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“MPS disorders have variable presentation and a wide spectrum of severity. They may present as a single organ dysfunction or a common pediatric problem. The condition can be easily missed even amongst the specialists. Without high index of suspicion and detailed work up, they can be missed for years even after surgery.” –Dr Choy Yew Sing

Recognise the possibility – raise your suspicion

In many genetic conditions, diagnostic delay is common due to lack of clinical suspicion

Many patients with mucopolysaccharidosis (MPS) disorders experience significant diagnostic delay because of disease rarity, phenotypic heterogeneity, and a myriad of seemingly unrelated symptoms associated with the disease.1-3 In a recent survey of patients with rare diseases (N=920) sponsored by the Global Genes Project, the mean reported length of time from symptom onset to accurate diagnosis was 4.8 years, with a range of 0 to 20 years.4 Commonly misperceived as musculoskeletal conditions, MPS disorders are a group of inherited enzyme deficiencies that manifest in progressive, multisystemic and life-threatening complications.5–7

The emergence of specific therapies for some MPS disorders has increased the need for accurate and early diagnosis.1,6,8-10 Any delay in diagnosis or treatment may result in:

  • Serious systemic complications11,12
  • Irreversible organ damage12
  • Delay in initiating enzyme replacement therapy (ERT) to address underlying enzyme deficiency2
  • Lack of access to disease-specific management, with concomitant increase in risk of surgical mortality1,6,9,10,13
Since treatment exists for a number of MPS disorders, delay in diagnosis can mean delay in therapy and/or delay in disease-specific management.6,9,10

MPS: hiding in plain sight

Early recognition hinges on early suspicion

MPS disorders are clinically heterogeneous and result in serious complications regardless of the rate of progression, which can range from slowly to rapidly progressing. While rates of progression are gross characterisations of disease severity, patients with slowly progressing disease are also at risk for the serious morbidities and mortality commonly associated with rapidly progressing disease.2,6,14

  • If untreated, many individuals with severe disease do not live far into adulthood (second and third decade)6,15
  • Individuals with slowly progressing disease typically present with symptoms later in life14,16

Patients with MPS can present with classical or non-classical patterns of signs and symptoms.16

  • Classical symptomology may present as more easily recognisable patterns of signs and symptoms that have been extensively documented in literature and in clinical practice16
  • Non-classical symptomology may present more subtly – without the distinct facial features, short stature or obvious musculoskeletal involvement of classical forms of MPS – making this phenotype more difficult to distinguish from other, more common skeletal or metabolic disorders16
  • As an example, recent research has indicated that approximately 25% of patients with Morquio A syndrome (MPS IVA) present with a non-classical phenotype17
  • overview1.1
    Non-classical patient
  • overview1.2
    Non-classical patient

Slowly progressing disease, and/or non-classical phenotypic appearance, can belie severe clinical course in specific organ progression.18 Regardless of phenotype, symptoms can progress into end organ damage.12

Overt and generally observable signs should pique your suspicion

Regardless of the clinical setting, there may be 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 MPS1,2,5,11,12,16-30


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
  • 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 spaces
  • 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.

As skeletal manifestations are common among individuals with MPS, these disorders may resemble or present as other musculoskeletal conditions.1,10,16 MPS should be considered in a variety of clinical settings, including:16,30

  • Skeletal dysplasia clinics
  • Orthopaedics
  • Paediatric rheumatology
  • Metabolic bone clinics
Cognitive and mental impairment are not hallmark signs of all MPS disorders. Never rule out MPS based on the absence of cognitive/mental impairment.1

Prompt referral and diagnosis is the best chance to improve patients’ lives.1,6 Understand the key clinical hallmarks of MPS and refer suspected patients immediately to a geneticist or metabolic centre for diagnostic testing.1,16,30

Patients with MPS are diverse – discover the full spectrum

In your everyday practice, diverse presentations can complicate patient identification

The best way to accurately diagnose MPS is to refer a patient to a geneticist who is familiar with MPS and knows how to confirm the diagnosis.1,19

You should suspect MPS when confronted by patients who:

  • Exhibit any number or pattern of heterogeneous and seemingly unrelated signs1,19
  • Have high surgical need and burden1,19

When you suspect MPS, refer immediately to a geneticist or metabolic centre.1,19

Early identification relies on seeing the full clinical picture and knowing the key clinical hallmarks of MPS.1,2,6,10,19

Discover the pathology behind the presentation

MPS is a category of lysosomal storage disorders. There are 11 identified MPS disorders with varying average ages of onset, which may not correlate to age of diagnosis. Each one is caused by a deficiency of a lysosomal enzyme.1,2,6,10,19

MPS disorders exhibit similar pathologies and mechanisms, regardless of the specific enzyme deficiency:1,6

  • Lysosomal enzymes break down glycosaminoglycans (GAGs)1,6
  • Accumulation of GAGs throughout the body causes progressive damage manifesting in a range of multisystemic consequences1,6

As an example, the video below illustrates the mechanism of disease for Morquio A (MPS IVA).

Optimise outcomes – change the clinical course for your patients

An optimal care-delivery model for MPS disorders

Decades of disease and therapeutic research and practice have culminated in new approaches to clinical management of MPS disorders. At the centre of today’s new era of management is – a coordinated, multidisciplinary care-delivery model.6,34-35

The unique risks and needs associated with these multisystemic, complex conditions are best addressed by coordinating ERT (if available) with the care-delivery model, creating three pillars of care.2,6,8,36-38

As the management paradigm continues to evolve, changes in best practices and strategies continue to show greater promise for the patients and families affected by the disorders.8,34

Prompt referral for diagnosis is essential to optimise care for patients with MPS.1,2,6

Read More

Early investigation leads to early intervention.
Avoid delay.

Stay informed about the latest updates and information about MPS.

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Mesolella M et al. Management of otolaryngological manifestations in mucopolysaccharidoses: our experience. Acta Otorhinolaryngol Ital 2013;33(4):267–272.  28. Martins AM et al. Guidelines for the management of mucopolysaccharidosis type I. J Pediatr 2009;155(4)(suppl 2):S32–S46.   29. Kakkis ED, Neufeld EF. The mucopolysaccharidoses. In: Berg BO, ed. Principles of child neurology. New York, NY: McGraw-Hill; 1996:1141–1166. 30. Wood TC et al. Diagnosing mucopolysaccharidosis IVA. J Inherit Metab Dis 2013;36(2):293–307.   31. Data on file. Biomarin Pharmaceutical, Inc.  32. Drummond JC et al. Paraplegia after epidural-general anesthesia in a Morquio patient with moderate thoracic spinal stenosis. Can J Anesth 2015;62(1):45–49.   33. Sharkia R et al. Sanfilippo type A: new clinical manifestations and neuro-imaging findings in patients from the same family in Israel: a case report. J Med Case Rep 2014;8:78.   34. Kakkis ED. 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