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MUCOPOLYSACCHARIDOSES

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INTRODUCTION

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The mucopolysaccharidoses (MPS) are a family of rare, progressive, multisystem lysosomal storage disorders that are caused by defects in the enzymes that catabolize glycosaminoglycans (GAGs). These disorders are clinically heterogeneous, but some common features include coarse facial features, hepatosplenomegaly, developmental delay/regression, umbilical/inguinal hernias, and a constellation of radiographic bone abnormalities known as dysostosis multiplex. There are 7 clinically defined MPS syndromes (MPS I, II, III, IV, VI, VII, and IX), which are caused by pathogenic variants in 1 of 11 genes (Table 155-1). Within each disorder, there is a wide spectrum of clinical effects ranging from mild to severe (phenotypic heterogeneity) depending on the degree of residual enzymatic activity. Intravenous enzyme replacement therapy is available for many of the MPS and is aimed at reducing the progression of non–central nervous system (CNS) symptoms. Hematopoietic stem cell transplantation (HCST), which is associated with substantial risks, may preserve cognitive function if performed early during the course of the disease.

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PATHOGENESIS AND EPIDEMIOLOGY

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With the exception of MPS II (Hunter syndrome; X-linked), MPS are inherited in an autosomal recessive manner. In affected individuals, 1 or more specific GAGs—dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS), and chondroitin-6-sulfate—accumulate within the lysosomes, interfering with recycling of cellular material (Fig. 155-1). GAGs build up in the lysosome over time, affecting cellular function. Different GAGs are expressed in different tissues, leading to the variable manifestations seen in each of the MPS disorders. The estimated prevalence of MPS in the United States is approximately 1 in 25,000, although prevalence estimates vary in different parts of the world. Prevalence varies by disease and ethnicity.

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CLINICAL PRESENTATION

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MPS disorders, like all lysosomal storage diseases, are progressive conditions. Infants typically do not manifest signs or symptoms at birth, and the disease is suspected as the phenotype evolves over time.

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MPS disorders tend to present in 1 of 3 ways:

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  • With “coarse” facial features (eg, MPS IH, MPS II)

  • With learning difficulties, behavioral disturbances, and developmental delay/regression (eg, MPS III)

  • As a skeletal dysplasia (eg, MPS IV, VI)

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When an MPS is suspected from clinical, laboratory, and radiologic findings, the diagnosis can be confirmed by enzyme assay on white blood cells or skin fibroblasts or by the identification of biallelic pathogenic variants in the particular gene. While qualitative or quantitative demonstration of increased urinary GAG excretion is supportive evidence of an MPS, urinary screening tests for MPS disorders have reduced ...

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