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“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


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

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

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

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

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

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)

General features

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

Features revealed by speciality-specific assessment

  • Hepatosplenomegaly

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


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

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


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.

Stay informed about the latest updates and information about MPS.

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