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MPS Reference
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ERT
Lifelong management
Procedural care

When available, enzyme replacement therapy (ERT) is the first step to optimal outcomes2

Supportive clinical evidence from sibling studies suggests that early intervention provides multiple opportunities to improve patient outcomes through disease-specific management and early initiation of ERT, if available.1-6

ERT, whether initiated early or later in life, has been shown to improve key clinical parameters, such as endurance and pulmonary measures, which are critical to quality of life, maintenance of ambulation and activities of daily living.7,8

  • ERT is currently available in many countries for the treatment of patients with mucopolysaccharidosis (MPS) I, II, IVA and VI.8,9
  • Clinical trials investigating the feasibility and potential benefits of ERT in other MPS disorders are ongoing.
  • When available, home-based infusion of ERT is an important clinical consideration.10-12
Management guidelines and expert reviews on MPS disorders call for initiation of ERT, when available, as soon as diagnosis is confirmed.6,8,13

Lifelong management in the new era of MPS

The new era of management for progressive, complex, genetic conditions, such as mucopolysaccharidosis (MPS) disorders, hinges on the efficient coordination of each patient’s healthcare team by a coordinated, multidisciplinary care-delivery model.1

Geneticists and/or metabolic specialists are typically at the centre of the coordinated, multidisciplinary care-delivery model and an individualised management plan.2,3

Given the nearly universal manifestation of musculoskeletal symptoms in patients with MPS, orthopaedic specialists are essential members of the multidisciplinary medical team.4

  • Patients with MPS require regular assessments by orthopaedic specialists to determine progression of musculoskeletal manifestations and identify appropriate surgical interventions.4
  • Patients with MPS tend to require frequent orthopaedic surgeries to prevent and correct skeletal manifestations of disease.5,6
  • Because of the elevated risk of surgical and anaesthetic complications, it is essential to be aware of best practices in surgical preparation and perioperative care specific to MPS.4,5
In patients with MPS disorders, the benefits of coordinated care may improve many aspects of a patient’s – and a family’s – outlook over the long term.3,7

Many MPS disorders have available management guidelines and specialty-specific consensus recommendations regarding lifelong management of MPS. Guidelines typically recommend the following3,7:

  • Comprehensive baseline assessments (e.g. specialty-specific evaluations, functional performance and disease burden) by appropriate specialists
  • Regular, defined monitoring intervals to assess multisystemic disease progression

Early and ongoing assessments from a coordinated care team can improve patient outcomes and may help prevent irreversible damage.7

Musculoskeletal manifestations are a universal feature of MPS disease progression and should be continually monitored4

The following common musculoskeletal manifestations should be assessed and monitored8,9:

  • Growth abnormalities
  • Joint involvement with or without inflammation
    • Joint stiffness and contractures
    • Joint hypermobility
    • Joint destruction or early degenerative changes
  • Carpal tunnel syndrome and trigger digits
  • Odontoid hypoplasia
  • Dysostosis multiplex

Similar musculoskeletal manifestations are seen in all types of MPS; in fact, it is usually other clinical manifestations that distinguish the MPS subtypes from one another. However, some notable differences are observed8:

  • Patients with Morquio A (MPS IVA) may present with features of skeletal dysplasia that differ from the dysostosis multiplex seen in other MPS subtypes.
  • Ligamentous laxity/joint hypermobility associated with Morquio A is unique – patients with other MPS subtypes generally present with decreased mobility and stiffness of the joints.

Common musculoskeletal features of MPS by subtype are outlined below.

Major-musculoskeletal-manifestations-of-MPS-by-type-of-disorder

Skeletal complications are universal in all MPS disorders, though progression of these complications varies among patients. Prevalence of specific orthopaedic manifestations across MPS subtypes varies, as detailed in the table below.

Orthopaedic-manifestations-of-MPS
Learn more about specific MPS types

Appropriate musculoskeletal imaging is recommended at initial assessment and in periodic annual assessments3

The guidelines include the following overarching recommendations3,11:

  • A comprehensive baseline rheumatological assessment
  • Regular, defined monitoring intervals (generally yearly)
  • Regular follow-up, which is essential to assessing rheumatological disease progression and response to treatment

A more comprehensive schedule of imaging assessments can be found below.

Musculoskeletal-imaging-recommendations-for-MPS-disorders

Initial and periodic annual assessments should be used to monitor musculoskeletal disease progression, determine if and when surgical interventions are needed, and provide guidance regarding increased frequency of evaluations. In particular, monitoring for spinal cord compression is critical.3,5

Learn more about orthopaedic management

Spinal cord compression at the occipitocervical junction is a potential cause of death4

Spinal cord compression is common in certain types of MPS – particularly in Morquio A and MPS VI – and poses significant risk of mortality in these patient populations.12

  • Vigilant monitoring of the cervical spine is essential in order to distinguish myelopathy from lower limb deformity-related functional impairments.12
  • Imaging modality selection for evaluation of spinal involvement is critical; a table comparing the strengths and limitations of MRI, CT and radiography is presented below.12
Neuro-lifelong-comparison-of-radiography-CT-MRI-for-evaluation-of-spinal-involvement-in-MPS-IVA

The above example is related to Morquio A and is similar to considerations given across MPS disorders. The goals of neural axis imaging in Morquio A are as follows12:

  • Detect treatable spinal cord compression
  • Stratify risk to the spinal cord prior to permanent damage
  • Assist in surgical planning
  • Assess the efficacy of surgical and medical treatment
Systemic imaging of the spine begins with pain radiographs, includes instability imaging, may require CT, and generally also requires MRI.12
Recommended-assessments-for-diagnosing-and-monitoring-spinal-involvement-in-patients-with-Morquio-A

Patients with MPS are at elevated risk of complications from anaesthetic and procedural sedation. When possible, general anaesthesia should be avoided and, when necessary, administered only by experienced anaesthesiologists.12,13

  • Procedural risk associated with necessary sedation and anaesthesia is a critical consideration in imaging modality selection.12
  • Plain radiography can be a useful initial imaging tool, as this does not require procedural sedation or anaesthesia.12
  • After initial imaging evaluation of the spine, subsequent imaging of the spinal cord can be limited to MRI.12

Of note, enzyme replacement therapy (ERT) can positively impact mobility and endurance, which could lower the threshold for orthopaedic surgery to facilitate a more active lifestyle.3

Learn more about spinal management

Frequency of assessments and involvement of specific specialists vary across the different MPS types. For patients with MPS diseases associated with primary neurodegenerative and cognitive complications, such as MPS I, II and III, additional and regular neurobehavioural and psychiatric evaluations are recommended.7,14,15

In addition to specialty-specific assessments that should be done to facilitate positive long-term outcomes for patients with MPS, important steps can be taken by the coordinating doctor, typically the geneticist and/or metabolic specialist, related to general health. Their role in educating other healthcare professionals (e.g. dentists, physiotherapists, paediatricians, family doctors) and families about the disease and general management strategies is critical and should include the following:

  • Discussing the risks and benefits of intervention and necessary precautions with treatments and evaluations3
  • Dental considerations
    • The wide range of craniofacial and dental abnormalities, which varies by MPS subtype may or may not predispose patients to an increased risk of dental disease16
    • Close monitoring of dental development (at least annually) and regular dental care to prevent caries and attrition of the teeth3
  • Overall health interventions, which may include supportive therapies such as regular influenza and pneumococcus vaccinations, bronchodilators, and aggressive and prompt treatment of upper respiratory tract3

Specialty-specific assessments, as well as regular physical examinations and overall health interventions, should follow recommended guidelines, which may vary among MPS subtypes.3

Learn more about specific MPS types

Continuity of care into adulthood optimises long-term outcomes

Improvements in the treatment of MPS disorders are contributing to long-term outcomes for patients, necessitating new approaches to lifelong management.

As patients age, some may begin to manage their own healthcare, making doctor-guided transition to the adult setting critical.3 Doctors should ensure the following:

  • Early and ongoing assessments from a coordinated care team to evaluate disease progression across organ systems7
  • Maintenance and assessment of patients’ abilities to perform activities of daily living7
  • Formal, site-specific transition strategies, including identification of adult specialists with long-term MPS management experience3
  • That patients are not lost to follow-up3
Encourage patients and their families to be involved in site-specific transition strategies, which can be tailored to optimise each individual’s long-term care plan.3

The transition from paediatric to adult care and long-term adult care are critical areas to address in care plans for adolescent and adult patients.3 Long-term care considerations are ideally best addressed in a centre with significant MPS experience, and they require careful coordination across specialties.3,17 Long-term issues include but are not limited to the following:

  • Best practices in adult-care transition
  • Gynaecological considerations
    • Pregnancy and maternity-related issues
    • ERT use during pregnancy and lactation
  • Long-term port management
  • Long-term pain management

Long-term management of MPS disorders – including ongoing assessments and a site-specific transition strategy from paediatric to adult care – may lead to sustained improvement in quality of life and a better future for your patients.3,17-19

Procedural care requires coordinated surgical planning across specialties

Because clinical manifestations of mucopolysaccharidosis (MPS) disorders are multisystemic, a patient-specific, multidisciplinary approach is required to proactively recognise and manage complications such as orthopaedic surgeries, which are frequent in patients with MPS.1,2

Patients with MPS disorders typically have a number of surgical interventions over their lifetimes. A natural history study assessing a cohort of 325 patients with Morquio A (MPS IVA) found that over 70% of patients had at least one surgical procedure.3

Surgical-burden-in-patients-with-Morquio-A-ortho

Patients with MPS have a high perisurgical mortality rate due to multiple factors, including upper and lower airway obstruction, cervical spinal instability, respiratory impairment, cardiovascular morbidities and frequent infections.1,3,4 For example, surgical complications resulted in an 11% mortality rate in patients with Morquio A (n=27).5

Imaging modality selection for evaluation of spinal involvement is critical; a table comparing the strengths and limitations of MRI, CT and radiography is presented below the patients with MPS.4

Ortho-procedural-symptom-based-intervention-for-MPS-disorders
  • Specialties represented may include anaesthesiology, pulmonology, neurosurgery, cardiology, ENT and radiology.1,6,7
  • In MPS disorders with neurodegenerative and cognitive implications, additional specialties, such as psychiatry and neurology, may be involved.8
  • In addition to the management guidelines, specialists should consult orthopaedic and surgical guidelines.

Preparing for surgical and anaesthetic risk in patients with MPS requires an experienced, multidisciplinary care team consisting of anaesthesiology, cardiology, pulmonology and otolaryngology specialists.4

Anaesthetic risk factors include the following, outlined in the figure below.

Overview-of-anaesthetic-risk-factors-in-patients-with-MPS-ortho
Learn more about anaesthesia planning

Surgical risk assessment and operative planning are critical

Surgical risk assessment and perioperative monitoring are fundamental components of a tailored surgical plan, and they can reduce the risks of negative surgical outcomes and mortality in patients with MPS.4,10,11

Operative-care-considerations-ortho
anaesthesia-risk-flowchart-ortho
Skeletal and multisystemic complications increase the risk of perioperative morbidity and mortality – guidelines suggest combining surgeries to reduce risk of multiple anaesthetic episodes. Identify risks to lower the likelihood of surgical complications in MPS disorders.10,13

Orthopaedic surgical considerations in MPS14

Orthopaedic manifestation

Considerations

Cervical spine and atlantoaxial instability
  • Surgical indications not well-established
  • Signs/symptoms are indication for treatment (i.e. unsteady gait, upper/lower extremity weakness, dysesthesias and urinary retention)
  • Prophylactic fusion may be considered in an individualised approach
  • For cervical disease with isolated stenosis at the occipitocervical junction, decompression without fusion may be recommended
Gibbus deformity/thoracolumbar kyphosis
  • Progressive curves up to 70 degrees observed
  • Tend to sit below cord level
  • Myelopathy uncommon
  • Progression/myelopathy may warrant fusion
  • Recommend anterior/posterior fusion using combined approach
  • Postoperative bracing for 3 months with instrumentation, 6 months without instrumentation
  • Delay tactics not well defined but should be considered
Hip dysplasia and osteonecrosis
MPS I
  • Abduction bracing has not been studied
  • Surgical management is well described
  • San Diego (i.e. Dega) innominate osteotomy combined with proximal femoral varus osteotomy may be considered

MPS III/IV/VI

  • Limited benefit due to femoral head osteonecrosis
  • May be appropriate with painful subluxation
Genu valgum
  • May develop severe enough genu valgum to require treatment
  • May consider 2-hole growth modulation plates
  • Growth patterns should be taken into consideration when using growth modulation techniques
Carpal tunnel syndrome
  • Common and typically requires carpal nerve release
  • Nerve recovery is more likely with early intervention
  • Open carpal tunnel release with tenosynovectomy and concomitant A1 pulley releases with resection of thickened tendon slips for trigger digits may be considered

Optimise patient outcomes through coordinated management.

It's a new era in management. Stay informed.

References:  1. McGill JJ, Inwood AC, Coman DJ, et al. Enzyme replacement therapy for mucopolysaccharidosis VI from 8 weeks of age—a sibling control study. Clin Genet. 2010;77(5):492-498. doi:10.1111/j.1399-0004.2009.01324.x.  2. Furujo M, Kubo T, Kosuga M, Okuyama T. Enzyme replacement therapy attenuates disease progression in two Japanese siblings with mucopolysaccharidosis type VI. Mol Genet Metab. 2011;104(4):597-602. doi:10.1016/j.ymgme.2011.08.029.  3. Clarke LA. Pathogenesis of skeletal and connective tissue involvement in the mucopolysaccharidoses: glycosaminoglycan storage is merely the instigator. Rheumatology (Oxford). 2011;50(suppl 5):v13-18.  4. Lehman TJA, Miller N, Norquist B, Underhill L, Keutzer J. Diagnosis of the mucopolysaccharidoses. Rheumatology. 2011;50(suppl 5):v41-v48.  5. Morishita K, Petty RE. Musculoskeletal manifestations of mucopolysaccharidoses. Rheumatology. 2011;50(suppl 5):v19-v25. doi:10.1093/rheumatology/ker397.  6. Muenzer J, Beck M, Eng CM, et al. Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome. Genet Med. 2011;13(2):95-101. doi:10.1097/GIM.0b013e3181fea459.  7. Hendriksz C. Improved diagnostic procedures in attenuated mucopolysaccharidosis. Br J Hosp Med. 2011;72(2):91-95.  8. Muenzer J. Early initiation of enzyme replacement therapy for the mucopolysaccharidoses. Mol Genet Metab. 2014;111(2):63-72. doi:10.1016/j.ymgme.2013.11.015.  9. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.  10. Bagewadi S, Roberts J, Mercer J, Jones S, Stephenson J, Wraith JE. Home treatment with Elaprase® and Naglazyme® is safe in patients with mucopolysaccharidoses types II and VI, respectively. J Inherit Metab Dis. 2008;31(6):733-737. doi:10.1007/s10545-008-0980-0.  11. BioMarin Pharmaceutical Inc. VIMIZIM website. http://www.vimizim.com/. Accessed December 21, 2015.  12. BioMarin Pharmaceutical Inc. NAGLAZYME website. http://www.naglazyme.com/. Accessed December 21, 2015.  13. Muenzer J, Wraith JE, Clarke LA, International Consensus Panel on the Management and Treatment of Mucopolysaccharidosis I. Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics. 2009;123(1):19-29. doi:10.1542/peds.2008-0416.

References:  1. Agency for Healthcare Research and Quality. Defining the PCMH. https://pcmh.ahrq.gov/page/defining-pcmh. Accessed December 15, 2015.  2. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr. 2004;144(suppl 5):S27-S34.  3. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.  4. White KK. Orthopaedic aspects of mucopolysaccharidoses. Rheumatology (Oxford). 2011;50(suppl 5):v26-v33. doi:10.1093/rheumatology/ker393.  5. Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):211-219. doi:10.1007/s10545-012-9563-1.  6. Harmatz P, Mengel KE, Giugliani 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(1):54-61. doi:10.1016/j.ymgme.2013.01.021.  7. Muenzer J, Wraith JE, Clarke LA, International Consensus Panel on the Management and Treatment of Mucopolysaccharidosis I. Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics. 2009;123(1):19-29. doi:10.1542/peds.2008-0416.  8. Morishita K, Petty RE. Musculoskeletal manifestations of mucopolysaccharidoses. Rheumatology. 2011;50(suppl 5):v19-v25. doi:10.1093/rheumatology/ker397.  9. Hendriksz C. Improved diagnostic procedures in attenuated mucopolysaccharidosis. Br J Hosp Med. 2011;72(2):91-95.  10. White KK, Sousa T. Mucopolysaccharide disorders in orthopaedic surgery. J Am Acad Orthop Surg. 2013;21:12-22. doi:10.5435/JAAOS-21-01-12.  11. Valayannopoulos V, Wijburg FA. Therapy for the mucopolysaccharidoses. Rheumatology (Oxford). 2011;50 Suppl 5:v49-59. doi:10.1093/rheumatology/ker396.  12. Solanki GA, Martin KW, Theroux MC, et al. Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management. J Inherit Metab Dis. 2013;36(2):339-355. doi:10.1007/s10545-013-9586-2.  13. Spinello CM, Novello LM, Pitino S, et al. Anesthetic management in mucopolysaccharidoses. ISRN Anesthesiol. 2013;2013:1-10. doi:10.1155/2013/791983.  14. Neufeld EF, Muenzer J. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001:3421-3452.  15. Scarpa M, Almassy Z, Beck M, et al. Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease. Orphanet J Rare Dis. 2011;6:72. doi:10.1186/1750-1172-6-72.  16. James A, Hendriksz CJ, Addison O. The oral health needs of children, adolescents and young adults affected by a mucopolysaccharide disorder. JIMD Rep. 2012;2:51-58. doi:10.1007/8904_2011_46.  17. Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage disorders: a review. Biochem Res Int. 2012;2012:471325. doi:10.1155/2012/471325.  18. Kakkis ED, Neufeld EF. The mucopolysaccharidoses. In: Berg BO, ed. Principles of child neurology. New York, NY: McGraw-Hill; 1996:1141-1166.  19. Lehman TJA, Miller N, Norquist B, Underhill L, Keutzer J. Diagnosis of the mucopolysaccharidoses. Rheumatology. 2011;50(suppl 5):v41-v48.

References:  1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.  2. Muenzer J, Beck M, Eng CM, et al. Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome. Genet Med. 2011;13(2):95-101. doi:10.1097/GIM.0b013e3181fea459.  3. Harmatz P, Mengel KE, Giugliani 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(1):54-61. doi:10.1016/j.ymgme.2013.01.021.  4. Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):211-219. doi:10.1007/s10545-012-9563-1.  5. Lavery C, Hendriksz C. Mortality in patients with Morquio syndrome A. J Inherit Metab Dis Rep. 2015;15:59-66. doi:10.1007/8904_2014_298.  6. Theroux MC, Nerker T, Ditro C, Mackenzie WG. Anesthetic care and perioperative complications of children with Morquio syndrome. Paediatr Anaesth. 2012;22(9):901-907. doi:10.1111/j.1460-9592.2012.03904.x.  7. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr. 2004;144(suppl 5):S27-S34.  8. Scarpa M, Almassy Z, Beck M, et al. Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease. Orphanet J Rare Dis. 2011;6:72. doi:10.1186/1750-1172-6-72.  9. Valayannopoulos V, Wijburg FA. Therapy for the mucopolysaccharidoses. Rheumatology (Oxford). 2011;50 Suppl 5:v49-59. doi:10.1093/rheumatology/ker396.  10. Solanki GA, Martin KW, Theroux MC, et al. Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management. J Inherit Metab Dis. 2013;36(2):339-355. doi:10.1007/s10545-013-9586-2.  11. Vitale MG, Skaggs DL, Pace GI, et al. Delphi Consensus Report: Best practices in intraoperative neuromonitoring in spine deformity surgery: development of an intraoperative checklist to optimize response. Spine Deformity. 2014;2(5):333-339. doi:10.1016/j.jspd.2014.05.003.  12. Solanki GA, Alden TD, Burton BK, et al. A multinational, multidisciplinary consensus for the diagnosis and management of spinal cord compression among patients with mucopolysaccharidosis VI. Mol Genet Metab. 2012;107:15-24. doi:10.1016/j.ymgme.2012.07.018.  13. Spinello CM, Novello LM, Pitino S, et al. Anesthetic management in mucopolysaccharidoses. ISRN Anesthesiol. 2013;2013:1-10. doi:10.1155/2013/791983.  14. White KK, Sousa T. Mucopolysaccharide disorders in orthopaedic surgery. J Am Acad Orthop Surg. 2013;21:12-22. doi:10.5435/JAAOS-21-01-12.