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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

Cardiac involvement: common, severe and under-recognised in MPS

Cardiology plays a critical role in MPS diagnosis

Cardiac involvement is commonly seen in individuals with mucopolysaccharidosis (MPS) and leads to extensive morbidity and, potentially, premature mortality.1 Early suspicion is therefore critical, regardless of whether cardiac symptoms are seen alone or in combination with other symptoms. Patients with MPS disorders, especially those with MPS I, II, and VI, suffer from a high prevalence of cardiac disease, with a rate of approximately 60% to 100%.1,2 Cardiac manifestations are often a predominant feature of the disease and frequently occur early.1

Delayed diagnosis can lead to:

  • Severe multisystemic complications6–8
  • Irreversible or end-organ damage8
  • Delayed treatment9
  • Lack of access to disease-specific management, with concomitant increase in risk of surgical mortality3,10–13
Signs and symptoms are unpredictable and clinically heterogeneous across and within MPS disorders, making diagnosis challenging.3,4 Typically, patients present with either rapidly or slowly progressing disease, although symptom progression can be highly variable across this spectrum.4,5

Suspect, refer and rule out MPS

Because of emerging knowledge and therapeutic options, cardiology 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.3,10 Be aware of signs and symptoms to expedite early intervention.3,12

Cardiac involvement is uniformly progressive, with incidence and severity increasing over time.1 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.4,14
Common-cardiac-symptoms-from-echocardiographic-evaluation-AMc

Along with the preceding common cardiac signs, the following signs should raise your index of suspicion for MPS:

  • Severe cardiac disease presentation, particularly early in life1,16
  • Presence of broad, thickened, paddle-shaped ribs as shown by chest X-ray17
  • Older patients who present with cardiac signs and symptoms, whether alone or in combination with other MPS symptoms9
  • overview1.1
    Mitral valve involvement in a patient with MPS at 6 months.15
  • overview1.2
    Mitral valve involvement in a patient with MPS at 6 months.15
  • overview1.2
    Aortic valve involvement, with valve leaflet retraction.15
  • overview1.2
    Aortic valve involvement, with valve leaflet retraction.15
  • overview1.2
    Pseudohypertrophy of the intraventricular septum in a patient with MPS.15

Take a deep dive into 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.3

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.9,11 Become familiar with the diverse signs and symptoms of MPS that may present in your department.

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

Signs and symptoms of MPS1,3,4,6,9,17–30

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.

Cardiology can play a key role in identifying individuals with MPS, and appropriate patients should be referred to a geneticist or metabolic centre for definitive diagnosis and, when available, initiation of treatment.14

A more common cardiac disorder or MPS?

MPS disorders can mimic, and thus be confused with, cardiac conditions.32 Because 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 centre3,9,32

Differential-diagnoses-to-rule-out-MPS-54_AMc

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Early investigation leads to early intervention.
Avoid delay.

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

References:  1. Braunlin EA et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis 2011;34(6):1183–1197.   2. Fesslová V et al. The natural course and the impact of therapies of cardiac involvement in the mucopolysaccharidoses. Cardiol Young 2009;19(2):170–178.   3. Lehman TJA et al. Diagnosis of the mucopolysaccharidoses. Rheumatology 2011;50(suppl 5):v41–v48.  4. Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr 2004;144(suppl 5):S27-S34.  5. Lampe C. Attenuated mucopolysaccharidosis: are you missing this debilitating condition? Rheumatology (Oxford) 2012;51(3):401–402.   6. 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.   7. Northover H et al. Mucopolysaccharidosis type IVA (Morquio syndrome): a clinical review. J Inherit Metab Dis 1996;19(3):357–365.  8. Tomatsu S et al. Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment: a special review. Curr Pharm Biotechnol 2011;12(6):931–945.   9. Hendriksz C. Improved diagnostic procedures in attenuated mucopolysaccharidosis. Br J Hosp Med 2011;72(2):91–95.  10. Clarke LA. Pathogenesis of skeletal and connective tissue involvement in the mucopolysaccharidoses: glycosaminoglycan storage is merely the instigator. Rheumatology (Oxford) 2011;50(suppl 5):v13–18.   11. Morishita K, Petty RE. Musculoskeletal manifestations of mucopolysaccharidoses. Rheumatology 2011;50(suppl 5):v19–v25.   12. Muenzer J, Beck M, Eng CM, et al.Genet Med. 2011;13(2):95–101. doi:10.1097/GIM.0b013e3181fea459.  13. Spinello CM, Novello LM et al. Anesthetic management in mucopolysaccharidoses. ISRN Anesthesiol 2013;2013:1–10.   14. Wood TC et al. Diagnosing mucopolysaccharidosis IVA. J Inherit Metab Dis 2013;36(2):293–307.   15. Data on file. Biomarin Pharmaceutical, Inc.  16. Mohan UR et al. Cardiovascular changes in children with mucopolysaccharide disorders. Acta Paediatr 2002;91(7):799–804.  17. Lachman R et al. Radiologic and neuroradiologic findings in the mucopolysaccharidoses. J Pediatr Rehabil Med 2010;3(2):109–118.   18. 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.   19. 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.   20. 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.   21. Kinirons MJ, Nelson J. Dental findings in mucopolysaccharidosis type IV A (Morquio’s disease type A). Oral Surg Oral Med Oral Pathol 1990;70(2):176–179.  22. Cimaz R et al. Joint contractures in the absence of inflammation may indicate mucopolysaccharidosis [hypothesis]. Pediatr Rheumatol Online J 2009;7:18.   23. Fahnehjelm KT et al. Clinical guidelines for diagnosing and managing ocular manifestations in children with mucopolysaccharidosis. Acta Ophthalmol 2012;90(7):595–602.   24. Zafeiriou DI, Batzios SP. Brain and spinal MR imaging findings in mucopolysaccharidoses: a review. AJNR Am J Neuroradiol. 2013;34(1):5–13.   25. Braunlin E et al. Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review. Cardiovasc Pathol 2014;23(3):145–151.   26. Mesolella M et al. Management of otolaryngological manifestations in mucopolysaccharidoses: our experience. Acta Otorhinolaryngol Ital 2013;33(4):267–272.  27. Berger KI et al. Respiratory and sleep disorders in mucopolysaccharidosis. J Inherit Metab Dis 2013;36(2):201–210.   28. Martins AM et al. Guidelines for the management of mucopolysaccharidosis type I. J Pediatr 2009;155(4)(suppl 2):S32–S46.   29. Clarke LA et al. Biomarkers for the mucopolysaccharidoses: discovery and clinical utility. Mol Genet Metab 2012;106(4):396–402.   30. Kakkis ED et al. The mucopolysaccharidoses. In: Berg BO, ed. Principles of child neurology. New York, NY: McGraw-Hill; 1996:1141–1166.. 31. Maganti K et al. Valvular heart disease: diagnosis and management. Mayo Clin Proc 2010;85(5):483–500.   32. Muenzer J. Early initiation of enzyme replacement therapy for the mucopolysaccharidoses. Mol Genet Metab 2014;111(2):63–72.   33. 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.   34. 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.