Paediatric Endocrinology CE/CME ACCREDITED Watch Time: 34 mins

touchEXPERT OPINIONS Improving the alpha-mannosidosis patient journey

An expert gives her perspectives on the history and prevalence of alpha-mannosidosis, its diagnosis and treatment options

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Expert Interviews
Natural history and prevalence of alpha-mannosidosis

Prof. Barbara K Burton gives an overview of the prevalence, sub-types, and signs and symptoms of alpha-mannosidosis

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In this interview, Prof. Burton answers the following questions:

  • Why is early recognition of alpha-mannosidosis so clinically challenging?
  • What do we currently know about the natural history of alpha-mannosidosis?
  • What are the key signs and symptoms associated with alpha-mannosidosis that we should look out for in the clinic?
  • How could we improve early recognition of alpha-mannosidosis, now and in the future?
 
Establishing a diagnosis of alpha-mannosidosis

Prof. Barbara K Burton provides her perspectives on when to suspect alpha-mannosidosis, and discusses the diagnostic algorithm and the importance of timely diagnosis

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In this interview, Prof. Burton answers the following questions:

  • What warrants an index of clinical suspicion for alpha-mannosidosis? Does this change with age of presentation?
  • How do we reach a diagnosis of alpha-mannosidosis?
  • How informative are genetic tests for pathogenic variants to guide clinical management decisions in alpha-mannosidosis?
  • How can we address the challenges associated with timely and accurate differential diagnosis?
  • Why is a timely and accurate diagnosis so important in alpha-mannosidosis?
 
Current and emerging treatment options for patients with alpha-mannosidosis

Prof. Barbara K Burton considers the best supportive care, role of the multidisciplinary team, current treatment options in the US, and emerging treatments for alpha-mannosidosis

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In this interview, Prof. Burton answers the following questions:

  • What is the current standard of care for alpha-mannosidosis?
  • Why is multidisciplinary management so important? Is a picture of cross-speciality best practice emerging?
  • How might therapies address long-term needs in alpha-mannosidosis?
  • What therapy approaches are currently available?
  • What role might enzyme replacement and pharmacological chaperone therapies play in the future management of alpha-mannosidosis?
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Overview & Learning Objectives
Overview

In this activity, a leading expert will share her insights on the natural history and prevalence of alpha-mannosidosis, how to establish diagnosis, and the current and emerging treatment options for patients with this lysosomal storage disorder

This activity is jointly provided by USF Health and touchIME. read more

Target Audience

This activity has been designed to meet the educational needs of validated lysosomal storage disorder specialists including: geneticists, neurologists and paediatricians involved in the management of alpha-mannosidosis.

Disclosures

USF Health adheres to the Standards for Integrity and Independence in Accredited Continuing Education. All individuals in a position to influence content have disclosed to USF Health any financial relationship with an ineligible organization. USF Health has reviewed and mitigated all relevant financial relationships related to the content of the activity. The relevant relationships are listed below. All individuals not listed have no relevant financial relationships.

Faculty

Prof. Barbara K Burton discloses: Advisory board or panel: Agios, Alexion, Applied Therapeutics, Maze Therapeutics, Orchard Therapeutics. Consultant: Biomarin, Horizon, JCR Pharmaceuticals, Moderna, Passage Bio, Sanofi, Takeda, Ultragenyx. Grants/research support: Biomarin, Denali, Homology Medicines, JCR Pharmaceuticals, Sangamo, Ultragenyx. Speaker’s bureau: Biomarin, Horizon, Takeda.

Content reviewer

Larry J. Dishaw Ph.D. has no financial interests/relationships or affiliations in relation to this activity.

Touch Medical Director

Holly Gilbert has no financial interests/relationships or affiliations in relation to this activity.

USF Health Office of Continuing Professional Development and touchIME staff have no financial interests/relationships or affiliations in relation to this activity.

Requirements for Successful Completion

In order to receive credit for this activity, participants must review the content and complete the post-test and evaluation form. Statements of credit are awarded upon successful completion of the post-test and evaluation form.

If you have questions regarding credit please contact cpdsupport@usf.edu 

Accreditations

Physicians

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through a joint providership of USF Health and touchIME. USF Health is accredited by the ACCME to provide continuing medical education for physicians.

USF Health designates this enduring material for a maximum of 0.75 AMA PRA Category 1 CreditTM.  Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The European Union of Medical Specialists (UEMS) – European Accreditation Council for Continuing Medical Education (EACCME) has an agreement of mutual recognition of continuing medical education (CME) credit with the American Medical Association (AMA). European physicians interested in converting AMA PRA Category 1 CreditTM into European CME credit (ECMEC) should contact the UEMS (www.uems.eu)

Advanced Practice Providers

Physician Assistants may claim a maximum of 0.75 Category 1 credits for completing this activity. NCCPA accepts AMA PRA Category 1 CreditTM from organizations accredited by ACCME or a recognized state medical society.

The AANPCP accepts certificates of participation for educational activities approved for AMA PRA Category 1 CreditTM by ACCME-accredited providers. APRNs who participate will receive a certificate of completion commensurate with the extent of their participation.

Date of original release: 23 February 2023. Date credits expire: 23 February 2024.

If you have any questions regarding credit please contact cpdsupport@usf.edu

Learning Objectives
  • Describe the prevalence and natural history of the rare lysosomal storage disorder alpha-mannosidosis (AM)
  • Explain how diagnosis of AM may be approached, and describe the methods of disease identification
  • Outline current and emerging management and treatment options for patients with AM
Faculty & Disclosures
Prof. Barbara K Burton

Prof. Barbara K Burton is a professor of paediatrics (genetics, genomics and metabolism) at the Northwestern University Feinberg School of Medicine and director of the Mucopolysaccharidoses (MPS) and Mucolipidoses Treatment Program at the Ann & Robert H. Lurie Children’s Hospital of Chicago. She is board certified in paediatrics, clinical genetics and clinical biochemical genetics. Her clinical and research interests are focused on inborn errors of metabolism and newborn screening. Prof. Burton is an investigator in numerous natural history studies and clinical trials of new therapies for various metabolic disorders, with a focus on lysosomal disorders, including MPS. She has published over 200 peer-reviewed articles, 50 chapters in books and is an editor of two textbooks. read more

Prof. Burton is active in professional organizations and is a past president of the Society for Inherited Metabolic Disorders and the Chicago Pediatric Society. She served for 4 years as a member of the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children, the federal advisory committee that makes recommendations regarding newborn screening in the US, and currently serves as chairman of the Newborn Screening Advisory Committee for the Illinois Department of Public Health. She is an emeritus member of the board of directors of the Greater Chicago chapter of March of Dimes, a nonprofit organization from whom she received a Lifetime Achievement Award in 2018. She is a member of the Scientific Advisory Board of the National MPS Society and serves on the medical advisory board of a number of other patient advocacy organizations.

Disclosures

Advisory board or panel: Agios, Alexion, Applied Therapeutics, Maze Therapeutics, Orchard Therapeutics. Consultant: Biomarin, Horizon, JCR Pharmaceuticals, Moderna, Passage Bio, Sanofi, Takeda, Ultragenyx. Grants/research support: Biomarin, Denali, Homology Medicines, JCR Pharmaceuticals, Sangamo, Ultragenyx. Speaker’s bureau: Biomarin, Horizon, Takeda.
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This Activity Is Funded By:

An independent medical education grant from Chiesi USA Inc.
This activity is jointly provided by USF Health and touchIME.

The information provided by this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical/clinical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition.

USF is an Equal Opportunity / Affirmative Action / Equal Access Institution.

USF Health is accredited by the Accreditation Council for Continuing Medical Education, the American Nurses Credentialing Center and the Accreditation Council for Pharmacy Education to provide continuing education to healthcare professionals. As an accredited provider, USF Health is required to disclose personal information to relevant accredited bodies that certify CME to process credits /contact hours, comply with reporting requirements, and for internal recordkeeping and regulatory purposes. USF Health does not share or sell any individual’s contact information or unique identifiers to any commercial supporter, advertiser, or third party without the specific permission of the individual.

Unapproved products or unapproved uses of approved products may be discussed by the faculty; these situations may reflect the approval status in one or more jurisdictions. The presenting faculty have been advised by touchIME and USF Health to ensure that they disclose any such references made to unlabelled or unapproved use. No endorsement by touchIME or USF Health of any unapproved products or unapproved uses is either made or implied by mention of these products or uses in touchIME or USF Health activities. touchIME and USF Health accept no responsibility for errors or omissions

This content is intended for healthcare professionals.

Date of original release: 23 February 2023. Date credits expire: 23 February 2024.

This content is intended for healthcare professionals only. Please confirm that you are a healthcare professional.

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Question 1/5
Which of the following best summarizes current understanding of the prevalence of alpha-mannosidosis?

LSD, lysosomal storage disorder.
 Correct

Based on epidemiological data published in January 2022, alpha-mannosidosis has an estimated prevalence of 0.1 per 100,000 persons.1 Due to misdiagnosis and underdiagnosis, estimated prevalence is likely underestimated at present.2,3

References

  1. Orphanet (Report Series: Rare diseases collection). Prevalence and incidence of rare diseases: Bibliographic data. January 2022. Available at: www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_decreasing_prevalence_or_cases.pdf (accessed 16 December 2022).
  2. Wiesinger T, et al. Mol Genet Metab. 2020;130:149–52.
  3. Chen X, et al. J Human Genetics. 2016;61:345–9.
Question 2/5
Which of the following statements best summarizes current understanding of the natural history of alpha-mannosidosis?

CNS, central nervous system.
 Correct

Alpha-mannosidosis is a multisystem, progressive disorder. For untreated patients, prognosis remains poor with a disease course characterized by slowly progressive cognitive, neuromuscular and skeletal deterioration over several decades. Without appropriate treatment, most patients will eventually become wheel-chair dependent; however, many patients with alpha-mannosidosis live to over 50 years of age according to literature reporting physicians’ experiences.1 Age of symptom onset varies, but symptoms typically present in newborn, infant and childhood age groups.2 Early death from primary central nervous system involvement or myopathy is associated with severe forms of alpha-mannosidosis (type 3).3

References

  1. Guffon N, et al. Mol Genet Metabol. 2019;126:470–4.
  2. National Institutes of Health: Genetic and Rare Diseases Information Center. 2021. Available at: https://rarediseases.info.nih.gov/diseases/6968/alpha-mannosidosis (accessed 16 December 2022).
  3. Malm D, Nilssen Ø. Orphanet J Rare Dis. 2008;3:21.
Question 3/5
On clinical evaluation of your patient, you find features suggestive of a lysosomal storage disorder, possibly alpha-mannosidosis. Which of the following laboratory tests would you request to confirm a diagnosis of alpha-mannosidosis?
 Correct

In addition to clinical features, biochemistry findings of elevated mannose-rich oligosaccharides in urine, and enzymology demonstrating acid alpha-mannosidase activity of 5–10% of normal activity in peripheral blood leukocytes, are sufficient for diagnostic certainty of alpha-mannosidosis.1 As an autosomal recessive genetic disorder, identification of biallelic MAN2B1 pathogenic variants can confirm diagnosis but is not mandatory.1 Enzymology evaluation of acid alpha-mannosidase activity is recommended prior to genetic evaluation of MAN2B1.1 Elevated levels of glycosaminoglycans in urine are used in the diagnosis of mucopolysaccharidoses.2

References

  1. Malm D, Nilssen Ø. In: Adam MP, et al., (eds). GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023 (updated 2019). Available from: www.ncbi.nlm.nih.gov/books/NBK1396/ (accessed on 19 December 2022).
  2. Tomatsu S, et al. Mol Genet Metab. 2013;110:42–53.
Question 4/5
What do available study data indicate about the potential role of ERT in the management of alpha-mannosidosis?

CNS, central nervous system; ERT, enzyme replacement therapy; LSD, lysosomal storage disorder.
 Correct

Long-term data from the rhLAMAN studies demonstrated treatment of alpha-mannosidosis with human recombinant alpha-mannosidase ERT (velmanese alfa) improved biochemical and functional measures that were maintained for up to 4 years.1 Between baseline and follow-up, velmanese alfa improved serum oligosaccharide clearance (-72.7%; 95% CI -81.4 to -64.1; p<0.001), and physical functionality as assessed by the 3-minute stair-climb test (+9.3%; 95% CI 2.14 to 16.5; p=0.013). The authors concluded early ERT initiation during paediatric age may support better functional outcomes for patients with alpha-mannosidosis.1 Long-term ERT with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis.2,3

Available data demonstrate HSCT treatment for alpha-mannosidosis attenuated CNS disease and alleviated neuropathy.4 ERT promotes lysosomal storage clearance with exogenous functional acid alpha-mannosidase enzyme, whereas inhibition of substrate synthesis with SRT approaches prevents lysosomal accumulation.5

Abbreviations

CI, confidence interval; CNS, central nervous system; ERT, enzyme replacement therapy; HSCT, haematopoietic stem cell transplant; SRT, substrate replacement therapy.

References

  1. Lund AM, et al. J Inherit Metab Dis. 2018;41:1225–33.
  2. Guffon N, et al. Mol Genet Metabol. 2019;126:470–4.
  3. EMA. Velmanese alfa SmPC. Available at www.ema.europa.eu/en/medicines/human/EPAR/lamzede (accessed 28 Nov 2022)
  4. Naumchik BM, et al. Cells. 2020;9:1411.
  5. Diaz JCL, et al. Int J Mol Sci. 2022;1:232.
Question 5/5
Based on clinical features and results from urine biochemistry and enzymology, you have just reached a diagnosis of alpha-mannosidosis for your 9-year-old patient. Which of the following would you consider next in the management of this patient?
 Correct

Despite advances in treatment, the management of alpha-mannosidosis, as a progressive, multisystem disorder with a varied disease course, is complex and requires a coordinated multidisciplinary approach. Treatment is symptomatic and supportive, with the goals of preventing and treating associated complications; early, proactive intervention by relevant HCP specialties is essential.1–3

Abbreviation

HCP, healthcare professional.

References

  1. Guffon N, et al. Mol Genet Metabol. 2019;126:470–4.
  2. Adam J, et al. Mol Genet Metabol. 2019;20:100480.
  3. NORD. 2018. Available at: https://rarediseases.org/rare-diseases/alpha-mannosidosis/ (accessed 19 December 2022).
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