Evolution of adrenoleukodystrophy model systems,Journal of Inherited Metabolic Disease

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Evolution of adrenoleukodystrophy model systems
Journal of Inherited Metabolic Disease ( IF 4.2 ) Pub Date : 2020-12-29 , DOI: 10.1002/jimd.12357
Roberto Montoro ₁ , Vivi M Heine _{2,

3} , Stephan Kemp _{1,

4} , Marc Engelen ₁

Affiliation

X‐linked adrenoleukodystrophy (ALD) is a neurometabolic disorder affecting the adrenal glands, testes, spinal cord and brain. The disease is caused by mutations in the ABCD1 gene resulting in a defect in peroxisomal degradation of very long‐chain fatty acids and their accumulation in plasma and tissues. Males with ALD have a near 100% life‐time risk to develop myelopathy. The life‐time prevalence to develop progressive cerebral white matter lesions (known as cerebral ALD) is about 60%. Adrenal insufficiency occurs in about 80% of male patients. In adulthood, 80% of women with ALD also develop myelopathy, but adrenal insufficiency or cerebral ALD are very rare. The complex clinical presentation and the absence of a genotype‐phenotype correlation are complicating our understanding of the disease. In an attempt to understand the pathophysiology of ALD various model systems have been developed. While these model systems share the basic genetics and biochemistry of ALD they fail to fully recapitulate the complex neurodegenerative etiology of ALD. Each model system recapitulates certain aspects of the disorder. This exposes the complexity of ALD and therefore the challenge to create a comprehensive model system to fully understand ALD. In this review, we provide an overview of the different ALD modeling strategies from single‐celled to multicellular organisms and from in vitro to in vivo approaches, and introduce how emerging iPSC‐derived technologies could improve the understanding of this highly complex disorder.

中文翻译：

肾上腺脑白质营养不良模型系统的演变

X 连锁肾上腺脑白质营养不良 (ALD) 是一种影响肾上腺、睾丸、脊髓和大脑的神经代谢疾病。这种疾病是由ABCD1突变引起的基因导致超长链脂肪酸过氧化物酶体降解及其在血浆和组织中的积累缺陷。患有 ALD 的男性一生中患脊髓病的风险接近 100%。发生进行性脑白质病变（称为脑 ALD）的终生患病率约为 60%。大约 80% 的男性患者会出现肾上腺功能不全。在成年期，80% 的 ALD 女性也会出现脊髓病，但肾上腺功能不全或脑 ALD 非常罕见。复杂的临床表现和缺乏基因型-表型相关性使我们对这种疾病的理解复杂化。为了理解 ALD 的病理生理学，已经开发了各种模型系统。虽然这些模型系统共享 ALD 的基本遗传学和生物化学，但它们未能完全概括 ALD 复杂的神经退行性病因。每个模型系统都概括了疾病的某些方面。这暴露了 ALD 的复杂性，因此面临着创建一个全面的模型系统以完全理解 ALD 的挑战。在这篇综述中，我们概述了从单细胞到多细胞生物以及从体外到体内方法的不同 ALD 建模策略，并介绍了新兴的 iPSC 衍生技术如何提高对这种高度复杂疾病的理解。

更新日期：2020-12-29

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