Mucopolysaccharidoses (MPS) are a prominent group of genetic lysosomal storage diseases. The intralysosomal accumulation of glycosaminoglycans caused by several different enzyme deficiencies induces a cascade of responses that affect cellular functions and preservation of the extra-cellular matrix.
This results in the appearance of chronic and progressive syndromes that produce a wide array of clinical manifestations in multiple organ systems. While the disease may not always be apparent at birth, manifestations of the disease develop with age as more cells become damaged by the accumulation of cell materials.
Individuals affected by mucopolysaccharidosis share many similar symptoms – involvement of multiple organ systems, distinctive facial features, as well as abnormalities of the skeleton (namely problems with joints). The age of the onset and severity of clinical presentation may vary significantly both within and among the seven major types of mucopolysaccharidoses.
Patients are normal at birth, although some of them (mostly those with MPS 7) can present with hydrops fetalis – a severe and challenging fetal condition defined as the excessive accumulation of fluid within the fetal extravascular compartments and body cavities resulting in edema, effusions and ascites. In most of the other cases clinical signs appear after several months or years.
Organ involvement depends on the type of mucopolysaccharidosis – for example, patients with MPS 6 have severe skeletal and heart disease without cognitive impairment, those with MPS 4 have serious skeletal dysplasia and joint hypermobility, while patients with MPS 3 have little somatic involvement, but early and severe neurological impairment.
A wide phenotypic spectrum can be observed within the same type of mucopolysaccharidosis as well. For example, an early involvement of many organs and functions (cardiac, skeletal, auditory, visual and neurological systems) are practically the rule in the severe form of MPS 1 called Hurler syndrome; on the other hand, patients with the attenuated form of MPS 1 called Scheie syndrome can present with one isolated symptom or sign in the third decade of life.
Musculoskeletal involvement is a common feature in all types of mucopolysacchardioses. Differentiation of these disorders from the inflammatory arthritides is essential if early treatment is the end-goal. Attention to the characteristics of the musculoskeletal disease and appropriate radiographic investigation facilitates the timely diagnosis and appropriate management of the affected individuals.
Vision problems are also a common finding. Glaucomas have been reported in MPS 1 and MPS 6, while cataracts can be found in MPS 3 and MPS 4. Retinal degeneration can occur later in life, resulting in the loss of peripheral vision and night blindness.
Upper airway infections are frequently found in patients with these syndromes, albeit lower airway infections are not that common. Lung infections can be attributed to the narrow trachea and larynx, as well as alterations in chest mobility. Recurrent ear infections and subsequent hearing loss are characteristic for MPS 4.
Delays in diagnosis of mucopolysaccharidoses are common, thus many children and young adults will suffer for years with an unrecognized disease. In addition, predicting disease severity is a difficult task, and early recognition of the disease is often hampered by nonspecific presentation.
Clinicians hoped that analysis of urinary glycosaminoglycan levels would be a useful tool to predict disease severity, but it was found that this test cannot be employed as a reliable indicator of severity, even though a higher level can be suggestive of more severe disease form.
Correlations of genotype with phenotype have been curtailed by the rare appearance of mucopolysaccharidoses and the large number of possible mutations – many of which occur only in a single affected family. Therefore clinical severity associated with missense mutations and other types of mutations has remained difficult to predict for all types of disease.