Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology

Abstract

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues. If untreated, patients with the severe phenotype die within the first decade of life. Early diagnosis is crucial to prevent the development of fatal disease manifestations, prominently cardiac and respiratory disease, as well as cognitive impairment. However, the initial symptoms are nonspecific and impede early diagnosis. This review discusses common phenotypic manifestations in the order in which they develop. Similarities and differences in the three animal models for MPS I are highlighted. Earliest symptoms, which present during the first 6 months of life, include hernias, coarse facial features, recurrent rhinitis and/or upper airway obstructions in the absence of infection, and thoracolumbar kyphosis. During the next 6 months, loss of hearing, corneal clouding, and further musculoskeletal dysplasias develop. Finally, late manifestations including lower airway obstructions and cognitive decline emerge. Cardiac symptoms are common in MPS I and can develop in infancy. The underlying pathogenesis is in the intra- and extracellular accumulation of partially degraded GAGs and infiltration of cells with enlarged lysosomes causing tissue expansion and bone deformities. These interfere with the proper arrangement of collagen fibrils, disrupt nerve fibers, and cause devastating secondary pathophysiological cascades including inflammation, oxidative stress, and other disruptions to intracellular and extracellular homeostasis. A greater understanding of the natural history of MPS I will allow early diagnosis and timely management of the disease facilitating better treatment outcomes.

The cell surface hyaluronidase TMEM2 is essential for systemic hyaluronan catabolism and turnover

“…This is because extracellular GAG accumulation can occur as a long-term consequence of defects in lysosomal GAG-degrading enzymes. For example, patients suffering from various mucopolysaccharidoses (MPS), including MPS type I (Hurler and Hurler–Scheie syndromes), MPS type II (Hunter syndrome), and MPS type III (Sanfilippo syndrome), exhibit widespread extracellular deposition of GAGs ( 57 , 58 , 59 ), even though the causal defects in these disorders reside in lysosomal enzymes. It is thus possible that the extracellular accumulation of HA observed in constitutive Hyal2 knockout mice may not be the direct consequence of defects in cell surface HA degradation, but instead is caused by defects in lysosomal HS degradation.…”

Multicentric Osteolysis, Nodulosis, and Arthropathy in two unrelated children with matrix metalloproteinase 2 variants: Genetic-skeletal correlations

“…The characteristics of non-skeletal manifestations as oral and dental abnormalities may provide an additional differential diagnosis tool of MONA syndrome ( Mehrez et al, 2019 ). Genetic analysis remains important to the differential diagnosis of skeletal dysplasia with childhood-onset osteoporosis as pathogenic variants in SGMS2 gene ( Al Kaissi et al, 2011 ; Pekkinen et al, 2019 ; Robinson et al, 2020 ) and pathogenic variants of PLS3 gene ( Kämpe et al, 2017 ), to skeletal dysplasias simulating juvenile idiopathic arthritis as pathogenic variants in WISP3 gene ( Gaboon et al, 2019 ; Torreggiani et al, 2019 ) and to the differential diagnosis of MPS type-I ( Hampe et al, 2020 ).…”

“…The overlapping skeletal and non-skeletal features of these two genetic skeletal dysplasias compounds the diagnostic challenges. Additionally, MONA and Winchester syndromes ( Winchester et al, 1969 ; Al Aqeel et al, 2000 ) among others ( Al Kaissi et al, 2011 ; Li et al, 2020 ) can have a misleading radioclinical resemblance to juvenile idiopathic arthritis and mucopolysaccharidosis (MPS) type-I as Scheie syndrome ( Hampe et al, 2020 ; Gökay et al, 2018 ). The treatment of MONA syndrome is palliative ( Pichler et al, 2016 ) and little is known about the long-term prognosis apart from tendency to progression of skeletal features.…”

Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts

“…Mucopolysaccharidosis type I (MPS-I) is a progressively debilitating disorder which is caused by mutations of the gene encoding alpha-L-iduronidase (IDUA), an enzyme important for the degradation of glycosaminoglycans (GAGs) in the lysosomes ( Hampe et al. 2020 ).…”