Clinical and molecular spectrum of mucopolysaccharidosis IVA in Iraqi children: Allele-specific genotype–phenotype trends and novel GALNS variants

Abstract

Background

Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) is a rare lysosomal storage disorder that causes early-onset skeletal dysplasia and progressive multisystem involvement. Although international cohorts have been described, population-specific data from the Middle East remain limited.

Objective

This study aimed to characterize the clinical spectrum, functional status, and GALNS variant profile in Iraqi children with MPS IVA, and to assess diagnostic timing in comparison with international experience.

Methods

We retrospectively analyzed 33 children from 26 unrelated families with confirmed MPS IVA, recruited at the Children's Welfare Teaching Hospital in Baghdad between 2016 and 2022. Enzyme activity was measured on dried blood spots by LC-MS/MS, and GALNS variants were identified using next-generation sequencing with Sanger confirmation. Clinical evaluation included anthropometry, echocardiography, ophthalmologic and audiologic assessments, skeletal surveys, and functional endurance testing (6-min walk test and 3-min stair-climb).

Results

Fifteen distinct GALNS variants were identified, including five novel variants (three missense, two frameshift). The most common allele was c.949G > A (p.Gly317Arg), consistently associated with severe phenotypes and absent enzyme activity. Universal skeletal dysplasia was observed, with frequent corneal clouding, cardiac valve disease, and reduced functional endurance. Symptoms typically appeared in early childhood, but definitive diagnosis was often delayed until later childhood or adolescence. Allele-specific genotype–phenotype trends were observed, though no statistically significant correlations could be established due to limited cohort size.

Conclusion

This first Iraqi cohort expands the GALNS variant spectrum and highlights persistent diagnostic delays despite early clinical manifestations. Early molecular confirmation, establishment of national registries, and multidisciplinary surveillance are essential to reduce long-term morbidity.