一项针对L238Q突变杂合型Hurler-Scheie综合征患者神经认知与行为的纵向研究。

A longitudinal study of neurocognition and behavior in patients with Hurler-Scheie syndrome heterozygous for the L238Q mutation.

作者信息

Ahmed Alia, Ou Li, Rudser Kyle, Shapiro Elsa, Eisengart Julie B, King Kelly, Chen Agnes, Dickson Patricia, Whitley Chester B

机构信息

Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.

Gene Therapy Center, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.

出版信息

Mol Genet Metab Rep. 2019 Jun 27;20:100484. doi: 10.1016/j.ymgmr.2019.100484. eCollection 2019 Sep.

DOI:10.1016/j.ymgmr.2019.100484

PMID:31304092

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6603334/

Abstract

UNLABELLED

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.

摘要

未标注

先前的研究表明，在Hurler-Scheie综合征患者中，α-L-艾杜糖醛酸酶（IDUA）基因的c.712T>A（p.L238Q）突变与无义、缺失或剪接位点突变配对时相对严重。该突变还被发现与精神症状有关。本研究提供了纵向数据和蛋白质分析，以进一步研究这些独特患者的严重程度和自然病史。

方法

将6名L238Q杂合患者与6名无L238Q突变的Hurler-Scheie患者进行比较。从2009年到2014年，在2至4年的时间里，每年对疾病的躯体负担、智商、记忆力、注意力、适应性功能和行为指标进行评估。使用7种生物信息学工具和三维结构分析来研究L238Q对IDUA酶的影响。

结果

与横断面研究相似，L238Q患者在智商、注意力、适应性功能和行为功能方面的异常比对照组更严重。两组在随时间变化方面没有重大差异；两组的智商都很稳定，一些行为领域有所改善。随着时间的推移，两组在视觉空间记忆和注意力/视觉处理方面都有所下降。他们还表现出焦虑增加。对L238Q的结构和生物信息学分析表明，该突变导致IDUA酶的潜在催化活性显著降低，并且该突变可能比导致Hurler-Scheie综合征表型的其他突变更严重，可能导致精神疾病。