Mucopolysaccharidoses

The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by deficiency of enzymes required for the degradation of glycosaminoglycans (GAGs), formerly called mucopolysaccharides. Accumulation of GAGs in tissues leads to progressive multisystem disease with prominent skeletal manifestations. [1]

Glycosaminoglycan Metabolism: Glycosaminoglycans are long, unbranched polysaccharide chains composed of repeating disaccharide units. They are attached to core proteins to form proteoglycans, which are essential components of extracellular matrix, particularly in cartilage, bone, and connective tissue.

The Four Main GAGs:

Pathogenesis of Skeletal Disease:

1. Chondrocyte dysfunction - GAG accumulation impairs normal chondrocyte maturation
2. Growth plate disorganization - disrupted columnar arrangement reduces longitudinal growth
3. Abnormal endochondral ossification - leads to short stature and limb deformities
4. Bone matrix abnormalities - irregular mineralization causes osteopenia
5. Ligamentous laxity - accumulated GAGs weaken collagen cross-linking

Cervical Myelopathy:

• Most serious orthopaedic complication
• Results from atlantoaxial instability and/or stenosis
• Presents with weakness, hyperreflexia, gait disturbance
• May be sudden (trauma) or insidious
• Requires urgent surgical decompression and fusion

Anaesthetic Complications:

Natural History Without Treatment:

Global Epidemiology:

Combined birth incidence of all MPS types varies markedly by country and ascertainment method. According to PubMed, the US National MPS Society database (789 patients over 20 years) found an overall MPS birth incidence of 0.98 per 100,000 live births and prevalence of 2.67 per million, with MPS I, II and III having the highest birth incidence (0.26 per 100,000 each) — figures lower than several European series, reflecting under-ascertainment in large, fragmented populations (Puckett et al. Orphanet J Rare Dis 2021, PMID 34051828, DOI). European newborn-screening and registry studies typically report combined incidences of roughly 1 in 25,000 to 1 in 30,000, so the "1 in 25,000" figure quoted in textbooks reflects higher-ascertainment cohorts rather than a single global truth.

International Guidance — Side by Side:

There is no single orthopaedic college guideline for MPS; care is driven by international expert-consensus statements and disease registries. The table contrasts the major sources relevant to orthopaedic practice.

The defining therapeutic evidence is consistent worldwide: weekly elosulfase alfa improves endurance in MPS IVA (Hendriksz, phase 3 RCT) and early HSCT preserves cognition in MPS I-Hurler (Aldenhoven international cohort), but neither reverses established skeletal disease — so orthopaedic surveillance and surgery remain central everywhere regardless of access to disease-modifying therapy.

Registry Evidence:

International disease registries (the MPS VI Clinical Surveillance Programme, the International Morquio Registry / MorCAP, and national MPS Society databases) provide the bulk of natural-history and surgical-outcome data, because randomised surgical trials are impossible in such rare disease. They consistently show near-universal cervical cord compression risk in MPS IVA and VI and progressive multisystem decline.

Practice Variation:

• Newborn screening: MPS I is screened in a growing number of regional newborn-screening programmes, enabling pre-symptomatic HSCT; most countries still rely on clinical diagnosis, delaying the critical pre-age-2 transplant window.
• Access to ERT: Reimbursement differs by jurisdiction. In many high-income settings, enzyme replacement therapy for MPS I (laronidase), II (idursulfase), IVA (elosulfase alfa) and VI (galsulfase) is publicly funded or reimbursed through national high-cost drug programmes; many low- and middle-income countries have no funded access, shifting management entirely onto surveillance and surgery.
• Surgical thresholds: Centres vary in whether borderline atlantoaxial instability is fused prophylactically before major surgery or monitored, reflecting the absence of randomised data.
• Model of care: Specialist multidisciplinary MPS care is delivered through paediatric tertiary centres with metabolic, anaesthetic and genetics input, paediatric bone-marrow-transplant services, and access to international haematopoietic-cell donor registries; orthopaedic procedures (cervical and thoracolumbar fusion, carpal tunnel release, guided growth and corrective osteotomy) are performed at these centres, with patient advocacy and care coordination supported by national MPS societies in many countries.

Mucopolysaccharidoses (MPS) are lysosomal storage disorders with glycosaminoglycan accumulation causing progressive skeletal abnormalities. The hallmark radiographic pattern is dysostosis multiplex: J-shaped sella, paddle ribs, anterior vertebral beaking, and bullet-shaped metacarpals. MPS IV (Morquio syndrome) is unique—normal intelligence but most severe skeletal disease, with 50% having symptomatic atlantoaxial instability due to odontoid hypoplasia. All MPS patients carry significant anaesthetic risks (difficult airway, cervical instability, restrictive lung disease). Enzyme replacement therapy is available for MPS I, II, IVA, and VI but does not cross the blood-brain barrier; HSCT must be performed before age 2 for cognitive benefit in MPS I.

1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, et al. (eds). The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill; 2001:3421-3452.

2. Clarke LA. Pathogenesis of skeletal and connective tissue involvement in the mucopolysaccharidoses: glycosaminoglycan storage is merely the instigator. Rheumatology. 2011;50 Suppl 5:v13-18.

3. Puckett Y, Mallorga-Hernández A, Montaño AM. Epidemiology of mucopolysaccharidoses (MPS) in United States: challenges and opportunities. Orphanet J Rare Dis. 2021;16(1):241.

4. Lachman RS, et al. Mucopolysaccharidosis IVA (Morquio A Syndrome) and VI (Maroteaux-Lamy Syndrome): Under-recognized and Challenging to Diagnose. Insights Imaging. 2014;5(5):577-592.

5. White KK, Harmatz P. Orthopedic management of mucopolysaccharide disease. J Pediatr Rehabil Med. 2010;3(1):47-56.

6. Solanki GA, et al. Cervical cord compression in mucopolysaccharidosis VI (MPS VI): findings from the MPS VI Clinical Surveillance Program (CSP). Mol Genet Metab. 2016;118(4):310-318.

7. Hendriksz CJ, et al. Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study. J Inherit Metab Dis. 2014;37(6):979-990.

8. Aldenhoven M, et al. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood. 2015;125(13):2164-2172.

9. White KK, et al. Analysis of a national MPS IVA registry: clinical characteristics, surgical interventions, and outcomes. J Bone Joint Surg Am. 2019;101(14):1256-1265.

10. Harmatz P, et al. The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013;109(1):54-61.