Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
Ophthalmic Genet. 2023 Dec;44(6):530-538. doi: 10.1080/13816810.2023.2254830. Epub 2023 Nov 20.
Variants in the patatin-like phospholipase domain containing 6 (PNPLA6) gene cause a broad spectrum of neurological disorders characterized by gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. This review examines the clinical, cellular, and biochemical features found across the five PNPLA6-related diseases, with a focus on future questions to be addressed.
A literature review was performed on published clinical reports on patients with PNPLA6 variants. Additionally, in vitro and in vivo models used to study the encoded protein, Neuropathy Target Esterase (NTE), are summarized to lend mechanistic perspective to human diseases.
Biallelic pathogenic PNPLA6 variants cause five systemic neurological disorders: spastic paraplegia type 39, Gordon-Holmes, Boucher-Neuhäuser, Laurence-Moon, and Oliver-McFarlane syndromes. PNPLA6 encodes NTE, an enzyme involved in maintaining phospholipid homeostasis and trafficking in the nervous system. Retinal disease presents with a unique chorioretinal dystrophy that is phenotypically similar to choroideremia and Leber congenital amaurosis. Animal and cellular models support a loss-of-function mechanism.
Clinicians should be aware of choroideremia-like ocular presentation in patients who also experience growth defects, motor dysfunction, and/or hair anomalies. Although NTE biochemistry is well characterized, further research on the relationship between genotype and the presence or absence of retinopathy should be explored to improve diagnosis and prognosis.
载脂蛋白样磷脂酶域包含 6 号基因（PNPLA6）的变异可引起广泛的神经系统疾病，其特征为步态障碍、视力损害、前垂体功能减退和毛发异常。本综述检查了跨越五种 PNPLA6 相关疾病的临床、细胞和生化特征，并重点关注未来需要解决的问题。
对发表的 PNPLA6 变异患者的临床报告进行了文献回顾。此外，还总结了用于研究编码蛋白神经病变靶酯酶（NTE）的体外和体内模型，以从机制上为人类疾病提供视角。
双等位基因致病性 PNPLA6 变异可引起五种系统性神经系统疾病：痉挛性截瘫 39 型、Gordon-Holmes 综合征、Boucher-Neuhäuser 综合征、Laurence-Moon 综合征和 Oliver-McFarlane 综合征。PNPLA6 编码 NTE，这是一种参与维持神经系统中磷脂稳态和运输的酶。视网膜疾病表现为独特的脉络膜视网膜营养不良，其表型与脉络膜变性和莱伯先天性黑矇相似。动物和细胞模型支持功能丧失机制。
临床医生应注意到具有生长缺陷、运动功能障碍和/或毛发异常的患者可能出现类似于脉络膜变性的眼部表现。尽管 NTE 生化特性已经很好地描述，但应进一步研究基因型与视网膜病变存在与否之间的关系，以改善诊断和预后。
