Globoid cell leukodystrophy (GLD, Krabbe disease, Krabbe's disease) is caused by genetic mutations in the gene encoding, galactosylceramidase (GALC). Deficiency of this enzyme results in central and peripheral nervous system pathology, and is characterized by loss of myelin and an infiltration of globoid cells. The canine model of GLD provides a translational model which faithfully recapitulates much of the human disease pathology. Targeted lipidomic analysis was conducted in serum and cerebrospinal fluid (CSF) over the lifetime of GLD affected and normal canines, and in brain tissue at humane endpoint to better understand disease progression and identify potential biomarkers of disease. Psychosine, a substrate of GALC and primary contributor to the pathology in GLD, was observed to be significantly elevated in the serum and CSF by 2 or 4 weeks of age, respectively, and steadily increased over the lifetime of affected animals. Importantly, psychosine concentration strongly correlated with disease severity. Galactosylceramide, glucosylceramide, and lactosylceramide were also found to be elevated in the CSF of affected animals and increased with age. Psychosine and galactosylceramide were found to be significantly increased in brain tissue at humane endpoint. This study identified several biomarkers which may be useful in the development of therapeutics for GLD.

中文翻译：

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犬类球状细胞白细胞营养不良（Krabbe病）中的脑脊髓液和血清糖鞘脂生物标志物。

球状细胞白细胞营养不良（GLD，Krabbe病，Krabbe病）是由编码半乳糖苷神经酰胺酶（GALC）的基因中的遗传突变引起的。这种酶的缺乏会导致中枢神经系统和周围神经系统的病理，并以髓磷脂的丢失和球状细胞的浸润为特征。GLD的犬模型提供了一个转换模型，可以忠实地概括许多人类疾病的病理学。在受GLD影响的犬和正常犬的一生中，在血清和脑脊液（CSF）中以及人性终点的脑组织中进行了靶向脂质组学分析，以更好地了解疾病进展并确定潜在的疾病生物标志物。Psychosine是GALC的底物，是GLD病理学的主要贡献者，观察到，在2周或4周龄时，血清和脑脊液中的TNF-α显着升高，并且在患病动物的一生中稳定升高。重要的是，神经氨酸浓度与疾病的严重程度密切相关。还发现半乳糖基神经酰胺，葡萄糖基神经酰胺和乳糖基神经酰胺在患病动物的脑脊液中升高，并随着年龄的增长而增加。在人性终点时，发现脑组织中的神经氨酸和半乳糖神经酰胺显着增加。这项研究确定了几种生物标志物，这些标志物可能对GLD疗法的开发有用。还发现在患病动物的脑脊液中乳糖苷和乳糖苷神经酰胺含量升高，并且随着年龄的增长而升高。在人性终点时，发现脑组织中的神经氨酸和半乳糖神经酰胺显着增加。这项研究确定了几种生物标志物，这些标志物可能在GLD治疗药物的开发中有用。还发现在患病动物的脑脊液中乳糖苷和乳糖苷神经酰胺含量升高，并且随着年龄的增长而升高。在人性终点时，发现脑组织中的神经氨酸和半乳糖神经酰胺显着增加。这项研究确定了几种生物标志物，这些标志物可能在GLD治疗药物的开发中有用。