Kohlschütter Alfried
Children's Hospital, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Handb Clin Neurol. 2013;113:1611-8. doi: 10.1016/B978-0-444-59565-2.00029-0.
Genetic deficiencies of lysosomal catabolic pathways lead to storage disorders with multiple organ abnormalities or to degeneration of purely nervous structures. Krabbe disease and metachromatic leukodystrophy are caused by metabolic errors concerning lipids of neural membranes. They are characterized by demyelination of the central nervous system and, variably, the peripheral nerves. Their clinical presentation is a relentlessly progressive motor and mental deterioration starting at any age between infancy and adolescence. MRI demonstrates characteristic lesions of brain white matter. In Krabbe disease, deficient galactocerebroside β-galactosidase activity causes accumulation of lipids in "globoid" macrophages and of psychosine, which is toxic to oligodendrocytes. Diagnosis depends on demonstration of the enzyme deficiency. Experimental treatment is limited to hematopoietic stem cell transplantation, which can favorably alter the course of disease in certain situations. In metachromatic leukodystrophy, deficient activity of arylsulfatase A, or lack of a cofactor, causes accumulation of sulfatide in various tissues and diffuse demyelination. Symptoms are neurological, but gallbladder dysfunction may be present. Diagnosis depends on demonstrating the enzyme deficiency and elevated urinary sulfatide. In a rare variant, multiple sulfatases are deficient. Stem cell transplantation may prevent disease progression in selected cases. Enzyme replacement is being evaluated, and gene therapies are being developed.
溶酶体分解代谢途径的遗传缺陷会导致伴有多器官异常的贮积病，或导致纯神经结构的退化。克拉伯病和异染性脑白质营养不良是由涉及神经膜脂质的代谢错误引起的。它们的特征是中枢神经系统以及外周神经出现脱髓鞘，脱髓鞘程度因人而异。其临床表现为在婴儿期至青春期之间的任何年龄开始出现持续进展的运动和智力衰退。磁共振成像（MRI）显示脑白质有特征性病变。在克拉伯病中，半乳糖脑苷脂β - 半乳糖苷酶活性缺乏导致脂质在“球状”巨噬细胞中蓄积，以及精神鞘氨醇蓄积，而精神鞘氨醇对少突胶质细胞有毒性。诊断取决于酶缺乏的证明。实验性治疗仅限于造血干细胞移植，在某些情况下，造血干细胞移植可使疾病进程得到有利改变。在异染性脑白质营养不良中，芳基硫酸酯酶A活性缺乏或缺乏辅因子会导致硫脂在各种组织中蓄积以及弥漫性脱髓鞘。症状为神经方面的，但可能存在胆囊功能障碍。诊断取决于证明酶缺乏和尿硫脂升高。在一种罕见的变异型中，多种硫酸酯酶缺乏。干细胞移植在某些选定病例中可能会阻止疾病进展。酶替代疗法正在评估中，基因疗法也正在研发中。
