Back to Top

“We hope that when the paediatrician sees the physical findings, and if the radiologist gets some X-rays, [that] they can say that these vertebrae don’t look normal [and] we need to send this child to the geneticist.” – Dr. Paul Harmatz

Early diagnosis and treatment is critical for patients with MPS

Genetics is essential to diagnosis and long-term management of MPS

More than half a century of research, clinical experience and medical breakthroughs are culminating in a new era of multidisciplinary management and therapies for patients diagnosed with mucopolysaccharidosis (MPS) disorders. Early diagnosis is more important than ever to assure patients can benefit from advances in therapeutic care and disease-specific management.1

  • Age at diagnosis for patients with MPS ranges from 6 months old to decades

MPS disorders are a group of serious, progressive, genetically inherited, heterogeneously expressed enzyme deficiencies.3–5 MPS disorders are types of lysosomal storage disorders; patients are affected on a cellular level and have multisystemic clinical presentations.1,4,6

Variability in presentation and clinical course across the MPS disorders and within each type can significantly delay diagnosis.1 Factors that impact recognition and diagnosis include:7

  • Age of onset
  • Organ system involvement
  • Rate of disease progression
Patients with MPS may have significant delays in diagnosis, which can dramatically alter patient outcomes.2

Early diagnosis hinges on early recognition

Patients with slowly progressing MPS can easily remain undiagnosed familiarity with the full clinical spectrum is key to early and accurate diagnosis

Regardless of the clinical setting, there are overt and generally observable signs that should raise your suspicion. Upon further examination, additional symptomatology may be discovered through speciality-specific targeted clinical assessments, laboratory findings and patient history. This division is illustrated below.

Signs and symptoms of MPS1–4,8–22

Musculoskeletal

General features

  • Abnormal gait
  • Bone dysplasia
  • Claw hands
  • Coarse facial features
  • Joint pain
  • Macrocephaly
  • Pectus carinatum
  • Reduced endurance/exercise intolerance
  • Short stature/growth retardationa

Features revealed by speciality-specific assessment

  • Abnormal gait
  • Bone deformities
  • Dysostosis multiplex
  • Genu valgum
  • Joint involvement (contractures, joint laxity) without inflammation
  • Spinal subluxation
Rheumatological

General features

  • Decreased joint mobility
  • Hip stiffness and pain
  • Joint pain
  • Joint stiffness or laxity

Features revealed by speciality-specific assessment

  • Carpal tunnel syndrome
  • Joint involvement without joint swelling or erosive bone lesions
Ear, nose and throat

General features

  • Conductive and/or sensorineural hearing loss
  • Enlarged tongue
  • Recurrent otitis media

Features revealed by speciality-specific assessment

  • Abnormal epiglottis
  • Depressed nasal bridge
  • Hypertrophic adenoids
  • Hypertrophic tonsils
  • Middle ear mucus
  • Narrowing of supraglottic and infraglottic airway
  • Ossicular malformation
  • Recurrent and excessive rhinorrhea
  • Recurrent otitis media
  • Tracheal thickening/compression
  • Tubular obstruction
  • Tympanic membrane thickening
Ophthalmological

General features

  • Cataracts
  • Diffuse corneal clouding
  • Glaucoma

Features revealed by speciality-specific assessment

  • Amblyopia
  • Corneal clouding with characteristic ‘ground glass’ appearance
  • High hyperopia
  • Hypertelorism
  • Optic nerve abnormalities (swelling and atrophy)
  • Peripheral vascularisation of the cornea
  • Progressive pseudo-exophthalmos
  • Reduction in visual acuity
  • Retinopathy
  • Strabismus
Neurological

General features

  • Behavioural abnormalities (typically not present in MPS IVA and VI)
  • Developmental delay (typically not present in MPS IVA and VI)
  • Hearing impairment
  • Seizures (typically not present in MPS IVA and VI)

Features revealed by speciality-specific assessment

  • Arachnoid cysts (typically not present in MPS IVA and VI)
  • Brain atrophy (typically not present in MPS IVA and VI)
  • Carpal tunnel syndrome
  • Cervical cord compression/myelopathy/subluxation
  • Enlarged perivascular space
  • Hydrocephalus
  • Odontoid dysplasia
  • Pachymeningitis cervicalis
  • Papilledema/optic atrophy
  • Sensorineural deafness
  • Signal-intensity abnormalities
  • Spinal canal stenosis
  • Ventriculomegaly
Cardiovascular

General features

  • Reduced endurance/exercise intolerance

Features revealed by speciality-specific assessment

  • Pulmonary hypertension
  • Thickened, regurgitant, or stenotic mitral or aortic valves in presence of left ventricular hypertrophy
  • Tricuspid regurgitation
Pulmonary

General features

  • Reduced endurance/exercise intolerance
  • Sleep apnoea

Features revealed by speciality-specific assessment

  • Obstructed upper and lower airways (bronchial narrowing, narrowing of supraglottic and infraglottic airway)
  • Progressive reduction in lung volume
  • Respiratory infections
  • Sleep disorders (obstructive sleep apnoea/hypopnoea syndrome and upper airway resistance syndrome)
Gastrointestinal

General features

  • Abdominal pain
  • Constipation
  • Hepatosplenomegaly
  • Hernias
  • Loose stools

Features revealed by speciality-specific assessment

  • Hepatosplenomegaly
Dental

General features

  • Abnormal buccal surfaces
  • Dentinogenesis imperfecta
  • Hypodontia
  • Pointed cusps
  • Spade-shaped incisors
  • Thin enamel

Features revealed by speciality-specific assessment

  • Abnormal buccal surfaces
  • Thin enamel

aSkeletal involvement and short stature may be less overt in some patients.

Take a closer look at the systems affected by MPS

Presentation and disease progression are unpredictable, multisystemic and variable across and within MPS disorders, making diagnosis challenging.1 Delayed diagnosis is common and it can have devastating consequences for your patients. Early identification of signs and symptoms across systems can be critical to early and accurate diagnosis.2 Become familiar with the diverse signs and symptoms of MPS that may present in your department.


Consideration of MPS based on suspicious patterns of signs and symptoms is the first step to arriving at a definitive diagnosis of a specific MPS disorder. Of particular importance, recognition of the heterogeneous nature of slowly progressing disease is essential to reduce time to diagnosis for many patients.9

Growth impairment

Growth-comparison-between-patients-with-rapidly-progressing-MPS-VI- and-unaffected-age-adjusted-peers

Joint involvement without inflammation

Join--involvement

In MPS, even when the pattern is different, the risks are the same

Recognising slowly progressing and non-classical MPS is essential to reduce time to diagnosis8

In MPS, physical phenotype can belie rapid organ progression8

  • Patients with a slowly progressing or non-classical phenotype can have early, and sometimes fatal, organ involvement8
  • Recognising slowly progressing or non-classical MPS can enable early intervention and help improve outcomes.8

Slowly progressing or non-classical MPS should be considered when patients present with any of the following:

  • Skeletal dysplasia with evidence of systemic involvement8
  • Spondyloepiphyseal dysplasia8
  • Multiple epiphyseal dysplasia8
  • Legg-Calvé-Perthes disease8
  • Joint abnormalities without evidence of inflammation1

Differentiating enzyme deficiency and pathophysiology

The genetic and pathophysiological causes of MPS are diverse, although the symptoms are often shared

The common biochemical hallmark of MPS disorders is accumulation of lysosomal enzyme substrates.4,6,24 There are currently 11 enzyme deficiencies known to cause MPS.4,24,25 The pathophysiology of each MPS subtype is specific to:

  • The site of production and degradation of the specific enzyme substrates24,25
  • The individual patient’s degree of residual enzyme activity4,25
Major-musculoskeletal-manifestations-of-MPS-by-type-of-disorder-01_AMc

Accurate determination of an MPS disorder has never been more important

Early discernment of specific enzyme deficiencies and resulting definitive diagnosis can lead to early intervention if enzyme replacement therapy (ERT) is available.2,24,25 Even when ERT is not available, disease-specific management can optimise patient outcomes.2 When MPS is suspected, a comprehensive enzyme panel is warranted.1 Detection of enzyme deficiencies relies on the measurement of enzyme activity in fibroblasts or leukocytes, which is the recommended method for confirming diagnosis.26 A comprehensive overview of the path to diagnosis of MPS VI is outlined below.

Diagnostic testing paradigm in MPS VI

Clinical and/or radiographic suspicion of MPS VI
Discuss testing with family

Select a screening option

  • DBS testing may be used in screening; current gold standard for diagnosis is leukocyte or fibroblast samples
  • Multiplex assays to screen for multiple lysosomal disorders are now available
  • Measurement of multiple enzymes required to rule out multiple enzyme deficiencies and lysosomal trafficking problems
  • Reference lysosomal enzyme should be assayed at same time to confirm sample integrity
  • Minimise blood sample shipment times; next-day arrival is recommended
  • When ASB activity is low, a second sulphatase must be measured to rule out multiple sulphatase deficiency

Diagnostic test for MPS VI

ASB activity measurement in leukocyte or fibroblast samples (gold standard)
  • Low ASB activity
  • Reference lysosomal enzyme should be assayed at same time to confirm sample integrity
  • When ASB activity is low, a second sulphatase must be measured to rule out multiple sulphatase deficiency
  • If using a fibroblast sample, a mannose 6-phosphate-guided reference enzyme must be measured to rule out I-cell disease

Additional testing options

  • Confirmation of low ASB enzyme activity by repeat measurement on separate sample or tissue

A basic algorithm depicting the tests that can be used for diagnostic confirmation of Morquio A (MPS IVA) is shown below.

Diagnostic algorithm for Morquio A27

Diagnostic-algorithm

Enzyme panels to test for low activity across all 11 enzymes are available. This methodology can quickly and accurately assess enzymatic activity for key enzymes across multiple MPS and lysosomal storage disorders.1,26

Read More

If you suspect MPS and need to understand how to access testing resources, locate treatment facilities, or refer for more specialised care, contact BioMarin for more details.

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

References:  1. Lehman TJA et al. Diagnosis of the mucopolysaccharidoses. Rheumatology 2011;50(suppl 5):v41–v48.  2. Hendriksz C. Improved diagnostic procedures in attenuated mucopolysaccharidosis. Br J Hosp Med 2011;72(2):91–95.  3. Clarke LA et al. Biomarkers for the mucopolysaccharidoses: discovery and clinical utility. Mol Genet Metab 2012;106(4):396–402.   4. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr 2004;144(suppl 5):S27–S34.  5. Muenzer J. Early initiation of enzyme replacement therapy for the mucopolysaccharidoses. Mol Genet Metab 2014;111(2):63–72.   6.Muenzer J. Overview of the mucopolysaccheridoses. Rheumatology 2011;50:v4–v12.   7. Valayannopoulos V et al. Mucopolysaccharidosis VI. Orphanet J Rare Dis 2010;5:5.   8. Lachman RS et al. Mucopolysaccharidosis IVA (Morquio A syndrome) and VI (Maroteaux-Lamy syndrome): under-recognized and challenging to diagnose. Skeletal Radiol 2014;43(3):359–369.   9. Thümler A et al. Clinical characteristics of adults with slowly progressing mucopolysaccharidosis VI: a case series. J Inherit Metab Dis 2012;35(6):1071–1079.   10. Montaño AM et al. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis 2007;30(2):165–174.   11. Kinirons MJ et al. Dental findings in mucopolysaccharidosis type IV A (Morquio’s disease type A). Oral Surg Oral Med Oral Pathol 1990;70(2):176–179.  12. Hendriksz CJ et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A 2014;9999A:1–15.   13. Lachman R et al. Radiologic and neuroradiologic findings in the mucopolysaccharidoses. J Pediatr Rehabil Med 2010;3(2):109–118.   14. Cimaz R et al. Joint contractures in the absence of inflammation may indicate mucopolysaccharidosis [hypothesis]. Pediatr Rheumatol Online J 2009;7:18.   15. Fahnehjelm KT et al. Clinical guidelines for diagnosing and managing ocular manifestations in children with mucopolysaccharidosis. Acta Ophthalmol 2012;90(7):595–602.   16. Zafeiriou DI et al. Brain and spinal MR imaging findings in mucopolysaccharidoses: a review. AJNR Am J Neuroradiol 2013;34(1):5–13.   17. Braunlin EA et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis 2011;34(6):1183-1197.   18. Braunlin E et al. Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review. Cardiovasc Pathol 2014;23(3):145–151.   19. Mesolella M et al. Management of otolaryngological manifestations in mucopolysaccharidoses: our experience. Acta Otorhinolaryngol Ital 2013;33(4):267–272.  20. Berger KI et al. Respiratory and sleep disorders in mucopolysaccharidosis. J Inherit Metab Dis 2013;36(2):201–210.  21. Martins AM et al. Guidelines for the management of mucopolysaccharidosis type I. J Pediatr 2009;155(4)(suppl 2):S32–S46.   22.Kakkis ED et al. The mucopolysaccharidoses. In: Berg BO, ed. Principles of child neurology. New York, NY: McGraw-Hill; 1996:1141–1166.  23. Quartel A et al. Growth charts for individuals with mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome). JIMD 2015;18:1–11.   24. Coutinho MF et al. Glycosaminoglycan storage disorders: a review. Biochem Res Int 2012;2012:471325.   25. Filocamo M, Morrone A. Lysosomal storage disorders: molecular basis and laboratory testing. Hum Genomics 2011;5(3):156–169.   26. Wood T et al. Expert recommendations for the laboratory diagnosis of MPS VI. Mol Genet Metab 2012;106(1):73–82.   27. Data on file. Biomarin Pharmaceutical, Inc.