Mucopolysaccharidoses

The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by deficiency of the enzymes that degrade glycosaminoglycans (GAGs), formerly called mucopolysaccharides. The undegraded GAG accumulates in tissues, and the result is progressive multisystem disease in which the skeleton is prominently involved. [1]

Pathophysiology. GAGs are complex carbohydrates that form essential components of the connective-tissue matrix: dermatan sulfate, heparan sulfate, keratan sulfate and chondroitin sulfate. When the lysosomal enzyme for a particular GAG is deficient that GAG cannot be broken down and accumulates in lysosomes, causing cellular dysfunction, inflammation and progressive tissue damage. [2]

Epidemiology. The combined incidence of all MPS types is approximately 1:25,000 live births, though this varies by population and type. [1,3] Approximate incidence by type:

• MPS I (Hurler/Scheie): 1:100,000
• MPS II (Hunter): 1:100,000-150,000 (X-linked, males only)
• MPS III (Sanfilippo): 1:70,000 (most common)
• MPS IV (Morquio): 1:75,000-100,000
• MPS VI (Maroteaux-Lamy): 1:250,000
• MPS VII (Sly): very rare, fewer than 1:250,000

Glycosaminoglycans. GAGs are long, unbranched polysaccharide chains of repeating disaccharide units. Attached to core proteins they form proteoglycans, essential components of the extracellular matrix, particularly in cartilage, bone and connective tissue. Each MPS type stores a particular GAG, and the table pairs each GAG with the tissues in which it is found.

How the skeleton is damaged. The pathogenesis of skeletal disease has five components:

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

Cervical instability. Odontoid hypoplasia results from the defective endochondral ossification. Combined with ligamentous laxity from GAG accumulation in the periarticular tissues, this creates atlantoaxial instability: the posterior arch of C1 moves anteriorly relative to C2 and compresses the cervical cord. It is most severe in MPS IV (Morquio syndrome).

Inheritance. MPS I, III, IV, VI and VII are autosomal recessive. MPS II (Hunter syndrome) is the exception: X-linked recessive, so males are affected and females are carriers.

Genetic counselling. For autosomal recessive MPS, carrier parents have a 25% risk of an affected child with each pregnancy. Prenatal diagnosis is available by CVS or amniocentesis for all MPS types, and preimplantation genetic diagnosis is an option for affected families.

Algorithm

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Anaesthetic mortality in MPS is high without precautions, and the work-up applies before any procedure, whatever it is.

Cervical myelopathy. The most serious orthopaedic complication, resulting from atlantoaxial instability, stenosis or both. It presents with weakness, hyperreflexia and gait disturbance, may be sudden (after trauma) or insidious, and requires urgent surgical decompression and fusion.

Anaesthetic complications. Each has a mechanism in the disease and a specific precaution:

Surgical complications. Each region has its own pattern:

• Spinal surgery - nonunion or pseudarthrosis (higher with poor bone quality), hardware failure, neurological deterioration (positioning, decompression), adjacent segment degeneration
• Lower limb surgery - recurrence of deformity (especially genu valgum), hardware prominence, wound healing problems, and the need for repeat procedures
• Upper limb surgery - carpal tunnel recurrence, incomplete release, trigger finger recurrence

Progression despite treatment. The skeletal manifestations continue to progress on disease-modifying therapy: multiple surgical procedures are often required throughout life, and mobility declines despite intervention.

Natural history without treatment. The leading causes of death across the MPS are respiratory failure (restrictive lung disease, sleep apnoea, recurrent infections), cardiac failure (valve disease, cardiomyopathy) and cervical myelopathy, which can cause sudden death from cord compression. Early ERT or HSCT and proactive orthopaedic management have improved survival but do not fully normalise life expectancy.

HSCT for MPS I. Cognitive stabilisation is best when transplant is early. Aldenhoven's 217-patient international cohort found younger age at transplant, preserved cognition before HCT and a normal post-transplant alpha-L-iduronidase level to be the predictors of superior outcome; the widely used "before age 2" cut-off comes from the Muenzer consensus guideline rather than from a measured threshold, and Aldenhoven's relationship with age is continuous. Donor choice matters, because a noncarrier donor with complete chimerism is what yields a normal enzyme level, and it gave the best multisystem result.

Somatic disease continues after transplant. This is the finding to carry from Aldenhoven: considerable residual disease burden persisted in the majority of successfully engrafted patients, with skeletal and cardiac manifestations prominent. Transplant is disease-modifying, not curative, and orthopaedic surveillance continues for life.

ERT outcomes. In the pivotal Morquio A trial, weekly elosulfase alfa gained an estimated 22.5 m over placebo at 24 weeks on the 6-minute walk test (95% CI 4.0-40.9, P=0.017). Keep that figure beside the natural-history spread, MorCAP's baseline 6MWT of 212.6 m with an SD of 152.2 m, and the treatment effect is small relative to the variation between patients. The every-other-week regimen showed nothing (0.5 m, P=0.954), and the 3-minute stair-climb test did not improve on either regimen. Urinary keratan sulfate falls on treatment, and reduced hepatosplenomegaly and some pulmonary benefit are reported in the MPS I and II literature; the limited skeletal benefit and the blood-brain barrier are why HSCT rather than ERT is the option that can preserve CNS function in severe MPS I.

Surgical outcomes: what is measured. Where a real number exists it is given with its source; where it does not, the statement is qualitative, because no MPS-specific series supports a round percentage for cervical fusion rate, hardware revision or carpal tunnel recurrence. MPS anatomy and airway plausibly make these outcomes worse than the general paediatric figures, not better, so borrowing a general rate would understate the risk.

Cervical fusion. Fusion is generally achieved, but the construct is technically demanding in hypoplastic, GAG-laden bone with a small posterior arch. Neurological stabilisation, rather than recovery of lost function, is the realistic goal, which is the argument for operating before fixed myelopathy. Hardware problems and revision are recognised; no MPS-specific revision rate is established.

Genu valgum correction. Guided growth is effective, with measured gains: intermalleolar distance fell 6.12 cm and 6-minute walk distance rose 69.5 m in Cooper's series, the rare instance where a deformity correction in MPS demonstrably improved function. Repeat intervention should be anticipated: 3 of 23 patients needed repeat plating and 1 a femoral osteotomy, and consensus guidance expects further surgery during growth. Osteotomy provides definitive correction at maturity but carries a far greater surgical insult, which in this population can itself reduce mobility.

Carpal tunnel release. Symptom relief is generally good, and because children with MPS are frequently asymptomatic despite severe nerve conduction abnormalities, the indication rests on surveillance testing rather than on complaint. Recurrence is recognised but not quantified in an MPS-specific series; extended release with complete division of the transverse carpal ligament is recommended because of the GAG-laden tissue.

Multidisciplinary care. Specialised MPS clinics coordinate metabolic, surgical, cardiac, respiratory and anaesthetic care, and the Muenzer consensus requires a comprehensive baseline multisystem evaluation with review every 6 to 12 months. Surveillance detects complications earlier; it does not prevent them.

Global Epidemiology:

Combined birth incidence of all MPS types varies markedly by country and ascertainment method. 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.

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, Burton BK, Clarke LA, 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. PMID 24389823. doi:10.1007/s00256-013-1797-y

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, Jester A, Bache CE, Harmatz PR, Shediac R, Thacker MM, Mackenzie WG. Orthopedic management of the extremities in patients with Morquio A syndrome. J Child Orthop. 2014;8(4):295-304. PMID 25001525. doi:10.1007/s11832-014-0601-4

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.

11. Cooper GA, Southorn T, Eastwood DM, Bache CE. Lower extremity deformity management in MPS IVA, Morquio-Brailsford syndrome: preliminary report of hemiepiphysiodesis correction of genu valgum. J Pediatr Orthop. 2016;36(4):376-381. PMID 25887816. doi:10.1097/BPO.0000000000000464

12. Muenzer J, Wraith JE, Clarke LA; International Consensus Panel on Management and Treatment of Mucopolysaccharidosis I. Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics. 2009;123(1):19-29. PMID 19117856. doi:10.1542/peds.2008-0416

Citation note. An earlier version of this reference list carried, as reference 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." No such paper exists. A title search, an author search across this author's complete Morquio bibliography, and a deterministic lookup of the stated journal, year, volume and first page all returned nothing. It has been replaced by the real consensus article on extremity management in Morquio A (reference 9 above). Reference 4 previously gave Lachman's journal as Insights into Imaging 2014;5(5):577-592; the paper is in Skeletal Radiology 2014;43(3):359-369, and the citation has been corrected.