Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation
Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation
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DOI：
10.1203/00006450-200008000-00018
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发表时间：
2000-08-01
影响因子：
3.6
通讯作者：
Ginns, EI
中科院分区：
文献类型：
--
作者：
Orvisky, E;Sidransky, E;Ginns, EI
戈谢病是最常见的鞘脂病，由遗传性葡萄糖脑苷酶缺乏引起（EC 3.2.1.45）。虽然2型（急性神经病变）戈谢病与快速进展和致命的神经系统恶化有关，但导致神经系统症状和早期死亡的病理生理机制仍不清楚。虽然戈谢病的病理是由于葡萄糖脑苷的储存，但一种细胞毒性化合物葡糖苷（Glc-sph）也会在组织中积累。脑Glc-sph升高在2型和3型戈谢病患者中有报道。在这项研究中，用高效液相色谱法测量了葡萄糖脑苷酶等位基因为空的2型戈谢病小鼠组织中的葡萄糖-sph水平。与未受影响的幼崽相比，患有2型戈谢病的纯合子小鼠大脑中Glc-sph升高约100倍，其他组织中的Glc-sph水平也升高。这种积累在子宫内被e13检测到，并在整个妊娠期间逐渐增加。同样，人类2型戈谢病胎儿的Glc-sph水平升高，表明出生后开始治疗可能太晚，无法预防妊娠早期开始的进行性神经损伤的后遗症。这些发现表明，Glc-sph的积累可能是2型戈谢病小鼠快速死亡和2型戈谢病患者破坏性临床过程的原因。
Gaucher disease, the most common of the sphingolipidoses, results from the inherited deficiency of the enzyme glucocerebrosidase (EC 3.2.1.45). Although type 2 (acute neuronopathic) Gaucher disease is associated with rapidly progressive and fatal neurologic deterioration, the pathophysiologic mechanisms leading to the neurologic symptoms and early demise remain uncharacterized. While the pathology encountered in Gaucher disease has been attributed to glucocerebroside storage, glucosylsphingosine (Glc-sph), a cytotoxic compound, also accumulates in the tissues. Elevations of brain Glc-sph have been reported in patients with types 2 and 3 Gaucher disease. In this study, Glc-sph levels were measured using HPLC in tissues from mice with type 2 Gaucher disease created with a null glucocerebrosidase allele. Compared with unaffected littermates, homozygous mice with type 2 Gaucher disease had approximately a 100-fold elevation of Glc-sph in brain, as well as elevated levels in other tissues. This accumulation was detected in utero by E 13 and increased progressively throughout gestation. Similarly, elevated Glc-sph levels were seen in human fetuses with type 2 Gaucher disease, indicating that therapy initiated after birth may be too late to prevent the sequaelae of progressive neurologic damage that begins early in gestation. These findings suggest that the accumulation of Glc-sph may be responsible for the rapid demise of mice with type 2 Gaucher disease and the devastating clinical course seen in patients with type 2 Gaucher disease.