Hematopoietic Stem Cell Transplantation in Children with Mucopolysaccharidosis IVA: Single Center Experience

Hematopoietic Stem Cell Transplantation in Children with Mucopolysaccharidosis IVA: Single Center Experience | 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 Article Hematopoietic Stem Cell Transplantation in Children with Mucopolysaccharidosis IVA: Single Center Experience Koray Yalcin, Vedat Uygun, Burcu Ozturk Hismi, Suna Celen, Seda Öztürkmen, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4409630/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Oct, 2024 Read the published version in Bone Marrow Transplantation → Version 1 posted 8 You are reading this latest preprint version Abstract Mucopolysaccharidosis IVA (MPS IVA; Morquio syndrome) is a lysosomal storage disorder and features systemic skeletal dysplasia that is caused by defective Nacetylgalactosamine-6-sulfate sulfatase (GALNS). Although there are convincing data for hematopoietic stem cell transplantation (HSCT) in certain types of MPS, the studies are limited for MPS IVA and more data is still pending to show the efficacy/safety of HSCT. This study included 3 girls and 7 boys with MPS IVA who underwent allogeneic HSCT between February 12, 2021, and March 10, 2023. Enzyme levels, height growth, the most involved organs (ear, eye, and heart), and the activities of daily living (ADL) scoring system were monitored to assess the benefit of HSCT. In a median follow-up of 20 months (9–34 months), there is no severe transplant-related adverse event was observed. In all cases, normal enzyme levels were reached after HSCT. During the short follow-up period, our cases showed an increase in stature and improvement in daily activity functions. Here we present the data of our HSCT experience in MPS IVA with promising results regarding both safety and efficacy. We need more data and long-term follow-up to comment properly on the benefits of HSCT in MPS IVA. Health sciences/Medical research/Translational research Health sciences/Medical research/Clinical trial design/Clinical trials/Phase III trials activities of daily living scoring system hematopoietic stem cell transplantation mucopolysaccharidosis IVA morquio syndrome Introduction Hematopoietic stem cell transplantation has been a therapy option for mucopolysaccharidosis (MPS) for decades and the cross-correction mechanism is the main rationale for HSCT. 1, 2 Although there are convincing data for HSCT in certain types of MPS, the studies are limited for MPS IVA and more data is still pending to show the efficacy/safety of HSCT. 2–6 MPS IVA (Morquio A syndrome) is an autosomal recessive MPS disorder caused by a deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme. 7–9 The prevalence range of MPS IVA is estimated from 1 in 76,000 to 1 in 640,000 births. 10, 11 The definite diagnosis is achieved through the demonstration of reduced GALNS activity with molecular confirmation of biallelic pathogenic variants in the GALNS gene. 12 Skeletal and joint abnormalities are the most prevalent manifestations, and patients require regular assessment of multiorgan involvement such as heart, eye, and ear. 13, 14 MPS IVA is a heterogeneous and progressive disorder, some severely affected patients could become wheelchair-bound when they are teenagers and die of respiratory problems, cervical spinal cord complications, or heart valve disease in their 20s or 30s if untreated. 9, 13, 15 Two different treatment options are currently available for MPS IVA patients; the first one is enzyme replacement therapy (ERT) which is not curative and needs life-long weekly intravenous infusions, the second one is hematopoietic stem cell transplantation (HSCT) which is a one-time procedure allowing a continuous source of deficient enzyme . 16 ERT for the management of MPS IVA was approved in 2014 by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). However, there are some limitations such as weekly infusions, short half-life time (35 minutes), developing antibodies, and high cost. 16–18 In addition, there is controversial data about the efficacy of ERT in skeletal dysplasia. 19, 20 There is an unmet need for MPS IVA patients. As the currently approved therapy option has certain limitations, the other therapy options should be evaluated seriously to decide the best treatment modality. For this purpose, we presented our report to show the efficacy and safety of HSCT on MPS IVA patients. Patients and Methods All members of the cohort were treated at Medicalpark Göztepe/Antalya Hospitals under the Declaration of Helsinki and following the provision of informed consent by patients or their guardians. This study was approved by the institutional review board of Medicalpark Göztepe and Antalya Hospitals. Patients The study cohort included 3 girls and 7 boys with MPS IVA who underwent allogeneic HSCT (total of 12 HSCT, two patients received 2nd HSCT) between February 12, 2021, and March 10, 2023. 21 Data were collected from the medical records and retrospectively analyzed in an explorative fashion until December 1, 2023. Diagnosis of MPS IVA was confirmed in all patients both by the enzyme assay of GALNS and by documented biallelic pathogenic variants in the GALNS gene. Regarding height according to the growth chart of MPS IVA (Morquio A), all of the patients had a severe phenotype (their height < 75th percentile on the growth chart of Morquio A patients). 22 In line with the clinical findings, all of the genetic variations included in our cohort are known to be associated with severe phenotypes. All the patients except one had received ERT before HSCT. Enzyme replacement therapy was terminated after HSCT for all the patients. We followed the enzyme levels every 3 months while doing chimerism analysis in the first month, 3rd month, 6th month, and first year. The height growth and the most involved organs such as the ear, eye, and heart were monitored routinely. Some of the patients were unaffected regarding these organs and some patients were better/worse compared to pre-HSCT status. Lastly, the activities of daily living (ADL) scoring system was used to assess the benefit of HSCT. The ADL questionnaire (12 items) used consisted of three domains (“movement,” “movement with cognition,” and “cognition”); each with four subcategories scored from 0 to 5 (0 being the inability to perform task without maximum assistance and 5 being the ability to perform a task without any assistance). “Movement” comprised basic motor skills needed for normal daily function with the subcategories: ( 1 ) walking, ( 2 ) movement on stairs, ( 3 ) grasping/finger movement, and ( 4 ) endurance in a 6-minute walk (6 MWT). According to MPS IVA clinical characteristics, only the movement section of the ADL scoring system was applied over only 20 points. 23 Questionnaires were performed by calling families on the phone, completed directly by the patient and/or the patient's parent/guardian, and then returned to the study group. Results Patient Characteristics We present the data of 10 patients who received a total of 12 HSCTs (two patients received a second HSCT) with the diagnosis of MPS IVA. All the patients had short stature with the specific skeletal features of the disease, had low N-Acetylgalactosamine-6-sulfatase enzyme levels, and specific genetic variations were associated with severe phenotypic features. (Table 1 ) (Supplementary Data 1) We particularly investigated certain dysfunctions and organ systems that could be affected by the disease. All the patients had shorter heights compared to their peers but seven of them were shorter even compared to the standard particular percentile of MPS IVA patients. 22 According to ADL scoring, only one patient had a full ADL movement score (20 points) before HSCT. Three of the patients needed minimum assistance while walking or climbing stairs and one of the patients had severe movement disabilities. Regarding ear problems, six patients (P1, P3, P6, P7, P8, and P10) had recurrent otitis media before HSCT and 3 of them (P1, P3, and P10) needed intervention and one of them (P10) had moderate hearing loss. Regarding eye involvement, three of the patients (P3, P7, and P8) were affected, two of them (P3 and P8) had mild cataracts and the other one (P7) had hypermetropy and astigmatism. Lastly, six of the patients (P1, P3, P4, P6, P8, and P9) had heart involvements before HSCT (mild aortic, mitral, and tricuspid regurgitation for P6, mild aortic and mitral regurgitation for P1, mild mitral stenosis for one patient P3, and mild mitral and tricuspid regurgitation for P4, P8 and P9). All of the patients except one had enzyme replacement before HSCT and they received regular enzyme replacement from the initial diagnosis median 32,5 months (0–151 months). While enzyme replacement 4 of the 10 patients (40%) experienced mild or moderate allergic reactions, but all of them continued enzyme therapy with desensitization protocols if needed. Table 1 The Characteristics of the Patients Patient/Gender Age at Diagnosis (Month) ERT duration before HSCT (month) Age at HSCT (Month) Height/percentile before HSCT (cm) Organ involvement before HSCT (except skeletal system) Homozygous pathogenic GALNS variant (c.DNA) 1/M 22 97 (allergy) 119 98 cm (50p) Ear/Heart c.1168del 2/F 40 13 (allergy) 53 82 cm (3p) None c.421T > A 3/M 29 40 (allergy) 69 82 cm (3p) Ear/Eye/Heart c.1168del 4/F 59 57 116 98 cm (25p) Heart c.860C > T 5/M 18 17 (allergy) 35 86 cm (10p) None c.139G > A 6/M 19 0 82 86 cm (3p) Ear/Heart c.1019G > A 7/M 22 25 47 96 cm (50p) Ear/Eye c.230C > G 8/F Prenatal 81 129 102 cm (50p) Ear/Eye/Heart c.1168del 9/M 27 19 46 90 cm (25p) Heart c.1157G > A 10/M 35 151 186 96 cm (3p) Ear c.149del Outcomes of HSCT The characteristics of HSCT and the outcomes are presented in Table 2 . All the HSCT procedures were performed from matched unrelated donors except for one patient who received HSCT from a matched sibling donor (carrier of disease). Mostly, peripheral blood stem cell was used because of the unrelated donor preference except for two patients who received bone marrow stem cells. Busulfan-Fludarabin-based conditioning was used for all HSCT procedures. Two patients had secondary graft failure because of CMV infections, both were transplanted from the same donor with Treosulfan-based regimens. After the second HSCT, they were engrafted with full donor chimerism and followed up without any complications. ATG was included in all the conditioning regimens and to enhance the engraftment, thiotepa or cyclophosphamide was added in selected patients. Table 2 The characteristics and the outcomes of HSCT Patient/Gender Donor Stem Cell Source Conditioning Regimen GvHD Prophylaxis Last Chimerism Enzyme Level GvHD Graft Failure 1/M MSD BM Flu + Bu + Cyc + ATG CNI + MTX Full Normal - - 2/F MUD PBSC Flu + Bu + TT + ATG CNI + MTX Full Normal - - 3/M MUD BM Flu + Bu + Cyc + ATG CNI + MTX Full Normal - - 4/F MUD PBSC Flu + Bu + Cyc + ATG CNI + MTX Full Normal Skin/Grade 2 - 5/M MUD PBSC Flu + Bu + Cyc + ATG CNI + MTX Mixed Normal - - 6/M MUD PBSC Flu + Bu + ATG (Flu + Treo + ATG + TT) CNI + MTX Full Normal - + (2nd HSCT) 7/M MUD PBSC Flu + Bu + Cyc + ATG CNI + MTX Full Normal - - 8/F MUD PBSC Flu + Bu + ATG CNI + MTX Mixed Normal - - 9/M MUD PBSC Flu + Bu + ATG (Flu + Treo + TT + ATG) CNI + MTX Full Normal - + (2nd HSCT) 10/M MUD PBSC Flu + Bu + TT + ATG CNI + MTX Full Normal - - Regarding GvHD, calcineurin inhibitors and methotrexate were used for all patients, only one of them developed acute GvHD with grade 2 skin involvement. None of the patients had chronic GvHD features. Enzyme levels were measured at the earliest 90 days after HSCT and the levels were found above the limits for all of the patients. Although two patients had mixed chimerism and one patient was transplanted from a carrier-sibling donor, they also had normal enzyme levels after HSCT. The enzyme levels did not change according to the chimerism ratios, the levels could be high even in mixed chimeric cases. At the last follow-up time, all the patients are alive and GvHD-free. (Table 2 ) Clinical Comparison Pre vs Post HSCT In this study, we presented a median follow-up of 20 months (9–34 months) and evaluated height, ADL scoring, and certain organ systems to determine the benefits of HSCT in this time frame. (Table 3 ) We observed an increment of height in all patients with various rates and this increment corresponds to a positive change according to MPS IVA percentile charts for 7 patients. 22 Of these 7 patients, three of them were above 10 years old. For ADL scoring, all of the patients with a low ADL score before HSCT achieved an increment after HSCT (Supplementary Data 2). The most significant increment was observed in walking, stairs and endurance scores while the less affected hand movements stayed stable for most of the patients. Regarding ear problems, all of the affected patients (P1, P3, P6, P7, and P8) had less or no acute otitis media attack, and the patient (P10) with moderate hearing loss had a recovery to mild hearing loss after HSCT. Heart involvement was better after HSCT only for one patient (P6) who had mild regurgitation for mitral, tricuspid, and aortic valves and heart involvement was stable for the other 5 patients (P1, P3, P4, P8, and P9) who had problems before HSCT. There were three patients with eye involvement two of them were stable with mild cataracts and the other patient was better with hypermetropia (+ 3.00 D >> +1,50 D) and astigmatism (+ 0,75 D > > 0,25 D) after HSCT. Table 3 Clinical Comparison of Pre vs Post HSCT Patient/ Gender Age at HSCT > Last Follow-up (month) Height/Percentile ADL Movement Score Eye Ear Heart 1/M 119 > 138m 98 > 103 cm (50p > 75p) 16 > 20 Unaffected Better Stabile 2/F 53 > 66 m 82 > 82 cm (3p > 3p) 17 > 20 Unaffected Unaffected Unaffected 3/M 69 > 92 m 82 > 87 cm (3p > 10p) 16 > 20 Stabile Better Stabile 4/F 116 > 141 m 98 > 100 cm (25p > 25p) 17 > 20 Unaffected Unaffected Stabile 5/M 35 > 56 m 86 > 91 cm (10p > 25p) 20–20 Unaffected Unaffected Unaffected 6/M 82 > 116 m 86 > 97 cm (3p > 10p) 16 > 20 Unaffected Better Better 7/M 47 > 68 m 96 > 102 cm (50p > 75p) 18 > 20 Better Better Unaffected 8/F 129 > 148 m 102 > 105 cm (50p > 75p) 13 > 17 Stabile Stabile Stabile 9/M 46 > 65 m 90 > 94 cm (25p > 25p) 11 > 16 Unaffected Unaffected Stabile 10/M 186 > 195 m 96 > 100 cm (3p > 10p) 5 > 11 Unaffected Better Unaffected Discussion This study was planned for long-term follow-up of MPS IVA cases after HSCT. For this purpose, a 2-year follow-up was aimed. Long-term follow-up results of the study will allow comparison of HSCT with other treatment modalities. The results of our study are promising. Regarding safety, there is no transplant-related adverse event was observed except only one grade 2 skin GvHD case. In all cases, normal enzyme levels were reached after HSCT. During the short follow-up period, our cases showed an increase in stature and improvement in daily activity functions. In our cohort, all of the patients had one of the genetic variations that were defined before with an association of severe phenotype. 24 Detailed physical examinations of our patients revealed the skeletal dysmorphism which is one of the main findings of the disease and the degree of the skeletal dysmorphism could identify the disease severity. Although we identified skeletal dysmorphisms, all of our patients except one had a mild functional disability and could achieve all the movements with at least minimal assistance. The only patient with a severe functional disability was 15 years old and needed extensive assistance for motor functions, but after HSCT he is doing well with mild/moderate assistance. In our study, we used ADL scoring which included cognitive and movement parameters 23 but, it was known that MPS IVA doesn’t affect cognitive performance so, we analyzed our patients only with movement parameters over 20 points. Although all patients except one had at least one low point with any of the certain movement parameters, they all achieved better points for every movement after HSCT. However, the movement scoring of ADL has parameters that give rise to subjective evaluation so our findings should be verified in a long follow-up period. One of the main problems of MPS IVA patients is short stature and according to current data the height is arrested around the age of 8. 22 Six of our patients had height percentile increments according to specific charts for MPS IVA. It is noteworthy that we detected continuous height increments after HSCT in three of our patients who are over 10 years old. Although all of the patients had GALNS enzyme levels below the normal limits before HSCT, we detected higher enzyme levels over or within the normal limits after HSCT. This data supported the effectiveness of HSCT and made it comparable to enzyme replacement therapies. Two patients had mixed chimerism but they also had high enzyme levels similar to full chimeric patients. Although it is difficult to comment with one case, one of our patients received HSCT from a carrier match sibling donor and we observed that the carrier donor status could be sufficient to maintain a normal GALNS enzyme level after HSCT. We think that the recovery or the reduction of the frequency of ear infections following the HSCT is a significant parameter indicating the benefits of the therapy. Although we can not observe a similar significant recovery for the heart or eye, we did not observe any regression in these organ functions after HSCT. We hope to comment accurately on the long-term follow-up data in future reports. The busulfan-fludarabine combination was the recommended regimen for MPS patients and we applied this regimen for all the patients except two second transplants. 2 ATG was used in all the regimens and thiotepa or cyclophosphamide was added in selected patients to enhance the engraftment. Two second HSCTs were performed with treosulfan-based regimens with thiotepa and both were engrafted successfully without HSCT-related toxicity. Although matched umbilical cord blood (UCB) and noncarrier sibling bone marrow were the preferred cell sources, we had to use mostly PBSC because of the unrelated donor preference and our results were comparable with other MPS HSCT studies using UCB. 25 One of the limitations of this study is not including quality of life (QoL) documentation both for patients and the parents. Although comment without proper data is not considerable, it is easy to observe the positive changes after HSCT in terms of both physical and psychological parameters. (such as feeling better and more active or happy not to be dependent on weekly replacement therapies) While evaluating the safety concerns of HSCT, historical data should be considered carefully. The application of HSCT is fast developing and the survival rates are improving for mucopolysaccharidoses. 2, 6 We did not observe any serious complications in our cohort and all the patients are alive. Acute GvHD (Grade 2 skin) emerged for only one patient and all the patients were GvHD-free at the last follow-up time. Although there were two secondary graft failures, the second HSCT procedure was uneventful. According to our data, HSCT for MPS IVA could meet the expected safety criteria without serious adverse events. Cost effectivity is another key point for MPS therapies. Enzyme replacements are life-long continuous therapies that need medical interventions regularly and also they are very expensive drugs. 16 Although accurately estimating the cost of HSCT is not easy due to many influencing factors like type of donor, stem cell source, complications, and out-of-pocket expenses which differ according to different countries, HSCT is a one-time therapy and cheaper than the cost of one-year enzyme replacement therapy. Besides the direct costs, the economic and psychological burden of weekly transfusion therapy for the family is mostly underestimated. Hospital dependency causes work-hours lost for the parents and the enzyme replacements could be longer than expected because of intravenous route issues and allergic complications. Conclusion Here we present the data of our HSCT experience in MPS IVA with promising results regarding both safety and efficacy. It is obvious that we need more data and long-term follow-up to comment properly on the benefits of HSCT in MPS IVA. Also, there is a need to compare the two treatment modalities; HSCT vs enzyme replacement therapy in terms of efficacy, safety, and QoL. Declarations Author Contributions KY and AY designed the study, analyzed, and interpreted the clinical data and wrote the manuscript. VU, GK and BOH analyzed, interpreted the data and contributed to the writing of the manuscript. SC, SZ, SO and HD acquired the data and contributed to the writing of the manuscript. All authors read and approved the final version of the manuscript. Funding Information No funds were received for this work Conflict of Interest Statement The authors declare no conflicts of interest. Data Availability Statement The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics Statement The study was approved by the institutional review board of the Bahcesehir University (#20240503). The study was in compliance with the Declaration of Helsinki. Consent Statement Written informed consent was obtained from the parents. References Fratantoni JC, Hall CW, Neufeld EF. Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science. 1968; 162 (3853): 570-2. Taylor M, Khan S, Stapleton M, Wang J, Chen J, Wynn R, et al. Hematopoietic Stem Cell Transplantation for Mucopolysaccharidoses: Past, Present, and Future. 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Supplementary Files SupplementaryData1.docx SupplementaryData2.docx Cite Share Download PDF Status: Published Journal Publication published 14 Oct, 2024 Read the published version in Bone Marrow Transplantation → Version 1 posted Editorial decision: revise 01 Jul, 2024 Review # 1 received at journal 21 Jun, 2024 Reviewer # 1 agreed at journal 04 Jun, 2024 Reviewers invited by journal 31 May, 2024 Submission checks completed at journal 21 May, 2024 First submitted to journal 20 May, 2024 Unknown event 13 May, 2024 Editor assigned by journal 12 May, 2024 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4409630","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":309072532,"identity":"aad53058-c3e0-4593-a24e-7e4a41766258","order_by":0,"name":"Koray Yalcin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYBACCSgtw8DeAKQMLIjXwsPAcwCkRQKPWgwtEgnIfDxAsr334WcehsM8/DOfX93wo0CCgb+9OwGvFmme48bSIC0St3PKbvYAHSZx5uwGvFrkJNIYwFoMpHPSbvAAtRhI5BLUwvwbrEXyTNrNP8RokZZIY4PYIsF+7DZRtkj2HGOznGOQziNxJofttoyBBA9Bv0gcb2O+8abCWo6//fizm2/+2AAZvfi1gAATj0EzkOIxAHF4CCoHAcYfDHVAiv0BUapHwSgYBaNg5AEAfts9a1YQ9Y0AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-3454-9870","institution":"Bahcesehir University Medicalpark Göztepe Hospital","correspondingAuthor":true,"prefix":"","firstName":"Koray","middleName":"","lastName":"Yalcin","suffix":""},{"id":309072533,"identity":"25bc4a05-4ede-453c-87a4-50bcb03c5525","order_by":1,"name":"Vedat Uygun","email":"","orcid":"","institution":"Istinye University Medicalpark Antalya 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Seda","middleName":"","lastName":"Öztürkmen","suffix":""},{"id":309072537,"identity":"e7654a2c-2777-49f1-90c6-71a6556c7496","order_by":5,"name":"Suleimen Zhumatayev","email":"","orcid":"","institution":"Medicalpark Göztepe Hospital","correspondingAuthor":false,"prefix":"","firstName":"Suleimen","middleName":"","lastName":"Zhumatayev","suffix":""},{"id":309072538,"identity":"47e5e681-46f6-444b-8332-7200728c35da","order_by":6,"name":"Hayriye Daloglu","email":"","orcid":"","institution":"Antalya Bilim University Medicalpark Antalya Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hayriye","middleName":"","lastName":"Daloglu","suffix":""},{"id":309072539,"identity":"089f3d53-f55f-47db-b0e1-cbd87dcdfe16","order_by":7,"name":"Gulsun Karasu","email":"","orcid":"","institution":"MedicalPark Göztepe Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gulsun","middleName":"","lastName":"Karasu","suffix":""},{"id":309072540,"identity":"e0b7d9ad-6f9f-43e2-8102-11712e71393e","order_by":8,"name":"Akif Yesilipek","email":"","orcid":"https://orcid.org/0000-0002-4514-8637","institution":"MedicalPark Antalya Hospital","correspondingAuthor":false,"prefix":"","firstName":"Akif","middleName":"","lastName":"Yesilipek","suffix":""}],"badges":[],"createdAt":"2024-05-12 20:00:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4409630/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4409630/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41409-024-02439-4","type":"published","date":"2024-10-14T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66651863,"identity":"e4572512-f401-4de2-838f-2190913824fa","added_by":"auto","created_at":"2024-10-15 07:42:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":593117,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4409630/v1/a9d5241a-a464-4b4d-9fa5-6d818accbc33.pdf"},{"id":58283078,"identity":"c716cf1b-5597-4e7f-b5fe-7cd2118b33ed","added_by":"auto","created_at":"2024-06-13 11:24:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1661792,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryData1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4409630/v1/8db834294a783a121c1409ea.docx"},{"id":58283076,"identity":"c1d9c291-19b2-4e7a-88ac-f64db76463b4","added_by":"auto","created_at":"2024-06-13 11:24:31","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":15621,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryData2.docx","url":"https://assets-eu.researchsquare.com/files/rs-4409630/v1/8a6758b34164afb1b16992a1.docx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Hematopoietic Stem Cell Transplantation in Children with Mucopolysaccharidosis IVA: Single Center Experience","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHematopoietic stem cell transplantation has been a therapy option for mucopolysaccharidosis (MPS) for decades and the cross-correction mechanism is the main rationale for HSCT.\u003csup\u003e1, 2\u003c/sup\u003e Although there are convincing data for HSCT in certain types of MPS, the studies are limited for MPS IVA and more data is still pending to show the efficacy/safety of HSCT.\u003csup\u003e2\u0026ndash;6\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMPS IVA (Morquio A syndrome) is an autosomal recessive MPS disorder caused by a deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme.\u003csup\u003e7\u0026ndash;9\u003c/sup\u003e The prevalence range of MPS IVA is estimated from 1 in 76,000 to 1 in 640,000 births.\u003csup\u003e10, 11\u003c/sup\u003e The definite diagnosis is achieved through the demonstration of reduced GALNS activity with molecular confirmation of biallelic pathogenic variants in the GALNS gene.\u003csup\u003e12\u003c/sup\u003e Skeletal and joint abnormalities are the most prevalent manifestations, and patients require regular assessment of multiorgan involvement such as heart, eye, and ear.\u003csup\u003e13, 14\u003c/sup\u003e MPS IVA is a heterogeneous and progressive disorder, some severely affected patients could become wheelchair-bound when they are teenagers and die of respiratory problems, cervical spinal cord complications, or heart valve disease in their 20s or 30s if untreated.\u003csup\u003e9, 13, 15\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTwo different treatment options are currently available for MPS IVA patients; the first one is enzyme replacement therapy (ERT) which is not curative and needs life-long weekly intravenous infusions, the second one is hematopoietic stem cell transplantation (HSCT) which is a one-time procedure allowing a continuous source of deficient enzyme .\u003csup\u003e16\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e ERT for the management of MPS IVA was approved in 2014 by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). However, there are some limitations such as weekly infusions, short half-life time (35 minutes), developing antibodies, and high cost.\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e In addition, there is controversial data about the efficacy of ERT in skeletal dysplasia.\u003csup\u003e19, 20\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThere is an unmet need for MPS IVA patients. As the currently approved therapy option has certain limitations, the other therapy options should be evaluated seriously to decide the best treatment modality. For this purpose, we presented our report to show the efficacy and safety of HSCT on MPS IVA patients.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003eAll members of the cohort were treated at Medicalpark G\u0026ouml;ztepe/Antalya Hospitals under the Declaration of Helsinki and following the provision of informed consent by patients or their guardians. This study was approved by the institutional review board of Medicalpark G\u0026ouml;ztepe and Antalya Hospitals.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThe study cohort included 3 girls and 7 boys with MPS IVA who underwent allogeneic HSCT (total of 12 HSCT, two patients received 2nd HSCT) between February 12, 2021, and March 10, 2023.\u003csup\u003e21\u003c/sup\u003e Data were collected from the medical records and retrospectively analyzed in an explorative fashion until December 1, 2023.\u003c/p\u003e \u003cp\u003eDiagnosis of MPS IVA was confirmed in all patients both by the enzyme assay of GALNS and by documented biallelic pathogenic variants in the GALNS gene. Regarding height according to the growth chart of MPS IVA (Morquio A), all of the patients had a severe phenotype (their height\u0026thinsp;\u0026lt;\u0026thinsp;75th percentile on the growth chart of Morquio A patients).\u003csup\u003e22\u003c/sup\u003e In line with the clinical findings, all of the genetic variations included in our cohort are known to be associated with severe phenotypes.\u003c/p\u003e \u003cp\u003eAll the patients except one had received ERT before HSCT. Enzyme replacement therapy was terminated after HSCT for all the patients. We followed the enzyme levels every 3 months while doing chimerism analysis in the first month, 3rd month, 6th month, and first year.\u003c/p\u003e \u003cp\u003eThe height growth and the most involved organs such as the ear, eye, and heart were monitored routinely. Some of the patients were unaffected regarding these organs and some patients were better/worse compared to pre-HSCT status.\u003c/p\u003e \u003cp\u003eLastly, the activities of daily living (ADL) scoring system was used to assess the benefit of HSCT. The ADL questionnaire (12 items) used consisted of three domains (\u0026ldquo;movement,\u0026rdquo; \u0026ldquo;movement with cognition,\u0026rdquo; and \u0026ldquo;cognition\u0026rdquo;); each with four subcategories scored from 0 to 5 (0 being the inability to perform task without maximum assistance and 5 being the ability to perform a task without any assistance). \u0026ldquo;Movement\u0026rdquo; comprised basic motor skills needed for normal daily function with the subcategories: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) walking, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) movement on stairs, (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) grasping/finger movement, and (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) endurance in a 6-minute walk (6 MWT). According to MPS IVA clinical characteristics, only the movement section of the ADL scoring system was applied over only 20 points.\u003csup\u003e23\u003c/sup\u003e Questionnaires were performed by calling families on the phone, completed directly by the patient and/or the patient's parent/guardian, and then returned to the study group.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePatient Characteristics\u003c/h2\u003e \u003cp\u003eWe present the data of 10 patients who received a total of 12 HSCTs (two patients received a second HSCT) with the diagnosis of MPS IVA. All the patients had short stature with the specific skeletal features of the disease, had low N-Acetylgalactosamine-6-sulfatase enzyme levels, and specific genetic variations were associated with severe phenotypic features. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) (Supplementary Data 1) We particularly investigated certain dysfunctions and organ systems that could be affected by the disease. All the patients had shorter heights compared to their peers but seven of them were shorter even compared to the standard particular percentile of MPS IVA patients.\u003csup\u003e22\u003c/sup\u003e According to ADL scoring, only one patient had a full ADL movement score (20 points) before HSCT. Three of the patients needed minimum assistance while walking or climbing stairs and one of the patients had severe movement disabilities. Regarding ear problems, six patients (P1, P3, P6, P7, P8, and P10) had recurrent otitis media before HSCT and 3 of them (P1, P3, and P10) needed intervention and one of them (P10) had moderate hearing loss. Regarding eye involvement, three of the patients (P3, P7, and P8) were affected, two of them (P3 and P8) had mild cataracts and the other one (P7) had hypermetropy and astigmatism. Lastly, six of the patients (P1, P3, P4, P6, P8, and P9) had heart involvements before HSCT (mild aortic, mitral, and tricuspid regurgitation for P6, mild aortic and mitral regurgitation for P1, mild mitral stenosis for one patient P3, and mild mitral and tricuspid regurgitation for P4, P8 and P9). All of the patients except one had enzyme replacement before HSCT and they received regular enzyme replacement from the initial diagnosis median 32,5 months (0\u0026ndash;151 months). While enzyme replacement 4 of the 10 patients (40%) experienced mild or moderate allergic reactions, but all of them continued enzyme therapy with desensitization protocols if needed.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe Characteristics of the Patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient/Gender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge at Diagnosis (Month)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eERT duration before HSCT (month)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge at HSCT (Month)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHeight/percentile\u003c/p\u003e \u003cp\u003ebefore HSCT (cm)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOrgan involvement before HSCT\u003c/p\u003e \u003cp\u003e(except skeletal system)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHomozygous pathogenic \u003cem\u003eGALNS\u003c/em\u003e variant (c.DNA)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97 (allergy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e98 cm (50p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEar/Heart\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1168del\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (allergy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e82 cm (3p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.421T\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (allergy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e82 cm (3p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEar/Eye/Heart\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1168del\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e116\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e98 cm (25p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHeart\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.860C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (allergy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e86 cm (10p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.139G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e86 cm (3p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEar/Heart\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1019G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e96 cm (50p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEar/Eye\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.230C\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrenatal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e102 cm (50p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEar/Eye/Heart\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1168del\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90 cm (25p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHeart\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.1157G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e96 cm (3p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEar\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ec.149del\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eOutcomes of HSCT\u003c/h2\u003e \u003cp\u003eThe characteristics of HSCT and the outcomes are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. All the HSCT procedures were performed from matched unrelated donors except for one patient who received HSCT from a matched sibling donor (carrier of disease). Mostly, peripheral blood stem cell was used because of the unrelated donor preference except for two patients who received bone marrow stem cells. Busulfan-Fludarabin-based conditioning was used for all HSCT procedures. Two patients had secondary graft failure because of CMV infections, both were transplanted from the same donor with Treosulfan-based regimens. After the second HSCT, they were engrafted with full donor chimerism and followed up without any complications. ATG was included in all the conditioning regimens and to enhance the engraftment, thiotepa or cyclophosphamide was added in selected patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe characteristics and the outcomes of HSCT\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient/Gender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDonor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStem Cell Source\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eConditioning Regimen\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGvHD Prophylaxis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLast Chimerism\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEnzyme Level\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGvHD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eGraft Failure\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;Cyc\u0026thinsp;+\u0026thinsp;ATG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFull\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePBSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;TT\u0026thinsp;+\u0026thinsp;ATG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFull\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;Cyc\u0026thinsp;+\u0026thinsp;ATG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFull\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePBSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;Cyc\u0026thinsp;+\u0026thinsp;ATG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFull\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSkin/Grade 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePBSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;Cyc\u0026thinsp;+\u0026thinsp;ATG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMixed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePBSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;ATG\u003c/p\u003e \u003cp\u003e(Flu\u0026thinsp;+\u0026thinsp;Treo\u0026thinsp;+\u0026thinsp;ATG\u0026thinsp;+\u0026thinsp;TT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFull\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+ (2nd HSCT)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePBSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;Cyc\u0026thinsp;+\u0026thinsp;ATG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFull\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePBSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;ATG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMixed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePBSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;ATG (Flu\u0026thinsp;+\u0026thinsp;Treo\u0026thinsp;+\u0026thinsp;TT\u0026thinsp;+\u0026thinsp;ATG)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFull\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+ (2nd HSCT)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePBSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFlu\u0026thinsp;+\u0026thinsp;Bu\u0026thinsp;+\u0026thinsp;TT\u0026thinsp;+\u0026thinsp;ATG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCNI\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFull\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding GvHD, calcineurin inhibitors and methotrexate were used for all patients, only one of them developed acute GvHD with grade 2 skin involvement. None of the patients had chronic GvHD features. Enzyme levels were measured at the earliest 90 days after HSCT and the levels were found above the limits for all of the patients. Although two patients had mixed chimerism and one patient was transplanted from a carrier-sibling donor, they also had normal enzyme levels after HSCT. The enzyme levels did not change according to the chimerism ratios, the levels could be high even in mixed chimeric cases. At the last follow-up time, all the patients are alive and GvHD-free. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eClinical Comparison Pre vs Post HSCT\u003c/h2\u003e \u003cp\u003eIn this study, we presented a median follow-up of 20 months (9\u0026ndash;34 months) and evaluated height, ADL scoring, and certain organ systems to determine the benefits of HSCT in this time frame. (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) We observed an increment of height in all patients with various rates and this increment corresponds to a positive change according to MPS IVA percentile charts for 7 patients.\u003csup\u003e22\u003c/sup\u003e Of these 7 patients, three of them were above 10 years old. For ADL scoring, all of the patients with a low ADL score before HSCT achieved an increment after HSCT (Supplementary Data 2). The most significant increment was observed in walking, stairs and endurance scores while the less affected hand movements stayed stable for most of the patients. Regarding ear problems, all of the affected patients (P1, P3, P6, P7, and P8) had less or no acute otitis media attack, and the patient (P10) with moderate hearing loss had a recovery to mild hearing loss after HSCT. Heart involvement was better after HSCT only for one patient (P6) who had mild regurgitation for mitral, tricuspid, and aortic valves and heart involvement was stable for the other 5 patients (P1, P3, P4, P8, and P9) who had problems before HSCT. There were three patients with eye involvement two of them were stable with mild cataracts and the other patient was better with hypermetropia (+\u0026thinsp;3.00 D \u0026gt;\u0026gt; +1,50 D) and astigmatism (+\u0026thinsp;0,75 D\u0026thinsp;\u0026gt;\u0026thinsp;\u0026gt;\u0026thinsp;0,25 D) after HSCT.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical Comparison of Pre vs Post HSCT\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient/\u003c/p\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge at HSCT\u0026thinsp;\u0026gt;\u0026thinsp;Last Follow-up (month)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHeight/Percentile\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eADL Movement Score\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEye\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEar\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHeart\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119\u0026thinsp;\u0026gt;\u0026thinsp;138m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98\u0026thinsp;\u0026gt;\u0026thinsp;103 cm (50p\u0026thinsp;\u0026gt;\u0026thinsp;75p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u0026thinsp;\u0026gt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBetter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStabile\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53\u0026thinsp;\u0026gt;\u0026thinsp;66 m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82\u0026thinsp;\u0026gt;\u0026thinsp;82 cm (3p\u0026thinsp;\u0026gt;\u0026thinsp;3p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u0026thinsp;\u0026gt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69\u0026thinsp;\u0026gt;\u0026thinsp;92 m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82\u0026thinsp;\u0026gt;\u0026thinsp;87 cm (3p\u0026thinsp;\u0026gt;\u0026thinsp;10p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u0026thinsp;\u0026gt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eStabile\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBetter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStabile\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e116\u0026thinsp;\u0026gt;\u0026thinsp;141 m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98\u0026thinsp;\u0026gt;\u0026thinsp;100 cm (25p\u0026thinsp;\u0026gt;\u0026thinsp;25p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u0026thinsp;\u0026gt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStabile\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u0026thinsp;\u0026gt;\u0026thinsp;56 m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86\u0026thinsp;\u0026gt;\u0026thinsp;91 cm (10p\u0026thinsp;\u0026gt;\u0026thinsp;25p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20\u0026ndash;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82\u0026thinsp;\u0026gt;\u0026thinsp;116 m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86\u0026thinsp;\u0026gt;\u0026thinsp;97 cm (3p\u0026thinsp;\u0026gt;\u0026thinsp;10p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u0026thinsp;\u0026gt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBetter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBetter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47\u0026thinsp;\u0026gt;\u0026thinsp;68 m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e96\u0026thinsp;\u0026gt;\u0026thinsp;102 cm (50p\u0026thinsp;\u0026gt;\u0026thinsp;75p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u0026thinsp;\u0026gt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBetter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBetter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129\u0026thinsp;\u0026gt;\u0026thinsp;148 m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e102\u0026thinsp;\u0026gt;\u0026thinsp;105 cm (50p\u0026thinsp;\u0026gt;\u0026thinsp;75p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u0026thinsp;\u0026gt;\u0026thinsp;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eStabile\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eStabile\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStabile\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46\u0026thinsp;\u0026gt;\u0026thinsp;65 m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90\u0026thinsp;\u0026gt;\u0026thinsp;94 cm (25p\u0026thinsp;\u0026gt;\u0026thinsp;25p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u0026thinsp;\u0026gt;\u0026thinsp;16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStabile\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e186\u0026thinsp;\u0026gt;\u0026thinsp;195 m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e96\u0026thinsp;\u0026gt;\u0026thinsp;100 cm (3p\u0026thinsp;\u0026gt;\u0026thinsp;10p)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u0026thinsp;\u0026gt;\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBetter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUnaffected\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study was planned for long-term follow-up of MPS IVA cases after HSCT. For this purpose, a 2-year follow-up was aimed. Long-term follow-up results of the study will allow comparison of HSCT with other treatment modalities. The results of our study are promising. Regarding safety, there is no transplant-related adverse event was observed except only one grade 2 skin GvHD case. In all cases, normal enzyme levels were reached after HSCT. During the short follow-up period, our cases showed an increase in stature and improvement in daily activity functions.\u003c/p\u003e \u003cp\u003eIn our cohort, all of the patients had one of the genetic variations that were defined before with an association of severe phenotype.\u003csup\u003e24\u003c/sup\u003e Detailed physical examinations of our patients revealed the skeletal dysmorphism which is one of the main findings of the disease and the degree of the skeletal dysmorphism could identify the disease severity. Although we identified skeletal dysmorphisms, all of our patients except one had a mild functional disability and could achieve all the movements with at least minimal assistance. The only patient with a severe functional disability was 15 years old and needed extensive assistance for motor functions, but after HSCT he is doing well with mild/moderate assistance.\u003c/p\u003e \u003cp\u003eIn our study, we used ADL scoring which included cognitive and movement parameters\u003csup\u003e23\u003c/sup\u003e but, it was known that MPS IVA doesn\u0026rsquo;t affect cognitive performance so, we analyzed our patients only with movement parameters over 20 points. Although all patients except one had at least one low point with any of the certain movement parameters, they all achieved better points for every movement after HSCT. However, the movement scoring of ADL has parameters that give rise to subjective evaluation so our findings should be verified in a long follow-up period.\u003c/p\u003e \u003cp\u003eOne of the main problems of MPS IVA patients is short stature and according to current data the height is arrested around the age of 8.\u003csup\u003e22\u003c/sup\u003e Six of our patients had height percentile increments according to specific charts for MPS IVA. It is noteworthy that we detected continuous height increments after HSCT in three of our patients who are over 10 years old.\u003c/p\u003e \u003cp\u003eAlthough all of the patients had GALNS enzyme levels below the normal limits before HSCT, we detected higher enzyme levels over or within the normal limits after HSCT. This data supported the effectiveness of HSCT and made it comparable to enzyme replacement therapies. Two patients had mixed chimerism but they also had high enzyme levels similar to full chimeric patients. Although it is difficult to comment with one case, one of our patients received HSCT from a carrier match sibling donor and we observed that the carrier donor status could be sufficient to maintain a normal GALNS enzyme level after HSCT.\u003c/p\u003e \u003cp\u003eWe think that the recovery or the reduction of the frequency of ear infections following the HSCT is a significant parameter indicating the benefits of the therapy. Although we can not observe a similar significant recovery for the heart or eye, we did not observe any regression in these organ functions after HSCT. We hope to comment accurately on the long-term follow-up data in future reports.\u003c/p\u003e \u003cp\u003eThe busulfan-fludarabine combination was the recommended regimen for MPS patients and we applied this regimen for all the patients except two second transplants.\u003csup\u003e2\u003c/sup\u003e ATG was used in all the regimens and thiotepa or cyclophosphamide was added in selected patients to enhance the engraftment. Two second HSCTs were performed with treosulfan-based regimens with thiotepa and both were engrafted successfully without HSCT-related toxicity. Although matched umbilical cord blood (UCB) and noncarrier sibling bone marrow were the preferred cell sources, we had to use mostly PBSC because of the unrelated donor preference and our results were comparable with other MPS HSCT studies using UCB.\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOne of the limitations of this study is not including quality of life (QoL) documentation both for patients and the parents. Although comment without proper data is not considerable, it is easy to observe the positive changes after HSCT in terms of both physical and psychological parameters. (such as feeling better and more active or happy not to be dependent on weekly replacement therapies)\u003c/p\u003e \u003cp\u003eWhile evaluating the safety concerns of HSCT, historical data should be considered carefully. The application of HSCT is fast developing and the survival rates are improving for mucopolysaccharidoses.\u003csup\u003e2, 6\u003c/sup\u003e We did not observe any serious complications in our cohort and all the patients are alive. Acute GvHD (Grade 2 skin) emerged for only one patient and all the patients were GvHD-free at the last follow-up time. Although there were two secondary graft failures, the second HSCT procedure was uneventful. According to our data, HSCT for MPS IVA could meet the expected safety criteria without serious adverse events.\u003c/p\u003e \u003cp\u003eCost effectivity is another key point for MPS therapies. Enzyme replacements are life-long continuous therapies that need medical interventions regularly and also they are very expensive drugs.\u003csup\u003e16\u003c/sup\u003e Although accurately estimating the cost of HSCT is not easy due to many influencing factors like type of donor, stem cell source, complications, and out-of-pocket expenses which differ according to different countries, HSCT is a one-time therapy and cheaper than the cost of one-year enzyme replacement therapy. Besides the direct costs, the economic and psychological burden of weekly transfusion therapy for the family is mostly underestimated. Hospital dependency causes work-hours lost for the parents and the enzyme replacements could be longer than expected because of intravenous route issues and allergic complications.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eHere we present the data of our HSCT experience in MPS IVA with promising results regarding both safety and efficacy. It is obvious that we need more data and long-term follow-up to comment properly on the benefits of HSCT in MPS IVA. Also, there is a need to compare the two treatment modalities; HSCT vs enzyme replacement therapy in terms of efficacy, safety, and QoL.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKY and AY designed the study, analyzed, and interpreted the clinical data and wrote the manuscript. VU, GK and BOH analyzed, interpreted the data and contributed to the writing of the manuscript. SC, SZ, SO and HD acquired the data and contributed to the writing of the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funds were received for this work\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the institutional review board of the Bahcesehir University (#20240503).\u003c/p\u003e\n\u003cp\u003eThe study was in compliance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the parents.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFratantoni JC, Hall CW, Neufeld EF. 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Molecular genetics and metabolism. 2015; \u003cstrong\u003e114\u003c/strong\u003e(2): 161-9.\u003c/li\u003e\n\u003cli\u003eZanetti A, D\u0026apos;Avanzo F, AlSayed M, Brusius-Facchin AC, Chien YH, 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. Human mutation. 2021; \u003cstrong\u003e42\u003c/strong\u003e(11): 1384-98.\u003c/li\u003e\n\u003cli\u003eBoelens JJ, Aldenhoven M, Purtill D, Ruggeri A, Defor T, Wynn R, et al. Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning. Blood. 2013; \u003cstrong\u003e121\u003c/strong\u003e(19): 3981-7.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"activities of daily living scoring system, hematopoietic stem cell transplantation, mucopolysaccharidosis IVA, morquio syndrome","lastPublishedDoi":"10.21203/rs.3.rs-4409630/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4409630/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMucopolysaccharidosis IVA (MPS IVA; Morquio syndrome) is a lysosomal storage disorder and features systemic skeletal dysplasia that is caused by defective Nacetylgalactosamine-6-sulfate sulfatase (GALNS). Although there are convincing data for hematopoietic stem cell transplantation (HSCT) in certain types of MPS, the studies are limited for MPS IVA and more data is still pending to show the efficacy/safety of HSCT.\u003c/p\u003e \u003cp\u003eThis study included 3 girls and 7 boys with MPS IVA who underwent allogeneic HSCT between February 12, 2021, and March 10, 2023. Enzyme levels, height growth, the most involved organs (ear, eye, and heart), and the activities of daily living (ADL) scoring system were monitored to assess the benefit of HSCT.\u003c/p\u003e \u003cp\u003eIn a median follow-up of 20 months (9\u0026ndash;34 months), there is no severe transplant-related adverse event was observed. In all cases, normal enzyme levels were reached after HSCT. During the short follow-up period, our cases showed an increase in stature and improvement in daily activity functions.\u003c/p\u003e \u003cp\u003eHere we present the data of our HSCT experience in MPS IVA with promising results regarding both safety and efficacy. We need more data and long-term follow-up to comment properly on the benefits of HSCT in MPS IVA.\u003c/p\u003e","manuscriptTitle":"Hematopoietic Stem Cell Transplantation in Children with Mucopolysaccharidosis IVA: Single Center Experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-13 11:24:26","doi":"10.21203/rs.3.rs-4409630/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-07-01T13:35:54+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-21T17:43:52+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-04T12:02:38+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-05-31T11:52:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-21T09:17:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bone Marrow Transplantation","date":"2024-05-20T18:44:52+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2024-05-13T10:58:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-12T19:56:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"dc0448ab-5da1-40be-9581-c0b92721963d","owner":[],"postedDate":"June 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":32657926,"name":"Health sciences/Medical research/Translational research"},{"id":32657927,"name":"Health sciences/Medical research/Clinical trial design/Clinical trials/Phase III trials"}],"tags":[],"updatedAt":"2024-10-15T07:10:45+00:00","versionOfRecord":{"articleIdentity":"rs-4409630","link":"https://doi.org/10.1038/s41409-024-02439-4","journal":{"identity":"bone-marrow-transplantation","isVorOnly":false,"title":"Bone Marrow Transplantation"},"publishedOn":"2024-10-14 04:00:00","publishedOnDateReadable":"October 14th, 2024"},"versionCreatedAt":"2024-06-13 11:24:26","video":"","vorDoi":"10.1038/s41409-024-02439-4","vorDoiUrl":"https://doi.org/10.1038/s41409-024-02439-4","workflowStages":[]},"version":"v1","identity":"rs-4409630","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4409630","identity":"rs-4409630","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}