Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism.
Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism.
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DOI：
10.1038/jid.2011.189
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发表时间：
2011-11
影响因子：
6.5
通讯作者：
Elias, Peter M.
中科院分区：
文献类型：
--
作者：
Paller, Amy S.;van Steensel, Maurice A. M.;Rodriguez-Martin, Marina;Sorrell, Jennifer;Heath, Candrice;Crumrine, Debra;van Geel, Michel;Noda Cabrera, Antonio;Elias, Peter M.
识别脂质代谢紊乱的潜在遗传、细胞和生化基础提供了部署纠正性的、机制靶向的局部治疗的机会。我们评估了两名先天性半侧发育不良伴鱼鳞状红皮病和肢体缺陷(CHILD)综合征患者的这种治疗方法，这是一种X连锁的远端胆固醇代谢的显性疾病。基于途径产物胆固醇缺乏和有毒代谢中间产物堆积的可能致病作用，我们评估了洛伐他汀和胆固醇联合治疗的疗效。我们还通过分析异常皮肤和未受影响的皮肤中的基因激活，评估了儿童综合征皮肤和骨骼畸形缺乏了解、独特的偏侧化的基础。对受影响皮肤的超微结构分析显示，有证据表明胆固醇消耗和有毒代谢积聚。局部使用洛伐他汀/胆固醇(但不只是胆固醇)在3个月内几乎清除了皮肤损伤，并伴随着表皮结构和脂肪分泌的组织学和超微结构正常化。CHILD综合征异常偏侧的异常反映了表达突变等位基因的健侧角质形成细胞和成纤维细胞的选择性清除。这些发现验证了基于发病机制的治疗方法的有效性，这种治疗方法可以提供有缺陷的最终产物并防止有毒代谢物的积累，这是一种对其他综合征脂代谢紊乱具有潜在实用价值的方法。
Identification of the underlying genetic, cellular, and biochemical basis of lipid metabolic disorders provides an opportunity to deploy corrective, mechanism-targeted, topical therapy. We assessed this therapeutic approach in two patients with Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD) syndrome, an X-linked dominant disorder of distal cholesterol metabolism. Based upon the putative pathogenic role of both pathway-product deficiency of cholesterol and accumulation of toxic metabolic intermediates, we assessed the efficacy of combined therapy with lovastatin and cholesterol. We also evaluated the basis for the poorly understood, unique lateralization of the cutaneous and bone malformations of CHILD syndrome by analyzing gene activation in abnormal and unaffected skin. Ultrastructural analysis of affected skin showed evidence of both cholesterol depletion and toxic metabolic accumulation. Topical treatment with lovastatin/cholesterol (but not cholesterol alone) virtually cleared skin lesions by 3 months, accompanied by histologic and ultrastructural normalization of epidermal structure and lipid secretion. The unusual lateralization of abnormalities in CHILD syndrome reflects selective clearance of keratinocytes and fibroblasts that express the mutant allele from the unaffected side. These findings validate pathogenesis-based therapy that provides the deficient end-product and prevents accumulation of toxic metabolites, an approach of potential utility for other syndromic lipid metabolic disorders.
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影响因子：
3.6
作者：
Chan YM;Merkens LS;Connor WE;Roullet JB;Penfield JA;Jordan JM;Steiner RD;Jones PJ
通讯作者：
Jones PJ
影响因子：
2.7
作者：
Chiang, C;Swan, RZ;Dlugosz, AA
通讯作者：
Dlugosz, AA
影响因子：
--
作者：
MAN, MQ;FEINGOLD, KR;ELIAS, PM
通讯作者：
ELIAS, PM
影响因子：
3.8
作者：
Cunningham, David;Spychala, Kaitlyn;Herman, Gail E.
通讯作者：
Herman, Gail E.
影响因子：
30.8
作者：
Liu, XY;Dangel, AW;Herman, GE
通讯作者：
Herman, GE