BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA), or Morquio A syndrome, is a rare inherited metabolic disorder caused by deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. A progressive systemic skeletal chondrodysplasia, leading to significant morbidity and reduced life expectancy is the main clinical feature of this multisystemic disease. Although enzyme replacement therapy with elosulfase alfa is established in Europe, the rarity of disease and other factors still set hurdles in having patients treated in some countries. Aim of this statement is to provide evidence-based guidance for the enzyme replacement treatment of Morquio A patients, harmonizing recommendations from published guidelines with the real-life clinical practice in the Central and South-Eastern European region. PARTICIPANTS: The Consensus Group, convened by 8 Steering Committee (SC) members from 7 Central and South-Eastern European countries, consisted of a multidisciplinary group of 17 experts in the management of MPS in Central and South-Eastern Europe. CONSENSUS PROCESS: The SC met in a first virtual meeting with an external scientific coordinator, to discuss on clinical issues to be analyzed in guidance statements. Statements were developed by the scientific coordinator, evaluated by the SC members in a first modified-Delphi voting and adapted accordingly, to be submitted to the widest audience in the Consensus Conference. Following discussion and further modifications, all participants contributed to a second round of modified-Delphi voting. RESULTS: Nine of ten statements, concerning general guidelines for management of MPS IVA patients and specific recommendations for treatment, received final consensus. CONCLUSIONS: European guidelines and evidence-based recommendations for Morquio A patients should be considered in the real life of Central and South-Eastern European countries and adapted to unique clinical practice approaches and criteria for patients' access to treatment and reimbursement in the region.

1st Department of Pediatrics Hippokratio General Hospital Aristotle University Thessaloniki Greece

Department of Child Neurology Epileptology and Social Pediatrics Centre for Rare Diseases University of Giessen Giessen Germany

Department of Paediatrics and Inherited Metabolic Disorders General University Hospital and 1st Faculty of Medicine Charles University KPDPM 1 LF UK a VFN Praha Ke Karlovu 2 128 08 Prague Czech Republic

Department of Pediatric Nutrition and Metabolic Diseases The Children's Memorial Health Institute Warsaw Poland

Department of Toxicology and Metabolic Diseases Heim Pal National Pediatric Institute Budapest Hungary

Neurogenetics Laboratory Neurology Department University Hospital of Heraklion University of Crete Heraklion Greece

Regional Centre of Medical Genetics INSMC Alessandrescu Rusescu Bucharest Romania

Unit of Rare Metabolic Diseases Department of Metabolic Diseases Jagiellonian University Medical College University Hospital Krakow Poland

University Children's Hospital Skopje North Macedonia

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Khan S, Peracha H, Ballhausen D, Wiesbauer A, Rohrbach M, Gautschi M, et al. Epidemiology of mucopolysaccharidoses. Mol Genet Metab. 2017;121:227–240. doi: 10.1016/j.ymgme.2017.05.016. PubMed DOI PMC

Tomatsu S, Yasuda E, Patel P, Ruhnke K, Shimada T, Mackenzie WG, et al. Morquio A syndrome: diagnosis and current and future therapies. Pediatr Endocrinol Rev. 2014;12 Suppl 1(0 1):141–51. PubMed PMC

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(6):931–945. doi: 10.2174/138920111795542615. PubMed DOI

Morrone A, Caciotti A, Atwood R, Davidson K, Du C, Francis-Lyon P, et al. Morquio A syndrome-associated mutations: a review of alterations in the GALNS gene and a new locus-specific database. Hum Mutat. 2014;35(11):1271–1279. doi: 10.1002/humu.22635. PubMed DOI PMC

Montano 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(2):165–174. PubMed

Lavery C, Hendriksz C. Mortality in patients with Morquio syndrome A. JIMD Rep. 2015;15:59–66. PubMed PMC

Mikles M, Stanton RP. A review of Morquio syndrome. Am J Orthop (Belle Mead NJ) 1997;26(8):533–540. PubMed

Tomatsu S, Mackenzie WG, Theroux MC, Mason RW, Thacker MM, Shaffer TH, et al. Current and emerging treatments and surgical interventions for Morquio A syndrome: a review. Res Rep Endocr Disord. 2012;2012(2):65–77. PubMed PMC

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(6):979–990. doi: 10.1007/s10545-014-9715-6. PubMed DOI PMC

Hendriksz CJ, Parini R, AlSayed MD, Raiman J, Giugliani R, Mitchell JJ, et al. Impact of long-term elosulfase alfa on activities of daily living in patients with Morquio a syndrome in an open-label, multi-center, phase 3 extension study. Mol Genet Metab. 2018;123:127–134. doi: 10.1016/j.ymgme.2017.11.015. PubMed DOI

Hendriksz C, Santra S, Jones SA, Geberhiwot T, Jesaitis L, Long B, et al. Safety, immunogenicity, and clinical outcomes in patients with Morquio a syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment. Mol Genet Metab. 2018;123:479–487. doi: 10.1016/j.ymgme.2018.02.011. PubMed DOI

Hendriksz CJ. Elosulfase alfa (BMN 110) for the treatment of mucopolysaccharidosis IVA (Morquio A Syndrome) Expert Rev Clin Pharmacol. 2016;9(12):1521–1532. doi: 10.1080/17512433.2017.1260000. PubMed DOI

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(1):38. doi: 10.1186/s13023-021-01675-x. PubMed DOI PMC

Harmatz P, Mengel KE, Giugliani R, Valayannopoulos V, Lin SP, 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. doi: 10.1016/j.ymgme.2013.01.021. PubMed DOI

Harmatz PR, Mengel KE, Giugliani R, Valayannopoulos V, Lin SP, 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(2):186–194. doi: 10.1016/j.ymgme.2014.10.015. PubMed DOI

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(1–2):131–143. doi: 10.1016/j.ymgme.2016.05.018. PubMed DOI

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(1):137. doi: 10.1186/s13023-019-1074-9. PubMed DOI PMC

Tylki-Szymańska A, Almássy Z, Christophidou-Anastasiadou V, Avdjieva-Tzavella D, Barisic I, Cerkauskiene R, et al. The landscape of Mucopolysaccharidosis in Southern and Eastern European countries: a survey from 19 specialistic centers. Orphanet J Rare Dis. 2022;17(1):136. doi: 10.1186/s13023-022-02285-x. PubMed DOI PMC

NICE. Elosulfase alfa for treating mucopolysaccharidosis type IVA. 2015. https://www.nice.org.uk/guidance/hst2. Accessed 3 November 2021.

Moisan L, Iannuzzi D, Maranda B, Campeau PM, Mitchell JJ. Clinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study. Orphanet J Rare Dis. 2020;15(1):270. doi: 10.1186/s13023-020-01545-y. PubMed DOI PMC

Treadwell M, Harmatz P, Burton B, Mitchell J, Muschol N, Jones S, et al. Impact of Elosulfase alfa on pain in patients with Morquio a syndrome over 52 weeks: MOR-008—a randomized, Double-blind, Pilot Study. J Inborn Errors Metab Screen. 2017;5:1–12. doi: 10.1177/2326409817718850. DOI

Hendriksz CJ, Berger KI, Lampe C, Kircher SG, Orchard PJ, Southall R, et al. Health-related quality of life in mucopolysaccharidosis: looking beyond biomedical issues. Orphanet J Rare Dis. 2016;11(1):119. doi: 10.1186/s13023-016-0503-2. PubMed DOI PMC

Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories-IA and -II in psychiatric outpatients. J Pers Assess. 1996;67:588–597. doi: 10.1207/s15327752jpa6703_13. PubMed DOI

Hughes D, Giugliani R, Guffon N, Jones SA, Mengel KE, Parini R, et al. Clinical outcomes in a subpopulation of adults with Morquio a syndrome: results from a long-term extension study of elosulfase alfa. Orphanet J Rare Dis. 2017;12:98. doi: 10.1186/s13023-017-0634-0. PubMed DOI PMC

Vimizim® (elosulfase alfa) Prescribing Information (EU). 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002779/WC500169239.pdf Accessed 1 October 2021.

Khan S, Alméciga-Díaz CJ, Sawamoto K, Mackenzie WG, Theroux MC, Pizarro C, et al. Mucopolysaccharidosis IVA and glycosaminoglycans. Mol Genet Metab. 2017;120(1–2):78–95. doi: 10.1016/j.ymgme.2016.11.007. PubMed DOI PMC

Lampe C, McNelly B, Gevorkian AK, Hendriksz CJ, Lobzhanidze TV, Pérez-López J, et al. Transition of patients with mucopolysaccharidosis from paediatric to adult care. Mol Genet Metab Rep. 2019;21:100508. doi: 10.1016/j.ymgmr.2019.100508. PubMed DOI PMC

Stepien KM, Kieć-Wilk B, Lampe C, Tangeraas T, Cefalo G, Belmatoug N, et al. Challenges in transition from childhood to adulthood care in rare metabolic diseases: results from the first multi-center European Survey. Front Med (Lausanne) 2021;8:652358. doi: 10.3389/fmed.2021.652358. PubMed DOI PMC

Jorm AF. Using the Delphi expert consensus method in mental health research. Aust N Z J Psychiatry. 2015;49(10):887–897. doi: 10.1177/0004867415600891. PubMed DOI