Wiesmann U N
Bull Schweiz Akad Med Wiss. 1978 Mar;34(1-3):33-47.
Metachromatic leucodystrophies (MLD) comprise a small group of heredodegenerative disorders of the nervous system. Deficiency of sulfatide-sulfatase or arylsulfatase A is the common defect in all forms of MLD leading to lysosomal sulfatide storage in the nervous tissue and in the kidney. On the basis of animal experiments, experiments with cultured fibroblasts of the patients as well as ultrastructural studies in a case of prenatal MLD, the following pathomechanism is proposed: 1. Lysosomal degradation of a large portion newly synthetised sulfatide normally regulating the net synthesis and incorporation of sulfatide into myelin, causes early accumulation of sulfatide in lysosomes of myelinating cells and in neurons in the genetic deficiency of arylsulfatase A. 2. Early accumulation of sulfatide does not lead to disturbance in myelination. Demyelination occurs possibly by storage of a cytotoxic compound, psychosin sulfate, also a substrate for the missing enzyme. Prevention of MLD is possible by prenatal diagnosis of arylsulfatase A deficiency in cultured amniotic cells. Enzyme substitution of the missing arylsulfatase A is possible by exogenous uptake of the enzyme in cultured fibroblasts. Thereby the defect of sulfatide degradation can be corrected. Although principles of enzyme substitution have been demonstrated, the problems of treating patients with MLD with arylsulfatase A infusions have yet to be overcome.
异染性脑白质营养不良（MLD）是一组罕见的遗传性神经系统退行性疾病。芳基硫酸酯酶A（一种硫酸脑苷脂硫酸酯酶）缺乏是所有类型MLD的共同缺陷，导致神经组织和肾脏中溶酶体硫酸脑苷脂蓄积。基于动物实验、患者培养成纤维细胞实验以及一例产前MLD的超微结构研究，提出了以下发病机制：1. 新合成的大部分硫酸脑苷脂的溶酶体降解通常调节硫酸脑苷脂的净合成及其掺入髓鞘的过程，在芳基硫酸酯酶A基因缺陷时，导致硫酸脑苷脂在髓鞘形成细胞和神经元的溶酶体中早期蓄积。2. 硫酸脑苷脂的早期蓄积不会导致髓鞘形成障碍。脱髓鞘可能是由于一种细胞毒性化合物——硫酸精神鞘脂（也是缺失酶的底物）蓄积所致。通过对培养羊膜细胞进行芳基硫酸酯酶A缺乏的产前诊断可以预防MLD。在培养的成纤维细胞中外源摄取该酶，可以对缺失的芳基硫酸酯酶A进行酶替代。由此可纠正硫酸脑苷脂降解缺陷。虽然已经证明了酶替代的原理，但用芳基硫酸酯酶A输注治疗MLD患者的问题仍有待解决。
