Nucleotide metabolism, leukodystrophies, and CNS pathology

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Francesco Gavazzi, Carlos Dominguez Gonzalez, Kaley Arnold, Meghan Swantkowski, Lauren Charlton, Nicholson Modesti, Asif A. Dar, Adeline Vanderver, Mariko Bennett, Laura A. Adang
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Abstract

The balance between a protective and a destructive immune response can be precarious, as exemplified by inborn errors in nucleotide metabolism. This class of inherited disorders, which mimics infection, can result in systemic injury and severe neurologic outcomes. The most common of these disorders is Aicardi Goutières syndrome (AGS). AGS results in a phenotype similar to “TORCH” infections (Toxoplasma gondii, Other [Zika virus (ZIKV), human immunodeficiency virus (HIV)], Rubella virus, human Cytomegalovirus [HCMV], and Herpesviruses), but with sustained inflammation and ongoing potential for complications. AGS was first described in the early 1980s as familial clusters of “TORCH” infections, with severe neurology impairment, microcephaly, and basal ganglia calcifications (Aicardi & Goutières, Ann Neurol, 1984;15:49–54) and was associated with chronic cerebrospinal fluid (CSF) lymphocytosis and elevated type I interferon levels (Goutières et al., Ann Neurol, 1998;44:900–907). Since its first description, the clinical spectrum of AGS has dramatically expanded from the initial cohorts of children with severe impairment to including individuals with average intelligence and mild spastic paraparesis. This broad spectrum of potential clinical manifestations can result in a delayed diagnosis, which families cite as a major stressor. Additionally, a timely diagnosis is increasingly critical with emerging therapies targeting the interferon signaling pathway. Despite the many gains in understanding about AGS, there are still many gaps in our understanding of the cell-type drivers of pathology and characterization of modifying variables that influence clinical outcomes and achievement of timely diagnosis.

核苷酸代谢、白质营养不良症和中枢神经系统病理学。
保护性免疫反应和破坏性免疫反应之间的平衡可能岌岌可危,核苷酸代谢先天性错误就是一个例子。这类遗传性疾病模拟感染,可导致全身性损伤和严重的神经系统后果。这些疾病中最常见的是艾卡迪-古蒂耶尔综合征(AGS)。AGS 导致的表型类似于 "TORCH "感染(弓形虫、其他[寨卡病毒(ZIKV)、人类免疫缺陷病毒(HIV)]、风疹病毒、人类巨细胞病毒[HCMV]和疱疹病毒),但具有持续炎症和潜在并发症。AGS 在 20 世纪 80 年代初首次被描述为家族性的 "TORCH "感染,伴有严重的神经功能损害、小头畸形和基底节钙化(Aicardi & Goutières,Ann Neurol,1984;15:49-54),并与慢性脑脊液(CSF)淋巴细胞增多和 I 型干扰素水平升高有关(Goutières 等人,Ann Neurol,1998;44:900-907)。自首次描述以来,AGS 的临床范围已从最初的严重受损儿童群组急剧扩大到包括智力一般和轻度痉挛性瘫痪的个体。这种广泛的潜在临床表现可能会导致诊断延迟,而这正是家庭面临的主要压力。此外,随着针对干扰素信号通路的新疗法的出现,及时诊断变得越来越重要。尽管我们对 AGS 的认识有了很大提高,但在了解病理的细胞类型驱动因素以及影响临床结果和及时诊断的调节变量特征方面仍有很多不足之处。
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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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