Mucopolysaccharidoses

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.

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]

Pathophysiology: GAGs are complex carbohydrates that form essential components of connective tissue matrix, including dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate. In MPS, deficient lysosomal enzymes cannot break down specific GAGs, leading to accumulation in lysosomes. This causes 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]

Individual MPS Incidence (approximate):

• 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

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

Inheritance Patterns:

• Autosomal recessive: MPS I, III, IV, VI, VII (all except Hunter)
• X-linked recessive: MPS II (Hunter syndrome) - males affected, females are carriers

Genetic Counseling Implications: For autosomal recessive MPS, carrier parents have a 25% risk of affected offspring with each pregnancy. Prenatal diagnosis is available via CVS or amniocentesis for all MPS types. Preimplantation genetic diagnosis is an option for affected families.

Screening and Diagnostic Tests:

Urine GAG Analysis:

• Initial screening test
• Quantitative total GAG and qualitative GAG pattern
• Elevated in most MPS, but can be normal in attenuated forms
• Pattern suggests MPS type (dermatan, heparan, keratan sulfate)

Enzyme Assay:

• Gold standard for diagnosis
• Performed on leukocytes, fibroblasts, or dried blood spots
• Each MPS type has specific enzyme deficiency
• Confirms diagnosis and allows carrier testing

Genetic Testing:

• Identifies specific mutations
• Enables prenatal diagnosis and family screening
• Genotype-phenotype correlation possible for some types

Radiographic Assessment - Dysostosis Multiplex:

Cervical Spine Imaging Protocol:

Plain Radiographs:

• Lateral (neutral, flexion, extension)
• AP and open mouth odontoid views
• Measure atlantodental interval (ADI): greater than 5mm concerning in children

MRI Cervical Spine:

• Gold standard for cord compression assessment
• Indicated if ADI greater than 5mm or neurological symptoms
• Shows soft tissue GAG deposition causing stenosis

CT Cervical Spine:

• Best for bony anatomy - odontoid hypoplasia, os odontoideum
• 3D reconstructions helpful for surgical planning

Additional Investigations:

Differential Diagnosis:

The combination of coarse facies, short stature, joint disease and dysostosis multiplex overlaps with several other storage and skeletal dysplasias. Key discriminators are corneal clouding, intelligence, urine GAG/oligosaccharide pattern and the specific enzyme assay.

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:

Surgical Complications:

Spinal Surgery:

• Nonunion/pseudarthrosis (higher in 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 issues
• Need for repeat procedures

Upper Limb:

• Carpal tunnel recurrence
• Incomplete release
• Trigger finger recurrence

Disease Progression Despite Treatment:

• ERT does not reverse established skeletal disease
• Skeletal manifestations continue to progress
• Multiple surgical procedures often required throughout life
• Mobility decline despite intervention

Natural History Without Treatment:

Impact of Disease-Modifying Therapy:

HSCT for MPS I:

• Survival greater than 90% with current protocols
• Cognitive stabilization if transplanted early (before age 2)
• Somatic disease continues to progress (skeletal, cardiac)
• 10-15 year post-transplant data shows improved survival

ERT Outcomes:

• 6-minute walk test improvement
• Reduced hepatosplenomegaly
• Some pulmonary function improvement
• Limited skeletal benefit - does not reverse deformity

Surgical Outcomes:

Cervical Fusion:

• High fusion rates (greater than 90%) but technical challenges
• Neurological stabilization in most
• Revision rates 10-20% for hardware issues

Genu Valgum Correction:

• Guided growth effective but recurrence common
• Osteotomy provides definitive correction at maturity
• Improves ambulation and quality of life

Carpal Tunnel Release:

• Good outcomes, symptom relief in 90%
• Recurrence rate 5-10%

Multidisciplinary Care Impact:

• Specialized MPS clinics improve outcomes
• Coordinated medical, surgical, and supportive care
• Regular surveillance prevents complications
• Australian centres: Sydney Children's Hospital, Royal Children's Melbourne

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 FRACS/FRCS-style 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 US states and in some Australian state programmes (NSW, Victoria), 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 Australia, enzyme replacement therapy for MPS I (laronidase), II (idursulfase), IVA (elosulfase alfa) and VI (galsulfase) is publicly subsidised through the PBS Life Saving Drugs / high-cost programme; 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.

Australian Context:

Specialist multidisciplinary MPS care in Australia is delivered through paediatric tertiary centres (Sydney Children's Hospitals Network, Royal Children's Hospital Melbourne, Queensland Children's Hospital, Perth Children's Hospital), with paediatric bone-marrow-transplant services and access to international donor registries via the Australian Bone Marrow Donor Registry. Orthopaedic procedures — cervical and thoracolumbar fusion, carpal tunnel release, guided growth and corrective osteotomy — are performed at these centres with metabolic, anaesthetic and genetics input. Patient advocacy and clinical coordination are supported by the MPS Society Australia.

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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.