BACKGROUND: Alpha-mannosidosis is a rare recessive lysosomal storage disorder with progressive multi-systemic impacts. In the absence of standardized monitoring protocols, there is insufficient understanding of disease progression over time. This study explored the evolution of the burden of illness and quality of life (QoL) experienced by patients with alpha-mannosidosis via an international patient and caregiver-based survey. The online survey was distributed to adult patients/caregivers of patients ≥ 10 years old. It included visual analogue scales (VAS; timepoints 5 years ago and now), multiple choice, and open text questions. We report a subset of functional and QoL data: walking ability, pain/discomfort, ability to self-care, and mental health. RESULTS: Analyses include 51 responses from 18 countries: 26 patients were on velmanase alfa enzyme replacement therapy (ERT), seven had been treated with hematopoietic stem cell transplantation (HSCT) and 18 were untreated patients (UP). Over 5 years, VAS scores showed the least decline in walking ability for HSCT patients (+ 0.1 ± 1.9) compared to patients receiving ERT (+ 0.7 ± 1.2) and UP (+ 1.8 ± 2.0). A trend towards improvement in pain was only observed for those on ERT (-0.2 ± 2.0), both for pediatric and adult patients. Ability to self-care improved for patients treated with HSCT (-1.0 ± 1.8) and slightly improved with ERT (-0.3 ± 1.5) but worsened for UP (+ 0.6 ± 0.9). Similarly, a trend towards improvement in mental health scores was observed for patients on ERT (-0.4 ± 2.2). CONCLUSIONS: Alpha-mannosidosis is associated with a substantial and progressive burden in UP, including deterioration in walking ability, pain, self-care and mental health. The survey results suggest that treatment with ERT or HSCT may slow this natural progression of alpha-mannosidosis, with these patients following a different disease trajectory to those solely receiving supportive care. This study could inform the natural pathway of alpha-mannosidosis to recognize patients' needs, courses of care, and the design of interventional studies.

Adult Inherited Metabolic Disorders Salford Care Organisation Northern Care Alliance NHS Foundation Trust Salford UK

Asociación MPS Lisosomales España Barcelona Spain

Centre for Inherited Metabolic Diseases Copenhagen University Hospital Copenhagen Denmark

Centre for Rare Diseases University Hospital of Giessen Giessen Germany

Chiesi Farmaceutici S p A Parma Italy

Chiesi USA Inc Boston USA

Department of Pediatrics and Inherited Metabolic Disorders General University Hospital and 1st Faculty of Medicine Charles University Prague Czech Republic

Hospital Universitario Ramón y Cajal IRYCIS Madrid Spain

Hospital Universitario Virgen de la Arrixaca Murcia Spain

Instituto Fernandes Figueira Fiocruz Rio de Janeiro Brazil

Reference Center for Inherited Metabolic Disorders Femme Mère Enfant Hospital Hospices Civils de Lyon Lyon France

Regional Center of Medical Genetics Bucharest INSMC Alessandrescu Rusescu Bucharest Romania

The Society for Mucopolysaccharide and Related Diseases MPS House Amersham UK

University Medical Center Hamburg Eppendorf Hamburg Germany

Villa Metabolica University Medical Center Mainz Mainz Germany

Zobrazit více v PubMed

OMIM®. Mannosidosis, Alpha B, Lysosomal, MANSA. Available online: https://www.omim.org/entry/248500. (Accessed: 6 February 2024).

Malm D, Nilssen Ø. Alpha-mannosidosis. Orphanet J Rare Dis. 2008;3:21. PubMed PMC

Malm D, Nilssen Ø. Alpha-mannosidosis. Orphanet encyclopedia. Available online: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en%26Expert=61. (Accessed: 2 January 2024).

Ficicioglu C, Stepien KM. Alpha-Mannosidosis. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al. editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle. Copyright © 1993–2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 2001. Oct 11 [updated 2024 Jun 13].

Hennermann JB, Guffon N, Cattaneo F, Ceravolo F, Borgwardt L, Lund AM, et al. The SPARKLE registry: protocol for an international prospective cohort study in patients with alpha-mannosidosis. Orphanet J Rare Dis. 2020;15(1):271. PubMed PMC

Malm D, Nilssen Ø. Alpha-Mannosidosis. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K editors GeneReviews(®). Seattle (WA): University of Washington, Seattle; 1993–2020; 2001 [updated 2019].

Malm D, Halvorsen DS, Tranebjaerg L, Sjursen H. Immunodeficiency in alpha-mannosidosis: a matched case-control study on Immunoglobulins, complement factors, receptor density, phagocytosis and intracellular killing in leucocytes. Eur J Pediatr. 2000;159(9):699–703. PubMed

Hennermann JB, Raebel EM, Donà F, Jacquemont ML, Cefalo G, Ballabeni A, et al. Mortality in patients with alpha-mannosidosis: a review of patients’ data and the literature. Orphanet J Rare Dis. 2022;17(1):287. PubMed PMC

Adam J, Malone R, Lloyd S, Lee J, Hendriksz CJ, Ramaswami U. Disease progression of alpha-mannosidosis and impact on patients and carers - A UK natural history survey. Mol Genet Metab Rep. 2019;20:100480. PubMed PMC

Ceccarini MR, Codini M, Conte C, Patria F, Cataldi S, Bertelli M et al. Alpha-Mannosidosis: therapeutic strategies. Int J Mol Sci. 2018; 19(5). PubMed PMC

Mynarek M, Tolar J, Albert MH, Escolar ML, Boelens JJ, Cowan MJ, et al. Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients. Bone Marrow Transpl. 2012;47(3):352–9. PubMed

Guffon N, Konstantopoulou V, Hennermann JB, Muschol N, Bruno I, Tummolo A, et al. Long-term safety and efficacy of Velmanase Alfa treatment in children under 6 years of age with alpha-mannosidosis: A phase 2, open label, multicenter study. J Inherit Metab Dis. 2023;46(4):705–19. PubMed

Naumchik BM, Gupta A, Flanagan-Steet H, Steet RA, Cathey SS, Orchard PJ et al. The role of hematopoietic cell transplant in the glycoprotein diseases. Cells. 2020; 9(6). PubMed PMC

Borgwardt L, Lund AM, Dali CI. Alpha-mannosidosis - a review of genetic, clinical findings and options of treatment. Pediatr Endocrinol Rev. 2014;12(Suppl 1):185–91. PubMed

European Medicines Agency. Lamzede velmanase alfa. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/lamzede. (Accessed: 6 March 2024).

Food and Drug Administration. LAMZEDE (velmanase alfa). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761278s000lbl.pdf. (Accessed: 6 March 2024).

Borgwardt L, Guffon N, Amraoui Y, Jones SA, De Meirleir L, Lund AM, et al. Health related quality of life, disability, and pain in alpha Mannosidosis:Long-Term data of enzyme replacement therapy with Velmanase Alfa (Human Recombinant alpha Mannosidase). J Inborn Errors Metab Screen. 2018;6:2326409818796854.

Lund AM, Borgwardt L, Cattaneo F, Ardigò D, Geraci S, Gil-Campos M, et al. Comprehensive long-term efficacy and safety of Recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis. J Inherit Metab Dis. 2018;41(6):1225–33. PubMed PMC

Phillips D, Hennermann JB, Tylki-Szymanska A, Borgwardt L, Gil-Campos M, Guffon N, et al. Use of the Bruininks-Oseretsky test of motor proficiency (BOT-2) to assess efficacy of Velmanase Alfa as enzyme therapy for alpha-mannosidosis. Mol Genet Metab Rep. 2020;23:100586. PubMed PMC

Borgwardt L, Guffon N, Amraoui Y, Dali CI, De Meirleir L, Gil-Campos M, et al. Efficacy and safety of Velmanase Alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial. J Inherit Metab Dis. 2018;41(6):1215–23. PubMed PMC

Harmatz P, Cattaneo F, Ardigò D, Geraci S, Hennermann JB, Guffon N, et al. Enzyme replacement therapy with Velmanase Alfa (human Recombinant alpha-mannosidase): novel global treatment response model and outcomes in patients with alpha-mannosidosis. Mol Genet Metab. 2018;124(2):152–60. PubMed

Malm D, Riise Stensland HMF, Edvardsen Ø, Nilssen Ø. The natural course and complications of alpha-mannosidosis—a retrospective and descriptive study. J Inherit Metab Dis. 2014;37(1):79–82. PubMed

Zielonka M, Garbade SF, Kölker S, Hoffmann GF, Ries M. Ultra-orphan lysosomal storage diseases: A cross-sectional quantitative analysis of the natural history of alpha-mannosidosis. J Inherit Metab Dis. 2019;42(5):975–83. PubMed

Guffon N, Burton BK, Ficicioglu C, Magner M, Gil-Campos M, Lopez-Rodriguez MA et al. Monitoring and integrated care coordination of patients with alpha-mannosidosis: A global Delphi consensus study. Mol Genet Metab. 2024:108519. PubMed

Makatsori M, Pfaar O, Calderon MA. Allergen immunotherapy: clinical outcomes assessment. J Allergy Clin Immunology: Pract. 2014;2(2):123–9. PubMed

Klimek L, Bergmann KC, Biedermann T, Bousquet J, Hellings P, Jung K, et al. Visual analogue scales (VAS): measuring instruments for the Documentation of symptoms and therapy monitoring in cases of allergic rhinitis in everyday health care: position paper of the German society of allergology (AeDA) and the German society of allergy and clinical immunology (DGAKI), ENT section, in collaboration with the working group on clinical immunology, allergology and environmental medicine of the German society of otorhinolaryngology, head and neck surgery (DGHNOKHC). Allergo J Int. 2017;26(1):16–24. PubMed PMC

Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol. 2006;3(2):77–101.

British Healthcare Business Intelligence Association (BHBIA). Legal and Ethical Guidelines for Healthcare Market Research. 2023.

Broomfield AA, Chakrapani A, Wraith JE. The effects of early and late bone marrow transplantation in siblings with alpha-mannosidosis. Is early Haematopoietic cell transplantation the preferred treatment option? J Inherit Metab Dis. 2010;33(Suppl 3):S123–7. PubMed

Guffon N, Borgwardt L, Tylki-Szymańska A, Ballabeni A, Dona F, Joseph A, et al. Long-term efficacy of Velmanase Alfa treatment in patients with alpha-mannosidosis: pooled data from two extension studies (up to 12 years of therapy). Mol Genet Metab. 2024;141(2):107866.

Cathey SS, Sarasua SM, Simensen R, Pietris K, Kimbrell G, Sillence D, et al. Intellectual functioning in alpha-mannosidosis. JIMD Rep. 2019;50(1):44–9. PubMed PMC

Bertolini A, Rigoldi M, Cianflone A, Mariani R, Piperno A, Canonico F, et al. Long-term outcome of a cohort of Italian patients affected with alpha-Mannosidosis. Clin Dysmorphol. 2024;33(1):1–8. PubMed PMC

Lipiński P, Różdżyńska-Świątkowska A, Iwanicka-Pronicka K, Perkowska B, Pokora P, Tylki-Szymańska A. Long-term outcome of patients with alpha-mannosidosis - A single center study. Mol Genet Metab Rep. 2022;30:100826. PubMed PMC

Hooten WM. Chronic pain and mental health disorders: shared neural mechanisms, epidemiology, and treatment. Mayo Clin Proc. 2016;91(7):955–70. PubMed

Yao C, Zhang Y, Lu P, Xiao B, Sun P, Tao J, et al. Exploring the bidirectional relationship between pain and mental disorders: a comprehensive Mendelian randomization study. J Headache Pain. 2023;24(1):82. PubMed PMC

Dueñas M, Ojeda B, Salazar A, Mico JA, Failde I. A review of chronic pain impact on patients, their social environment and the health care system. J Pain Res. 2016;9:457–67. PubMed PMC

Seaton N, Moss-Morris R, Norton S, Hulme K, Hudson J. Mental health outcomes in patients with a long-term condition: analysis of an improving access to psychological therapies service. BJPsych Open. 2022;8(4):e101. PubMed PMC

Beck M, Olsen KJ, Wraith JE, Zeman J, Michalski JC, Saftig P, et al. Natural history of alpha mannosidosis a longitudinal study. Orphanet J Rare Dis. 2013;8:88. PubMed PMC

Malm D, Pantel J, Linaker OM. Psychiatric symptoms in alpha-mannosidosis. J Intellect Disabil Res. 2005;49(Pt 11):865–71. PubMed

Dewsbury MR, Hargreaves IP, Morgan HM, Stepien KM. Molecular basis of neurocognitive dysfunction and psychosis in Alpha-Mannosidosis. J Translational Genet Genomics. 2024;8(2):85–101.