Molecular Genetics: Screening Strategies for Diagnosing Mucopolysaccharidosis Type IVA

Abstract

Mucopolysaccharidosis type IVA (MPS IVA) is a rare autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme N-acetylgalactosamine-6-sulfatase (GALNS). Enzyme deficiency leads to progressive accumulation of glycosaminoglycans, particularly keratan sulfate (KS) and chondroitin-6-sulfate (C6S), resulting in early-onset skeletal dysplasia, airway obstruction, and spinal cord compression. Diagnosis of MPS IVA commonly relies on age-adjusted measurements of KS and C6S in blood and urine; however, this approach has limitations due to phenotypic heterogeneity and age-related changes in biomarker levels. This review summarizes current clinical, biochemical, and molecular diagnostic strategies for MPS IVA, including genotype–phenotype correlations and structural evaluation of GALNS variants using protein modeling. Evidence indicates that urinary KS and C6S levels remain elevated into adulthood, whereas circulating KS levels tend to normalize after 20 years of age. Therefore, integrated diagnostic algorithms combining clinical, radiographic, biochemical, and molecular assessments are essential to improve early detection and reduce diagnostic delays in MPS IVA.