Abstract
Previous research has demonstrated the mutation, c.712T>A (p.L238Q) of the gene for α-L- iduronidase (IDUA) in patients with Hurler-Scheie syndrome is relatively severe when paired with a nonsense or deletion or splice-site mutation. This mutation was also found to be associated with psychiatric symptoms. This research presents longitudinal data and protein analysis to further investigate the severity and natural history of these unique patients. METHODS: Six patients heterozygous for L238Q were compared to six patients with Hurler-Scheie without the L238Q mutations. Somatic burden of disease, IQ, memory, attention, adaptive functioning and behavioral measures were given yearly over 2 to 4 years from 2009 to 2014. The impact of L238Q on the IDUA enzyme was examined using 7 bioinformatics tools and a 3D structural analysis. RESULTS: Similar to the cross sectional study, the L238Q patients had more severe abnormalities in IQ, attention, adaptive functioning, and behavioral functioning than the comparison group. There were no major differences between the two groups in change over time; IQ for both groups was stable with some behavioral areas showing improvement. Over time, both groups declined in visual spatial memory and, attention/visual processing. They also showed increased anxiety. Structural and bioinformatics analysis of the L238Q suggest that this mutation causes a significant reduction in the IDUA enzyme's potential catalytic activity, and this mutation may be more severe than other mutations contributing to the Hurler-Scheie syndrome phenotype, presumably causing the psychiatric disease. CONCLUSION: L238Q patients demonstrate severe neurocognitive and neurobehavioral deficits but are relatively stable. Like the comparison group, decreasing visual spatial memory and attention and increasing anxiety suggest more intervention in life skills and emotional social supports are needed.