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

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 VI8,9
  • 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 consideration10,12
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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 medical home.1

Geneticists and/or metabolic specialists are typically at the centre and help to coordinate multidisciplinary care and an individualised management plan.2,3

Neurologists play a critical role in multidisciplinary coordinated care. Brain and spinal involvement are often prominent features of the disease, and some manifestations can be addressed with surgical intervention.3–6

Signs and symptoms can vary widely in frequency and disease progression across and within MPS subtypes, making continued neurological assessment a key component to effective management of these patients.3–6

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
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Many MPS disorders have available management guidelines and
speciality-specific consensus recommendations regarding lifelong management of MPS. Guidelines typically recommend the following:3,7

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

For neurologists managing patients with MPS, an understanding of the exact neurological involvement associated with a patient’s specific MPS subtype can inform management approaches.2

  • In some MPS disorders, for example, enzyme deficiency leads to direct accumulation of lysosomal substrates within the central and peripheral neural systems6
  • Depending on subtype, intellectual disability may or may not be a factor
  • For some subtypes, central nervous system involvement is primarily due to cervical spinal subluxation and cord compression6
  • Neurological effects can also occur secondary to other symptoms of disease6

Common neurological features of MPS by subtype are outlined below.

Common-neurological-features-of-MPS-by-subtype

Neurological assessment goals and schedules are outlined in expert reviews and management guidelines

A number of expert reviews are available that present state‐of‐the‐art practices in the assessment and monitoring of brain and spinal abnormalities in patients with MPS.3–5,8 Many MPS disorders also have available management guidelines and neurology‐specific consensus recommendations regarding chronic care.3,7,9

The reviews and guidelines include the following overarching recommendations:

  • A comprehensive baseline neurological assessment
  • Regular, defined monitoring intervals to assess neurologic disease progression

The goals of these neurological assessments in patients with MPS include:4,5,8

  • Identify treatable spinal cord compression
  • Stratify risk to the spinal cord prior to permanent loss of function
  • Assist in surgical planning
  • Assess the efficacy of surgical and medical treatment
  • Monitor and assess disease progression

As an example, the tables below detail suggested schedules for general and spinal-specific neurological evaluation of patients with Morquio A (MPS IVA), an MPS subtype with predominant spinal abnormalities.

While these tables provide an illustrative example of monitoring schedules, frequency of assessment varies across different MPS subtypes. For patients with MPS diseases associated with primary neurodegenerative and cognitive complications (e.g. MPS I, II, III), management guidelines call for additional and regular neurobehavioural and psychiatric evaluations.7,10

A number of assessment modalities are available

As seen above, neurological examination, as well as brain and spinal imaging, are cornerstones of neurological assessment in patients with MPS.3,5,8

  • Imaging methodologies (plain radiograph, MRI, CT scan) are especially valuable for identifying and monitoring neurological abnormalities in these patients5
  • Selection of the appropriate imaging modality for assessment of spinal abnormalities should be guided by the strengths and limitations of each modality as detailed below5
  • MRI is generally considered the preferred imaging modality4,5

Common brain and spinal MRI findings according to MPS subtype are summarised below.

Common-brain-and-spinal-MRI-abnormalities-seen-in-patients-with-MPS

Spinal assessment is imperative

Initial and continued spinal imaging is critical for patients with MPS, as spinal abnormalities account for a high proportion of neurological manifestations and can lead to paraplegia, quadriparesis, and death.4 In Morquio A and MPS VI especially, spinal abnormalities are some of the most prominent features of neurological disease and frequently require surgical intervention.4–6

Comprehensive risk assessment and stratification for spinal abnormalities in MPS generally consists of:5

  • Systematic and careful imaging of the spine by CT instability imaging
  • Imaging of the spinal cord by MRI
  • Clinical and physiologic assessment

Spinal MRI features most commonly associated with MPS include these vertebral/disc abnormalities and craniocervical junction abnormalities:4

  • Spinal stenosis
  • Compressive myelopathy
  • Odontoid dysplasia
  • Atlantoaxial instability
  • Dural thickening

Brain imaging is also critical

Brain imaging by MRI is another key component of initial patient assessment and ongoing monitoring. The majority of MPS subtypes (I, II, III, VII) are associated with MRI abnormalities consistent with progressive and primary neurological etiology.4,8

In patients with MPS disorders with primary neurological progression, the following are the most common MRI features in the brain:4,6

  • White and grey matter signal‐intensity abnormalities
  • Cystic lesions that correspond to enlargement of Virchow‐Robin perivascular spaces
  • Hydrocephalus
  • Ventricular enlargement
  • Enlarged subarachnoid spaces
  • Brain atrophy
  • Posterior fossa abnormalities

Of note, a unique MRI feature described in patients with MPS disorders with primary neurological progression is the ‘honeycomb‐like’ appearance in the basal ganglia and thalami.4 Additional MRI features have been described in multiple case reports across MPS disorders, although these are much less frequently observed.

MRI scoring systems are helping to standardise monitoring and evaluation of patients with MPS

Existing MRI scoring systems for both spinal cord and brain disease in MPS are intended to standardise procedures for evaluating and monitoring neuroimaging alterations in patients with MPS so that proper treatment can be offered before irreversible damage occurs. These scoring systems are detailed in the tables below.8

Scoring-severity-of-brain-MRI-findings

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 neurobehavioral and psychiatric evaluations are recommended.7,10,11

In addition to speciality-specific assessments that should be done to facilitate positive long-term outcomes for patients with MPS, important steps can be taken by the coordinating physician, 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:

  • 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 disease12
    • 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 infections3

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

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 physician-guided transition to the adult setting critical.3 Physicians 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’ ability 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.2 Long-term care considerations are ideally best addressed in a centre with significant MPS experience, and they require careful coordination across specialities.3,13 Long-term issues include but are not limited to the following:

  • Best practices in adult-care transition
  • Gynaecological considerations
    • Pregnancy- and maternity-related issues
    • Enzyme replacement therapy 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.3,6,13

Procedural care requires coordinated surgical planning across specialities

Because clinical manifestations of mucopolysaccharidosis (MPS) disorders are multisystemic, a patient-specific, multidisciplinary approach is required to proactively recognise and manage complications. The involvement of a neurologist in this process is key, as surgical management of spinal complications (e.g. cervical fusion and/or decompression) is often necessary.1

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.2

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

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.2-4 For example, surgical complications resulted in an 11% mortality rate in patients with Morquio A (n=27).5

Creating a surgical plan is crucial and involves a multidisciplinary team of specialists who are, ideally, also experienced in treating patients with MPS.3

  • Specialities represented may include anaesthesiology, pulmonology, neurosurgery, cardiology, ENT, and radiology4,6,7
  • In MPS disorders with neurodegenerative and cognitive implications, additional specialities, such as psychiatry and neurology, may be involved8
  • In addition to the management guidelines, specialists should consult orthopaedic and surgical guidelines

Neurology-specific procedural care often includes surgical management of spinal complications. The overall goals of spinal surgery in patients with MPS include the following:1

  • Protect the spinal cord
  • Relieve neural compression
  • Eliminate instability
  • Reduce deformity or malalignment
  • Relieve pain

Additional neurology-specific procedural interventions are presented below.

clinical-neurological-manifestations-and-associated-surgical-interventions

Indications for spinal surgery include the development of pathological reflexes and neurological deficits on neurological examination with instability, or cord compression with signal change on magnetic resonance imaging (even without symptoms).1

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.1,3,11

Operative-care-considerations-neuro
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.1,10

Optimise patient outcomes through coordinated management.

It's a new era in management. Stay informed about the latest updates and information about MPS.

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 mucopolysaccharidosis: 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 mucopolysaccharidosis. Rheumatology. 2011;50(suppl 5):v41–v48.  5. Morishita K, Petty RE. Musculoskeletal manifestations of mucopolysaccharidosis. Rheumatology. 2011;50(suppl 5):v19–v25. doi:10.1093/rheumatology/ker397.  6. Muenzer J, Beck M, Eng CM, et al.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 mucopolysaccharidosis. 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 mucopolysaccharidosis 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 Web site. http://www.vimizim.com/. Accessed December 21, 2015.  12. BioMarin Pharmaceutical Inc. Naglazyme Web site. 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 mucopolysaccharidosis: 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. Zafeiriou DI, Batzios SP. Brain and spinal MR imaging findings in mucopolysaccharidosis: a review. AJNR Am J Neuroradiol. 2013;34(1):5–13. doi:10.3174/ajnr.A2832.  5. 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.  6. Kakkis ED, Neufeld EF. The mucopolysaccharidosis. In: Berg BO, ed. Principles of Child Neurology. New York, NY: McGraw-Hill; 1996:1141–1166.  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. Lachman R, Martin KW, Castro S, Basto MA, Adams A, Teles EL. Radiologic and neuroradiologic findings in the mucopolysaccharidosis. J Pediatr Rehabil Med. 2010;3(2):109–118. doi:10.3233/PRM-2010-0115.  9. Giugliani R, Harmatz P, Wraith JE. Management guidelines for mucopolysaccharidosis VI. Pediatrics. 2007;120:405–418. doi:10.1542/peds.2006–2184.  10. 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.  11. Neufeld EF, Muenzer J. The mucopolysaccharidosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York: McGraw-Hill; 2002:2465–2494.  12. 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.  13. Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage disorders: a review. Biochem Res Int. 2012;2012:471325. doi:10.1155/2012/471325.

References:  1. 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.  2. 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.  3. 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.  4. 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.  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 mucopolysaccharidosis: 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 mucopolysaccharidosis. Rheumatology (Oxford). 2011;50 Suppl 5:v49–59. doi:10.1093/rheumatology/ker396.  10. Spinello CM, Novello LM, Pitino S, et al. Anesthetic management in mucopolysaccharidosis. ISRN Anesthesiol. 2013;2013:1–10. doi:10.1155/2013/791983.  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.