IRF2BPL-Related Disorder, Causing Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech and Seizures (NEDAMSS) Is Characterized by Pathology Consistent with DRPLA

IF 7.4 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders Pub Date : 2024-09-03 DOI:10.1002/mds.29938

Sunita Venkateswaran MD, Jean Michaud MD, Yoko Ito PhD, Michael Geraghty MD, MSc, Evan C. Lewis MD, Benjamin Ellezam MD, PhD, Kym M. Boycott MD, PhD, David A. Dyment MD, PhD, Kristin D. Kernohan PhD, Care4Rare Canada Consortium

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引用次数: 0

Abstract

Background

Childhood neurodegenerative diseases often pose a challenge to clinicians to diagnose because of the degree of genetic heterogeneity and variable presentations. Here, we present a child with progressive neurodegeneration consisting of spasticity, dystonia, and ataxia in which postmortem pathological analysis led to the diagnosis of interferon regulatory factor 2 binding protein like (IRF2BPL)-related disorder.

Methods

Detailed postmortem gross and histological examination was conducted, and findings consistent with dentatorubral-pallidoluysian atrophy (DRPLA) and included polyglutamine (polyQ) inclusions. Follow up testing for the CAG repeat expansion at ATN1 was non-diagnostic.

Results

Subsequent exome sequencing reanalysis of the research exome identified a pathogenic de novo IRF2BPL variant. The IRF2BPL c.562C>T, p.(Arg188Ter) variant, distal to the polyQ repeat tract, results in variable mRNA levels depending on the cell type examined with decreased mRNA in the brain, as well as destabilization of the protein product and corresponding downstream molecular abnormalities in patient derived cells.

Conclusion

We provide the first detailed pathological description for IRF2BPL-related disorder, termed NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures; Mendelian Inheritance in Man, 618088) and evidence for the inclusion of this condition in the differential diagnosis of spastic-ataxic neurodegenerative conditions, reminiscent of DRPLA. Although the individuals with NEDAMSS do not carry an expansion, the polyQ repeat tract may play a role in the pathological inclusions that would represent a novel disease mechanism for polyQ repeats. © 2024 International Parkinson and Movement Disorder Society.

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IRF2BPL相关障碍，导致神经发育障碍，伴有退行、异常运动、失语和癫痫发作（NEDAMSS），其病理特征与DRPLA一致。

背景：儿童神经退行性疾病由于其遗传异质性和多变的表现形式，常常给临床医生的诊断带来挑战。在此，我们介绍了一名患有由痉挛、肌张力障碍和共济失调组成的进行性神经退行性疾病的患儿，其尸检病理分析导致了干扰素调节因子 2 结合蛋白样（IRF2BPL）相关疾病的诊断：进行了详细的死后大体和组织学检查，结果与齿槽苍白肌萎缩症（DRPLA）一致，包括多聚谷氨酰胺（polyQ）内含物。对ATN1的CAG重复扩增进行的后续检测未得出诊断结果：结果：对研究对象外显子组的后续外显子组测序重新分析发现了一个致病性的IRF2BPL新变异。IRF2BPL c.562C>T，p.(Arg188Ter)变异位于多Q重复序列的远端，导致不同细胞类型的mRNA水平不同，大脑中的mRNA减少，蛋白质产物不稳定，患者衍生细胞中相应的下游分子异常：我们首次提供了 IRF2BPL 相关疾病的详细病理描述，该疾病被称为 NEDAMSS（伴有退行性、异常运动、失语和癫痫发作的神经发育障碍；人类孟德尔遗传，618088），并提供了将该疾病纳入痉挛性共济失调神经退行性疾病鉴别诊断的证据，这让人联想到 DRPLA。虽然 NEDAMSS 患者并不携带扩增，但多 Q 重复序列可能在病理包涵体中发挥作用，这将代表多 Q 重复序列的一种新型疾病机制。© 2024 国际帕金森和运动障碍协会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.