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.
Bibliographical noteFunding Information:
The Lysosomal Disease Network (LDN) U54-NS065768 is a part of the National Institute of Health (NIH) Rare Diseases Clinical Research Network , supported through collaboration between the NIH Office of Rare Diseases Research at the National Center for Advancing Translational Science , the National Institute of Neurological Disorders and Stroke (NINDS) , and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) . Dr. Li Ou is a fellow of the Lysosomal Disease Network. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This project was supported in part (Dr. Rudser) by the National Center for Advancing Translational Sciences , (NCATS) National Institutes of Health , through University of Minnesota CTSI Grant Number NCATS UL1TR000114 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or CTSI.
We are grateful to all of the families at the participating sites, as well as the principal investigator, Dr. Paul Harmatz at Children's Hospital and Research Center, Oakland, California. We are thankful to Kathleen Delaney and Brianna Yund for their assistance with this research. We thank Brenda Diethelm-Okita, David Erickson, and Evelyn Redtree in the Lysosomal Disease Network office at the University of Minnesota for administrative assistance, and Renee Cooksley for assistance with genotyping. We are very thankful for the support provided by the National MPS Society, Ryan Foundation for Orphan Disease Research and Center for Neurobehavioral Development (CNBD).
© 2019 The Authors
- Hurler-Scheie syndrome
- L238Q mutation
- Mucopolysaccharidosis (MPS)