A review of the clinical presentation and diagnosis of Mucopolysaccharidosis IVA

Abstract

Mucopolysaccharidosis type IVA (MPS IVA) was described in 1929 by Luis Morquio from Uruguay and James Brailsford from England, and was later found as an autosomal recessive lysosomal storage disease. MPS IVA is caused by mutations in the gene encoding the enzyme, Nacetylgalactosamine-6-sulfate sulfatase (GALNS). Reduced GALNS activity results in impaired catabolism of two glycosaminoglycans (GAGs), chondroitin-6-sulfate (C6S) and keratan sulfate (KS). Clinical presentations of MPS IVA reflect a spectrum of progression from a severe "classical" phenotype to a mild "attenuated" phenotype. More than 180 different mutations have been identified in the GALNS gene, which likely explains the phenotypic heterogeneity of the disorder. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.All authors received reimbursement for participating in a BioMarin sponsored summit. The author contributions were presented in part at the summit and were not influenced by BioMarin. C.G. Gravance is an employee of BioMarin Pharmaceutical, Inc. NIH Public Access Author ManuscriptMol Genet Metab. Author manuscript; available in PMC 2014 September 01. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAccumulation of C6S and KS manifests predominantly as short stature and skeletal dysplasia (dysostosis multiplex), including atlantoaxial instability and cervical cord compression. However, abnormalities in the visual, auditory, cardiovascular, and respiratory systems can also affect individuals with MPS IVA. Diagnosis is typically based on clinical examination, skeletal radiographs, urinary GAG, and enzymatic activity of GALNS in blood cells or fibroblasts. Deficiency of GALNS activity is a common assessment for the laboratory diagnosis of MPS IVA; however, with recently increased availability, gene sequencing for MPS IVA is often used to confirm enzyme results. As multiple clinical presentations are observed, diagnosis of MPS IVA may require multi-system considerations.This review provides a history of defining MPS IVA and how the understanding of the disease manifestations has changed over time. A summary of the accumulated knowledge is presented, including information from the International Morquio Registry. The classical phenotype is contrasted with attenuated cases, which are now being recognized and diagnosed more frequently. Laboratory based diagnoses of MPS IVA are also discussed.

Evading the AAV Immune Response in Mucopolysaccharidoses

“…However, organs typically affected include the brain, eyes, respiratory tract, heart, liver, spleen, bone, and cartilage [1,2]. Severe MPS phenotypes are associated with early death occurring within the first two decades of life [3][4][5][6][7][8], while others with an attenuated phenotype may have near-normal life expectancies [3,[7][8][9]. Current therapy options for MPS patients include enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) [2].…”