Mucopolysaccharidoses (MPS)

The mucopolysaccharidoses are a clinically heterogeneous spectrum of progressive multisystem disorders. Age of onset and rate of progression vary substantially across types, with overlapping clinical features. Characteristic findings may emerge in infancy or early childhood, although onset can range from the first months of life in severe forms to later childhood or adolescence in attenuated phenotypes, and include short stature, characteristic facial features, hepatosplenomegaly, joint contractures, recurrent ear and respiratory tract infections, and umbilical hernias.

Skeletal involvement consistently produces dysostosis multiplex on radiographic evaluation, often accompanied by with or without communicating hydrocephalus, macroglossia, hoarse voice, conductive and sensorineural hearing loss, spinal stenosis, and carpal tunnel syndrome. Additional features may include corneal clouding (in several subtypes), recurrent hernias, and progressive joint stiffness. Cardiac and respiratory involvement, including valve thickening and airway obstruction, contributes substantially to morbidity.

Central nervous system involvement and the degree of cognitive decline vary by subtype and correlate with residual enzyme activity, with attenuated phenotypes presenting later in childhood or adolescence with predominantly somatic features and preserved cognition.

The estimated combined birth prevalence is approximately 3.5–5 per 100,000 live births, with substantial geographic variability. Individual subtype prevalence varies widely, with MPS III among the most frequent forms and MPS VII among the rarest.

A large number of genes have been associated with the mucopolysaccharidoses. Different MPS types may predominantly affect the central nervous system (neuronopathic forms), the skeleton (skeletal dysplasias) or present with combined multisystem involvement. Across cohorts, MPS III (Sanfilippo syndrome; genes include SGSH, NAGLU, HGSNAT, and GNS; characterised by heparan sulphate accumulation with progressive central nervous system deterioration) and MPS I (Hurler/Scheie; IDUA; α-L-iduronidase deficiency with multisystem involvement) are most prevalent; MPS IVA (Morquio A; GALNS; keratan sulphate accumulation with severe skeletal dysplasia) represents skeletal forms.

The genetic conditions associated with the mucopolysaccharidoses follow heterogeneous inheritance patterns. Most types, including MPS I, MPS III, MPS IVA, MPS VI, and MPS VII, are inherited in an autosomal recessive manner, whereas MPS II is inherited in an X-linked recessive manner, with hemizygous males affected and heterozygous females typically asymptomatic.

• Where a mucopolysaccharidosis is suspected, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion. Diagnosis is typically based on clinical suspicion, supported by biochemical testing (e.g., urinary glycosaminoglycans), and confirmed by molecular analysis.
• The identified entity confirms the diagnosis, enables precise subtype classification, and may support genotype–phenotype correlation, guides further clinical management, and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians. It may also inform eligibility for enzyme replacement therapy, haematopoietic stem cell transplantation, or clinical trials.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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• Ramarajan MG, Garapati K, Ghose V, Pandey A. Advances in mucopolysaccharidosis research: the impact of mass spectrometry-based approaches. Clin Proteomics. 2025;22(1):44. doi:10.1186/s12014-025-09562-4. PMID: . PMCID: PMC12641947.