The mucopolysaccharidoses: Clinical and biochemical experience at the adelaide children’s hospital

Abstract

The mucopolysaccharidoses (MPSs) are a group of genetically transmitted lysosomal storage disorders characterized by the excessive accumulation and abnormal excretion of mucopolysaccharides. All of the known types of MPSs are manifest in a wide variety of clinical phenotypes although each individual type occurs as a result of a single lysosomal enzyme deficiency of one or other of the exohydrolascs involved in the degradation of dcrmatan sulphate, heparan sulphate and keratan sulphate. The mainstay of MPSs diagnosis in the past has been the clinical recognition of a phenotype supported by supposedly characteristic radiology and the finding of excess mucopolysaccharide in the urine. However, it is now recognized that because of the almost bewildering degree of variation in clinical phenotype, reliance on radiological and urine mucopolysaccharide excretion criteria can be misleading. As genetic counselling and selected termination remains the main intervention available for the MPSs it is vital that the diagnosis applied is correct. Over the past 3 yr we have developed and systematically employed methods that enable us to specifically estimate the activity of the 10 known exohydrolascs involved in the MPSs. In collaboration with hospitals from all Australian States and New Zealand we have enzymically diagnosed and categorized more than 60 MPSs representing 6 different enzyme deficiencies (14 MPS 1, 16 MPS 11, 14 MPS 111A, 4 MPS 111B, 5 MPS IVA and 8 MPS VI) and performed 15 prenatal assessments in pregnancies at risk for 4 types of MPS enzyme deficiencies. In our diagnostic protocol, to prevent needless waste of time, tissue and hard-won substrates, we prefer to identify first (by high resolution electrophoresis) the nature of the excreted polysaccharide(s) and thus focus attention to a single enzyme or at the most 2 or 3 enzyme assays. Identification of the exact enzyme deficiency is then rapidly determined using leucocytes and/or plasma and later checked using cultured skin fibroblasts, which can then be cryogenically stored for future reference. The mucopolysaccharidoses (MPSs) are a group of genetically transmitted lysosomal storage disorders characterized by the excessive accumulation and abnormal excretion of mucopolysaccharides. All of the known types of MPSs are manifest in a wide variety of clinical phenotypes although each individual type occurs as a result of a single lysosomal enzyme deficiency of one or other of the exohydrolascs involved in the degradation of dcrmatan sulphate, heparan sulphate and keratan sulphate. The mainstay of MPSs diagnosis in the past has been the clinical recognition of a phenotype supported by supposedly characteristic radiology and the finding of excess mucopolysaccharide in the urine. However, it is now recognized that because of the almost bewildering degree of variation in clinical phenotype, reliance on radiological and urine mucopolysaccharide excretion criteria can be misleading. As genetic counselling and selected termination remains the main intervention available for the MPSs it is vital that the diagnosis applied is correct. Over the past 3 yr we have developed and systematically employed methods that enable us to specifically estimate the activity of the 10 known exohydrolascs involved in the MPSs. In collaboration with hospitals from all Australian States and New Zealand we have enzymically diagnosed and categorized more than 60 MPSs representing 6 different enzyme deficiencies (14 MPS 1, 16 MPS 11, 14 MPS 111A, 4 MPS 111B, 5 MPS IVA and 8 MPS VI) and performed 15 prenatal assessments in pregnancies at risk for 4 types of MPS enzyme deficiencies. In our diagnostic protocol, to prevent needless waste of time, tissue and hard-won substrates, we prefer to identify first (by high resolution electrophoresis) the nature of the excreted polysaccharide(s) and thus focus attention to a single enzyme or at the most 2 or 3 enzyme assays. Identification of the exact enzyme deficiency is then rapidly determined using leucocytes and/or plasma and later checked using cultured skin fibroblasts, which can then be cryogenically stored for future reference.