N-acetylgalactosamine-6-sulfatase protein detection in MPS IVA patient and unaffected control samples.

BACKGROUND: Mucopolysaccharidosis type IVA (MPS IVA; Morquio syndrome) is a lysosomal storage disorder caused by a deficiency in the activity of the lysosomal hydrolase N-acetylgalactosamine-6-sulfatase (GALNS). MPS IVA patients can present with severe myelopathy, hearing loss, heart valve involvement, short trunk/dwarfism and corneal clouding. Early diagnosis of MPS IVA will allow potential treatments to be implemented before the onset of irreversible pathology. METHODS: We have developed a sensitive immune-quantification assay for the accurate detection of GALNS protein in skin fibroblasts, blood and plasma from unaffected control and MPS IVA patients. RESULTS: MPS IVA patient fibroblast extracts (n=11) had non-detectable (ND)-10 ng/mg of 6-sulfatase protein compared to 3-82 ng/mg for normal controls (n=19). Dried blood-spots from MPS IVA patients (n=4) contained ND-1.3 ng/L of 6-sulfatase protein compared to 18-145 ng/L for normal controls (n=49). Plasma from MPS IVA patients (n=7) contained ND 6-sulfatase protein compared to 1-9 ng/L for normal controls (n=49). CONCLUSIONS: The immune assay described here had the capacity to accurately measure the amount of GALNS protein in various biological samples, providing the basis of an assay that could be further developed to enable newborn and high-risk population screening for MPS IVA patients.

Stop-codon read-through for patients affected by a lysosomal storage disorder.

Lysosomal storage disorders are a group of inherited diseases that can result in severe and progressive pathology due to a specific lysosomal dysfunction. Current treatment strategies include bone-marrow transplantation, substrate reduction, chemical-chaperone and enzyme-replacement therapy. However, each of these treatments has its limitations. Enhanced stop-codon read-through is a potential alternative or adjunct therapeutic strategy for treating lysosomal-storage-disorder patients. Premature stop-codon mutations have been identified in a large cohort of patients with a lysosomal storage disorder, making stop-codon read-through a possible treatment for this disease. In lysosomal-storage-disorder cells (mucopolysaccharidosis type I, alpha-L-iduronidase deficient), preclinical studies have shown that gentamicin induced the read-through of premature stop codons, resulting in enzyme activity that reduced substrate storage.