GALNS – Mucopolysaccharidosis IVA (Morquio A Syndrome)

GALNS encodes N-acetylgalactosamine-6-sulfate sulfatase, and biallelic GALNS pathogenic variants cause mucopolysaccharidosis type IVA (MPS IVA; Morquio A), an autosomal recessive lysosomal storage disorder characterized by systemic skeletal dysplasia, short stature, pectus carinatum and kyphoscoliosis. Patients accumulate keratan sulfate and chondroitin-6-sulfate in cartilage and connective tissues, leading to progressive bone deformities and multisystem involvement PMID:22178352.

Genetic evidence for GALNS–MPS IVA is definitive. Over 170 unique GALNS variants have been reported in more than 200 unrelated patients worldwide, including missense (∼78%), splice‐site, nonsense, small indels and structural rearrangements PMID:36000290. Founder alleles include p.Ile113Phe in Caucasians (22.5% of alleles) PMID:7668283 and p.Gly301Cys in Colombians (78.3% of alleles) PMID:34542925. A novel splice acceptor variant c.423-1G>A, abolishing exon 5 and introducing a premature stop at Trp141, was identified homozygous in a patient with classical Morquio A PMID:9290256.

Segregation analyses in multiplex families demonstrate clear autosomal recessive inheritance. In a two-generation pedigree, compound heterozygosity for p.Arg259Gln and p.Arg94Gly segregated with disease in two probands, while homozygosity for p.Arg259Gln in the mother and her siblings correlated with a milder phenotype (4 additional affected relatives) PMID:9660054.

Functional studies corroborate variant pathogenicity. Transient expression of missense alleles (I113F, R94C, P151L) in GALNS-deficient fibroblasts resulted in severely reduced enzyme activity PMID:7795586. A high-resolution GALNS crystal structure revealed disruption of the hydrophobic core and active-site geometry by patient variants, supporting misfolding as the predominant mechanism PMID:22940367. Patient-derived iPSC models harboring p.Arg61Trp and p.Arg61Gly exhibit diminished GALNS activity at both RNA and protein levels, providing a platform for pathogenesis studies and drug screening PMID:30797135.

Therapeutic interventions align with mechanistic insights: long-term allogeneic bone marrow transplantation restores ~50% of normal GALNS activity and improves skeletal and respiratory parameters over 9+ years PMID:25593792. Early initiation of elosulfase alfa enzyme replacement therapy ameliorates visceral and soft-tissue manifestations, though skeletal outcomes remain limited, underscoring the need for adjunctive surgical management PMID:32024277.

References

• Genetics in Medicine • 2024 • Implementation of newborn screening for mucopolysaccharidosis type IVA and long-term monitoring in Taiwan PMID:39375993
• American Journal of Human Genetics • 1995 • Mucopolysaccharidosis IVA: identification of a common missense mutation I113F in the N-Acetylgalactosamine-6-sulfate sulfatase gene PMID:7668283
• Journal of Molecular Biology • 2012 • The structure of human GALNS reveals the molecular basis for mucopolysaccharidosis IV A PMID:22940367
• Stem Cell Research • 2019 • Generation of an induced pluripotent stem cell line (TRNDi005-A) from a Mucopolysaccharidosis Type IVA patient PMID:30797135
• Molecular Genetics and Metabolism Reports • 2014 • Long-term therapeutic efficacy of allogenic bone marrow transplantation in a patient with mucopolysaccharidosis IVA PMID:25593792
• International Journal of Molecular Sciences • 2020 • A Case Report of a Japanese Boy with Morquio A Syndrome: Effects of Enzyme Replacement Therapy Initiated at the Age of 24 Months PMID:32024277

Evidence Based Scoring (AI generated)