Iran J Pathol. 02.2025; 20(1): 138-139 

Moeinadin Safavi, Aria Setoodeh, Mahdiieh Ghoddoosi 

Highlights: A newly reported missense mutation (c.965C>T, p.Ala322Val) in the GALNS gene leads to a severe phenotype of Morquio syndrome (MPS IVA), a rare lysosomal storage disease. A 3-year-old girl showed pronounced skeletal abnormalities, including genu valgum, pectus carinatum, wrist cupping, and spinal deformities. Urinalysis via Berry spot test indicated mucopolysaccharide accumulation. Whole-exome sequencing detected the homozygous c.965C>T variant in the GALNS gene, classified as “likely pathogenic” according to ACMG guidelines. Early diagnosis can facilitate prompt enzyme replacement therapy (ERT) and supportive measures, potentially improving long-term outcomes. 

Background: Mucopolysaccharidosis IVA is a lysosomal storage disease caused by a deficiency in GALNS enzyme activity. It is characterized by the accumulation of keratan sulfate, which leads to severe impairment of cartilage and bone structure. Typical findings include short stature, skeletal deformities (genu valgum, spinal curvatures), respiratory problems, and cardiac, neurological, and sensory issues. 

Objective and methods: A genetic test was performed on a 3-year-old girl, who had skeletal abnormalities observed on X-ray imaging, due to a suspicion of severe MPS IVA. The Berry spot test, indicating mucopolysaccharide accumulation in the patient’s urine, was found to be positive. Along with routine laboratory analyses (complete blood count, calcium, phosphorus, etc.), whole exome sequencing (WES) was carried out. The sequencing results obtained for the GALNS gene were then interpreted according to ACMG criteria. 

Material and Methods: WES sequencing was performed at 100x coverage with 151 bp read lengths using the Illumina Novaseq 6000 system, and the sequencing results were aligned to the human genome (hg19). The homozygous c.965C>T (p.Ala322Val) mutation was classified as “likely pathogenic” according to ACMG. 

Results: This study demonstrates that the newly identified p.Ala322Val mutation in the GALNS gene is responsible for a severe form of Morquio syndrome. Early genetic diagnosis is critically important for the management of symptoms through enzyme replacement therapy and multidisciplinary approaches. In this way, a significant step can be taken toward preventing or delaying the patient’s neurological and skeletal complications. 

Keywords: Mucopolysaccharidosis IVA, Morquio A syndrome Metabolic disordes Lysosomal enzymes