缺陷的 HLCS 导致多种羧基酶缺乏
中文名称
通路描述
HLCS 缺陷导致全羧基酶合成酶缺乏症（HLCS 缺乏症，也称为早期 onset 多种羧基酶缺乏症；MIM:253270）。HLCS 缺乏症是一种常染色体隐性遗传病，其中缺乏的 HLCS 活性导致所有五种生物素依赖性羧基酶活性降低。症状包括代谢性酸中毒、有机酸尿、嗜睡、低张力、抽搐和皮炎（Suzuki et al. 2005）。患者可能在出生后不久到早期儿童期出现症状，并通常被处方口服生物素补充剂，通常为每日 10-20 毫克。根据患者对生物素治疗的反应，已报道两类 HLCS 缺乏症。大多数患者对治疗反应良好，并显示出生物化学和临床症状的完全逆转（Morrone et al. 2002, Dupuis et al. 1999）。此处 HLCS 活性位点的突变导致对生物素亲和力降低，可通过药典剂量的维生素克服（Pendini et al. 2008）。显示对生物素治疗反应不完全的患者预后较差（Bailey et al. 2008）。此处位于酶活性位点之外的突变不影响生物素结合，但损害 HLCS 与其底物之间的蛋白质 - 蛋白质相互作用，导致所有五种羧基酶的生物素化减少，从而降低其酶活性（Mayende et al. 2012）。
英文描述
Defective HLCS causes multiple carboxylase deficiency Defects in HLCS causes holocarboxylase synthetase deficiency (HLCS deficiency aka early onset multiple carboxylase deficiency; MIM:253270). HLCS deficiency is an autosomal recessive disorder whereby deficient HLCS activity results in reduced activity of all five biotin-dependent carboxylases. Symptoms include metabolic acidosis, organic aciduria, lethargy, hypotonia, convulsions and dermatitis (Suzuki et al. 2005). Patients can present symptoms shortly after birth to up to early childhood and will be prescribed oral biotin supplements, typically 10-20 mg daily. Two classes of HLCS deficiency have been reported depending on whether patients respond to biotin therapy. Most patients respond favourably to treatment and show complete reversal of biochemical and clinical symptoms (Morrone et al. 2002, Dupuis et al. 1999). Here mutations in the HLCS active site cause a reduced affinity for biotin that can be overcome by pharmacological doses of the vitamin (Pendini et al. 2008). Patients who display incomplete responsiveness to biotin therapy have a poor long-term prognosis (Bailey et al. 2008). Here mutations that reside outside of the enzyme's active site have no effect on biotin binding but do compromise the protein-protein interaction between the HLCS and its substrates, resulting in reduced biotinylation of all five carboxylases thus reducing their enzymatic activity (Mayende et al. 2012).
所含基因
6 个基因