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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

Neurological involvement in MPS: developmental delay may not always be a distinguishing feature

Neurology plays a critical role in MPS diagnosis

Neurological involvement is common in individuals with mucopolysaccharidosis (MPS) and may constitute some of the first presenting symptoms of disease. It is important for neurology to consider MPS in a variety of presentations, as patterns of neurological involvement vary substantially by MPS subtype. MPS may present with or without intellectual disability and, for some subtypes, central nervous system involvement is primarily due to cervical spinal subluxation and cord compression.1-3

Delayed diagnosis can lead to:

  • Severe multisystemic complications5,7
  • Irreversible or end-organ damage7
  • Delayed treatment4
  • Lack of access to disease-specific management, with concomitant increase in risk of surgical mortality7–11
Signs and symptoms are unpredictable and clinically heterogeneous across and within MPS disorders, making diagnosis challenging. Patients may exhibit non-classical and/or classical signs of MPS, as well as rapidly or slowly progressing disease.4–6

Suspect, refer and rule out MPS

Because of emerging knowledge and therapeutic options, neurology has opportunities to positively impact the lives of patients and families living with MPS through early identification, which can enable disease-specific management and access to available therapies. Be aware of signs and symptoms to expedite early intervention.7

Although patients with MPS typically present with a wide range or cluster of symptoms, isolated symptoms may be sufficient to merit referral to a geneticist or metabolic centre.12

Neurological signs and symptoms can vary widely in frequency and disease progression across and within MPS types.1


Along with these common neurological signs and symptoms, the following should also raise your index of suspicion for MPS:1

  • Some MPS disorders lead to intellectual disability and behavioural abnormalities, while others are not associated with these neurological impairments
  • Carpal and tarsal tunnel syndromes represent the most common features of peripheral nervous system impairment
It is important to consider MPS regardless of intellectual disability status.

Take a deeper look at signs and symptoms that should elevate your suspicion of MPS

Presentation and disease progression are unpredictable, multisystemic and variable across and within MPS disorders, making diagnosis challenging.7

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. Become familiar with the diverse signs and symptoms of MPS that may present in your department.4, 7, 9

How else might you see MPS?

Patterns of signs and symptoms should elevate your clinical suspicion of MPS

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 specialty-specific targeted clinical assessments, laboratory findings and patient history. This division is illustrated below.

Signs and symptoms of MPS1,2,4-7,13–25


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.

The following symptom patterns include neurological signs that should trigger a high index of suspicion for MPS:

  • Global developmental delay along with coarse facial features1,17
  • Cognitive impairment, delayed language development, hyperactive behaviour and sleep disorders1,13
  • Signs of compressive myelopathy (easily tired, frequent falls, paraparesis)
  • Carpal tunnel syndrome1,17

As neurological manifestations may be important presenting signs, neurology can play a key role in identifying individuals with MPS. Appropriate patients should be referred to a geneticist or metabolic centre for definitive diagnosis and, when available, initiation of treatment.12

A more common neurological disorder or MPS?

Patients with MPS often require multiple corrective surgeries and procedures necessitating sedation and/or anaesthesia, which incur significant risk in this population due to airway abnormalities, orthopaedic deformities, and pulmonary, cardiac and neurological involvement.11 Early and accurate diagnosis is essential for proper planning and management of patients.

Many MPS-associated neurological abnormalities are nonspecific and have been described in numerous static and degenerative neurological conditions. Consider MPS when you see:

  • Genetic disease with global developmental delay, coarse facial features and/or organomegaly17
  • Neurodegenerative diseases characterised by cognitive impairment and behaviour disorders1
  • Cervical spinal myelopathy in patients with skeletal dysplasia3

Signal-intensity abnormalities, enlarged perivascular spaces (PVS), ventriculomegaly and hydrocephalus, atrophy and spinal stenosis are prominent neurologic features in almost all types of MPS:1

  • By MRI, the most prominent brain features of MPS are white- and grey-matter changes, ventriculomegaly and hydrocephalus, cortical atrophy, and enlarged PVS1
  • A unique MRI imaging feature described in patients with MPS disorders with primary neurological progression is the ‘‘honeycomb-like” appearance in the basal ganglia and thalami1
  • By MRI, canal stenosis, cord compression and myelopathy are usually present1
As MPS treatment can have a life-changing impact, early and accurate diagnosis is critical. If there is any suspicion of MPS, consider referring to a geneticist or local metabolic centre.12

Read More

Early investigation leads to early intervention.
Avoid delay.

Stay informed about the latest updates and information about MPS.

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