Casazza Krista, Cologna Stephanie M, Berry-Kravis Elizabeth, Jarnes Jeanine, Porter Forbes D
Purity Health, Columbia, Tennessee, USA.
Department of Chemistry, University of Illinois Chicago, Chicago, Illinois, USA.
J Inherit Metab Dis. 2025 Sep;48(5):e70075. doi: 10.1002/jimd.70075.
Niemann-Pick Type C1 (NPC1) disease is a rare, autosomal recessive, neurovisceral lysosomal storage disorder caused by mutations in the NPC1. This condition leads to defective intracellular cholesterol and lipid trafficking, resulting in the accumulation of unesterified cholesterol and glycosphingolipids in late endosomes and lysosomes. Clinically, NPC1 manifests with a heterogeneous spectrum of progressive neurological symptoms, including ataxia, vertical supranuclear gaze palsy, dysarthria, cognitive decline, and dystonia, often accompanied by systemic signs such as hepatosplenomegaly and neonatal cholestasis. The age of neurological symptom onset, rather than age at diagnosis, better reflects disease severity and progression, as delays in diagnosis are common due to phenotypic variability and lack of awareness. Therapeutic development for NPC1 has been historically limited, with miglustat approved in some regions for off-label use and 2-hydroxypropyl-β-cyclodextrin currently under clinical investigation. Recent advances in disease understanding have prompted the development of pharmacodynamic, diagnostic, and prognostic biomarkers to support earlier diagnosis and monitor therapeutic efficacy. Dysregulation of cholesterol homeostasis, neuroinflammation, and neuronal loss have guided biomarker discovery, with promising candidates including 24(S)-hydroxycholesterol, neurofilament light chain, and bile acid derivatives such as 3β,5α,6β-trihydroxycholanic acid. Novel lipid biomarkers including N-palmitoyl-O-phosphocholine-serine and oxysterols such as 7-ketocholesterol and cholestane-3β,5α,6β-triol also show diagnostic value. Despite growing mechanistic insight and a robust pipeline of candidate biomarkers and therapies, NPC1 remains a life-limiting disease with significant diagnostic and therapeutic gaps. Ongoing clinical trials and translational research are essential to accelerate biomarker qualification and regulatory approval of disease-modifying treatments. A comprehensive, mechanistically driven approach that integrates molecular, biochemical, and clinical endpoints is key to advancing precision medicine for NPC1.
尼曼-匹克C1型（NPC1）病是一种罕见的常染色体隐性神经内脏溶酶体贮积症，由NPC1基因突变引起。这种疾病导致细胞内胆固醇和脂质转运缺陷，致使晚期内体和溶酶体中未酯化胆固醇和糖鞘脂蓄积。临床上，NPC1表现为一系列异质性的进行性神经症状，包括共济失调、垂直性核上性凝视麻痹、构音障碍、认知衰退和肌张力障碍，常伴有肝脾肿大和新生儿胆汁淤积等全身症状。神经症状出现的年龄，而非诊断时的年龄，更能反映疾病的严重程度和进展情况，因为由于表型变异和认识不足，诊断延迟很常见。NPC1的治疗进展历来有限，米格列醇在一些地区被批准用于标签外使用，2-羟丙基-β-环糊精目前正在进行临床研究。对疾病认识的最新进展促使了药效学、诊断和预后生物标志物的开发，以支持早期诊断和监测治疗效果。胆固醇稳态失调、神经炎症和神经元丢失指导了生物标志物的发现，有前景的候选物包括24（S）-羟基胆固醇、神经丝轻链以及胆汁酸衍生物，如3β，5α，6β-三羟基胆烷酸。新型脂质生物标志物，包括N-棕榈酰-O-磷酸胆碱-丝氨酸以及氧化甾醇，如7-酮胆固醇和胆甾烷-3β，5α，6β-三醇，也显示出诊断价值。尽管对发病机制的认识不断增加，且有大量候选生物标志物和治疗方法，但NPC1仍然是一种危及生命的疾病，在诊断和治疗方面存在重大差距。正在进行的临床试验和转化研究对于加速生物标志物的鉴定和疾病修饰治疗的监管批准至关重要。一种综合的、由发病机制驱动的方法，整合分子、生化和临床终点，是推进NPC1精准医学的关键。
