Neuronal ceroid lipofuscinoses (NCL) is an inherited neurodegenerative disorder in children. Presently there is no effective treatment and the disorder is lethal. NCL occur in a variety of non-human species including sheep, which are recognised as valuable large animal models for NCL. This experiment investigated the progressive postural, behavioural and liveweight changes in NCL-affected lambs, to establish practical, non-invasive biomarkers of disease progression for future preclinical trials in a CLN6 Merino sheep model. A flock of eight lambs at pasture was studied, with the observer blind to the disorder status. Three genotypes were compared: homozygous affected NCL; n = 4), clinically normal heterozygous (Carrier; n = 2) and homozygous normal (non-carrier control (Normal); n = 2). Direct observation during daylight and continuous accelerometer measurements over 72 h were used to quantify lamb posture and behaviour in 11 sessions between 26-60 weeks of age, conducted at 3-5 week intervals. There was a Genotype (G) × Age (A) interaction (P = 0.001) for liveweight of the lambs in the experiment, with NCL, Carrier and Normal lambs gaining 11.8, 16.5 and 23.4 kg, respectively, between 26 and 60 weeks of age. G×A interactions were also found for walking behaviour (means for NCL, Carrier and Normal genotype groups at 26 and 60 weeks, were 1.7 and 7.9%, 3.3 and 3.1%, and 2.5 and 1.9% of observations, P = 0.008) and a composite variable of key behaviours identified in the principal components analysis (P < 0.001), with mean values for NCL lambs increasing three-fold compared to non-affected lambs as age increased. Similarly, NCL lambs became less responsive to visual and auditory stimuli as they aged. Mean responsiveness scores (out of 3) to visual stimuli for the NCL, Carrier and Normal genotypes at 26 and 60 weeks of age were 2.7 and 1.4, 2.8 and 2.9, and 3.0 and 3.0, respectively (G × A, P < 0.001). Changes in response to auditory stimuli were similar to visual stimuli. NCL lambs took more (P = 0.015) steps per 24 h than Carrier and Normal genotype lambs, but there was no G × A interaction. At 26 and 60 weeks of age respectively, NCL lambs took 2724 and 4121 steps per 24 h, compared to Carrier (1708 and 3105 steps) and Normal genotype lambs (2109 and 3506 steps). NCL lambs also performed less (P = 0.018) grazing behaviour than Carrier and Normal genotype lambs (66.5, 72.3 and 72.5% of observations for NCL, Carrier and Normal lambs, respectively). A number of behavioural changes identified in the experiment could form the basis for a protocol for monitoring and evaluation of disease progression.

中文翻译：

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澳大利亚美利奴绵羊神经元蜡样脂褐质沉积症的表现：对行为和生长改变的观察

神经元蜡样脂褐质沉积症 (NCL) 是一种儿童遗传性神经退行性疾病。目前没有有效的治疗方法，这种疾病是致命的。NCL 发生在包括绵羊在内的多种非人类物种中，被公认为 NCL 的有价值的大型动物模型。该实验调查了受 NCL 影响的羔羊的渐进姿势、行为和体重变化，以建立实用的、非侵入性的疾病进展生物标志物，用于未来在 CLN6 美利奴绵羊模型中进行的临床前试验。研究了牧场上的 8 只小羊群，观察者对疾病状态视而不见。比较了三种基因型：纯合子受影响的 NCL；n = 4)，临床上正常的杂合子（携带者；n = 2）和纯合子正常（非携带者对照（正常）；n = 2）。在日光期间的直接观察和超过 72 小时的连续加速度计测量用于量化 26-60 周龄之间的 11 个会话中的羔羊姿势和行为，每隔 3-5 周进行一次。实验中羔羊的体重存在基因型 (G) × 年龄 (A) 交互作用 (P = 0.001)，NCL、载体和正常羔羊在 26 周和 60 周之间分别增重 11.8、16.5 和 23.4 kg。年龄。步行行为也发现 G×A 相互作用（NCL、携带者和正常基因型组在 26 周和 60 周时的平均值，分别为观察值的 1.7% 和 7.9%、3.3% 和 3.1% 以及 2.5% 和 1.9%，P = 0.008）和主成分分析中确定的关键行为的复合变量（P < 0.001），随着年龄的增加，与未受影响的羔羊相比，NCL 羔羊的平均值增加了三倍。相似地，随着年龄的增长，NCL 羔羊对视觉和听觉刺激的反应减弱。26 周龄和 60 周龄时 NCL、携带者和正常基因型对视觉刺激的平均反应性评分（满分 3 分）分别为 2.7 和 1.4、2.8 和 2.9、3.0 和 3.0（G × A，P < 0.001） . 对听觉刺激的反应变化与视觉刺激相似。NCL 羔羊每 24 小时比载体和正常基因型羔羊采取更多 (P = 0.015) 步，但没有 G × A 相互作用。与 Carrier（1708 和 3105 步）和正常基因型羔羊（2109 和 3506 步）相比，NCL 羔羊分别在 26 和 60 周龄时每 24 小时走 2724 和 4121 步。NCL 羔羊的放牧行为也比 Carrier 和 Normal 基因型羔羊少（P = 0.018）（分别为 NCL、Carrier 和 Normal 羔羊观察结果的 66.5%、72.3% 和 72.5%）。