\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2nd allele\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e1/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e3.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003ekyphosis, scoliosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ehepatomegaly, corneal clouding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-2.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-5.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.151G\u0026gt;A (p.Glu51Lys)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1219A\u0026gt;C (p.Asn407His)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e2/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003epectus carinatum, kyphosis, scoliosis, genu varum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ecoarse facies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-1.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-4.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.421_422dupTG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1219A\u0026gt;C (p.Asn407His)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e3/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e11.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e6.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eabnormal gait, pectus carinatum, acetabular dysplasia, kyphosis, scoliosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003erecurrent acute otitis media, recurrent respiratory infections\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-2.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-4.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.502G\u0026gt;A (p.Gly168Arg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1219A\u0026gt;C (p.Asn407His)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e4/F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e17.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e11.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eshort growth, pedes plani, genu varum, pectus carinatum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-3.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-10.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.1156C\u0026gt;T (p. Arg386Cys)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1156C\u0026gt;T (p. Arg386Cys)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e5/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e5.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e5.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003epectus excavatum, pedes equinovarus, acetabular dysplasia, short growth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003erecurrent respiratory infections, recurrent acute otitis media\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-3.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-5.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.139G\u0026gt;A (p.Gly47Arg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1520G\u0026gt;T (p.Cys507Phe)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e6/M#\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e5.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e15.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eabnormal gait, - lower limb pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-1.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.740G\u0026gt;A (p.Gly247Asp)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1219A\u0026gt;C (p.Asn407His)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e7/F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e6.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e22.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e20.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eshort growth, pectus carinatum, genu varum, pedes plani, ulnar deviation of the wrist\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-3.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-11.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.482G\u0026gt;C (p.Gly161Ala)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1219A\u0026gt;C (p.Asn407His)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e8/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eabnormal gait, pectus carinatum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ecoarse facies, delay of gross motor skills\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-2,94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-9.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.1019G\u0026gt;A (p.Gly340Asp)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1483-15A\u0026gt;G\u003c/p\u003e\n \u003cp\u003e(p.Asn495Phefs*15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e9/F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e23.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eshort growth, pectus carinatum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-4.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-6.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.116A\u0026gt;G (p.Asp39Gly)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e39 kb deletion incl. ex1 part - ex 13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e10/M*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e24.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eabnormal gait, Skeletal changes without further specification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003efamily history, recurrent respiratory infections\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-5.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-5.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.286G\u0026gt;T (p.Gly96Cys)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1156C\u0026gt;T (p. Arg386Cys)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e11/M*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e12.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eacetabular dysplasia, genu varum, short growth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-9.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.740G\u0026gt;A (p.Gly247Asp)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.860C\u0026gt;T (p.Ser287Leu)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e12/M*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e16.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e35.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003epectus carinatum, acetabular dysplasia, short growth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003efamily history, recurrent respiratory infections\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-9.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.740G\u0026gt;A (p.Gly247Asp)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.860C\u0026gt;T (p.Ser287Leu)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e13/F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e48.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eacetabular dysplasia, short growth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-9.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.463G\u0026gt;A (p.Gly155Arg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1219A\u0026gt;C (p.Asn407His)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e14/F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e32.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003epedes plani, genu varum, pectus carinatum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-7.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.1156C\u0026gt;T (p. Arg386Cys)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1156C\u0026gt;T (p. Arg386Cys)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e15/M*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e9.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e27.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eSkeletal changes without further specification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ecoarse facies, recurrent acute otitis media\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-5.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-1,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.286G\u0026gt;T (p.Gly96Cys)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1156C\u0026gt;T (p. Arg386Cys)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e16/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e36.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eshort growth, kyphosis, pectus carinatum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ecoarse facies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-4.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.1219A\u0026gt;C (p.Asn407His)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1219A\u0026gt;C (p.Asn407His)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e17/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026dagger; 30.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eacetabular dysplasia, pectus carinatum, kyphosis, scoliosis, genu varum, pedes plani\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ecoarse facies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-9.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003edel (100 kb, GALNS in.2 to APRT in. 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e18/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eshort growth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003erecurrent respiratory infections\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-4.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-11.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.482G\u0026gt;C (p.Gly161Ala)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.1156C\u0026gt;T (p. Arg386Cys)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e19/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e52.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eacetabular dysplasia, pectus carinatum, kyphosis, scoliosis, ulnar deviation of the wrist\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ehernia, recurrent acute otitis media\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e-3.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e-10.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003ec.853_855delTTC (p.Phe285del)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003ec.860C\u0026gt;T (p.Ser287Leu)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Patients 10 and 15 are brothers, patients 11 and 12 are brothers, #only patient 6 had attenuated phenotype, + residual activity in leukocytes, percentage of long-term average of controls (34,5 nmol/17h/mg)\u003c/p\u003e\n\u003cp\u003eERT \u0026ndash; enzyme replacement therapy, F- female, GALNS - galactosamine (N-acetyl)-6-sulfatase M \u0026ndash; male, NA \u0026ndash; not available, , y \u0026ndash; years, \u0026nbsp;\u0026dagger; death,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2:\u003c/strong\u003e Spirometry results in the Czech MPS IVA cohort compared with those of natural history studies*\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"698\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge range (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 172px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eERT-treated patients from our study\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 305px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNATURAL HISTORY STUDIES\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eERT-na\u0026iuml;ve \u0026nbsp;patients from our study\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBurton et al.\u003csup\u003e20\u003c/sup\u003e ERT-na\u0026iuml;ve\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeong HY et al.\u003csup\u003e14\u003c/sup\u003e ERT-na\u0026iuml;ve\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHarmatz et al.\u003csup\u003e29\u003c/sup\u003e ERT-na\u0026iuml;ve\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFVC \u0026plusmn; SD (L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFEV1 \u0026plusmn; SD (L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFVC \u0026plusmn; SD (L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFEV1 \u0026plusmn; SD (L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFVC \u0026plusmn; SD (L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFVC \u0026plusmn; SD (L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFVC \u0026plusmn; SD (L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFEV1 \u0026plusmn; SD (L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e5-7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1.0 \u0026plusmn; 0.2 (25 tests, 5 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e0.9\u0026plusmn; 0.2 (25 tests, 5 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.75 \u0026plusmn; 0.21 (n=31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.71 \u0026plusmn; 0.19 (n=31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e9-11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1.77 \u0026plusmn; 0.87 (21 tests, 6 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e1.51 \u0026plusmn; 0.69 (21 tests, 6 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.11\u0026plusmn; 0.58 (n=35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.95 \u0026plusmn; 0.45 (n=35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.77 (1 test, 1 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e14-16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e2.53 \u0026plusmn; 2.1 (7 tests, 2 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e2.15 \u0026plusmn; 1.77 (7 tests, 2 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.48 \u0026plusmn; 1.09 (n=32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.26 \u0026plusmn; 0.92 (n=32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1.05 \u0026plusmn; 0.51 (6 tests, 3 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e1.02 \u0026plusmn; 0.52 (6 tests, 3 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026le; 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1.52\u0026plusmn;1.07 (74 tests, 6 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e1.51 \u0026plusmn; 0.92 (74 tests, 6 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.11 \u0026plusmn; 0.62 (n=98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.97 \u0026plusmn; 0.52 (n=98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.6 \u0026plusmn; 0.1 (n=5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e1.1 \u0026plusmn; 0.7 (n=256)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.97 \u0026plusmn; 0.38 (11 tests, 4 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e1.07 \u0026plusmn; 0.67 (13 test, 4 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026gt; 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.49 \u0026plusmn; 1.27 (n=37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.26 \u0026plusmn; 1.03 (n=37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e0.9 \u0026plusmn; 0.2 L (n=3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e1.5 \u0026plusmn; 1.1 L (n=69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1.59 \u0026plusmn; 0.94 (5 test, 5 pt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e1.42 \u0026plusmn; 1.07 (5 tests, 5 pt)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*including 90 evaluations presented as volumes with means \u0026plusmn; SD across age groups for ERT-treated and ERT-na\u0026iuml;ve patients relative to published natural history data. Forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) are shown in litres (L). Results are presented as means and standard deviations.\u003c/p\u003e\n\u003cp\u003eERT- enzyme replacement therapy, pt - patients\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3:\u003c/strong\u003e Results of the 6MWT in the Czech MPS IVA cohort compared with those of natural history studies *\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"601\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge range (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 159px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eERT-treated patients from our study\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 353px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNATURAL HISTORY STUDIES\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeong HY et al.\u003csup\u003e14\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eERT-na\u0026iuml;ve \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHarmatz et al.\u003csup\u003e29\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eERT-na\u0026iuml;ve \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBurton et al.\u003csup\u003e20\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eERT-na\u0026iuml;ve \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 512px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6MWT average + SD (m)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 159px;\"\u003e\n \u003cp\u003e347.8 \u0026plusmn; 98.5 (4 pt, 12 tests)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e246.9 \u0026plusmn; 87.4 (n=1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e251.6 \u0026plusmn; 121.5 (n=37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e5-11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 159px;\"\u003e\n \u003cp\u003e387.1 \u0026plusmn; 94.7 (6 pt, 64 tests)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e218.8 \u0026plusmn; 98.2 (n=4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e232.5 \u0026plusmn; 140.1 (n=127)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e259.2 \u0026plusmn; 102.1 (n=154)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e12-18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 159px;\"\u003e\n \u003cp\u003e347.8 \u0026plusmn; 33 (3 pt, 14 tests)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e123.7 \u0026plusmn; 116.4 (n=5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e181.2 \u0026plusmn; 177.3 (n=84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e167.2 \u0026plusmn; 168.7\u003csup\u003e#\u003c/sup\u003e (n=65)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026gt; 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 159px;\"\u003e\n \u003cp\u003e436.3 \u0026plusmn; 62.9 (1 pt, 4 exams)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e119.3 \u0026plusmn; 121.2 (n=3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e193.1 \u0026plusmn; 148.5 (n=68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e157 \u0026plusmn; 158.1 (n=76)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*displaying mean distances \u0026plusmn; SD across different age groups for ERT-treated and ERT-na\u0026iuml;ve patients,\u0026nbsp;\u003csup\u003e#\u003c/sup\u003edata from patients aged 14-16 years, 6MWT - 6-minute walking test , ERT \u0026ndash; enzyme replacement therapy\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"mucopolysaccharidosis type IVA, enzyme replacement therapy, natural history, long-term, spinal stenosis, cervical myelopathy","lastPublishedDoi":"10.21203/rs.3.rs-9023839/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9023839/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e \u0026nbsp;Mucopolysaccharidosis type IVA (MPS IVA, Morquio A syndrome) is a rare lysosomal storage disease primarily characterized by severe skeletal dysplasia. Clinical and laboratory data, including treatment responses, are reported for a cohort of Czech patients with MPS IVA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e\u0026nbsp;Nineteen patients with MPS IVA from 17 families (13M/6F) were included; only one patient exhibited a mild form. The median age at disease onset was 3.0 ± 1.4 years, whereas the median age at confirmed diagnosis was 5.0 ± 3.5 years. At the time of diagnosis, all patients had skeletal symptoms (pectus carinatum in 58%, short stature in 47%, hip dysplasia in 47%), and 63% had nonskeletal symptoms. Each patient underwent at least one surgical procedure (77% knee, 59% spine, 41% adenotomy). On spinal MRI, 76% of patients presented with cervical stenosis, and 41% presented with cervical myelopathy. Eight patients received ERT for a median duration of 5.5 ± 2.6 years. Compared with non-ERT patients from natural history studies and non-ERT patients within our cohort, beneficial effects were evident in monitored parameters such as changes in the mean FVC and FEV1 volumes and the mean 6MWT distance. Additionally, the hidradenitis suppurativa observed in three patients improved with biologic therapy. We also describe two novel mutations (c.421_422dupTG, c.482G\u0026gt;C).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eDocumenting the natural history of MPS IVA in this population may aid in early diagnosis. Despite the disease's progressive nature, ERT was effective in our MPS IVA patients, demonstrating a consistent impact on endurance across all age groups.\u003c/p\u003e","manuscriptTitle":"Long-term Natural History and Elosulfase Alfa Treatment for Mucopolysaccharidosis Type IVA: A Single-Center Study in the Czech Republic","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-26 13:05:38","doi":"10.21203/rs.3.rs-9023839/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2026-04-18T02:33:10+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-03-27T16:19:19+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-24T10:10:01+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Orphanet Journal of Rare Diseases","date":"2026-03-16T01:26:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-05T17:45:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2026-03-04T11:02:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1cafe8fc-b40a-4b0f-9e64-9f86a1ae06e8","owner":[],"postedDate":"March 26th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-10T20:47:53+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-26 13:05:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9023839","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9023839","identity":"rs-9023839","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}