Natural History of Morquio A Syndrome.

Abstract

Mucopolysaccharidosis IVA (Morquio A) is a progressive lysosomal disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase, resulting in the accumulation of glycosaminoglycans, primarily in cartilage and bone. The condition leads to skeletal dysplasia, impaired ossification, and growth imbalance, causing cervical compression, tracheal obstruction, hip dysplasia, and cardiopulmonary complications. Although existing natural history studies have clarified several aspects of disease progression, objective methods to quantify skeletal pathology and its functional impact remain limited. Standard endurance-based assessments, including the 6-min walk test, 3-min stair climb, and spirometry, are variable and infeasible for young children, wheelchair-dependent individuals, or patients with respiratory or postoperative limitations. Their dependence on motivation, training, and site-specific differences restricts their value as reliable endpoints. Significant gaps persist in the objective evaluation of skeletal dysplasia progression and its functional impact. There remains an unmet need for non-invasive, quantitative tools that capture multisystem involvement across the full phenotypic spectrum. Objective tools exist as we reported but have not been widely implemented or standardized, and data supporting their use as regulatory endpoints remain limited. Emerging longitudinal, multidisciplinary evaluations and surrogate biochemical biomarkers show potential to define disease severity, support prognosis, and serve as validated endpoints for therapeutic monitoring and surgical risk stratification. In conclusion, to address the limitations of prior studies, we propose a novel natural history program of innovative, non-invasive assessments based on our compiled data. Such approaches may contribute to more consistent longitudinal data and help inform the development of clinical endpoints for emerging therapies.