GALNS gene variants and clinical severity in pediatric mucopolysaccharidosis type IV: A retrospective cohort study from Duhok, Iraq.

Abstract

Mucopolysaccharidosis type IV (MPS IV; Morquio syndrome) is a rare lysosomal storage disorder caused by pathogenic variants in the GALNS gene, resulting in deficiency of N-acetylgalactosamine-6-sulfatase and progressive accumulation of glycosaminoglycans. The disease exhibits substantial clinical heterogeneity, and the relationship between specific GALNS variants and disease severity remains incompletely understood. This retrospective cross-sectional observational study evaluated the association between GALNS variants and clinical severity in 10 children with genetically confirmed MPS IV treated at a tertiary pediatric center in Duhok, Iraq, with data collected up to September 2025. Clinical, radiological, echocardiographic, and genetic data were retrospectively extracted from medical records. A study-derived, non-validated Clinical Severity Index (CSI; range, 0-6) was constructed from six clinically relevant skeletal, neurological, and functional manifestations, with higher scores indicating greater recorded disease burden. Three GALNS variants were identified: c.860C>T (50%), c.421T>A (30%), and c.1196delA (20%). The overall mean CSI was 2.9 ± 2.0. Patients with the frameshift variant c.1196delA had the highest mean CSI (4.0 ± 1.4), followed by c.860C>T (2.8 ± 2.6) and c.421T>A (2.3 ± 0.6); however, the difference among mutation groups was not statistically significant (Kruskal-Wallis p = 0.564). Overall, 20% of patients had mild, 50% had moderate, and 30% had severe disease according to the study-derived CSI. Multisystem involvement was common, including skeletal abnormalities in 70%, abnormal echocardiographic findings in 70%, cervical spinal cord compression in 30%, and carpal tunnel syndrome and/or communicating hydrocephalus in 40% of patients. The findings demonstrate substantial clinical variability among children with MPS IV and suggest a possible trend toward greater disease burden among patients with the frameshift variant c.1196delA, although this association was not statistically significant. Given the small sample size and the non-validated nature of the CSI, these findings should be considered exploratory and require confirmation in larger, multicenter cohorts using standardized clinical and biochemical measures.